U.S. patent application number 11/039514 was filed with the patent office on 2005-07-21 for iontophoretic drug delivery device and reservoir and method of making same.
This patent application is currently assigned to Vyteris, Inc.. Invention is credited to Eliash, Bruce Michael, Keusch, Preston, Vilambi, Nrk.
Application Number | 20050159698 11/039514 |
Document ID | / |
Family ID | 46303739 |
Filed Date | 2005-07-21 |
United States Patent
Application |
20050159698 |
Kind Code |
A1 |
Keusch, Preston ; et
al. |
July 21, 2005 |
Iontophoretic drug delivery device and reservoir and method of
making same
Abstract
A reservoir electrode assembly of the present invention for an
iontophoretic drug delivery device includes an electrode and a
hydrophilic reservoir situated in electrically conductive relation
to the electrode. The hydrophilic reservoir is formed from a
bibulous hydrophilic crosslinked polymeric material having a first
surface and a second surface that is adhesively adherent to the
electrode. The first surface of the polymeric material is
releasably adhesively adherent when applied to an area of a
patient's skin. The polymeric material has a cohesive strength
forms an adhesive bond with a bond strength between the second
surface of the polymeric material to the electrode that is greater
than the cohesive strength of the polymeric material. Additionally,
an adhesive bond strength of the first surface of the polymeric
material to the applied area of the patient is less than the
cohesive strength of the polymeric material so that upon removal of
the reservoir assembly of the invention from the applied area of
the patient, substantially no polymeric material remains on the
applied area and the hydrophilic reservoir remains substantially
intact and adhesively adherent to the electrode.
Inventors: |
Keusch, Preston; (Hazlet,
NJ) ; Vilambi, Nrk; (Jamaica Estates, NY) ;
Eliash, Bruce Michael; (Franklin Lakes, NJ) |
Correspondence
Address: |
KIRKPATRICK & LOCKHART NICHOLSON GRAHAM LLP
535 SMITHFIELD STREET
PITTSBURGH
PA
15222
US
|
Assignee: |
Vyteris, Inc.
|
Family ID: |
46303739 |
Appl. No.: |
11/039514 |
Filed: |
January 19, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11039514 |
Jan 19, 2005 |
|
|
|
10085428 |
Feb 28, 2002 |
|
|
|
6862473 |
|
|
|
|
10085428 |
Feb 28, 2002 |
|
|
|
09328329 |
Jun 9, 1999 |
|
|
|
6377847 |
|
|
|
|
09328329 |
Jun 9, 1999 |
|
|
|
08533979 |
Sep 26, 1995 |
|
|
|
08533979 |
Sep 26, 1995 |
|
|
|
08129222 |
Sep 30, 1993 |
|
|
|
Current U.S.
Class: |
604/22 |
Current CPC
Class: |
A61N 1/044 20130101;
A61N 1/0436 20130101; A61N 1/0448 20130101 |
Class at
Publication: |
604/022 |
International
Class: |
A61B 017/20 |
Claims
1-21. (canceled)
22. An iontophoretic drug delivery device, comprising: a reservoir
including epinephrine, wherein the iontophoretic drug delivery
device is prepackaged as a ready to use device.
23. The iontophoretic drug delivery device of claim 22, wherein the
reservoir further comprises lidocaine.
24-70. (canceled)
Description
[0001] This application is a continuation-in-part of application
Ser. No. 08/533,979 filed Sep. 26, 1995, which is a
continuation-in-part of application Ser. No. 08/129,222 filed Sep.
30, 1993, now abandoned.
FIELD OF THE INVENTION
[0002] The present invention generally relates to iontophoretic
systems for delivering medicaments such as therapeutic drugs and
medicines to patients transdermally, i.e., through the skin, and
more specifically relates to a stable iontophoretic drug delivery
device and a reservoir for use in the same. In addition, the
present invention relates to a method for making a stable
iontophoretic drug delivery device with long shelf life and the
reservoir for use in such a device.
BACKGROUND
[0003] Transdermal drug delivery systems have, in recent years,
become an increasingly important means of administering drugs. Such
systems offer advantages clearly not achievable by other modes of
administration such as avoiding introduction of the drug through
the gastro-intestinal tract or punctures in the skin to name a
few.
[0004] Presently, there are two types of transdermal drug delivery
systems, i.e., "Passive" and "Active." Passive systems deliver drug
through the skin of the user unaided, an example of which would
involve the application of a topical anesthetic to provide
localized relief, as disclosed in U.S. Pat. No. 3,814,095 (Lubens).
Active systems on the other hand deliver drug through the skin of
the user, such as a patient, using iontophoresis, which according
to Stedman's Medical Dictionary, is defined as "the introduction
into the tissues, by means of an electric current, of the ions of a
chosen medicament."
[0005] Conventional iontophoretic devices, such as those described
in U.S. Pat. No. 4,820,263 (Spevak et al.), U.S. Pat. No. 4,927,408
(Haak et al.) and U.S. Pat. No. 5,084,008 (Phipps), the disclosures
of which are hereby incorporated by reference, for delivering a
drug or medicine transdermally through iontophoresis, basically
consist of two electrodes--an anode and a cathode. Usually,
electric current is driven from an external supply into the skin at
the anode, and back out at the cathode. Accordingly, there has been
considerable interest in iontophoresis to perform delivery of drugs
for a variety of purposes. Two such examples, involve the use of
Novocaine,.TM. which is usually injected prior to dental work to
relieve pain, and Lidocaine,.TM. which is usually applied as a
topical, local anesthetic.
[0006] Such prior devices have prior hereto not been pre-loaded and
self adhering, e.g., they have typically utilized an absorbent pad
or porous solid sheet that can be filled with drug solution as the
drug reservoir. These absorbent pads or porous sheets have three
major disadvantages. First, they must be filled with the drug
solution after removal from the package since these pads or porous
sheets do not hold the drug solution as the solution is subject to
removal and leakage under pressure or flexure. In addition, even
after the inconvenient addition of the drug solution and after
removal from the package, the absorbent pad or porous sheet
reservoir remain subject to leakage and smearing of the drug
solution due to pressure or flexure upon the skin. Furthermore,
absorbent pads or porous solid sheets can not provide the
electrical continuity to complete intimate contact since they lack
adhesiveness and flexibility with the skin and its contours.
[0007] In addition, prior drug reservoirs have included pastes and
unformed viscous semi-solid gels such as for example agar that have
both solid and liquid characteristics as described, for example, in
U.S. Pat. No. 4,383,529 (Webster), the disclosure of which is
hereby incorporated by reference.
[0008] Powers et al., U.S. Pat. No. 4,886,277, although suggesting
that Lidocaine could be incorporated into the reservoir, fails to
solve the resulting problem associated with compatibility with
adjacent materials such as conductive layers. Accordingly, such a
device would fail to provide sufficient stability for extended
shelf life, i.e., more than one year.
[0009] However, several disadvantages and limitations have been
associated with the use of such devices, including handleability
and loadability. For example, the semi-solid agar reservoir
disclosed in Webster flows under shear or stress. Furthermore, this
disclosed reservoir may melt upon exposure to modest elevated
temperatures. The agar is unstable, spontaneously releasing aqueous
solution.
[0010] Thus, there has been a need for an iontophoretic drug
delivery device and a reservoir for use in the same, as well as a
method for making the reservoir, which would eliminate the problems
and limitations associated with the prior devices discussed above,
most significant of the problems being associated with stability,
handleability, loadability and electrocontinuity of the reservoir,
including chemical and thermal stability of the reservoir and the
electrode.
SUMMARY
[0011] A reservoir electrode assembly of the present invention for
an iontophoretic drug delivery device includes an electrode and a
hydrophilic reservoir situated in electrically conductive relation
to the electrode. The hydrophilic reservoir is formed from a
bibulous hydrophilic cross-linked polymeric material having a first
surface and a second surface that is adhesively adherent to the
electrode. The first surface of the polymeric material is
releasably adhesively adherent when applied to an area of a
patient's skin. The polymeric material has a cohesive strength
forms an adhesive bond with a bond strength between the second
surface of the polymeric material to the electrode that is greater
than the cohesive strength of the polymeric material. Additionally,
an adhesive bond strength of the first surface of the polymeric
material to the applied area of the patient is less than the
cohesive strength of the polymeric material so that upon removal of
the reservoir assembly of the invention from the applied area of
the patient, substantially no polymeric material remains on the
applied area and the hydrophilic reservoir remains substantially
intact and adhesively adherent to the electrode.
[0012] The reservoir electrode of the present invention provides
solutions for several problems seen with available iontophoretic
reservoir electrodes. The reservoir electrode of the invention, by
being adherent to the skin of the patient minimizes current pathway
concentrations that often result in irritation and burning caused
by incomplete contact of the reservoir electrode assembly to the
patient's skin. Because the adhesive bond of the electrode to the
patient's skin is less than the cohesive strength of the polymeric
material used for the reservoir, substantially no residue from the
reservoir material is left behind on the patient's skin.
Additionally, since the polymeric reservoir material forms an
adhesive bond with the electrode, there is intimate and effective
electrical contact between the electrical circuit and the polymeric
reservoir material. The reservoir electrode assembly of the
invention can be physically smaller than most currently available
electrode assemblies because the entire polymeric reservoir is
hydrophilic and is utilized to contain drugs and electrolytes. Many
current electrode assemblies require hydrophobic polymeric
materials to achieve an adhesive tack and another hydrophilic
material to retain the aqueous drug and electrolyte used for the
iontophoretic delivery. When a hydrophobic and a hydrophilic
component are used to form a reservoir, as in the currently
available materials, some partitioning of the medicament may occur
or there may be some binding of the active compound with the
hydrophobic material that reduces the availability of the
medicament for delivery. These effects are not seen with the
hydrophilic reservoir of the invention.
[0013] In contrast to the prior devices discussed above, it has
been found that a iontophoretic drug delivery device particularly
suited for use to deliver at least one medicament, particularly in
a high dose efficiency, can be constructed in accordance with the
present invention by the incorporation of an aqueous swollen cross
linked water soluble polymeric drug delivery reservoir adhesively
coupled to the electrode such that the adhesive strength of the
electrode material is greater than the cohesive strength of the
reservoir material. In addition, the device of the present
invention can easily fit over any contour of the body and provide
excellent electrocoupling with the electrode and the skin, while
still being capable of flexing and adhering to the skin. Also the
device of the present invention can be applied over a range of
temperatures and is stable for over one year at controlled room
temperature to provide a commercially advantageous shelf-life.
[0014] The iontophoretic drug delivery device of the present
invention for delivering at least one medicament to an applied area
of a patient, such as the skin, mucous membrane and the like,
including electrode assembly means for driving a medication into
the applied area of the patient to be absorbed by the body of the
patient, the electrode include an electrode material, and a
covalently cross linked hydrophilic reservoir situated in
electrically conductive relation to the electrode assembly means,
with the reservoir including an aqueous swollen cross linked water
soluble polymer material having an adhesive strength to the
electrode material, an adhesive strength to the applied area and a
cohesive strength to itself, with the reservoir containing at least
one medicament, wherein the adhesive strength of the polymer
material to the electrode material is greater than the cohesive
strength of the polymer material and the adhesive strength of the
polymer material to the applied area is less than the cohesive
strength of the polymer material so that upon removal of the device
from the applied area little if any polymer material remains on the
applied area, while maintaining the reservoir intact and in
intimate contact with the electrode material.
[0015] In the preferred embodiment, the device of the invention
further includes a structurally reinforcing member situated within
the reservoir including the aqueous swollen cross linked water
soluble polymer, with the structurally reinforcing member having an
open area that is thin and of sufficient voidage so as not to
impede the flow of ions. In addition, the structurally reinforcing
member is a thermoplastic polymeric scrim and the aqueous swollen
cross linked water soluble polymer is cross linkable by high energy
irradiation with the scrim being wettable enough and with open area
of greater than 40% to insure phase continuity though the scrim,
along with sufficient adhesion to contribute strength to the
aqueous cross linked polymeric reservoir. Also, the aqueous swollen
cross linked water soluble polymer is selected from the group
including polyethylene oxide, polyvinyl pyrrolidone, polyvinyl
alcohol, polyethylene glycol, and polyacrylamide. The at least one
medicament includes Lidocaine and the reservoir also includes a
vasoconstrictor, stabilizers and glycerin. Further, the reservoir
further includes additives and conductive salts, with the additives
selected from the group including glycerin, propylene glycol,
polyethylene glycol and preservatives.
[0016] The reservoir of the present invention for use in an
iontophoretic drug delivery device having an electrode assembly
including an electrically conductive electrode material for
delivering at least one medicament through an applied area of a
patient, such as the skin, mucous membrane and the like, includes a
layer of a aqueous swollen cross linked water soluble polymer
material capable of having electrocontinuity with the electrode
assembly, with the aqueous swollen cross linked water soluble
polymer material having sufficient adhesive tack including the at
least one medicament for delivery through an applied area of a
patient, such as the skin, mucous membrane and the like, and the
aqueous swollen cross linked water soluble polymer material having
an adhesive strength to the electrode material greater than the
cohesive strength of the polymer material, and the cohesive
strength being greater than an adhesive strength to the applied
area.
[0017] In the preferred embodiment, the reservoir also includes a
structurally reinforcing member situated within the layer of
aqueous swollen cross linked water soluble polymer material, with
the structurally reinforcing member having approximately 40%
porosity so as not to impede the flow of ions, with the
structurally reinforcing member being a wettable, scrim of a
aqueous insoluble thermoplastic polymeric material and the aqueous
swollen cross linked water soluble polymer material is cross linked
by high energy irradiation. Also, aqueous swollen cross linked
water soluble polymer is selected from the group including
polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol,
polyacrylamide and polyethylene glycol. In addition, the at least
one medicament includes Lidocaine and the aqueous swollen cross
linked water soluble polymer material includes a vasoconstrictor,
stabilizers and glycerin. Further, the reservoir includes additives
and conductive salts, with the additives selected from the group
including glycerin, propylene glycol and polyethylene glycol and
preservatives.
[0018] The method of making a reservoir for an iontophoretic drug
delivery device of the present invention includes the steps of
providing a structurally reinforcing member, coating the
reinforcing member with a viscous water soluble polymer solution on
both sides of the structurally reinforcing member such that the
polymer solution penetrates the open area, wets the reinforcing
member, and cross linking the layer by high energy irradiation,
with the cross-linked layer of polymer having an adhesive strength
to an electrode material greater than a cohesive strength of the
polymer, and the cohesive strength being greater than an adhesive
strength to an applied area.
[0019] In the preferred embodiment of the method, the step of
coating includes the steps of applying a layer of the viscous
solution to one side of the reinforcing member, applying a layer of
the viscous solution to one side of a release liner and laminating
the release liner and the reinforcing material together such that
both surfaces of the reinforcing member are coated with the viscous
solution. In addition, the viscous solution is applied to the
reinforcing member and the release liner to a thickness of about
Ca. 5 mil to 70 mil. The method also includes the step of applying
final release liners to the remaining exposed viscous solution
coated surfaces of the reinforcing member to form a laminate and
cross linking the viscous solution. Also, the method includes the
steps of replacing one of the final release liners with an
electrode in flexible sheet form, and adding at least one
medicament to the cross linked water soluble polymer, with the at
least one medicament includes Lidocaine and the cross linked water
soluble polymer includes a vasoconstrictor, stabilizers, glycerin
and preservative. Further, the method includes the of cutting the
laminate into a suitable shape and area and laminating it to a
conductive metal for use in an iontophoretic drug delivery
device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The various features, objects, benefits, and advantages of
the present invention will become more apparent upon reading the
following detailed description of the preferred embodiment along
with the appended claims in conjunction with the drawings, wherein
like reference numerals identify corresponding components, and:
[0021] FIG. 1 is a schematic view of the iontophoretic drug
delivery device of the present invention illustrating placement of
the device on a user;
[0022] FIG. 2 is a cross sectional view of the device of the
present invention;
[0023] FIGS. 3A, 3B, 3C and 3D are schematic views of the various
steps of the method for making the reservoir of the present
invention;
[0024] FIG. 4 is a logic flow diagram depicting the various steps
of the method for making the reservoir of the present
invention;
[0025] FIG. 5 is a cross-sectional view of the reservoir electrode
assembly of the invention;
[0026] FIG. 6 is a schematic perspective view of the reservoir of
the invention from FIG. 5;
[0027] FIG. 7 is a schematic cross-sectional view of the coating
and cross-linking of the web for forming the PVP reservoir; and
[0028] FIG. 8 is a schematic top plan view of the web illustrating
punching out individual reservoir units.
DETAILED DESCRIPTION
[0029] The iontophoretic drug delivery device of the present
invention is illustrated in FIGS. 1 and 2, and generally includes
the designation 10. Referring to FIGS. 1 and 2, the device 10 of
the present invention includes an electrode assembly 12, having at
least one electrode and at least one reservoir, with the reservoir
and electrode held or contained within a suitable structure 16,
with a skin adhesive 18. Also, as is well known in the art, a power
source 19 is provided in circuit with the electrode assembly 12 for
supplying a source of electrical current. It should be appreciated
that a return electrode and reservoir may be combined into a single
electrode assembly 12 or separately provided as illustrated in FIG.
1.
[0030] In the preferred embodiment, the device is divided or
otherwise separated into two portions 20 and 22, with the electrode
assembly 12 including two electrodes 24 and 26. One portion 20
(first) includes the electrode 24 and a reservoir 28, with the
reservoir being situated adjacent and coupled to the electrode 24
and holding at least one medicament or drug 30, preferably in
ionized or ionizable forms, to be delivered iontophoretically. The
other portion 22 (second) includes the electrode 26 and a reservoir
32, with the reservoir being situated adjacent to the electrode 26
and holding an electrolyte 34. The particular electrolyte is not
essential to the present invention and is merely a matter of
choice. However, in this embodiment the electrolyte may include
sodium chloride in an aqueous solution, matrix or the like as
explained in greater detail hereinbelow.
[0031] A schematic diagram of the first portion 20 of the device 10
is illustrated in FIG. 2. In this case, the medicament 30 to be
delivered through the skin is a cation and the reservoir 28 is
connected to the electrode 24, which acts as an anode. The return
electrode 26 (cathode) may be constructed in the manner as the
working electrode 24. If the drug is an anion, then the drug
containing reservoir would be connected to the cathode and the
return reservoir would be connected to the anode.
[0032] As is well known within the field, the device can be
situated on the area of the patient to which the medicament is to
be applied (the applied area) and a voltage impressed across the
electrodes 24, 26 of the electrode assembly 12 to cause current to
flow through the skin 60 of the patient to drive the ionic
medicament locally into the skin and the tissue or to be absorbed
systematically by the body of the patient. It should also be
appreciated that the device of the present invention can be applied
to other areas of the body such as mucous membranes and the like
depending upon the desired therapy and medicaments to be
delivered.
[0033] In order to transport the medicament through intact skin 60
at least the reservoir 28 containing the medicament includes an
aqueous swollen cross linked water soluble polymer, which for
simplicity is hereinafter referred to as a cross linked water
soluble polymer. The cross linked water soluble polymer can be
incorporated into the reservoir as a homogeneous solid cut or
molded sheet 40 of suitable shape and area which can be attached to
the electrode as illustrated in FIGS. 1 and 2. However, it should
be appreciated that the reservoir 32 (cathode) may also be made of
the same material as the reservoir 28 containing the medicament,
i.e., to include the cross linked water soluble polymer sheet 40
illustrated in FIGS. 3A-3D. Accordingly, the cross linked water
soluble polymer sheet 40 containing either the medicament and/or
the electrolyte serves as the reservoirs 28, 32 and the electrical
coupling to the skin while being able to conform to all contours of
the body. In addition, the reservoir may include additives selected
from the group including glycerin, propylene glycol, polyethylene
glycol and conductive salts, as well as preservatives.
[0034] The particular cross linked water soluble polymer material
may be made from a variety of commercially available water soluble
polymers known to those skilled in the art as long as it is of low
bioburden, is electrically conductive, readily conforms to the
contours of the body, is capable of being cross linked and can hold
or otherwise retain the drug solution under pressure and
flexure.
[0035] Cross linked water soluble polymers are preferred reservoirs
as they provide a conformable interface with good electrical
coupling and excellent biocompatibility. Examples of such cross
linked water soluble polymers are irradiated cross linked
polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), polyvinyl
alcohol (PVA), polyethylene glycol (PEG), polyacrylamide and
polyethylene glycol (PEG). The cross linked water soluble polymer
sheet 40 by nature of its preparation by irradiation cross linking
is of low bioburden and is non toxic, non irritating and non
sensitizing to the skin. This is particularly assured by the fact
that no chemical cross linking agents or organic solvents are
required to synthesize the cross linked water soluble polymer
material. It should be appreciated, that the techniques of
irradiation cross linking the water soluble polymer material are
well known in the art.
[0036] In the preferred embodiment, the cross linked water soluble
polymer sheet 40 may include a netting or non-woven material 42
such as an inert and wetable polyethylene terphthalate (PET)
material is the form of a scrim commercially available from Reemay,
Inc. The scrim utilized for this application is preferably an open
web, inert, water insoluble material that does not change the
conductivity or ionic flow of the materials in the water soluble
polymer. In addition, the scrim is wetable and porous. The basis
weight of the scrim being of a basis weight between Ca. 4 to 60
grams/square yard. Also, in this way, the cross linked water
soluble polymer sheet 40 can be formed from a solution 44 of
pre-mixes after dispersion and full solution, with the solution
then applied on both sides of the scrim 42 to a thickness of Ca. 5
mil to 40 mil and then cross linked by high energy irradiation such
as for example, electron beam or gamma irradiation to form covalent
cross links. The particular thickness of the cross linked water
soluble polymer sheet may vary depending upon, e.g., the medicament
to be delivered, the applied area and the like, from a very thin
sheet, i.e., film, for high drug efficiency to a very thick sheet
for minimization of sensation when an electrical current is
applied. However it should also be appreciated that suitable scrim
materials may include inorganic materials such as ceramics and
composites such as fiber glass.
[0037] As illustrated in FIGS. 3A, 3B, 3C and 3D, and the flow
diagram illustrated in FIG. 4, preferably the cross linked water
soluble polymer sheet 40 is formed by providing the release liner
46 and the scrim 42, applying or otherwise coating a release liner
or other backing material 46 with one-half of the viscous solution
44 of water soluble polymer to form a layer 44A (FIG. 3B) and
coating or otherwise applying the other half of the viscous
solution 44 to one side of the scrim 42 to form a layer 44B (FIG.
3C). The coated liner 46 is then laminated to the coated scrim 42
such that the scrim has the viscous solution on both sides (FIG.
3D). Next, a final liner or other backing material 48 is then
applied to the exposed surface, with the cross linked water soluble
polymer sheet 40 sandwiched between the two release liners 46, 48
to form a laminate 50, which in the preferred embodiment is then
exposed to high energy irradiation to cross link the water soluble
polymer solution. In the alternative, to provide ease of handling,
the final release liner 48 can be applied to the coated scrim prior
to lamination with the coated liner 46.
[0038] The scrim 42 itself imparts structural support and
mechanical strength to the final cross linked water soluble polymer
sheet to prevent shearing. Thereafter, the laminate 50 can be
easily handled and cut or otherwise formed into the desired shape
for the particular reservoir 28, 32. In this way, the release liner
46 can be subsequently removed and the exposed surface of the cross
linked water soluble polymer adhered to the electrode 24, 26, or
removed and the medicament 30 added and the release liner replaced
or adhered to the electrode. Also, the release liner 48 can remain
until being removed for application of the device 10 to the applied
area of the patient.
[0039] In the alternative, the release liner 48 (or 46) can be
replaced by the electrode in the form of a thin metal sheet or
polymer sheet coated with a conductive ink or metal foil laminated
to the polymeric sheet such as for example as disclosed in
co-pending application Ser. No. 08/012,168, the disclosure of which
is hereby incorporated by reference. In this way, the reservoir can
be coupled to the electrode in one step. It should also be
appreciated that a conductive scrim may be incorporated into the
reservoir with the scrim being placed asymmetrically within the
reservoir by placing different thicknesses of the viscous solution
on each side of the scrim.
[0040] The use of an easily handled cross linked water soluble
polymer sheet as the reservoir 28, 32 to replace a paste,
semi-solid gel or an absorbent pad has many advantages over
existing coupling reservoirs. The cross linked water soluble
polymer is solid and shape retaining and it exhibits no leakage of
medicament or electrolyte under flexure or applied pressure. It is
also drapeable and flexible and adhesive to the skin. This assures
that the cross linked water soluble polymer maintains the required
medicament and electrolyte concentration as well as reproducible
delivery by its adherence and conformability to the contours of the
skin or other applied area.
[0041] Also, the adhesive strength of the gel and the electrode
material is greater than the cohesive strength of the gel material
and the cohesive strength of the gel is greater than the adhesive
strength of the gel to the applied area, e.g., skin of the patient.
In this way, a intimate electrical contact between the electrode
and the reservoir is achieved which insures electrical continuity
(and uniformity) between the interface of the electrode and the gel
during applications of he device to the applied area. Also, upon
removal of the device, little, if any, material remains on the
applied area after removal of the device.
[0042] Due to its high water content, the cross linked water
soluble polymer is highly conductive to ionic transport, yet in
combination with the scrim, it possesses sufficient mechanical
strength for processing and use. Also, despite its high water
content, the cross linked water soluble polymer is a single phase
solid solution which does not synerese liquid spontaneously or upon
applied pressure or flexure.
[0043] The ability of the cross linked water soluble polymer to
retain aqueous solution and its stability over extremes of ambient
temperature, allow the iontophoretic drug delivery device 10 to be
prepackaged and stored as a ready to use device, eliminating the
need for loading a drug solution after opening and assembly.
[0044] In addition, the various reservoirs 28, 32 formed from the
cross linked water soluble polymer sheet 40 are easily and stabably
coupled with the electrically conductive electrodes 14, 26 to form
a highly electrically conductive electrode assembly 12. Also,
because of the handleability of the cross linked water soluble
polymer, the medicament can either be added to the viscous water
soluble polymer solution or subsequently added after cross linking
depending upon the application and/or the medicament to be
administered.
[0045] As previously discussed, the two portions of the device 20,
22 are placed over the applied area, i.e., the portion of the skin
where the medicament is to be delivered such as the arm as
illustrated in FIG. 1 with other electrode 32, i.e., the return
electrode, placed on the skin 60 at an appropriate location
relative to the first or working electrode 14.
[0046] Further, the cross linked water soluble polymer 40 in the
preferred embodiment of the present invention is self-adhering to
the skin of the patient and therefore provides intimate contact for
ionic transport. Accordingly, the cross linked water soluble
polymer sheet 40 contained in the drug reservoir 28 and used for
the electrolyte reservoir 32 may also act as an adhesive,
eliminating the need in prior devices for an adhesive layer or the
like.
[0047] The following formulations for the cross linked water
soluble polymer sheet 40 were used in connection with the device of
the present invention for the reservoirs in the iontophoretic
delivery of a topical anesthetic and a vasoconstrictor, with the
device 10 including one active electrode 24 having a surface area
between 2-10 cm.sup.2 and one to three return electrodes 26 having
a total surface area between 1-5 cm.sup.2. The electrode reservoir
28 was comprised of the following active and inert components to a
thickness of between 10-50 mils by making a viscous stock solution
containing the medicaments and the excipients that was 3 times more
concentrated than the intended final formulation. The stock
solution was then added to pre-existing sheets as one part solution
to two parts sheet (by weight) and allowed to diffuse and
equilibrate in the sheets.
EXAMPLE 1
[0048]
1 Mass per Active Inert Concentration 2.5 cmsq Components
Components (%, w/w) (mg) Lidocaine 10.00 45.000 hydrochloride,
U.S.P. Epinephrine 0.10 0.450 Bitartrate Glycerin, U.S.P. 10.00
45.000 Cross linked 16.67 75.020 polyvinyl pyrrolidone (PVP),
U.S.P. Sodium 0.05 0.230 metabisulphite, U.S.P. EDTA 0.01 0.045
disodium, U.S.P. Citric acid, 0.02 0.090 U.S.P. Water 63.15 450
Total 100.00 450.000
[0049] In the preferred embodiment, the Lidocaine is an anesthetic,
the Epinephrine Bitartrate ("Epinephrine") is a vasoconstrictor,
and the composition of PVP is 10% to 20%, preferably 15%, known as
K-90F from BASF Corp. However, it should be appreciated that the
concentration of the PVP may vary from approximately 10% to 60%
w/w. In addition, it should be appreciated that L-Adrenaline can be
substituted for the Epinephrine.
[0050] After cross-linking the gel material of Example 1 having 25%
PVP, 75% water and 1% preservative PHENONIP manufactured NIPA
Corporation by exposure to 2 Mrad (20 kGy) and loaded with drug and
excipients, it was found that this gel material when applied to an
electrode comprised of silver/silver chloride ink printed onto a
polyester substrate, such that the surface resistance is less than
3 ohm per square, and the dried coating is porous yielded an
average adhesive strength greater than 40 grams/inch which was on
average greater than the cohesive strength (peel strength) of the
gel material as evident by gel material tearing apart upon peeling,
which remained on the electrode surface. Despite this relatively
low cohesive strength, it was still sufficiently greater than the
adhesive strength to the skin as evident by little, if any, gel
material remaining on the skin upon removal of the reservoir.
[0051] In another, after cross-linking the gel material of Example
1 having 25% PVP, 75% water and 1% preservative PHENONIP
manufactured NIPA Corporation by exposure to 1.5 Mrad (15 kGy) and
loaded with drug and excipients, it was found that this gel
material when applied to an electrode comprised of silver/silver
chloride ink printed onto a polyester substrate, such that the
surface resistance is less than 3 ohm per square, and the dried
coating is porous yielded an average adhesive strength greater than
60 grams/inch which was on average greater than the cohesive
strength (peel strength) of the gel material as evident by gel
material tearing apart upon peeling, which remained on the
electrode surface. Despite this relatively low cohesive strength,
it was still sufficiently greater than the adhesive strength to the
skin as evident by little, if any, gel material remaining on the
skin upon removal of the reservoir.
EXAMPLE 2
[0052] Same as Example 1, however, Polyethylene oxide (PEO) NF was
substituted for the PVP with the unloaded reservoir polymer
concentration being around 1% to 6%, preferably 5.0%, however, it
should be appreciated that the concentration of the PEO may varying
from approximately 1-10% w/w depending upon its molecular
weight.
[0053] Further, material remaining on the electrode is preferred as
evidencing intimate contact between the electrode and the
reservoir.
EXAMPLE 3
[0054] Same as Example 1, with polyvinyl alcohol (PVA) being
substituted for the PVP, and the preferred unloaded reservoir
polymer concentration of the PVA varying from approximately 10-30%
w/w.
EXAMPLE 4
[0055] Same as Example 1, with polyethylene glycol (PEG) being
substituted for the PVP, and the preferred unloaded reservoir
polymer concentration of the PEG varying from approximately 20-60%
w/w.
EXAMPLE 5
[0056] Same as Example 1, with the addition of about 5-20%
glycerin, preferably 10%, to the reservoir to keep the aqueous drug
solution form diffusing into all other phases in contact with the
reservoir which is defined herein as a "synerisis inhibitor".
[0057] Each of the above applications involved the use of devices
for the delivery of Lidocaine and Epinephrine for short application
times, i.e., less than 30 minutes.
[0058] Drug, medication, medicament and active compound have been
used herein to mean any ionicly charged pharmaceutical agent, such
as therapeutic compounds, diagnostic agents and the like.
[0059] In addition, it should be appreciated that the device and
reservoir of the present invention may be packaged in a nitrogen
rich environment as disclosed in co-pending application Ser. No.
08/316,741, the disclosure of which is hereby incorporated by
reference.
[0060] Further, while the present invention has been described in
connection with iontophoresis, it should be appreciated that it may
be used in connection with other principles of electroactive
introduction, i.e., motive forces, such as electrophoresis which
includes the movement of particles in an electric field toward one
or other electric pole, anode, or cathode and electro-osmosis which
includes the transport of uncharged compounds due to the bulk flow
of water induced by an electric field. Also, it should be
appreciated that the patient may include humans as well as
animals.
[0061] While the preferred embodiments of the present invention
have been described so as to enable one skilled in the art to
practice the device and method of the present invention, it is to
be understood that variations and modifications may be employed
without departing from the concept and intent of the present
invention as defined in the following claims. The preceding
description is intended to be exemplary and should not be used to
limit the scope of the invention. The scope of the invention should
be determined only by reference to the following claims.
[0062] While this invention is satisfied by embodiments in many
different forms, there are shown in the drawings and herein
described in detail, embodiments of the invention with the
understanding that the present disclosure to be considered as
exemplary of the principles of the present invention and is not
intended to limit the scope of the invention to the embodiments
illustrated. The scope of the invention is measured by the appended
claims and the equivalents.
[0063] Referring to FIGS. 5-8, a reservoir electrode assembly 110
of the present invention for an iontophoretic drug delivery device
includes an electrode 112 and a hydrophilic reservoir 114 situated
in electrically conductive relation to electrode 112. Hydrophilic
reservoir 114 is formed from a bibulous hydrophilic cross-linked
polymeric material 116 having a first surface 118 and a second
surface 120 that is adhesively adherent to electrode 112. First
surface 118 of polymeric material 116 is releasably adhesively
adherent when applied to an area 122 of a patient's skin. Polymeric
material 116 has a cohesive strength and forms an adhesive bond 124
with a bond strength between second surface 120 of the polymeric
material to electrode 112 that is greater than the cohesive
strength of polymeric material 116. Additionally, an adhesive bond
strength of first surface 118 of polymeric 116 material to applied
area 122 of the patient is less than the cohesive strength of
polymeric material 116 so that upon removal of reservoir assembly
110 of the invention from the applied area of the patient,
substantially no polymeric material 116 remains on applied area 122
and hydrophilic reservoir 114 remains substantially intact and
adhesively adherent to electrode 112.
[0064] Adverting to FIG. 6, reservoir electrode assembly 110
preferably includes a reinforcement 126 to provide two-dimensional
stability, indicated by reference characters x and y, to polymeric
material 116 and allow a swelling of polymeric material 116 in a
third dimension z. Reinforcement 126 may be formed from a woven
material or a non-woven material. Preferably, reinforcement 126 is
formed from a non-woven material with a basis weight about ten to
about thirty grams per square meter. Reinforcement 126 is
preferably disposed in a layer 128 substantially intermediate first
surface 118 and said second surface 120 of bibulous hydrophilic
polymeric material 116 so that when polymeric material 116 imbibes
an aqueous solution, swelling of polymeric material 116 is
substantially limited to increasing a distance "d" between first
surface 118 and second surface 120. Preferably, first surface 118
and second surface 120 are substantially parallel to each other.
Suitable non-woven materials are available from Reemay as a
spun-bonded poly(ethyleneterephthalate) 2004 (PET) with a basis
weight of about 14 grams per square meter. Other materials with
other basis weights may be preferred for particular applications
and are considered within the scope of this disclosure.
[0065] A preferred material for forming hydrophilic reservoir 114
is poly(vinylpyrollidone) (PVP) with a number average molecular
weight greater than about 360,000 daltons. A suitable PVP is
available from BASF, NJ as PVP K-90F. When this material is
prepared as a concentrated aqueous solution it forms a viscous
syrup which is preferably applied to both sides of the
reinforcement 126, placed between two release webs to a thickness
of about of about 40 mils and subjected to ionizing radiation
sufficient to cross-link the PVP sufficiently to substantially be
shape retaining, flexible and having a degree of tack. A preferred
ionizing radiation is an electron beam having at least about a 1
MeV to deliver between about 1.5 and 2.5 megarads. Other sources of
ionizing radiation such as .sup.60Co or .sup.137CS may be used for
particular applications. The degree of cross-link has considerable
effect on the degree of tack. If there is insufficient
cross-linking, resultant PVP reservoir 114 does not retain shape,
may detach from reinforcement 126 and is extreme difficult to
handle. If the degree of crosslinking is too great, the resultant
PVP reservoir 114 has insufficient tack to adhere to electrode 112
or to patient contact area 122.
[0066] The use of the electron beam for cross-linking the PVP for
reservoir 114 has a particular benefit to the present invention.
Unlike gamma radiation that has a potential penetration of several
feet of concrete, the electron beam penetration depth is described
in the units of cm of water. This property of the electron beam can
be utilized in controlling the degree of cross-link in reservoir
114. The exposure can be controlled so that there is a differential
degree of tack on surface 118 than on surface 120 of reservoir 114.
The differential degree of tack on the first surface and the second
surface may be preselected to allow a sufficient degree of tack on
surface 120 to ensure a sufficiently strong bond between electrode
112 and reservoir 114 to substantially prevent separation of the
electrode and the reservoir while allowing the reservoir to be
removed from the patient's skin.
[0067] The preferred degree of cross-link is determined by the
degree of tack as described below. The preferred which results in a
swelling ratio of greater than 3. Additionally, because the
bibulous material is constrained in the "x" and "y" directions by
the reinforcement 126, best seen in FIG. 6, the swelling that
occurs upon imbibement of aqueous solution, preferably occurs
substantially only in the "z" direction, i.e., to increase the
distance "d" between first surface 118 and second surface 120.
[0068] The manufacture of hydrophilic reservoir 114 is preferably
begun with a web of reinforcement 126 being coated on both sides
with a viscous solution of the PVP with a concentration of between
about twenty percent to about thirty percent, preferably about 24
percent, (w/w) in an aqueous solution. When prepared in this
fashion, the preferred PVP solution has a viscosity similar to that
of molasses and is adherent to reinforcement 126. As the coating of
PVP is applied, web 126, with the coating is preferably sandwiched
between two release liners. Preferably, one of the release liners
130 is formed from a stiff polymeric material, such as PET coated
with polyethylene or silicone and the like. Stiff release liner 130
serves as an anvil for die cutting out sections of hydrophilic
reservoir 114 in the shape desired for incorporation into the
iontophoretic device electrode reservoir assembly. Once the PVP is
coated onto reinforcement 126 and placed between the release
liners, the entire web, i.e., reinforcement 126, the PVP coating
and the release liners, is exposed to the preselected dose of
ionizing radiation for crosslinking. Preferably, the thickness of
the cross-linked material is between about 35 to about 45 mils. For
particular applications, other thickness may be preferred. Upon
crosslinking, the reinforced PVP reservoir material preferably has
a cohesive strength, a tackiness sufficient to adhere releasably to
a patient's skin and to form an adhesive bond 124 with conductive
ink electrode 112 on a flexible substrate 140. Preferably, the
adhesive bond formed between reservoir 114 and conductive ink
electrode 112 is stronger that the cohesive strength of the
cross-linked PVP used to form the reservoir. This strong bond
between electrode 112 and reservoir 114 ensures good electrical
contact and substantially prevents the reservoir from detaching
from the electrode. Additionally, it is also preferred that the
strength of adhesive bond 124 formed between the reservoir 114 and
conductive ink electrode 112 is stronger than an adhesive bond
formed between the surface of the patient's skin and reservoir 114
and that the cohesive strength of the reservoir is greater than the
strength of the adhesive bond between the patient's skin and the
reservoir. This substantially ensures that when reservoir 114 is
removed from the patient's skin, the reservoir is substantially
removed from the patient's skin, leaving substantially no
residue.
[0069] In addition to the PVP in aqueous solution, preferably, the
coating solution may also include preservative materials to inhibit
microbial growth such as para-benzoic acid (paraben) and the like.
A suitable preservative includes a series of mixed parabens
including, methyl paraben, ethyl paraben, n-propyl paraben,
iso-propyl paraben, n-butyl paraben and 2-phenoxyethanol and is
sold under the tradename "Phenonip" by Nipa Laboratories, Wilm. DE.
In the present invention, the material has been shown effective at
substantially preventing microbial growth at a concentration of
about one-percent in the 24% aqueous PVP solution. A further
benefit of the radiation cross-linking of the PVP with preservative
is that the radiation dose used for cross-linking is sufficient to
substantially eliminate most microorganisms and the presence of the
preservative then substantially inhibits and further growth after
loading and during shelf storage.
[0070] A preferred technique for measuring tack is called described
in an ASTM method No. D3121-94 entitled: "TACK ROLLING BALL METHOD"
(TRBM). This standardized test method utilizes a standard inclined
trough that delivers a standard ball bearing onto the surface of
the material being tested. The ball is released from a standard
height in the trough onto the surface of the test material and a
measurement is made of the distance in mm that the ball rolls on
the surface being tested. The greater the tack exhibited by the
test material, the shorter the distance the ball rolls. For the
preferred cross-linked PVP used in reservoir 114, the TRBM values
are preferably between about 15 mm to about 40 mm. If the tack is
substantially greater than the preferred value, reservoir 114 may
lack cohesive strength and not be shape retaining. If the tack is
substantially less than the preferred value, there is insufficient
adherence to the skin and to the electrode. Other methods of
measuring adhesive ability are also useful for characterizing the
preferred cross-linked PVP. These methods include the probe tack
and peel from steel. These tests are useful to characterize the
cross-linked hydrophilic polymeric material used to form reservoir
114. An empirical description of the preferred material is that,
when cut into discs of the a size about 5 square centimeters, the
discs are sufficiently adherent when loaded with the aqueous
medicament to be lifted after a gentle pressure with an index
finger on the surface of the disc.
[0071] When cross-linked PVP as described above is used in an
iontophoretic device of the invention, the PVP concentration is
preferably about twenty-four percent w/w and after imbibement of an
aqueous solution of the desired medicament to be delivered, the PVP
concentration is about fifteen percent. Other reservoirs used in
iontophoretic devices have significantly higher concentrations of
materials required as carriers. The reservoir of the invention in
having only about fifteen percent PVP provides the an unexpected
benefit to the art by allowing the reservoir to be physically
smaller and to increase the efficiency of the drug delivery by
making the drug more available for delivery and to provide
sufficient tack to both patient skin and electrode to ensure
substantially uniform electrical contact.
[0072] An example of a drug delivery system using the reservoir
assembly of the invention is prepared as follows. A solution of
poly(vinylpyrolidone), (PVPK90-F BASF) at a concentration of 24%
w/w containing 1% w/w mixed parabens (Phenonip, Nipa Laboratories)
in 0.06% sodium chloride was prepared. After thorough mixing the
resultant viscous solution was coated onto both sides, best seen in
FIG. 7, of a reinforcement (Reemay 2004, spun bonded polyester to a
thickness of about 40 thousandths of an inch (40 mils). The coated
reinforcement was applied to a release liner 132 formed form low
density polyethylene (LDPE) film on one side and stiffer laminate
130 of 2 mil polyester and 2 mil LDPE disposed so that the LDPE
laminate was on the other side of the viscous solution. The
material was then exposed to electron beam irradiation with the
LDPE film was closest to the source of the electron beam energy. A
dosage of about 2 megarad was administered to the material causing
the PVP to crosslink. LDPE film 132 was then removed from one side
of the PVP and the material was cut into the desired, best seen in
FIGS. 6 and 8, five square centimeter shapes for the active
electrode. The material with laminate release liner 132 remaining
on the other side was bonded on exposed side 120 onto a flexible
substrate coated with conductive ink electrode 112 containing
silver and silver chloride in a suitable vehicle covering between
about 60% to about 90% of the surface are of substrate 140 in the
region where reservoir 114 is positioned, preferably about 90% of
its surface with a loading of one and one half to about five grams
of ink per square centimeter of surface area. By keeping the
coverage of the ink electrode below about 90%, direct contact
between the patient's skin and the ink electrode is substantially
precluded. After cross-linked material 114 is bonded to flexible
ink electrode 112, reservoir 114 is ready to be loaded with the
aqueous drug solution.
[0073] Flexible ink electrode 112 containing silver and silver
chloride is applied to the flexible substrate to connect the power
source to the reservoir 114. The ink preferably has a resistivity
of less than about 120 ohms per square. A suitable ink is available
from E.I.du Pont de neumours, Wilm. DE. The terminology of "ohms
per square" is developed from the thin film electrode art. A term
"ohm-cm" is used to define the specific resistance or resistivity
of a material and is labeled by the Greek letter P(RHO). Since the
metric system is the standard measuring used in laboratories. P is
defined as the number for ohms resistance between parallel faces of
a cubic centimeter of a material. Every material has a specific
conductivity, so P is different for each material. This term is
also known as ohms per centimeter cubed. In the case where the
material is in the form of a thin (i.e., about 0.00025 cm to about
0.025 cm) the term is defined as ohms per square. This is defined
as the resistance of a square surface area of film and is
independent of the size of the square. In the first instance
R=PL/A, in the case of a film A=Wt, where t is the thickness of the
film so that now R=PL/Wt, since L=W for any size square, this leads
to R=P/t. As P is a constant for any given material, it is apparent
that R varies inversely as the film thickness. As a consequence,
when a resistance is specified in ohms per square and the
resistivity of the conductive ink or film is known, the effective
film thickness is thus specified. In the instant example, a
preferred thickness is achieved with at loading of between about
one and one-half to about five grams of conductive ink per square
centimeter of surface for electrode 112 which provides a
resistivity of less than about 120 ohms.
[0074] In the present example, an aqueous loading solution of 30%
lidocaine HCl, 3% epinephrine, 30% glycerin, 0.05% sodium
metabisulfite, 0.03% ethylene diamine tetraacetic acid, and 0.06%
citric acid are used for the loading solution. The medicaments for
delivery are lidocaine HCl and epinephrine, the glycerin serves as
a humectant, the other minor components serve to enhance drug
stability by chelating metal ions and serving as antioxidants. In
order to load this solution onto the reservoir with electrode 112,
laminate release liner 132 is removed from side 118 of reservoir
114 and a three-hundred microliter aliquot of this loading solution
is applied to exposed surface 118, which is then covered with a
final cover that remains in place until the reservoir is applied to
a patient to protect the reservoir. Other aqueous formulations of
other medicaments and other concentrations may be envisioned for
the electrode assembly of the invention and are to be considered
within the scope of the invention. The electrode assembly 110 of
the invention when loaded with the aqueous medicament solution
described above has demonstrated sufficient shelf stability when
stored in a package formed from materials substantially resistant
to the passage of moisture and oxygen at accelerated, ambient and
cycled temperatures for two years.
[0075] A counter electrode assembly for the iontophoretic device of
the invention is formed by cutting a second shape from the
cross-linked PVP with a surface area of about 2.75 square
centimeter area. A counter electrode reservoir is assembled in the
same fashion as the active electrode described above. This counter
electrode reservoir is preferably loaded with an aqueous solution
containing about 30% glycerin, 1% mixed parabens, 0.06% sodium
chloride. The aqueous carrier for both of the solutions preferably
meets the standard for purified water in the USP XXXIII.
[0076] It has been shown that if the loading solutions are not
loaded substantially uniformly across surface 118 of reservoir 114,
that localized thickness variations of the reservoir may develop in
the cross-linked PVP with adverse effects on attachment to
electrode 112 and subsequent attachment to the patient.
Additionally, the localized concentration differentials of chloride
ion may facilitate deterioration of the silver/silver chloride
electrode. Therefore, it is preferred that the loading solutions be
substantially uniformly loaded across surface 118 of the electrode
reservoir. For the active electrode containing the lidocaine and
epinephrine, a loading level of about three hundred microliters is
preferred for a five square centimeter, forty-thousandths thick
reservoir with a uncharged volume of about 0.5 cc resulting in a
charged volume of about 0.8 cc. For the counter or return electrode
with an area of about two and three-quarters square centimeter
surface area, the preferred loading is about two hundred
microliters of the aqueous solution.
[0077] When the cross-linked PVP material is loaded with the
aqueous charging solutions, the final PVP concentration of in the
electrode is reduced from about twenty-four percent to about
fifteen percent. The cross-linked PVP swells to about one hundred
fifty percent of its uncharged volume, and because of the
reinforcement, the swelling occurs primarily in the "z" direction
or increases the thickness of the reservoir 114 about sixty
percent.
[0078] The reservoir electrode of the invention is an improvement
to the art of iontophoretic electrode reservoirs. The reservoir is
efficient in its utilization of available drug. Medicaments known
to be labile, such as epinephrine, have satisfactory shelf
stability when incorporated into the reservoir. Since the reservoir
of the invention is flexible and adhesive, the reservoir electrode
makes good uniform contact with the patient's skin, minimizing any
tendency for the current to concentrate at a particular point
causing irritation or burns to the patient's skin. The reservoir
electrode is easily prepared and its properties such as adhesion,
size and medicament loading are easily adjustable during
manufacture.
* * * * *