U.S. patent application number 10/274533 was filed with the patent office on 2003-04-03 for medicament-loaded transdermal reservoir and method for its formation.
This patent application is currently assigned to Becton, Dickinson and Company. Invention is credited to Bernhard, Michael I., Ewall, Ralph, Karl, Curtis, Keusch, Preston, Kupperblatt, Gary, O'Grady, Daniel.
Application Number | 20030065304 10/274533 |
Document ID | / |
Family ID | 24337374 |
Filed Date | 2003-04-03 |
United States Patent
Application |
20030065304 |
Kind Code |
A1 |
Bernhard, Michael I. ; et
al. |
April 3, 2003 |
Medicament-loaded transdermal reservoir and method for its
formation
Abstract
A transdermal reservoir and a method of the present invention
for loading a material into a reservoir includes providing an
reservoir including a backing with an interior surface comprising a
bibulous reservoir having a patient contact surface with a shape
disposed on the interior surface of the backing. The method
includes providing a closure sized and shaped to engage the backing
for forming a releasable seal to isolate the bibulous reservoir
from the ambient environment, the closure is removable from the
housing to expose the patient contact surface for use. The provided
closure has an inside surface with a section of an absorbent
material disposed thereon. The provided section has a first surface
so that when the closure is disposed on the backing, the absorbent
material first surface is positioned in intimate physical contact
with the reservoir. The method includes applying an aliquot of a
material to the absorbent material. The method further includes
placing the closure on the backing so that the first surface of
said absorbent material is in intimate physical contact with the
contact surface of the bibulous reservoir and the closure forms the
releasable seal with the backing. The method includes allowing the
reservoir--with the closure applied thereto to stand for a
sufficient time to allow the aliquot of the material to be absorbed
into the bibulous material thereby loading the reservoir.
Inventors: |
Bernhard, Michael I.;
(Summit, NJ) ; Ewall, Ralph; (Long Valley, NJ)
; Karl, Curtis; (Somerset, NJ) ; Keusch,
Preston; (Hazlet, NJ) ; Kupperblatt, Gary;
(Belle Mead, NJ) ; O'Grady, Daniel; (Edison,
NJ) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Assignee: |
Becton, Dickinson and
Company
|
Family ID: |
24337374 |
Appl. No.: |
10/274533 |
Filed: |
October 18, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10274533 |
Oct 18, 2002 |
|
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|
09584453 |
May 31, 2000 |
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6496727 |
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Current U.S.
Class: |
604/500 ;
604/20 |
Current CPC
Class: |
A61N 1/30 20130101 |
Class at
Publication: |
604/500 ;
604/20 |
International
Class: |
A61N 001/30 |
Claims
What is claimed is:
1. A method for loading a material into a hydrophilic transdermal
medicament delivery reservoir comprises: providing a transdermal
delivery device including a backing having an interior surface
comprising a bibulous reservoir having a patient contact surface
disposed on said inside surface; placing a section of an absorbent
material on said patient contact surface of said bibulous
reservoir; applying a preselected aliquot of a material to be
charged into said bibulous reservoir onto said absorbent material;
and allowing said absorbent reservoir having said absorbent
material with said aliquot of the material applied thereto to stand
for a sufficient time for the material to be absorbed into said
bibulous material, thereby loading said material into said
reservoir.
2. The method of claim 1 further comprising providing a closure
sized and shaped to engage said backing for forming a releasable
seal to isolate said bibulous reservoir from ambient environment,
said closure engaging said backing after placing and said applying
step, said closure being removable from said housing to expose said
patient contact surface for use.
3. The method of claim 1 wherein said applying step for applying
said aliquot of said material to said absorbent material is
performed before said placing step of placing said absorbent
material on said patient contact surface of bibulous material.
4. The method of claim 1 wherein said providing step for providing
said transdermal delivery device including a backing further
comprises said interior surface comprising an electrode, said
bibulous reservoir being disposed on and in electrical contact with
said electrode.
5. A method for loading a material into an iontophoresis reservoir
electrode comprises: providing an iontophoresis reservoir-electrode
including a backing with an interior surface comprising an
electrode, a bibulous reservoir having a patient contact surface
with a shape disposed on said electrode and in electrical contact
with said electrode; providing a closure sized and shaped to engage
said backing for forming a releasable seal to isolate said bibulous
reservoir from ambient environment, said closure being removable
from said housing to expose said patient contact surface for use,
said closure having an inside surface with a section of an
absorbent material disposed thereon, said section having a first
surface so that when said closure is disposed on said housing, said
absorbent material first surface is positioned in intimate physical
contact with said patient contact surface of said reservoir;
applying a preselected aliquot of a material to said absorbent
material on said inside surface of said closure; placing said
closure on said backing so that said first surface of said
absorbent material is in intimate physical contact with said
patient contact surface of said bibulous reservoir and said closure
forms said releasable seal with said backing; allowing said
iontophoretic reservoir-electrode having said closure applied
thereto to stand for a sufficient time, thereby allowing said
aliquot of said material to be absorbed into said bibulous
reservoir thereby loading said reservoir-electrode.
6. The method of claim 5 wherein said step of providing said
closure having said section of said absorbent material disposed
thereon further comprises providing a section of absorbent material
having a similar shape to said shape of said patient contact
surface of said bibulous material.
7. The method of claim 5 wherein said providing step for said
iontophoresis reservoir-electrode further comprises providing said
backing in the form of a first web having a plurality of
reservoir-electrodes spaced apart thereon.
8. The method of claim 7 wherein said providing step further
comprises providing said closure in the form of a second web having
a plurality of said sections of absorbent material spaced apart
thereon to be in registration with said iontophoresis
reservoir-electrodes on said first web.
9. The method of claim 8 wherein said providing step for said
closure in the form of said second web further comprises forming a
depression in said closure being sized and shaped to accept said
section of said absorbent material so that when said aliquot of
said loading material is applied to said section, said aliquot is
substantially retained about said section.
10. The method of claim 9 wherein said providing step for said for
said first web and said second web further comprises applying a
releasable sealing material to one of said first web and said
second web so that when said first web and said second web are
disposed so said closure is being placed on said backing, said
releasable sealing material forms said releasable seal between said
first web and said second web.
11. The method of claim 10 further comprising positioning said
first web with respect to said second web so that as said first web
and said second web are advanced in a direction so that said
closure is disposed to form said seal with said backing.
12. The method of claim 11 further comprising at least one cutting
step for freeing each of said plurality of reservoir-electrodes
each having said closure thereon from said webs as a unit.
13. The method of claim 12 wherein said providing step for said
reservoir-electrode further comprises providing at least a first
reservoir-electrode and a second reservoir-electrode, each
reservoir-electrode comprising an electrode, a bibulous reservoir
with a patient contact surface having a shape, said
reservoir-electrodes being disposed on said interior surface of
said backing.
14. The method of claim 13 wherein said providing step for said
reservoir-electrode further comprises said first
reservoir-electrode and said second reservoir-electrode being
arranged in pairs electrically isolated from one another on said
backing.
15. The method of claim 14 wherein said applying step for said
reservoir electrode further comprises applying a first aliquot to
said section of absorbent material in registration with said first
reservoir-electrode and a second aliquot, different from said first
aliquot, to said section of said section of absorbent material in
registration with said second reservoir-electrode.
16. The method of claim 15, wherein said providing step for said
reservoir-electrode further comprises providing said first
reservoir-electrode and said second reservoir-electrode having a
different shape from each other.
17. The method of claim 5 wherein providing step for said closure
further comprises selecting said absorbent material from the group
consisting of paper, polymeric foam, porous polymeric sheeting,
non-woven matrices and combinations thereof.
18. The method of claim 17 wherein said selecting step further
comprises selecting a non-woven material having a basis weight
between about 5 mg and 20 mg per cm.sup.2.
19. The method of claim 18 wherein said providing step for said
closure further comprises fixedly attaching said absorbent material
to said inside surface of said closure, so that when said closure
is removed from said backing to prepare for a use of said
iontophoretic reservoir-electrode, said absorbent material is
removed as a part of said closure thereby exposing said patient
contact surface of said reservoir for application to the patient's
skin.
20. The method of claim 5 wherein said applying step for said
material to said absorbent material further comprises applying at
least one medicament in an aqueous solution.
21. The method of claim 20 wherein said applying step for said
material further comprises applying an aqueous solution having
materials selected from the group consisting of lidocaine
hydrochloride, epinephrine bitartrate, sodium chloride, glycerin,
phenoxy ethanol, citric acid, sodium meta-bisulfite, edetate
disodium and alkyl esters of para-hydroxy benzoic acid and
combinations thereof.
22. The method of claim 1 wherein said providing step for said
reservoir further comprises forming said bibulous reservoir from
hydrophilic polymeric materials selected from the group consisting
of gums, alginates, alkyl and hdroxyalkylalkylcellulose,
carbosymethylcellulose, gum agar, hydroxethylcellulose, locust bean
gum, pectins, polyacrylamide, polyethylene glycol, poly(ethylene
oxide), polyvinyl alcohol, poly(vinylpyrolidone) and combinations
thereof.
23. The method of claim 22 wherein said providing step for said
reservoir further comprises forming said bibulous reservoir from
cross-linked poly(vinylpyrolidone).
24. A method for preparing a charged reservoir-electrode unit
comprising a first reservoir-electrode disposed to operate as an
anode and a second reservoir-electrode disposed to operate as a
cathode comprises: providing a backing material in the form of a
first web having an interior surface; providing a first
reservoir-electrode having a first surface area, said first
reservoir-electrode comprising an first electrode disposed on said
interior surface of said backing, a first bibulous reservoir having
a first patient contact surface having a shape being disposed on
and in electrical contact with said first electrode; providing a
second reservoir-electrode having a second surface area, said
reservoir-electrode comprising a second electrode disposed on said
interior surface of said backing in electrical isolation from said
first electrode, a bibulous second reservoir having a second
patient contact surface having a shape being disposed on and in
electrical contact with said second electrode; providing a closure
in the form of a second web disposed to engage said backing for
forming a releasable seal to isolate said first and said second
bibulous reservoirs from ambient environment, said closure being
removable from said housing to expose said patient contact surfaces
for use, said closure having an inside surface with sections of an
absorbent material in register with said first and said second
reservoir-electrodes disposed thereon, each said sections having a
first surface with a similar shape to each of said patient
contacting surfaces of said bibulous reservoirs so that when said
closure is disposed on said housing, said absorbent materials first
surfaces are each positioned in intimate physical contact with said
contact surface of said reservoirs; applying a preselected aliquot
of a first material to said section in register with said first
reservoir and an aliquot a second material said section in register
with said second reservoir; advancing said first web and said
second web in a direction so that said first surface of said
absorbent materials are in intimate physical contact with said
patient contact surfaces of said bibulous reservoirs and said
closure forms said releasable seal with said backing; cutting each
of said units of first and said second reservoir-electrodes each
having said closure thereon from said webs as a unit; and allowing
said iontophoretic reservoir-electrode unit having said closure
applied thereto to stand for a sufficient time, thereby allowing
said aliquots of said materials to be absorbed into said bibulous
materials thereby loading said reservoir-electrodes.
25. An iontophoresis reservoir-electrode comprising: a backing with
an interior surface comprising an electrode, a bibulous reservoir
loaded with a preselected aliquot of a material and having a
patient contact surface with a shape disposed on said electrode and
in electrical contact with said electrode; a closure sized and
shaped to engage and being disposed on said backing for forming a
releasable seal to isolate said bibulous reservoir from ambient
environment, said closure being removable from said housing to
expose said patient contact surface for use, said closure having an
inside surface with a section of an absorbent material disposed
thereon, said section having a first surface with a similar shape
to said patient contact surface of said bibulous reservoir with
said closure disposed thereon, so that said absorbent material
first surface is positioned in intimate physical contact with said
contact surface of said bibulous reservoir when said closure is
disposed on said backing and removed from patient contact surface
of said bibulous reservoir when said closure is removed from said
backing.
Description
FIELD OF INVENTION
[0001] The present invention is related to a method of loading a
material into a bibulous reservoir useful for drug delivery and
more particularly into a method for loading a medicament into an
iontophoretic reservoir-electrode and a iontophoretic
reservoir-electrode formed by the method.
BACKGROUND
[0002] Iontophoretic delivery of a medicament is accomplished by
application of a voltage to a medicament loaded
reservoir-electrode, sufficient to maintain a current between the
medicament loaded reservoir-electrode and a return electrode
(another electrode) applied to a patient's skin so that an ionic
form of the desired medicament is delivered to the patient.
[0003] Shelf storage stability problems for many of the
iontophoresis devices reported in the literature require that the
medicament be stored separately from the reservoir-electrode until
immediately prior to use. Iontophoretic delivery of medicaments is
recognized as desirable for many medicaments, but it is not widely
used because no devices are commercially available that meet all of
the needs of the potential user population. An important
requirement for a product to enjoy widespread usage is shelf
storage stability. If a drug product is not stable under normal
shelf storage conditions, it is unlikely to be a successfully
commercialized product because the short shelf life limits the
product's utility to most potential users as most of the product's
useful life is exhausted during the time required for manufacturing
and the distribution process. Thus, determination of shelf storage
stability is an important part of a drug product's regulatory
approval process. If there are difficulties with storage stability,
regulatory approval may be withheld. Often, the reservoir-electrode
also is maintained in a dry (unhydrated) condition prior to use
also because of the tendency of the active electrode material to
undergo physical and chemical changes during shelf storage. The
need to store the several components separately has limited the use
of iontophoretic devices, since in order to use the device, the
reservoir-electrode needs to be charged with the medicament and
hydrated either by a practitioner or user immediately prior to use.
There are regulatory requirements related to the accuracy and
precision of content of a particular drug in an individual dosage
form. When a drug dosage form is a tablet, there are specific
requirements related to weight variation, dissolution, content and
stability. Parenteral dosage forms require concentration assay and
stability. Other more complex dosage forms such as transdermal or
iontophoretic delivery devices are developing similar standards,
but the problems related to loading the devices and the stability
of the charged devices are continuing problems.
[0004] Several United States Patents disclose devices that attempt
to overcome the problem of shelf storage stability and facilitate
the preparation of the device for use. U.S. Pat. No. 5,320,598
discloses a dry-state iontophoretic drug delivery device that has
drug and electrolyte reservoirs that are initially in a
non-hydrated condition. The device has a liquid containing pouch or
breakable capsules that contain water or other liquid, the liquid
being releasable by disrupting the liquid containers prior to use.
Commercial manufacture of a device utilizing this disclosure would
be complex.
[0005] U.S. Pat. No 5,385,543 also discloses a dry-state
iontophoretic drug delivery device that has drug and electrolyte
reservoirs. The disclosed device includes a backing layer with at
least one passageway therethrough that allows the introduction of
water or other liquids into the drug and electrolyte reservoirs
prior to use followed by joining the reservoirs to the electrodes.
The patent teaches that by joining the reservoirs to the electrodes
after hydration, delamination problems are reduced.
[0006] No commercial products utilizing the technology disclosed
either in the '598 or the '543 patents have been produced.
[0007] A different approach to the shelf storage stability problem
is disclosed in U.S. Pat. No. 5,817,044. In this disclosure, the
device is divided or otherwise separated into at least two
portions, with one portion containing the electrode reservoir and
the other containing the drug reservoir, which may include a
medication in a dry form. In this disclosure, the user causes the
two portions to come into electrical conducting contact with one
another to at least partially hydrate one of the reservoirs, by
either folding the device to bring the two portions into contact
with one another or by removing a barrier dividing the two
portions. While this device is somewhat seems to be somewhat easier
to use than the devices disclosed in the above patents, there
currently is no commercial device that utilizes this
disclosure.
[0008] International Application WO 98/208869 discloses an
iontophoretic device for delivery of epinephrine and lidocaine HCl.
The disclosed device includes materials that deter microbial growth
and anti-oxidants to enhance the stability of epinephrine. While
this disclosure recognizes the need for shelf storage stability and
addresses the problem of epinephrine stability by including
anti-oxidants, there is no teaching of the need or ability to
uniformly load the reservoir-electrode. Again, there is no
commercial product based on the information in this disclosure.
[0009] A further problem related to production of a successful
commercial pharmaceutical product is related to the requirements
for accuracy and precision of dosage. In some of the iontophretic
drug delivery devices described above, the user or the practitioner
is required to perform some action to hydrate the
reservoir-electrode and introduce the medicament introduce the
medicament to be delivered into the delivery device prior to use.
Such operations that depend upon the practitioner or user to charge
the medicament into the device under relatively uncontrolled
conditions may result in improper dosing. Regulatory requirements
for pharmaceutical products generally specify that not only
medicaments contain between ninety and one hundred-ten percent of
the label claim, but also that the delivery be uniform from sample
to sample.
[0010] It is well recognized that many medicaments are not stable
to conditions necessary for assembly and storage of iontophoretic
reservoir-electrodes. A method of accurately and repeatedly loading
the medicament and any required stability enhancing excipients
during the assembly process of reservoirs useful for passive
transdermal drug delivery and reservoir-electrodes for
iontophoretic drug delivery devices that was compatible with a
mechanized assembly process and also provided a charged
reservoir-electrode with satisfactory stability properties would
represent an advance to the art of delivery of medicaments. By
providing a stable ready-to-use device as disclosed below, the
method of the invention substantially eliminates used induced
variability due to loading.
SUMMARY
[0011] A method of the present invention for loading a material
into a hydrophilic transdermal medicament delivery reservoir
includes providing a transdermal delivery device including a
backing with an interior surface that has a bibulous reservoir
having a patient contact surface disposed on the inside surface.
The method of the invention further includes placing a section of
an absorbent material on the patient contact surface of the
bibulous reservoir, applying a preselected aliquot of a material to
be charged into said bibulous reservoir onto the absorbent material
and allowing the absorbent reservoir having the absorbent material
with the aliquot of the material applied thereto to stand for a
sufficient time for the material to be absorbed into the bibulous
material, thereby loading the material into the reservoir.
[0012] A method of the present invention for loading a material
into an iontophoresis reservoir-electrode includes providing an
iontophoresis reservoir-electrode including a backing with an
interior surface having an electrode thereon and a bibulous
reservoir having a patient contact surface with a shape disposed on
the interior surface of the backing in electrical contact with the
electrode. The method also includes providing a closure sized and
shaped to engage the backing for forming a releasable seal to
isolate the bibulous reservoir from the ambient environment, the
closure is removable from the housing to expose the patient contact
surface for use. The provided closure has an inside surface with a
section of an absorbent material disposed thereon. The provided
section has a first surface with a similar shape to the contact
surface of the bibulous reservoir so that when the closure is
disposed on the backing, the absorbent material first surface is
positioned in intimate physical contact with the contact surface of
the reservoir. The method further includes applying a preselected
aliquot of a material to the absorbent material on the inside
surface of the closure and placing the absorbent material on the
patient contact surface of the reservoir. The method also includes
allowing the reservoir-electrode with the closure applied thereto
to stand for a sufficient time to allow the aliquot of the material
to be absorbed into the bibulous reservoir thereby loading the
reservoir-electrode.
[0013] An iontophoresis reservoir-electrode of the invention
includes a backing with an interior surface including an electrode,
a bibulous reservoir that has a patient contact surface with a
shape disposed on and in electrical contact with the electrode. The
reservoir-electrode is charged with a preselected aliquot of a
material and has a closure that is sized and shaped to isolate the
bibulous reservoir from ambient environment. The closure is
removable from the backing to expose the patient contact surface
for use. The closure has an inside surface with a section of an
absorbent material disposed thereon. The section has a first
surface with a similar shape to the contact surface of the bibulous
reservoir and with the closure disposed on the backing, the
absorbent material first surface is positioned in intimate physical
contact with the contact surface of the bibulous reservoir and
removed from the patient contact surface of the bibulous material
when the closure is removed from the backing.
[0014] The device formed by the method of the invention overcomes
the problem of reliably applying the correct amount of the desired
materials to passive transdermal reservoirs and for iontophoretic
devices. Both the medicament and excipients for the active
reservoir-electrode or the materials necessary for the return
reservoir-electrode are accurately and precisely loaded into the
reservoir. Many materials that are suitable for forming the
reservoir are cross-linked by the application of ionizing radiation
or require application of thermal energy in forming. If the
medicaments are mixed with the material before forming or
cross-linking, the medicament is exposed to the forming conditions,
i.e., ionizing radiation, thermal energy, chemically reactive
cross-linking agents and the like, that may adversely effect the
medicament. Thus there is a need for a method of loading the
transdermal reservoir or the iontophoretic reservoir-electrode
after the reservoir is formed. The method of the invention
uniformly loads the reservoir-electrode of the invention during the
assembly process, improves the efficiency of assembly of both
passive transdermal reservoirs and iontophoresis
reservoir-electrodes and is compatible with the high-speed assembly
line manufacture necessary for a successful commercial product. The
method and the device of the invention greatly improve the
efficiency of assembly of complete medicament loaded
reservoir-electrodes and thus advances the art of iontophoretic
drug delivery by making a prefilled ready-to-use device available
that fulfills the regulatory requirements of accuracy and
precision..
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 is an exploded perspective view of the
reservoir-electrode unit prepared by the method of the
invention;
[0016] FIG. 2 is a cross-sectional view of a reservoir-electrode of
the unit of FIG. 1 taken along the line 2-2;
[0017] FIGS. 3a-3g are schematic cross-sectional views of the
assembly process of the reservoir-electrode unit of FIG. 1;
[0018] FIG. 4 is a flow chart of the method of the invention for
preparing a reservoir-electrode charged with medicament; and.
[0019] FIG. 5 is a top plan view of the backing web and the closure
web.
DETAILED DESCRIPTION
[0020] While this invention is satisfied by embodiments in many
different forms, there is shown in the drawings and is herein
described in detail, a preferred embodiment of the invention with
the understanding that the present disclosure is to be considered
exemplary of the principles of the invention and is not considered
to limit the invention to the embodiment illustrated. The scope of
the invention is measured by the appended claims and their
equivalents.
[0021] Referring to FIGS. 1-5, a method of the present invention
for loading a material into an iontophoresis reservoir-electrode 10
includes providing iontophoresis reservoir-electrode 10 of the
invention including a backing 12 with an interior surface 14 that
has an electrode 16 disposed thereon, a bibulous reservoir 18
having a patient contact surface 20 with a shape 22 disposed on
interior surface 14 of backing 12 in electrical contact with
electrode 16. The method also includes providing a closure 24 sized
and shaped to engage backing 12 for forming a releasable seal 26 to
isolate bibulous reservoir 18 from the ambient environment, closure
24 is removable from backing 12 to expose patient contact surface
20 for use. Provided closure 24 has an inside surface 28 with a
section 30 of an absorbent material disposed thereon. Provided
section 30 has a first surface 32 with a similar shape 22 to
contact surface 20 of bibulous reservoir 18 so that when closure 24
is disposed on backing 12, absorbent material first surface 32 is
positioned in intimate physical contact with patient contact
surface 20 of reservoir 18. While it is preferred that section 30
has a similar shape to contact surface 20 of reservoir 18, testing
has shown that if section 30 covers at least a portion of or is
even larger than contact surface 20, the method of the invention
still is applicable. The method further includes applying a
preselected aliquot 34 of a material to absorbent material 30 on
the inside surface 28 of the closure 24. The method further
includes placing closure 24 on backing 12 so that first surface 32
of absorbent material 30 is in intimate physical contact with
contact surface 20 of bibulous reservoir 18 and closure 24 forms
releasable seal 26 with backing 12. The method also includes
allowing reservoir-electrode 10 with closure 24 applied thereto to
stand for a sufficient time to allow aliquot 34 of the material to
be absorbed into bibulous reservoir 18 thereby loading
reservoir-electrode 10. For particular applications, it may be
preferred to load reservoir 18 with the aliquot of loading solution
prior to placement of the loaded reservoir on backing 12, and this
alternative is considered within the scope of the invention.
[0022] Preferably, backing 12 is formed from a film or sheet
material such as polyethyleneterephthalate (PET) or the like in the
form of a first web 36 having a plurality of electrodes 16 spaced
apart in electrical isolation thereon. Electrodes 16 are preferably
formed as a thin film of the desired shape printed onto interior
surface 14 of backing 12 using a conductive ink that includes
silver and silver chloride. Closure 24 is preferably a material
such as a polyethylene terephthalateglycol (PETG) or the like in
the form of a second web 38 with a plurality of recesses 40 formed
into closure inside surface 28 to receive sections 30 of the
absorbent material in registration with electrodes 16 on first web
36. Recesses 40 may be formed into surface 28 by thermoforming or
other equivalent methods of forming. Other film materials such as
polyamide, polyvinylchloride, polystyrene and the like may be
preferred for particular applications.
[0023] Absorbent material 30 may be a polymeric foam, porous
polymeric sheeting, absorbent paper, nonwoven or combinations of
these materials. The absorbent material should not adversely
interact with the material loading solution to induce any
decomposition or diminution of potency of any medicament or other
agent present in the solution. Preferably, absorbent material 30 is
a nonwoven with a basis weight of between about 5 and about 20 mg
per cm.sup.2 is selected. Nonwoven materials having a basis weight
lower than about 5 mg per cm.sup.2 apparently have too little
structure to provide sufficient void volume to sufficiently retain
the aqueous aliquot used in these experiments and those materials
having a basis weight greater than about 20 mg per cm.sup.2 have
sufficient void volume to accept the aqueous aliquot, but tend to
retain more of the aliquot, rather than allow transfer of it to the
reservoir than is desirable. For aliquots of other materials and
other concentrations, other absorbent materials having different
void volumes and properties may be preferred. Suitable nonwoven
materials include, but are not limited to, nonwovens formed from
viscose rayon, polyethylene, polyester, polyamide, polypropylene,
PET, and combinations of these polymers. A nonwoven thermal bonded
mixture of viscose-rayon and polyethylene, sold by Freudenberg,
under the trade name Vilmed M-1561 with a basis weight of about 10
mg per cm.sup.2 is preferred because of its properties of
absorbency and release of the aqueous medicament solutions, as well
as its wide acceptance in other medical applications, although
other similar materials are available and also are useful.
[0024] Preferably, absorbent material 30 is fixedly attached to
closure 24 so that when closure 24 is removed from backing 12 to
expose patient contact surface 20 for use, absorbent material 30 is
cleanly removed from the patient contact surface of the reservoir.
Heat staking, ultrasonic welding or adhesive bonding are suitable
techniques for fixedly attaching the absorbent material to closure
24. Ultrasonic welding is preferably used for the preferred
nonwoven absorbent material and the preferred PETG closure, because
no additional materials such as adhesives are used that may
adversely interact with the loading ingredients.
[0025] For particular applications, absorbent material 30 may be
preferably placed directly on patient contact surface 20 of the
reservoir for the addition of the aliquot and removed directly from
patient contacting surface 20 of the reservoir by the user.
Additionally, for particular applications, it may be desirable to
charge absorbent material 30 with the preselected aliquot of the
material prior to placement on the patient contacting surface of
the reservoir. These alternative sequences of loading and placement
are considered within the scope of the method of the invention.
[0026] A releasable adhesive 25 is applied to one or the other of
the backing 12 or closure 24 to form releasable seal 26. For the
preferred PET and PETG materials used for the backing and the
closure, a pressure sensitive adhesive material is preferably
applied to backing 12. Surface 28 of the closure material is
treated with a material such as silicone to facilitate adhesive
release of closure 24 from the backing 12. A preferred adhesive
material, polyisobutylene based and qualified for medical
applications, is available from Adhesive Research. The preferred
material has sufficient adhesion to a patient's skin that, once
closure 24 is removed and applied to the patient, adhesive 25 forms
a releasable bond with the patient's skin that serves to hold
reservoir-electrode 10 onto the patient for the delivery of the
medicament.
[0027] Preferably, absorbent reservoir 18 is formed from a
hydrophilic material, such as a bibulous hydrophilic cross-linked
polymeric material, that has an alkali metal salt, preferably
sodium chloride or other physiologically acceptable alkali metal
salt uniformly distributed therethrough to substantially eliminate
any corrosion of the electrode caused by formation of salt gradient
concentrations during the loading of the reservoir-electrode.
Suitable materials for forming reservoir 18 include, but are not
limited to, gum agar, hydroxethylcellulose, locust bean gum,
pectins, polyacrylamide, polyethylene glycol, poly(ethyleneoxide),
polyvinyl alcohol, poly(vinylpyrolidone), combinations thereof and
the like. Preferably, the bibulous hydrophilic cross-linked
polymeric material of reservoir 18 has a patient contact surface 20
and another surface 21 that is adhesively adherent to electrode 16.
Preferably, patient contact surface 20 of reservoir 18 is
releasably adhesively adherent when applied to the area of a
patient's skin. A preferred reservoir 18 is formed from the
cross-linked poly(vinylpyrolidone) that has a cohesive strength and
forms an adhesive bond with a bond strength between surface 21 of
the polymeric material to electrode 16 that is greater than the
cohesive strength of the polymeric material. Additionally, an
adhesive bond strength of patient contact surface 20 of preferred
polymeric reservoir 18 material to the applied area of the patient
is less than the cohesive strength of polymeric reservoir 18 so
that upon removal of reservoir-electrode 10 of the invention from
the applied area of the patient, substantially no preferred
polymeric reservoir 18 material remains on the applied area of the
patient's skin and the hydrophilic reservoir remains substantially
intact and adhesively adherent to electrode 16.
[0028] The preferred material for forming hydrophilic reservoir 18
is a cross-linked poly(vinylpyrolidone). The preferred material is
prepared as a viscous aqueous syrup that incorporates the selected
alkali halide, preferably sodium chloride, in the desired
concentration. A preferred material for forming hydrophilic
reservoir 18 is poly(vinylpyrolidone) (PVP) with a number average
molecular weight greater than about 360,000 daltons prior to
cross-linking by application of ionizing radiation. A suitable PVP
is available from BASF, NJ as PVP K-90F.
[0029] Referring to FIGS. 3a-3g, a schematic cross-sectional
illustration of one sequence useful for the formation of the device
the invention is shown. A flow chart of the method is illustrated
in FIG. 4. Other methods and sequences of assembly of the device of
the invention may be envisioned and are considered within the scope
of the invention. FIG. 3a illustrates backing 24 with recess 40
formed therein as part of a second web 50. FIG. 3b illustrates
section of absorbent material 30 being positioned in recess 40.
FIG. 3c shows the absorbent material 30 after fixedly attachment to
inside surface 28 of closure 24. In FIG. 3d, aliquot 34 of the
material to be charged into reservoir is applied to absorbent
material 30. FIG. 3e illustrates the absorbent material with the
aliquot in recess 40. FIG. 3f schematically illustrates backing 12
with electrode 16, adhesive 25 and reservoir 18 on first web 52
being positioned in register with absorbent material 30 on closure
24. In FIG. 3g, first web 52 and second web 50 are advanced and
moved together to bring reservoir 18 patient contact surface 20
into intimate physical contact with first surface 32 of absorbent
material 30 so that aliquot 34 may be absorbed into reservoir 18.
As the webs are brought together, adhesive 25 forms releasable seal
26 between backing 12 and closure 24. After seal 26 is formed, a
cutting step is used to separate the charged complete
reservoir-electrode 10 from the webs.
[0030] In the case where the device being formed is a passive
transdermal reservoir, all of the steps and illustrations given
above are applicable with the exception that backing 12 is provided
without electrode 16. In this passive transdermal case, reservoir
18 is preferably disposed directly onto inside surface 14 of
backing 12.
[0031] FIG. 5 illustrates backing 12 in the form of a first web 52
with a plurality of repeating electrodes 16 printed on interior
surface 14. In this preferred embodiment, electrodes 16 have
different shapes 22 and 22a that reflect their intended use. In
this embodiment, the electrode intended to operate as an anode is
designated as 60 and the electrode intended to operate as a cathode
is designated as 62. Anode 60 and cathode 62 with respective
electrode traces 17 are disposed in electrical isolation from each
other as repeating units 70 on web 52. Electrode traces 17 extend
on a connection section 72 to connectors 74 to facilitate
attachment into a power source (not shown). Closure 24 is also
shown in the form of a web 54 with a plurality of recesses 40
having shapes 22 and 22a similar to and in register to anode 60 and
cathode 62. The preferred placement of adhesive 25 about electrodes
16 is also shown. Closure 24 preferably includes a tab 76 to
facilitate removal of closure 24 from backing 12 to expose the
patient contact surface for use.
[0032] Production of a commercial scale preferred iontophoretic
product is based on the method of the invention with the assembly
of unit 70, best seen in FIG. 1, including anode 60, cathode 62,
their respective electrode traces 17, reservoirs 18, closure 24
with absorbent material 30 in recess 40 with aliquot 34 being
delivered into absorbent material 30 prior to forming adhesive seal
26, shown in FIG. 3G, on webs 50 and 52, as illustrated in FIG. 5.
Aliquot 34 may be delivered onto absorbent material 30 as a
preselected amount by a coarse or fine spray, dropping, or other
similar ways of controlled delivery of fluid onto a surface. Once
the assembly process is completed, the individual complete and
charged units are ready to be placed in a final package and
shipped.
[0033] In a preferred product based on the method of the invention,
anode 60 is loaded with an aliquot of at least one medicament that
is capable of being transported into a patient's body as a positive
ion. The term medicament as used in this disclosure is intended to
include any therapeutic agent or combination of therapeutic agents
capable of being ionized and transported into the body by an
electric current. In the case where the therapeutic agent to be
transported forms a negative ion, the active electrode is the
cathode 62 and the anode 60 would serve as the return electrode.
The composition of the aliquots of loading solutions and operation
of the active electrode as the cathode or the anode is determined
by the medicaments selected.
[0034] An example of a preferred embodiment of the invention is
where the material to be loaded and delivered includes two
medicaments, lidocaine, as the hydrochloride salt, and epinephrine,
as the bitartrate salt. In this example, the active
reservoir-electrode, i.e., containing the lidocaine and the
epinephrine, is anode 60 because the medicaments being delivered
are positive ions. Preferably, in aliquots of loading solution 34,
lidocaine hydrochloride is present in an amount between about 50 mg
to about 150 mg. Other amounts or other medicaments may be
preferred for particular applications. In this specific example,
about 100 mg of lidocaine hydrochloride is present. Epinephrine
bitartrate is preferably present in an amount equivalent to about
one-half to about one and one-half mg, and more preferably about
one mg, of the free base. Additionally, sodium chloride, glycerin,
sodium metabisulfite, editate disodium, citric acid, phenoxy
ethanol, alkyl esters of hydroxybenzoic acid are included as
excipients in the preferred example active electrode 60.
[0035] The method of the invention facilitates the use of automated
assembly equipment to prepare complete finished iontophoretic
units. The use of the absorbent material to receive an aliquot of
the medicament facilitates the use of adhesive hydrophilic
reservoir materials, such as poly(vinylpyrolidone) for
reservoir-electrodes. The hydrophilic electrodes are well suited to
contain and release ionized medicaments into the body under the
influence of applied electric current because they are highly
absorbent, adhesive and flexible. A problem with many of these
hydrophilic reservoir materials is that, while they are highly
absorbent, the rate of absorbency is relatively slow, i.e., they do
not rapidly absorb a delivered aliquot when they are loaded. Thus,
the conventional commercial manufacture of iontophoretic devices
with hydrophilic electrodes is slow and inefficient. If the
hydrophilic material is not substantially uniformly charged,
portions of the reservoir-electrode may not be fully functional
causing incomplete delivery and irritation of the patient's skin.
The method of the invention utilizes closure 24, which would be
needed in any case just to protect the reservoir-electrode, with
section 30, of absorbent material, to initially receive the aliquot
of the loading solution and keep substantially all of the aliquot
present at the surface of the reservoir for diffusing into the
reservoir material for as long as necessary during a portion of the
shelf storage period rather than extending the time required for
the production of the device. Additionally, absorbent material 30
substantially retains the aliquot of the loading liquid during the
assembly sequence and substantially prevents migration of the
liquid onto adhesive 25 or on portions of webs 50 and 52 away from
its intended target, reservoir 18. Tests of completed products
prepared using the method of the invention have shown that the
loading process for the preferred lidocaine, epinephrine loaded
reservoir-electrode is substantially completed within a few days.
Additionally, shelf stability testing at ambient conditions of the
completed devices shows acceptable performance, i.e., acceptable
drug potency and uniformity assay, of the reservoir-electrodes
after more than one year of storage.
[0036] The accuracy and precision of delivery of the preselected
aliquot by the method of the invention to form charged
iontophoretic reservoir-electrodes is demonstrated by an experiment
where preferred cross-linked poly(vinylpyrolidone) hydrogel
reservoir-electrodes 10 were prepared by the method of the
invention utilizing preferred non-woven absorbent material 30
(Vilmed, M-1561) to charge aliquots of aqueous lidocaine HCl,
epinephrine bitartrate and excipients into bibulous reservoir 18.
In this example, the aqueous aliquot of loading solution contained
103.8 mg of lidocaine, 1.10 mg of epinephrine and excipients.
Following the loading procedure, the poly(vinylpyrolidone)
reservoir materials were assayed for their lidocaine and
epinephrine content according to recognized analytical techniques.
The analytical results (n=10 reservoir-electrodes) are shown below
in Table I. The results show that the transfer efficiency of the
loading solution to reservoir 18 for the lidocaine was 96.4 percent
and 93.4 percent for the epinephrine. Additionally, after one month
at accelerated aging conditions of 40C, the results are
substantially unchanged.
1TABLE I Time (months) Lidocaine (mg) Epinephrine (mg) loading
solution 103.8 1.10 zero 99.98>1.07 1.035>0.016 one @ 40C
99.12>0.63 1.013>0.026
[0037] The method of the invention for loading a medicament into
iontophoretic reservoir-electrodes is suitable for use as a method
for loading reservoirs of passive transdermal devices. Most
conventional passive transdermal devices utilize a hydrophobic
reservoir material, often a hydrocarbon pressure-sensitive adhesive
base such as a polyisobutylene or the like. The active ingredient
to be transdermally delivered is mixed with the hydrocarbon base
and formed onto the substrate or backing material. Often, this
hydrocarbon base is maintained at an elevated temperature prior
with aliquots of the base already containing the medicament being
formed into the device. While the hydrophobic base is suitable for
alkaloids such as scopolamine or small molecules such as
nitroglycerine, many other drugs are more stable as salts and are
more easily used in a hydrophilic system. Additionally, many
medicament materials may not be sufficiently thermally stable to
the elevated temperatures used in melting and forming the
hydrophobic base. The method of the invention is suitable for
loading preselected uniform dosages of a medicament into a
hydrophilic reservoir for use in passive transdermal delivery as
well as the iontophoretic reservoir-electrodes. The benefits of
being able to form a hydrophilic gel reservoir using ionizing
radiation, chemical cross-linking agents or thermal energy without
subjecting the medicament to these conditions applies equally well
to a reservoir intended for passive transdermal delivery.
[0038] The method of the invention for loading a medicament into
transdermal reservoirs and iontophoretic reservoir-electrodes
improves the efficiency of manufacturing devices suitable for
commercial distribution. The method of the invention addresses the
regulatory requirements for accuracy, precision and repeatability
that are needed in a practical commercial product. The improved
stability and efficiency of iontophoretic devices manufactured
using the method of the invention should facilitate their
regulatory approval and result in benefits to the art of delivery
of medicaments to patients.
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