U.S. patent application number 15/285204 was filed with the patent office on 2017-05-04 for iontophoretic drug delivery method.
The applicant listed for this patent is TEVA PHARMACEUTICALS INTERNATIONAL GMBH. Invention is credited to Todd A. KRINKE.
Application Number | 20170120047 15/285204 |
Document ID | / |
Family ID | 41797377 |
Filed Date | 2017-05-04 |
United States Patent
Application |
20170120047 |
Kind Code |
A1 |
KRINKE; Todd A. |
May 4, 2017 |
IONTOPHORETIC DRUG DELIVERY METHOD
Abstract
The present invention relates generally to iontophoretic drug
delivery systems for transdermal delivery of therapeutic agents
and, more particularly, to packaging such systems for long shelf
life and easy assembly for use. The system package includes an
iontophoretic skin worn patch component that accommodates a power
source, electronics, electrodes and a drug pack component that
carries a therapeutic agent which is contained as a separate sealed
component. The packaged system further provides for ease of
assembly at the time of use.
Inventors: |
KRINKE; Todd A.; (Buffalo,
MN) |
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Applicant: |
Name |
City |
State |
Country |
Type |
TEVA PHARMACEUTICALS INTERNATIONAL GMBH |
Rapperswil-Jona |
|
CH |
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|
Family ID: |
41797377 |
Appl. No.: |
15/285204 |
Filed: |
October 4, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12597950 |
Oct 28, 2009 |
9492650 |
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PCT/US09/04969 |
Sep 3, 2009 |
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15285204 |
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61094442 |
Sep 5, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/0428 20130101;
A61N 1/325 20130101; A61N 1/303 20130101; A61N 1/30 20130101; A61N
1/044 20130101; A61N 1/0448 20130101 |
International
Class: |
A61N 1/30 20060101
A61N001/30; A61N 1/32 20060101 A61N001/32; A61N 1/04 20060101
A61N001/04 |
Claims
1. A method of administering a therapeutic agent to a patient with
an iontophoretic drug delivery system, the method comprising the
steps of: (a) removing a drug pack component of the iontophoretic
drug delivery system and an iontophoresis patch component of the
iontophoretic drug delivery system from a storage package and
removing one or more of the cover membranes and release liners; (b)
assembling the iontophoretic drug delivery system by combining the
drug pack component and the iontophoresis patch component, the
assembling step including aligning the drug pack component and the
iontophoresis patch component relative to one another with an
alignment structure and affixing the drug pack component and the
iontophoresis patch component into permanent adhesive contact
forming a transdermal iontophoresis patch that is ready to use,
wherein said alignment structure is either: (1) a folding support
structure associated with the drug pack component and the
iontophoresis patch component, the folding support structure
including a separator component configured to physically separate
and protect the drug pack component and the iontophoresis patch
component when the iontophoretic drug delivery system is present in
a folded storage state; or (2) a separate guide element including a
raised alignment members configured to register with the drug pack
component and the iontophoresis patch component for separate
consecutive alignment of the drug pack component with the
iontophoresis patch component; and (c) applying the transdermal
iontophoresis patch to the skin of the patient at a desired
location.
2. The method according to claim 1 wherein the iontophoresis drug
delivery system comprises a patch skin adhesive layer and the one
or more release liners comprise a half release liner, and wherein
about one half of the patch skin adhesive layer is exposed
initially when the patch is applied to the skin followed by removal
of the half release liner to achieve full patch adhesion.
3. The method according to claim 1, further comprising the step of:
unfolding the drug pack component from the iontophoresis patch
component to access the separator component for removal.
4. The method according to claim 1, further comprising the step of:
removing the transdermal iontophoresis patch from the folding
support structure prior to applying the transdermal iontophoresis
patch to the skin of the patient.
5. The method according to claim 1 wherein said drug pack component
includes a pair of gel pads including an anode gel pad and a
cathode gel pad isolated prior to assembly by a cover membrane
having low moisture permeability.
6. The method according to claim 5, further comprising the step of:
activating a current configured to draw the therapeutic agent from
the gel pad through the skin of the patient.
7. The method according to claim 5 wherein said gel pads comprise
one or more layers of non-woven polymer matrix.
8. The method according to claim 5 including an amount of
therapeutic agent ion species located in gel associated with at
least one of said gel pads.
9. The method according to claim 5 wherein said gel pads are fixed
to a substrate layer in said drug pack by adherence of a gel
material prior to assembly of said system.
10. The method according to claim 5 wherein said therapeutic agent
is present in said gel in a concentration from about 0.2% to
10%.
11. The method according to claim 5 wherein said iontophoresis
patch component includes electrodes comprising an anode and a
cathode and a source of electric power.
12. The method according to claim 11 wherein said drug pack
component comprises the gel pads and the electrodes are contained
in recesses adapted to receive the gel pads of the drug pack upon
assembly of the transdermal iontophoresis patch.
13. The method according to claim 5 further comprising a peripheral
adhesive layer bonding the gel pad to an electrode in the
transdermal iontophoresis patch.
14. The method according to claim 1 wherein said cover membrane
having low moisture permeability comprises a material selected from
the group consisting of metal/polymer composites and PVC.
15. A method of administering a therapeutic agent to a patient with
an iontophoretic drug delivery system, the method comprising the
steps of: removing a separator component from a drug pack component
having a gel pad, the separator component configured to be
interposed between and thereby physically separate and protect the
drug pack component and an iontophoresis patch component when the
iontophoretic drug delivery system is present in a fully folded
storage stage; folding a folding support structure to align an
iontophoresis patch component with the drug pack component, wherein
said iontophoresis patch component is configured to align said gel
pads of said drug pack component in conductive relation in an
assembled state, the folding support structure is associated with
the drug pack component and the iontophoresis patch component; and
applying the iontophoretic drug delivery system in the assembled
state to the skin of the patient.
16. The method according to claim 15, further comprising the step
of: unfolding the drug pack component from the iontophoresis patch
component to access the separator component for removal.
17. The method according to claim 15, further comprising the step
of: removing the iontophoretic drug delivery system in the
assembled state from the folding support structure prior to
applying the iontophoretic drug delivery system in the assembled
state to the skin of the patient.
18. The method according to claim 15, further comprising the step
of: activating a current configured to draw the therapeutic agent
from the gel pad through the skin of the patient.
19. The method according to claim 15, wherein said drug pack
component include a pair of gel pads including an anode gel pad and
a cathode gel pad isolated prior to assembly by a cover membrane
having low moisture permeability.
20. The method according to claim 19 wherein said gel pads comprise
one or more layers of non-woven polymer matrix.
21. The method according to claim 19 including an amount of
therapeutic agent ion species located in gel associated with at
least one of said gel pads.
22. The method according to claim 19 wherein said gel pads are
fixed to a substrate layer in said drug pack by adherence of a gel
material prior to assembly of said system.
23. The method according to claim 21 wherein said therapeutic agent
is present in said gel in a concentration from about 0.2% to
10%.
24. The method according to claim 15 wherein said iontophoresis
patch component includes electrodes comprising an anode and a
cathode and a source of electric power.
25. The method according to claim 24 wherein said drug pack
component comprises the gel pads and said electrodes are contained
in recesses adapted to receive said gel pads of said drug pack upon
assembly of said system into said assembled state.
26. The method according to claim 15 further comprising a
peripheral adhesive layer bonding the gel pad to an electrode in
the assembled state.
27. The method according to claim 19 wherein said cover membrane
having low moisture permeability comprises a material selected from
the group consisting of metal/polymer composites and PVC.
Description
CROSS-REFERENCED TO RELATED APPLICATIONS
[0001] This application is a Continuation application of
application Ser. No. 12/597,950, filed Oct. 28, 2009 which is a
National Stage Entry of Application PCT/US09/04969, filed Sep. 3,
2009 which claims priority from Application No. 61/094,442, filed
Sep. 5, 2008, the specifications of which are incorporated by
reference in their entireties in this application.
FIELD OF THE INVENTION
[0002] The present invention relates generally to iontophoretic
drug delivery systems for transdermal delivery of therapeutic
agents and, more particularly, to packaging such systems for long
shelf life and easy assembly for use. The system package includes
an iontophoretic skin worn patch component that accommodates a
power source, electronics, electrodes and a drug pack component
that carries a therapeutic agent which is contained as a separate
sealed component. The packaged system further provides for ease of
assembly at the time of use.
BACKGROUND
[0003] The process of iontophoresis is well known and has found
significant commercial use in the delivery of ionically charged
compounds across the skin at the sites of system electrodes of like
charge.
[0004] Self-contained, wearable iontophoretic systems have been
developed in which the electrical circuitry and power supply have
been integrated into a single, skin-worn patch. In many of these
devices, drug ions are delivered into the body from an aqueous
`drug` reservoir contained in the iontophoretic device, and counter
ions of opposite charge are delivered from a `counter` reservoir.
Because drug/ion solutions are often stored remotely in bulk
quantity and introduced to an absorbent layer of the iontophoresis
electrode of interest at the time of use, additional steps are
necessary to incorporate drug ions and counter ions into the
device. However, the electrodes can be easily over-filled or
under-filled, thus this aspect requires trained personnel with good
technique. Additionally, because the drug solution is stored
separately from the electrodes, management of two inventories is
required.
[0005] To avoid the need for users to incorporate the aqueous drug
or ion reservoir at the time of use, the drug solution can be
pre-packaged with an electrode, or an aqueous reservoir can be
stored in contact with an electrode assembly, and a dry medicament
layer introduced to the aqueous reservoir at the time of use.
Unfortunately, with either configuration, an electrode is still
stored in wet environment, and that and other components may
succumb to corrosive deterioration.
[0006] For the above and other reasons, co-packaging iontophoretic
transdermal drug delivery patches with active pharmaceuticals
remains a challenging problem. Because iontophoretic patches
contain electrodes and electronics and the drug solution is usually
aqueous in nature, without a barrier between the aqueous
environment and the electronics, degradation of both the
electronics and the drug solution will occur within the desired
shelf life, which may be 2 years. A packaging solution that
provides a barrier and therefore meets shelf life requirements
between the electronics and the drug solution, yet still allows the
drug solution and electrodes to be combined in an assembled device
at time of use is sought. A solution that not only addresses shelf
life stability issues surrounding co-packaging aqueous drug
solutions with electrodes and electronic circuits but which also
makes it easier for the operator or user to activate and apply the
patch is even more desirable.
SUMMARY
[0007] The present invention presents a pre-packaged complete
iontophoretic drug delivery system that is easily assembled from
the packaged state. Pre-packaged complete iontophoretic drug
delivery systems of the invention include both an iontophoresis
patch and an agent to be administered and enjoy a long shelf life.
The system includes two main components, namely, a drug pack
component containing one or more absorbent pads, at least one of
which contains an active agent, and an iontophoresis patch
component which contains electrodes and a source of electric power.
The drug pack and patch are packaged together, but as separated
components during storage of the system. They are readily
incorporated into an assembled state at the time of use by the use
of a built-in alignment technique that employs an alignment
structure that may take any of several forms. One form includes a
conjoined folding platform or support structure that carries the
components on separate panels and another involves the use of a
separate alignment fixture or guide element.
[0008] In one embodiment, an iontophoresis patch component and a
sealed therapeutic ion-containing or an active
ingredient-containing drug pack (also known as a "blister pack")
component are carried in a distinct arrangement by consecutive
supporting panel structures in a configuration that is designed to
fold on itself in different manners to accommodate both storage and
use. This type of an arrangement may be characterized as a folding
configuration or folding support structure.
[0009] Alternatively, an iontophoresis patch and a sealed drug pack
may be stored as separate components in a package and assembled
together using an alignment fixture or guide element prior to use.
The alignment fixture or guide element may be a separate component
or may be packaged as initially attached to either the
iontophoresis patch or the drug pack.
[0010] In addition, while most drug or therapeutic ion species
generally will be contained in gel form in the drug pack, some may
be carried in a dry state in the iontophoresis patch. In this
arrangement, the therapeutic ion species is combined with the gel
or other solution upon assembly of the system.
[0011] The folding embodiment features a plurality of consecutive
conjoined panels in a platform or support structure in which a
transdermal, iontophoretic patch is affixed to one panel support
structure and a formed and sealed therapeutic agent chamber or drug
pack is affixed to an adjacent panel with the corresponding drug
and electrode parts in aligned registration and an appropriate fold
line therebetween. The folding support configuration or platform
preferably is fabricated with a paper board or polymer material
with selectively applied release coatings and pressure sensitive
tapes for affixing the transdermal patch and drug pack to the
panels. The transdermal patch includes all necessary adhesive
tapes, liners, electrodes, and circuit elements of a typical
iontophoretic patch device except a drug imbibed absorbent pad.
[0012] The sealed drug pack is formed using low moisture vapor
transmission materials and contains at least one permeable
absorbent pad imbibed with the desired drug solution generally in
gel form. The drug imbibed pad or pads remain separately housed in
a sealed drug pack during its shelf life until time of use.
[0013] The folding configuration contains cut outs and fold lines
to allow and guide various panels to fold inward or collapse on top
of one another and includes a release coating (which may be
siliconized) applied to the back surface with a coating on the
front side having a surface on which printing can be applied. The
printable coating surface may include a conventional clay material.
The transdermal patch is affixed to a first panel on the
release-coated or back side of the platform. The drug pack is
bonded to the adjacent panel on the printable or clay coated front
side. The folding system further contains cut outs in the shape and
position of the adsorbent pads on the transdermal patch panel which
allows the patch to communicate and register with the contents of
the drug pack when the system is folded. As indicated, the patch
and drug pack are registered to the panels so that when the system
is folded together in an assembled arrangement, the formed blisters
or drug chambers of the tray are aligned with corresponding wells
of patch electrodes.
[0014] In certain of these embodiments where a folding support
structure associated with said drug pack component and said
iontophoresis patch component is present, the folding support
structure may further include a separator component configured to
physically separate the drug pack and iontophoresis patch
components when the iontophoretic drug delivery system is present
in a folded storage stage. As described above, in these embodiments
the support structure may include a first panel that is associated
with the iontophoresis patch component and a second panel that is
associated with the drug pack component, where these first and
second panels are joined by a fold line. The support structure
further includes a separator component that is made up of one or
more additional panels, e.g., joined to the second panel on a side
opposite the side that the second panel is joined to the first
panel, where these additional one or more panels are configured to
physically separate the iontophoretic and drug pack components when
the system is in the folded storage state, e.g., see FIG. 9A. The
separator component not only separates the drug pack from the patch
component in the folded storage state, but also acts as a
protective packaging for the system components.
[0015] Storing the aqueous drug imbibed absorbent pad or pads in a
generally inert sealed blister or drug pack prior to use prevents
the contents from interacting with the surroundings, thereby,
preventing any degradation of the drug solution or of any
electronic or other patch components housed in proximity to the
drug pack. In accordance with preserving the integrity of the
contents, the materials in direct contact with the drug solution
during storage are preferably limited to relatively inert
materials. These include a formed tray, the absorbent pad and the
lid or barrier layer of the blister or drug pack. Materials of low
water vapor transmission include vinyls, polyesters, polyamides,
including nylon, or polyalkylines, such as polyethylene and
polypropylene. The material may further be coated on one or both
sides with a material selected from a diverse fabric, foil,
metalized film or other materials to reduce water vapor
transmission still further. The tray and lid also should be formed
of materials that are inert to or stable in the presence of the
components of the drug solution and absorbent pads.
[0016] One embodiment includes a tray and lid of a composite
aluminum/polymer material. The lid is provided with an easily
peeled seal layer for easy removal at the time of use. In that
embodiment, the absorbent pads consist of a lamination of suitable
polymer layers and coatings that are stable in the presence of and
contact with the drug solution. The absorbent pads are preferably
of a non-woven matrix which has a known gel absorbency or take-up
rate. Examples of materials that may be suitable for the absorbent
non-woven matrix include cotton, polypropylene, polyethylene, and
polyester. Preferably, the absorbent material is polypropylene.
[0017] Alternate embodiments assemble the drug delivery device
system from separate components using an alignment fixture or guide
element which may be furnished as a separate component or combined
with a transdermal iontophoretic patch or a drug pack. Separation
of the assembled wearable iontophoresis device and drug pack is
similar in each case and the construction of the iontophoresis
patch and drug pack is similar to that described in connection with
the folding embodiments.
[0018] In the case of the folding panel embodiments, at time of
use, the operator first peels off the formed drug pack tray lid
held by the seal layer material exposing the drug imbibed pad or
pads which remain affixed to a panel of the system. The patch
component is attached to an adjacent panel. Next, the operator
folds the panels together bringing the drug imbibed pads in
intimate contact with the wells of the patch electrodes. The patch
electrodes are provided with a ring of adhesive that bonds to a
matching ring layer portion of the surface of the absorbent pads
when the two are brought into contact. The patch is then peeled
from a siliconized or other suitable release coating on the support
configuration leaving the drug-imbibed pads now permanently
attached to the electrodes of the patch by the peripheral adhesive.
Finally, the patch is applied to the patient. Multiple embodiments
or variations around this basic concept and method are
contemplated.
[0019] Embodiments with a separate alignment fixture component or
guide element are assembled by registering alignment openings in
drug pack and iontophoretic patch support structures consecutively
with guide members on an alignment fixture or guide element. The
drug pack on its flat substrate is first assembled on the guide
element and the lid is removed as in other embodiments. Next, the
iontopatch is assembled on top of the open drug pack which again
places gel-imbibed pads of the drug pack in alignment with
corresponding electrodes. This again results in a combined
configuration in which the drug-imbibed pads are permanently bonded
to the electrodes by peripheral adhesive and in which the assembly
can be separated and applied to a patient. In alternate
embodiments, the guide element can be packaged assembled and
carrying the blister or drug pack component and the iontophoretic
patch component assembled to that combination or the iontophoretic
patch component can be packaged assembled to the guide element and
thereafter combined with the drug pack component.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] In the drawings wherein like characters denote like parts
throughout the same:
[0021] FIG. 1A is an exploded cross sectional view through an
embodiment of a folding iontophoretic drug delivery system;
[0022] FIG. 1B is an assembled view of the device shown in FIG.
1A;
[0023] FIG. 1C is a greatly enlarged, fragmentary cross section of
a portion of the folding support structure of FIGS. 1A and 1B
showing release coating and printable layers.
[0024] FIG. 2 is a top view of the embodiment shown in section in
FIGS. 1A and 1B;
[0025] FIGS. 3A-3D are cross sectional views illustrating a
step-wise activation and deployment of the device of FIG. 4;
[0026] FIG. 4 is a top view of the embodiment in FIGS. 3A-3D with
the formed lid removed from the drug package;
[0027] FIGS. 5A-5E are cross sectional views illustrating a
step-wise method and design for packaging the drug and saline gels
on non-woven absorbent pads;
[0028] FIG. 6 is a top view of the embodiment shown section in
FIGS. 5A-5E as assembled;
[0029] FIGS. 7A and 7B are top and cross sectional views,
respectively, of the absorbent pad of the embodiment of FIG. 6;
[0030] FIGS. 8A and 8B are top and cross sectional views,
respectively, of an alternative embodiment of an absorbent pad;
[0031] FIG. 9A is a side view of a folding iontophoretic drug
delivery system in accordance with the invention in a folded
packaged (stored) configuration;
[0032] FIG. 9B is a top view of the packaged configuration of FIG.
9A;
[0033] FIG. 10 is a top view of an alternative embodiment of the
device in an opened, flat configuration;
[0034] FIG. 11A depicts an exploded cross-sectional view through an
alternate embodiment of the device of the present invention with
separate iontophoretic patch and drug pack components and a guide
element;
[0035] FIG. 11B is a cross-sectional view depicting the exploded
parts of FIG. 11A assembled together;
[0036] FIG. 11C depicts the separation for use of the assembled
transdermal iontophoretic drug delivery system of FIGS. 11A and
11B;
[0037] FIG. 12 is a top view of the assembly of FIG. 11B;
[0038] FIG. 13 is an exploded cross-sectional view of another
embodiment alternative to that shown in FIGS. 11A-11C with the drug
pack carried by the guide element; and
[0039] FIG. 14 is an exploded cross-sectional view of still another
embodiment alternative to that shown in FIGS. 11A-11C.
DETAILED DESCRIPTION
[0040] The invention provides for a fully functional,
self-contained, easy-to-use iontophoresis device in the form of a
pre-packaged drug delivery system which enjoys a relatively long
stable shelf life. The system contains a drug reservoir pack,
folding panel support structure construction, and a transdermal
patch containing a power source, current controlling electronics,
and electrodes. The device is ready to use and requires only a few
simple operations to activate and apply the patch to a treatment
site. The operations in some embodiments consist of removing a drug
pack barrier lid, folding the panels onto themselves, and peeling
the patch from a release coating. In others, the transdermal patch
and drug pack are assembled on an alignment fixture or guide
element which is then removed. Several preferred embodiments of the
devices will be described below to illustrate the concepts of the
invention, but they are not meant to limit the scope of the
inventive concept in any manner.
[0041] FIGS. 1A, 1B, and 2 respectively show exploded cross
sectional, assembled cross sectional, and top views of one
embodiment of a folding device, generally at 20, in an opened or
flat configuration. FIGS. 9A and 9B respectively show the
embodiment in a side cross sectional and top view of the device
folded in a packaged configuration for long term storage. The
device consists of 3 main elements: a folding support structure 22,
a transdermal iontophoretic patch 24, and a drug containing pack or
blister pack 26.
[0042] The folding support structure 22 may include a paperboard,
or similar material, substrate with a release coating layer 28
applied to one side and a printable coating 30 applied to the
opposite side. FIG. 1C is a greatly enlarged representative
fragmentary cross section of a portion of the folding support
structure 22, further illustrating the coating layer 28 and
printable coating 30. The release coating layer 28 may be a
siliconized coating and the printable coating 30 may be a clay
coating. An alternative folding substrate or support layer may be a
thermoformable polymer or the like. The support structure 22 may
contain several fold lines as at 32, 33 and 34 that are created by
perforating, scoring, and/or creasing. In the case of a
thermoformable substrate, living hinges may be thermoformed at 32,
33 and 34. Depending on the number of fold lines, the support
structure may be divided into a number of panels which provide
areas to attach various components of the device, apply printing
for directions, and/or provide a release coated barrier for exposed
adhesives on one panel from permanently sticking to other panels
when folded together during storage.
[0043] As shown, transdermal iontophoretic patch 24 is adhesively
attached to a first panel 36A of the support structure 22 on the
release coated side of the substrate. The transdermal iontophoretic
patch 24 includes an adhesive coated foam layer 38, an occlusive
double sided tape layer 40, an electrode subassembly layer 42
consisting of a power source, electronics and electrodes to operate
the patch (not shown), and an overlay tape layer 44. As shown in
FIG. 1B, the adhesive side of the foam and the overlay tape are
attached to the release coated side of the support structure.
[0044] As shown in FIG. 2, cut outs in the foam layer 38 and
support structure 22 layers create an empty anode well or recess 46
and an empty cathode well 48 aligned to receive the corresponding
anode and cathode imbibed drug pads, preferably gel pads during
assembly/activation. The anode and cathode cut outs 46, 48,
respectively, expose underlying electrodes, including anode 50 and
cathode 52. A half-panel release liner 54 is created by perforating
the first panel 36A as also shown in FIG. 2. The half-panel release
liner 54 serves to peel the patch off of the substitute layer of
the support structure after it is activated.
[0045] The half-panel release liner serves the purpose of
stiffening the flexible patch to aid in application and
additionally allows the operator to handle the patch easily without
the patch sticking to the operator's fingers. Preferably, the half
of the patch not covered by the half-panel release liner 54 is
affixed to the patient's skin first. Subsequently, the half-panel
release liner is removed by peeling at a tab 54A of the half-panel
release liner. Finally, the other half of the patch is affixed to
the patient's skin.
[0046] A strip of double-sided tape 56 is attached to the printable
side of the support structure 22 on the first panel 36A. The
adhesive strip 56 serves a dual function of keeping the structure
closed during its long term storage condition by temporarily
bonding to a release coated side as shown in FIG. 9A. The second
function is to permanently bond to a second panel 36B of the
support structure when the parts are folded together to transfer
the anode and cathode gel pads 60, 62 as shown in FIG. 3C so that
the first panel 36A cannot be re-opened.
[0047] As shown in FIG. 9A, the support structure also includes
third and fourth panels 36C and 36D, respectively. Third and fourth
panels 36C and 36D collectively make up a separator component that
is configured to physically separate the drug pack and
iontophoresis patch components when the iontophoretic drug delivery
system is present in a folded storage stage. The third and fourth
panels 36C and 36D of the support structure 22 as folded create a
release coated barrier that prevents the occlusive tape 40 in the
transdermal patch 24 from touching and permanently sticking to the
formed lid layer 64 of the drug pack 26 during long term
storage.
[0048] As shown in FIG. 2, when the system is present in a
pre-folded state prior to storage, the drug pack components are
present in the center region of the support structure and flanked
on a first side by the iontophoresis patch component and on a
second side opposite the first side by the separator component of
the support structure which affords both structured separation and
external protection for the stored system.
[0049] A second piece of double-sided tape 66 is attached to the
second panel 36B on the printable side of the support structure 22
to permanently bond the drug containing blister pack 26 to the
support structure 22. Alternatively, for example, instead of a
double-sided adhesive 66, the drug containing blister pack 26 could
be heat sealed to the support structure 22 as by applying a heat
seal coating to the bottom of the drug containing pack or to the
printable side of the support structure.
[0050] As indicated, the drug pack 26 is provided with a formed
barrier lid having low moisture vapor permeability, a generally
flat bottom layer, containing two spaced gel locations, one
containing an anode gel-imbibed non-woven pad 60, another
containing a cathode gel-imbibed non-woven pad 62. The low moisture
vapor permeable barrier formed lid layer is shown at 64.
Preferably, the generally flat bottom layer 68 is constructed of an
aluminum foil composite film that may or may not contain a heat
seal coating (not shown) on the side that contacts the gel pads. If
it is used, the heat seal coating is preferably a readily peelable
coating.
[0051] The gel-imbibed pads as at 58 are constructed of a composite
or laminated non-woven material. The anode and cathode gels are
dispensed onto the pads and soak into the composite non-woven
material.
[0052] The low moisture vapor permeable formed lid layer 64 has
been successfully constructed from a cold-formable aluminum
composite material consisting of a seal layer on the product
contacting under side and a nylon layer on the opposite side.
Alternatively, for example, the product contact side 64 may consist
of PVC with no seal layer. If a seal layer is employed, preferably
it is a peelable heat seal coating. Anode 72 and cathode 74
cavities may be mechanically formed with traditional cold form
tooling using Teflon.RTM. (polytetrafluorethylene) plugs or in
combination with vacuum or pressure assist. The material may be
thermoformed if using an alternative material including other
fluorine-containing plastics in sheet or film form such as material
sold under the trademark Aclar.RTM., PVDC, and other low moisture
vapor transmission barrier thermoformed packaging materials.
[0053] FIGS. 7A and 7B show top and side cross-sectional views,
respectively, illustrating the structure of one embodiment anode 72
or cathode 74 composite pad materials. As indicated, the anode and
cathode pad composite materials are preferably of a non-woven
structure to maintain the continuity of the drug-containing
material in the structure and may include a plurality of layers,
possibly up to three layers, of material. These may include a thick
needle-punched polypropylene layer 76, a thin, permeable
polyethylene net layer 78, and a thin, occlusive polypropylene
layer 80. The layers may be heat fused together without requiring
adhesives. All three layers are cut to have the same outside
perimeter shape. The occlusive layer 80 is cut to the shape of a
perimeter ring that remains intact and occlusive. Inside the ring,
the occlusive layer 80 is cut out completely or perforated so that
the inside region 84 becomes permeable. The permeable region 84 is
shaped to coincide with the shape of the anode 50 and cathode 52
electrodes, by allowing the gel to migrate through this layer and
contact the full area of the electrodes when the device is
assembled for use. Importantly, the occlusive ring 80 provides a
barrier for gel migration so the outside surface remains relatively
dry during storage to aid in adhesive transfer of the drug-imbibed
pad 70 during activation of the device.
[0054] In one embodiment, both the anode 72 and cathode 74
composite pads are similar in shape. Of course, the electrodes may
be any convenient shape and the electrodes in a given patch
embodiment may be of like or different shapes. FIGS. 8A and 88B
show a plan view and cross sectional view of an alternate shape of
what may be either an anode and/or cathode of composite non-woven
material 86. This embodiment has a shaped perimeter ring 88, with
permeable inside area 90. FIG. 10 is a top view of an alternative
embodiment showing a device 100 with a drug pack 102 having anode
and cathode formed cavities, 104 and 106, respectively, of
different shapes. In similar fashion, anode and cathode formed
cavities of different, but corresponding shapes, are reflected in
the anode 108 and cathode 110 in the foam, support structure 112,
and occlusive layers 114 and 116. Only corresponding components
that fit together in an assembled device need be of like shape.
[0055] An important aspect of the invention involves shelf life
stability of the co-packaged iontophoretic devices. This is of
paramount concern based on the history of such devices which have
had limited commercial success because of shelf life limitations.
As indicated, co-packaging techniques have included attempts to
package the wet drug gels in direct contact with the electrodes
during long term storage, and attempts to isolate the power source
and electronics in the same package through low moisture permeable
(high barrier) materials. Wet gels have been packaged in direct
contact with the electrodes only and connected to a power source
and electronics by a cable or other connector at time of use. As
indicated, each of these is fraught with challenges for long term
stability. For example, in time, wet gels may degrade the metals in
the electrodes, power source, and electronics which, in turn,
contaminates and degrades the stability of the gel.
[0056] In the present development, stable long term co-packaging is
realized by the provision of a storage container for the anode and
cathode gels in the form of a separate hermetically sealed drug
pack or blister cavity with product contact layers that do not
leach into the gel, react with the gel, or absorb the gel. Since
the gel material itself provides no form, a carrier substrate
material is used to give the gel form and structure, and provide a
stable support to facilitate transfer of the gel out of the long
term storage container when the system is assembled for use. The
carrier substrate should be composed of materials that do not
leach, react, or absorb the constituents of the gel. Preferably the
blister cavity and carrier substrate should be made from stable,
relatively inert, materials such as polypropylene and polyethylene.
Any suitable material can be used and may be selected based on the
nature of the gel.
[0057] Shelf life stability will vary with the construction of the
patch component and the stability of the integrity of the drug
composition. Patch shelf life depends on retention of adhesive
quality and the maintenance of the specified function of the
electrical circuit components. The device should have a stable
shelf life of at least two (2) years.
[0058] FIGS. 5A-5E show in step-wise cross sectional views of one
method for forming, filling, and sealing a drug-containing pack or
drug pack in accordance with the present development. FIG. 6 shows
a top view of the drug pack of FIG. 5, as assembled generally at
120. In the method of FIGS. 5A-5E, the drug containing pack is
assembled in an inverted position. The assembly starts with the
provision of a lid or cover membrane 122 of a low moisture vapor
transmission material formed to create anode and cathode gel cavity
shapes 124 and 126, respectively, at a specified spaced interval
and depth. Next, an anode pad 128 is placed into the formed anode
cavity 124, and likewise, a cathode pad 130 is placed into the
formed cathode cavity 126. The pads may be of similar construction
to those shown in FIGS. 7A-7B and 8A-8B. The anode and cathode pads
are oriented so that each occlusive layer 132, 134 is placed facing
into the cavity and in contact with the bottom of the corresponding
formed cavity. The anode and cathode pads are sized to just fit in
the bottom of the formed cavities. In this manner, the formed
cavities then initially provide registration of the pads to the
formed lid layer 122.
[0059] The remaining steps are performed in a timed sequence as
will be described. Allowable open time for the assembly is
determined by the rate of pad permeation which is related to the
viscosity of the gel used.
[0060] At time t=t.sub.0, as shown in FIG. 5C, an amount of a
viscous anode gel 136 is dispensed to uniformly cover the central
permeable region as at 84 (FIG. 7A) of the anode pad 128;
similarly, an amount of a viscous cathode gel 138A is dispensed to
uniformly cover a permeable region of the cathode pad 130. As also
seen in FIG. 5C, both the anode and cathode gels are dispensed in a
manner such that for a given amount of gel, once dispensed, the
total height of the pad plus the gel height somewhat exceeds the
depth of the formed anode or cathode cavity 124 or 126. The gel
must be of a relatively high viscosity range in order for it to
maintain its shape/height for a necessary duration during assembly
of the device. At time t>t.sub.0<t.sub.1, a flat bottom or
carrier substrate layer 140 is applied (FIG. 5D) and heat sealed to
the formed cover membrane 122. Application of the flat carrier
substrate layer 140 contacts and compresses the gel causing the gel
to wet the inner surface of the carrier substrate layer 140 and
spread out as also shown in FIG. 5D.
[0061] Alternatively, in another embodiment (not shown), the flat
bottom layer can be formed similarly to the formed cover membrane
layer to create a nested configuration, in which case, the gel plus
the pad height can be designed so that when the bottom and lid
layers are assembled, the gel will be in contact with the carrier
substrate layer in a similar manner as in the illustrated
embodiment.
[0062] In this procedure, time span t=t.sub.0 to t=t.sub.1 is
defined as the time it takes the dispensed anode and cathode gels
to soak through their respective pads and start to wet to the
bottom of the formed cavities of lid layer. Time is a factor
because it has been found that if the gels soak completely through
the respective pads and wet the bottom or inner surface of the
formed cover membrane cavity before the carrier substrate layer is
applied, the pads, once fully imbibed, may preferentially stick to
the inside of the formed lid. This, of course, is undesirable as
the imbibed gel pad would adhere to the lid layer 122 instead of
the carrier substrate layer 140 when one attempted to assemble the
system. Time span t=t.sub.0 to t=t.sub.1 also defines the time in
which the gel will adequately maintain its height so that the gel
will wet and adhere to the inner surface of the bottom layer 140
when that layer is applied.
[0063] For the above reasons, the gels are formulated in a
preferred viscosity range to provide the correct flow rate and
surface tension. For example, a 100,000 centipoise gel may have a
t.sub.0-t.sub.1 time window of about 2-4 minutes. This is adequate
for normal assembly to occur.
[0064] In this process, the gels initially contact and wet the
bottom layer member 140. This allows the gels to act as adhesives
as the surface tension of the gels between the member 140 and the
pads 128 and 130 exceeds the gravitational forces on the imbibing
pads. Therefore, as the pads slowly imbibe with gel, they will
stick to and be pulled towards the carrier substrate layer
regardless of the orientation of the device. Thus, after the bottom
and lid layers are sealed, the compressed gels imbibe (soak-in)
into the anode and cathode pads respectfully, creating a fully
imbibed non-woven anode pad 128A and fully imbibed pad 130B as
shown in FIG. 5E. As described previously, the fully imbibed anode
and cathode gel pads continue to adhere to the bottom layer 140
thereby creating anode and cathode headspaces 142 and 144,
respectively in the package as also shown in FIG. 5E. It has been
found that due to the high surface tension and high preferred
viscosity of the gels, the fully imbibed pads will remain
registered to their respective formed lid cavities and be attached
to the carrier substrate layer as shown throughout the anticipated
shelf life of the device.
[0065] It will be appreciated that the amount of gel added to each
cavity should be matched to the absorbency of each pad in order to
minimize excess gel. The amount and viscosity of the gels is
preferably such that imbibed gel does not wet the outer surface of
the occlusive ring on the pads. In this manner, the outer surface
of the occlusive ring 146, 148 should remain relatively dry to aid
adhesive transfer and adhesive attachment of imbibed gel pads into
corresponding empty anode and cathode wells of the transdermal
patch during activation. The inside surface of the formed lid
cavities in the anode and cathode headspace regions as at 142 and
144 should remain free of gel and relatively dry.
[0066] In order for this packaging concept to function, the gels
must be formulated with a preferred viscosity. The preferred range
is between 8,000-120,000 centipoise but is not limited so long as
the process can be successfully followed. The gels useful in the
system may be formulated by dissolving an appropriate amount of
drug or saline in water, and adding a gelling agent such as HPMC
(hydroxpropylmethylcellulose) such that a conductive gel of
appropriate viscosity is created. Other gelling agents, such as PVP
(polyvinylpyrrolidone), PEO (polyethyleneoxide), or PVA
(polyvinylalcohol) can also be used. Successful gels have been
formulated from a HPMC powder at 2% w/w.
[0067] The concentration of an active agent in the gel may vary
widely depending on the agent of interest and the desired patch
dosage and planned duration of application. Generally, the
concentration will range from about 0.2% to 10% (weight).
[0068] FIGS. 3A-3D show in step-wise fashion, in cross-sectional
views, how one preferred embodiment is activated and deployed to a
treatment site. FIG. 4 shows the top view of FIG. 3A after the
blister or drug pack lid 64 has been removed. FIGS. 9A and 9B show
a side sectional and top view, respectfully, of a fully packaged
device.
[0069] Beginning with the fully packaged device of FIGS. 9A and 9B,
a deployment or assembly process will be described. First, the
fully packaged device is opened and unfolded by pulling at the tab
160 to release adhesive strip 56 from the release liner coated side
of panel 36D. Second, the formed cover membrane layer 64 is removed
or peeled away from the bottom layer 68 exposing the gel-imbibed
anode and cathode pads 60, 62 which are adhered through surface
tension of the gels to the bottom layer 68 as shown in FIG. 3A. The
peel is initiated by peeling at the tab 78 (FIG. 2) on the formed
lid member 64.
[0070] Next, the first panel 36A is folded at the fold line 32 onto
the second panel 36B, thereby bringing the occlusive region as at
80 of the occlusive layer 80 of the anode and cathode gel pads 60,
62 in permanent adhesive contact with the occlusive tape layer 40
of the transdermal patch 24 as shown in FIG. 3C. Also, the adhesive
strip is brought into contact with the printable coating layer 30
of the support structure 22 and is permanently adhered to the
second panel 36B, thereby preventing the panel 36A from being
re-opened. FIG. 3B shows an intermediate view of the folding
action. The outer surface of the transdermal patch is preferably
pressed to ensure good permanent bonding of the occlusive tape 40
to the occlusive region as at 80 on the gel pads.
[0071] Finally, the half release liner 54 is peeled from the
support structure at the tab 54A bringing the fully assembled
transdermal patch 170 with it. The exposed half of the patch
adhesive can be applied to the treatment site and the half release
liner 54 thereafter can be peeled from the transdermal patch at the
tab 54B (FIG. 9B) and the remaining half of the patch adhered to
the treatment site.
[0072] FIGS. 11A-11C illustrate an alternative embodiment including
an alignment fixture or guide element and illustrating activation
of the embodiment. FIG. 12 shows a top view of the fully
assimilated embodiment of FIG. 11B from which the cross-sectional
views of 11A-11C are taken. As best seen in FIG. 11A, the device,
generally 200, as packaged, includes three main components. They
are a guide element 202 having spaced raised alignment members 204,
206, a drug pack arrangement 208 and a transdermal patch assembly
210. The main components are designed to be stored separately in a
common package and assembled when the device is prepared for
use.
[0073] The drug pack includes a flat card substrate layer 212 which
is designed with spaced alignment openings 214 and 216 which
register with alignment members 204 and 206 during assembly. Anode
and cathode non-woven, gel-imbibed pads 218 and 220 are
respectively carried on a bottom layer 222 and separated from drug
pack lid 224 in the manner of embodiments previously described and
illustrated in FIGS. 5A-5E. Drug pack 208 is adhered to card
substrate layer 212 as by a double-sided tape layer at 226.
[0074] The transdermal patch component 210 is mounted on a flat
card substrate layer 228 with spaced alignment openings 230 and 232
and, as with previously described embodiments, half release liner
234. The patch assembly may be quite similar in construction to
that previously described with foam layer 236 and double-sided tape
238, electrode subassembly layer 240 and overlaying tape layer
242.
[0075] At the time of use, individual components are aligned and
assembled to each other using features of a component to self-align
to adjacent components. In this manner, the guide element 202 may
be positioned on a flat surface with the spaced alignment members
204, 206 facing up as shown in FIG. 11A. Next, the drug blister
pack 208 is assembled to the alignment fixture or guide element 202
by registering alignment member 204 to the opening 214 in the drug
pack and alignment member 206 to opening 216. The lid 224 can then
be peeled off the drug pack 208 exposing the gel-imbibed, non-woven
anode and cathode pads 218 and 220, respectively. Next, the
transdermal iontophoresis patch 210 can be assembled to drug pack
208 by again using alignment members 204 and 206 with alignment
openings 230 and 232 thereby placing the gel-imbibed pads in
alignment with corresponding electrodes. This results in the
combined configuration depicted in the cross-sectional view of FIG.
1B and top view of FIG. 12 with the drug pack arrangement 208 and
the transdermal patch assembly 210 in consecutive assembled
registration on the guide element 202.
[0076] In this stacked condition, the assembled patch is ready to
be separated for placement on a patient. Separation can be
accomplished by simply peeling the half release liner 234 from the
card thereby separating the device from the card substrate layer
228 and bringing the fully assembled transdermal patch 250 with it
as shown in FIG. 11C. The patch is then ready to be applied to the
patient as described in relation to the previous embodiments.
[0077] It will be appreciated that the drug pack 208 and the
transdermal patch 210 are similar in construction to previously
described embodiments except that the card substrate layers in this
embodiment are separate flat members rather than folding connected
panels. The flat card substrate layers 212, 228 include alignment
openings corresponding to the members 204 and 206 on guide element
202 and they do not require a silicon or other release coating so
that both sides may contain a printable clay coating material or
the like.
[0078] The card layers 212, 228 may also be constructed from any
suitable polymer material. The alignment members 204 and 206 of the
guide element 202 are preferably thermoformed or injection molded
out of a suitable polymer material also.
[0079] FIG. 13 is an exploded cross-sectional view of an alternate
embodiment to that shown in FIGS. 11A-11C in which a guide element
302 with alignment members 304 and 306 is substituted in the drug
pack 308 for the flat card substrate layer 212. The drug pack is
otherwise similar to previously described drug packs and a lid is
shown at 324. The transdermal patch component 310 is also similar
to that shown in FIG. 1 IA and includes substrate 328 with spaced
alignment openings 330 and 332 and half release layer at 334. The
drug pack 308 is bonded to the guide element 302 by double-sided
tape 326.
[0080] Assembly and activation is similar to that of the embodiment
of FIG. 11A-11C. Thus, the drug pack lid 324 is removed and the
transdermal patch 310 is aligned with the drug pack over the
alignment members 304 and 306 using the openings 330 and 332. The
assembled patch thereafter being peeled away in the manner of FIG.
11C.
[0081] FIG. 14 shows an exploded cross-sectional view of yet
another embodiment of the device of the present invention which
represents another alternative to that shown in FIGS. 11A-11C. In
this embodiment, the alignment fixture 402 with alignment members
404 and 406 is substituted for the release card substrate layer 228
associated with the transdermal patch component 410. The alignment
fixture includes a silicone release coating on upper surface 402A
applied to the side to which the patch adheres prior to removal.
This embodiment is assembled and applied in a similar manner to
those described just above. Thus, the lid 424 of the drug pack 408
is removed and the openings 414 and 416 in the substrate 412 are
aligned with the members 404 and 406 and the fully aligned device
is peeled away in the manner of FIG. 11C.
[0082] It will further be appreciated that the assembled device or
patch to be applied to a user may be of any convenient size as from
as small as about 1 cm.times.2 cm to about 15 cm.times.20 cm. The
size can vary widely depending on the active agent administered and
the condition to be treated.
[0083] This invention has been described herein in considerable
detail in order to comply with the patent statutes and to provide
those skilled in the art with the information needed to apply the
novel principles and to construct and use embodiments of the
example as required. However, it is to be understood that the
invention can be carried out by specifically different devices and
that various modifications can be accomplished without departing
from the scope of the invention itself.
* * * * *