Note: Descriptions are shown in the official language in which they were submitted.
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Dermal Patch
This application claims the benefit of the filing date priority of Application
No. 60/330,526 filed October 24, 2001, which is incorporated herein in its
entirety
for background information. .
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to transdermal and/or intradermal drug delivery
devices, kits and methods and, more particularly, to a dermal path which is
capable
to of delivering an electric current for electrically including transdermal
and
intradermal delivery of a wide variety of substances or for enhancement of
wound
healing, scar prevention, scar reduction, tissue repair and/or tissue
regeneration via
electrical stimulation.
Much recent attention has been paid in the technical and patent literature to
15 the delivery of substances, both pharmaceuticals and cosmetics, such as
drugs and
other beneficial agents, into or through intact skin surfaces by passive
processes
such as diffusion and osmosis and by active processes such as electrically
induced
iontophoresis, electrophoresis, electroosmosis and/or electroporation. The
ubiquitous nicotine patch designed to assist in quitting smoking has caused
such
2o forms of transdermal delivery of medication to be widely known. (Hereunder,
the
term "iontophoresis" will collectively represent any of the terms
iontophoresis,
electrophoresis, electroosmosis and/or electroporation, and the term
"iontophoretic"
will encompass the respective adjectives.)
Indeed, there is now an extremely long list of pharmaceutical substances that
25 are routinely administered transdermally and/or intradermally and a
similarly long
list of devices and methods known in the art for administering same. A short
but
varied sampling includes the following: U.S. Patent No. 6,294,582 which
discloses a
device for treating asthma transdermally; U.S. Patent No. 5,899,856 which
discloses
a dermal patch for detecting alcohol consumption; U.S. Patent No. 6,291,677
which
3o teaches the transdermal administration of antiviral protease inhibitors;
U.S. Patent
No. 6,266,560 which discloses the transdermal treatment of erectile
dysfunction;
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
U.S. Patent No. 6,238,381 which discloses the transdermal delivery of
antiviral,
antibacterial and antiaging substances; and U.S. Patent No 6,288,104 which
discloses the transdermal administration of substances for treating congestive
heart
failure.
Although many substances are administered passively via a dermal patch,
there are also many that are electrically delivered intradermally or
transdermally.
The use of electrical stimulus to body parts is well known and has an equally
long and colorful history. Around the turn of the 20th century there was
available a
plethora of "electrodes" for applying "electric treatments" to the human body.
The
l0 electrodes were placed upon the body in relation to the organ to be
treated. Such
early "electric treatments" included popular galvanic stimulation which caused
ionized molecules to be driven into the body, usually superficially. This
early form
of iontophoresis, or ion transfer, was employed for the supposed beneficial
effects of
localized stimulation and the introduction of medicaments, often simply
moisture,
into the skin of a patient.
The technique of iontophoresis is in wide use today in the administration of
drugs as it effectively delivers electrically charged medicaments through the
skin.
and into the capillary structure and lymphatic system. This technique avoids
the
gastrointestinal side effects sometimes associated with orally ingested drugs
and is
2o preferable to subcutaneous injection because of its relatively benign and
painless
nature.
Another technique, known as electroporation, facilitates the transdermal or
intradermal delivery of uncharged substances by electrically inducing the
formation
of transient dermal micropores that allow mobilization of the uncharged
substances
by diffusion.
Accordingly, iontophoresis, as well as other electrically induced techniques,
such as electroporation, has been incorporated into many transdermal delivery
devices, including the popular dermal patch. Therefore, there are many dermal
patches known in the art today which incorporate a power source and electrical
3o circuitry for aiding transdermal delivery.
Most present dermal patches, including those that function passively and
those that function electrically, incorporate a substance for transdermal
delivery.
2
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Such patches are specifically designed and/or configured to deliver a
predetermined
dosage of a specific substance, and that substance forms an integral part of
the patch
in question, i.e., the "nicotine patch". One drawback of such dermal patches,
which
are manufactured with a predetermined type and amount of substance therein is
that
once the substance is depleted, the entire device is useless and must be
discarded.
This is a disadvantage because patches which employ electrically induced
delivery
techniques necessarily have components, e.g., batteries, electrodes, circuitry
and
other assemblies, which may be expensive and/or environmentally hazardous when
discarded in large quantities. Also, in order to change dosage, patches of
different
1o dosages must be provided.
There is also known in the art today a range of reusable dermal patches that
incorporate a reservoir for holding a medicinal substance prior to
administration.
Those dermal patches typically incorporate the reservoir as part of one or
both of the
electrodes which deliver the current to the skin of the subject. Such
electrodes are
often referred to as bioelectrodes.
Bioelectrodes come in many sizes, shapes and configurations such as
following assigned to Ioimed, Inc., which produces iontophoretic delivery
devices.
Examples of such bioelectrodes include those disclosed in U.S. Patent Nos.
5,037,380 and 5,248,295 which teach a patch having a refillable receptacle;
U.S.
Patent No. 5,846,217 which teaches a patch having a small access window for
refilling; and U.S. Patent Nos. 5,374,24, 5,730,716 and 6,223,075 which teach
a
patch that holds a dry medicament and must be hydrated. All such bioelectrodes
are
complex and consist of many parts and are therefore relatively bulky.
Accordingly,
those that are incorporated into dermal patches cause the patches to be large
and
relatively expensive. Moreover, such dermal patches must be charged, or
loaded, by
clinician and not by the subject.
There is thus a widely recognized need for, and it would be highly
advantageous to have, a thin, flexible and simple electrically active dermal
patch
that is simple to administer by the subject, versatile and capable of
application with a
range of substances and/or dosages and for a variety of purposes and that is
simple
in design and inexpensive to manufacture.
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a versatile
dermal patch that incorporates a power source that may be used to
transdermally or
intradermally deliver a range of different substances.
It is a further object of the present invention to provide a versatile dermal
patch that incorporates a power source that may be used to introduce an
electric
current to a skin portion for a variety of purposes.
It is a further object of the present invention to provide a versatile dermal
patch that incorporates a thin and flexible power source that may be used to
to introduce an electric current to a skin portion for a variety of purposes
and/or that
may be used to transdermally or intradermally deliver a range of different
substances.
According to one aspect of the present invention there is provided a kit for
transdermal or intradermal delivery of at least one substance, the kit
comprising (a) a
~ 5 dermal patch which comprises an electrochemical cell having at least two
electrodes
positioned on one side of the dermal patch for forming electrical contact with
a skin
portion of a subject; and (b) at least one retainer for retaining a conductive
fluid
containing the substance, the conductive fluid being for deposition on at
least one of
the electrodes and/or topical application onto the skin portion of the
subject; the
20 patch being designed and configured for delivering an electric current for
transdermal or intradermal delivery of the substance through the conductive
fluid
and the skin of the subject.
According ~to another aspect of the present invention there its provided a kit
for introduction of current and/or voltage to a skin portion of a subject, the
kit
25 comprising (a) a dermal patch which comprises an electrochemical cell
having at
least two electrodes positioned on one side of the dermal patch for forming
electrical
contact with the skin portion of the subject; and (b) at least one retainer
for retaining
a conductive fluid for deposition on at least one of the electrodes and/or
topical
application onto the skin portion of the subject; the patch being designed and
3o configured for delivering an electric current for introduction of current
and/or
voltage to the skin portion of the subject through the conductive fluid.
4
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
According to yet another aspect of the present invention there is provided a
dermal patch consisting essentially of an electrochemical cell having at least
two
electrodes positioned on one side of the dermal patch for forming electrical
contact
with a skin portion of a subject, the dermal path being designed and
configured for
delivering an electric current through a conductive fluid being deposited on
at least
one of the electrodes and/or being topically applied onto the skin portion of
the
subj ect.
According to a further aspect of the present invention there is provided a
method of transdermal or intradermal delivery of a substance comprising (a)
to topically applying a conductive fluid containing the substance into a skin
portion of
the subject and/or depositing the conductive fluid containing the substance on
at
least one electrode of a dermal patch which comprises an electrochemical cell
having at least two electrodes positioned on one side of the dermal patch; (b)
positioning the dermal patch such that the electrodes are in electrical
contact with
the skin portion of the subject; and (c) delivering an electric current
through the
conductive fluid and the skin portion so as to transdermally or intradermally
deliver
the substance.
According to a yet further aspect of the present invention there is provided a
method of introducing current and/or voltage to a skin portion of a subject
2o comprising (a) topically applying a conductive fluid onto a skin portion of
the
subject and/or depositing the conductive fluid on at least one electrode of a
dermal
patch which comprises an electrochemical cell having at least two electrodes
positioned on one side of the dermal patch; (b) positioning the dermal patch
such
that the electrodes are in electrical contact with the skin portion of a
subject; and (c)
delivering an electric current through the conductive fluid so as to introduce
current
and/or voltage to the skin portion of the subject.
According to features in the described preferred embodiments the conductive
fluid is an aqueous based fluid.
According to features in the described preferred embodiments the conductive
fluid is hydrogel.
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
According to features in the described preferred embodiments the conductive
fluid is selected from the group consisting of a gel, a cream, a paste, a
lotion, a
suspension, an emulsion and a solution.
According to features in the described preferred embodiments the conductive
fluid is for deposition on at least one of the two electrodes.
According to features in the described preferred embodiments the conductive
fluid is for topical application to the skin portion of a subject.
According to features in the described preferred embodiments the substance
is a charged substance.
1o According to features in the described preferred embodiments the substance
is an uncharged substance.
According to features in the described preferred embodiments the substance
is selected from the group consisting of a pharmaceutical, a cosmetic and a
cosmeceutical.
t 5 According to features in the described preferred embodiments the
pharmaceutical is selected from the group consisting of a therapeutic and an
anesthetic.
According to features in the described preferred embodiments the electric
current serves for causing iontophoresis, electrophoresip, electroporation or
any
2o combination thereof.
According to features in the described preferred embodiments the electric
current is for causing wound healing, scar prevention, scar reduction, body
tissue
repair and/or tissue regeneration.
According to features in the described preferred embodiments the retainer is
25 selected from the group consisting of a vessel, a tube, a jar, a container,
a dispenser
and an ampoule.
According to features in the described preferred embodiments the retainer is
a separator for deposition upon at least one of the two electrodes.
According to features in the described preferred embodiments the electric
3o current delivers the substance from the separator. Such separator is
intended to
6
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
prevent contact between the electrode and the skin and to provide an even
distribution of the electric current over the entire surface of the patch.
Such
separator being either an integral part of the electrode or attached thereto.
According to features in the described preferred embodiment the separator is
contained in a removable cover.
According to features in the described preferred embodiments the
electrochemical cell is a flexible thin layer electrochemical cell.
According to features in the described preferred embodiments the
electrochemical cell is a flexible thin layer open liquid state
electrochemical cell
which comprises a first layer of insoluble negative pole, a second layer of
insoluble
positive pole and a third layer of aqueous electrolyte, the third layer being
disposed
between the first and second layers and including (a) a deliquescent material
for
keeping the open cell wet at all times; (b) an electroactive soluble material
for
obtaining required ionic conductivity; and (c) a water-soluble polymer for
obtaining
a required viscosity for adhering the first and second layers to the third
layer.
According to features in the described preferred embodiments at~least one of
the two electrodes is for mobilizing the at least one substance.
According to features in the described preferred embodiments the at least
two electrodes are integrally formed with the electrochemical cell.
According to features in the described preferred embodiments the
electrochemical cell and the at least two electrodes are the sole constituents
of the
patch.
According to features in the described preferred embodiments the dermal
patch further comprises an attachment mechanism for attaching to the skin
portion
of the subject.
According to features in the described preferred embodiments the dermal
patch further comprises a circuitry for controlling the electric current.
According to features in the described preferred embodiments the kit is
packaged and identified for a wound healing application, a scar prevention
application, a scar reduction application, a tissue repair application, a
tissue
7
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
regeneration application, a transdermal delivery application and an
intradermal
delivery application.
The present invention successfully addresses the shortcomings of the
presently known configurations by providing a versatile dermal patch, operable
in
transdermal and/or intradermal delivery with any number of substances and
dosages.
BRIEF DESCRIPTION OF THE DRAWINGS
With specific reference now to the drawings in detail, it is stressed that the
particulars shown are by way of example and for the purposes of illustrative
discussion of the preferred embodiment of the present invention only, and are
presented in the cause of providing what is believed to be the most useful and
readily understood description of the principles and conceptual aspects of the
invention. In this regard, no attempt is made to show structural details of
the
invention in more detail that is necessary for a fundamental understanding of
the
invention, the description taken with the drawings making apparent to those
skilled
in the art how the several form of the invention may be embodied in practice.
In the drawings:
FIG. 1 is a sectional view of a dermal patch constructed in accordance with a
preferred embodiment of the present invention;
FIGS. 2a-g are illustrations of retainers according to different embodiments
of the present invention;
FIGS. 3a-d illustrate a first foolproof embodiment according to the present
invention;
FIGS. 4a-d illustrate a second foolproof embodiment according to the present
invention;
FIGS. Sa-c illustrate a third foolproof embodiment according to the present
invention; and
FIG. 6 is a sectional view of a different configuration of a dermal patch
according to the present invention.
8
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is of kits, dermal patches and methods which can be
used for transdermal and/or intradermal delivery of a variety of substances,
such as
pharmaceuticals, cosmetics and cosmeceuticals, by means of iontophoresis,
electrophoresis and/or electroporation. A dermal patch of the present
invention is
advantageously versatile in the sense that single patch is operative for
transdermal
and/or intradermal delivery of a versatile range of substances and/or dosages
and
that the patch may be simply charged and administered by the subject.
Before explaining at least one embodiment of the invention in detail, it is to
l0 be understood that the invention is not limited in this application to the
details of
construction and the arrangement of the components set forth in the following
description or illustrated in the drawings. The inventions is applicable to
other,
embodiments or of being practiced or carried out in various ways. Also, it is
to be
understood that the phraseology and terminology employed herein is for the
purpose
of description and should not be regarded as limiting.
The principles and operation of a kit for transdermal and intradermal
delivery of a substance and a kit for the introduction of current and/or
voltage to a
skin portion of a subject according to the present invention many be better
understood with reference to the drawings and accompanying descriptions.
Reference is now made to Figure l, which shows a dermal patch in
accordance with the teachings of the present invention, which is referred to
herein
below as patch 10. Patch 10 includes a top surface 12 and a skin contacting
bottom
surface 13, which together form patch body 11. Patch 10 is preferably
fabricated
from flexible materials, which enable surface 12 and/or 13 to conform to the
contours of a subject's skin portion when path 10 is applied thereon. It is
understood
that patch body 11 may be of any size and shape necessary according to the
relevant
application.
Patch 10 preferably further includes a skin attachment mechanism, which is
preferably an adhesive layer 28 which serves for attaching patch 10 to a skin
portion
of the subject. Adhesive layer 28 covers at least a portion of bottom surface
13 of
patch 10. Adhesive layer 28 preferably includes a biocompatible permeable
pressure
sensitive adhesive such as Bio-PSA from Dow Corning. Other examples of
9
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
biocompatible adhesives will be readily apparent to those of ordinary skill in
the art.
Adhesive layer 28 may be useful for either a single attachment or repeated
attachments.
Patch 10 includes therein an electrochemical cell 14, which is preferably a
flexible thin electrochemical cell, most preferably an open, liquid state
electrochemical cell. It is appreciated that patch 10 may employ any other
electrochemical cell or power generating device that serves to provide the
needed
electric current for the relevant application. Numerous types of miniature
power
sources, both disposable and rechargeable, which can be incorporated into
patch
body 11 are known in the art.
According to a preferred embodiment of the present invention
electrochemical cell 14 is a thin flexible electrochemical cell, which engages
most of
the entire volume of patch body 11. In the presently preferred embodiment,
electrochemical cell 14 includes a positive pole layer 16, a negative pole
layer 18
and an electrolyte layer 20 interposed therebetween. An example of a suitable
thin
and flexible electrochemical cell is described, for example, in U.S. Patent
Nos.
5,652,043, 5,897,522 and 5,811,204, which are incorporated herein by
reference.
Briefly, the electrochemical cell described in the above identified U.S.
Patents is an
open liquid state, electrochemical cell which can be used as a primary or
2o rechargeable power source for various miniaturized and portable
electrically
powered devices of compact design. The cell comprises a first layer of
insoluble
negative pole, a second layer of insoluble positive pole and a third layer of
aqueous
electrolyte being disposed between the first and second layers and including
(a) a
deliquescent material for keeping the open cell wet at all times; (b) an
electroactive
soluble material for obtaining required ionic conductivity; and, (c) a water-
soluble
polymer for obtaining a required viscosity for adhering the first and second
layers to
the first layer.
Several preferred embodiments of the disclosed electrochemical cell include
(i) engaging the electrolyte layer in a porous substance, such as, but not
limited to, a
filter paper, a plastic membrane, a cellulose membrane and a cloth; (ii)
having the
first layer of insoluble positive pole include manganese-dioxide powder and
the
second layer of insoluble negative pole include zinc powder; (iii) having the
first
layer of insoluble negative pole and/or the second layer of insoluble positive
pole
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
further include carbon powder; (iv) selecting the electroactive soluble from
zinc-chloride, zinc-bromide, zinc-fluoride and potassium-hydroxide; (v) having
the
first layer of insoluble negative pole include silver-oxide powder and the
second
layer of insoluble positive pole include zinc powder and the electroactive
soluble
material is potassium-hydroxide; (vi) having the first layer of insoluble
negative pole
include cadmium powder and the second layer of insoluble positive pole include
nickel-oxide powder and selecting the electroactive soluble material to be
potassium-hydroxide; (vii) having the first layer of insoluble negative pole
include
iron powder and the second layer of insoluble positive pole include nickel-
oxide
to powder and selecting the electroactive soluble material to be potassium-
hydroxide;
(viii) having the first layer of insoluble negative pole and the second layer,
of
insoluble positive pole include lead-oxide powder, then cell is charged by
voltage
applied to the poles and the electroactive soluble material is selected in
this case to
be sulfuric-acid; (ix) the deliquescent material and the electroactive soluble
material
can, be the same material such as zinc-chloride, zinc-bromide, zinc-fluoride
and
potassium-hydroxide; (x) the deliquescent material is selected from the group
consisting of calcium-chloride, calcium-bromide, potassium-biphosphate and
potassium-acetate; (xi) the water-soluble polymer can be polyvinyl alcohol,
polyacrylamide, polyacrylic acid, polyvinylpyrolidone, polyethylenoxide, agar,
2o agarose, starch, hydroxycthylcellulose and combinations and copolymers
thereof;
(xii) the water-soluble polymer and the deliquescent material can be the same
material such as dextrane, dextranesulfate and combinations and copolymer
thereof.
Electrochemical cell 14 preferably incorporates any one or more of the
embodiments
described above. Preferred configurations for electrochemical cell 14
according to
the present invention involve those combinations which are devoid of poisonous
compounds.
Electrochemical cell 14 includes terminals serving as electrodes referred to
hereinafter as positive electrode 22 and negative electrode 24 each of which
being in
electrical contact with positive pole layer 16 and negative pole layer 18,
respectively. Electrodes 22 and 24 are electrically connected to
electrochemical cell
14 using well known means, e.g., printed flexible circuits, metal foils,
wires,
electrically conductive adhesives or by direct contact. It is understood that
measures
are taken to avoid contact between the electrodes and between each of the
electrodes
11
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
and the opposite pole layer. In figure l, the measure taken is the
interposition of
insulating element 17 formed of a dielectric material.
Electrodes 22 and 24 are electrically conductive and may be formed of a
metal, e.g., a metal foil or metal deposited or painted on a suitable backing.
Examples of suitable metals include aluminum, platinum, stainless steel, gold
and
titanium. Alternatively, electrodes 22 and 24 may be formed of a hydrophobic
polymer matrix containing a conductive filler such as a metal powder/flakes,
powdered graphite, carbon fibers or other known electrically conductive filler
material.
1 o Electrodes 22 and 24 can be applied to the cell and the entire cell can be
manufactured by, for example, a suitable printing technology such as, but not
limited
to, silk print, offset print, jet printing, lamination, materials evaporation
or powder
dispersion. Accordingly, electrochemical cell 14 as described hereinabove is
among
the simplest of power sources.
t 5 It is appreciated that each of electrodes 22 and 24 may be of any size and
shape, and located with respect to one another, in any arrangement, as may be
required to cover the skin portion under treatment. Indeed, in accordance with
a
preferred embodiment of the present invention, electrochemical cell 14, in
conjunction with electrodes 22 and 24, constitute the sole internal elements
of patch
20 10. Accordingly, patch 10 is among the smallest and thinnest active
practice and
delivers the maximum power per unit of surface area.
Patch 10 of the present invention is preferably supplied within a protective
removable or reusable package, or liner, or cover 19, so as to provide
physical
protection and prolong shelf life prior to use.
25 Patch 10 is designed and configured to be used with at least one, and
preferably many, external substances. Such substances, described in detail
hereinafter, are designed to be contained in a conductive fluid, also
described in
detail hereinafter.
The conductive fluid is designed to be retained in at least one, preferably
30 many, retainers. The combination of patch 10 and the retainer form a kit
that may
be retained by a patient for use for a variety of applications.
12
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Reference is now made to Figures 2a-g, which shows a range of retainers for
retaining a conductive fluid. The formation of such conductive fluid will
generally
be "pharmaceutically acceptable" or "physiologically acceptable" formulations
for
cosmetic or therapeutic use. As used herein, the terms "pharmaceutically
acceptable" and "physiologically acceptably" refer to substances that can be
administered to a subject, preferably without excessive adverse side effects
(e.g., for
a topically applied formulation, skin rash, irritation, etc.). Particular
formulations
include aqueous gels, cream, pastes, lotions, suspensions, emulsions and
solutions or
other liquid formulations suitable for topical application known in the art.
In a presently preferred embodiment, the conductive fluid is electrically
conductive and adhesive hydrogel, suitable for use as a skin contact adhesive
and,
particularly, suitable for use as an electrical interface for electrodes of
medical
devices. The hydrogels are cationic acrylates and may be, for example,
preferably
made from acrylic esters of quatemry chlorides and/or sulfates or acrylic
amides of
quaternary chlorides. They can be formed by free radical polymerization in the
presence of water, preferably by ultra-violet curing with initiator and
multi-functional cross-linking agent. The hydrogel may preferably include a
buffer
system to help prevent discoloration of the hydrogels and/or hydrolysis of the
hydrogels and/or to improve shelf life.
2o Other additives may be incorporated into the present hydrogels either
before
or after curing (e.g., conductivity enhancers, pharmaceuticals, humectant
plasticizers, etc.) depending on intended end-use. An additive that is
preferably
added to the hydrogel is a conductive adhesive matter (additive) that serves
to allow
the conductive fluid to both attach patch 10 to the skin of the subject and to
serve as
the conductive interface between the electrode and the skin. The adhesive
additive
is preferably a polymeric adhesive and may be pressure or temperature
activatable or
it may be activated by the exposure to the ambient atmosphere.
The preferred hydrogel is sufficiently cohesive, yet remains readily
separable. Further details pertaining to hydrogels suitable for use in the
context of
3o the present invention are described in, for example, U.S. Patent No.
5,800,685,
which is incorporated herein by reference.
13
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
In any case, an aqueous conductive fluid in accordance with the teachings of
the present invention will typically comprise water, alcoholic/aqueous
solutions, at
least one salt or any other charged agent and preferably a buffering medium.
It is appreciated that non-aqueous conductive fluids may also be employed.
The conductive fluids used in conjunction with patch 10 preferably
administered by deposition on one or both electrodes. It is appreciated that
the
conductive fluid may alternatively or in addition be administered by topical
application to the skin. The term "topical" is used herein to refer to
administration
of a substance on the surface of the skin or mucosal tissue, which can be
applied via
direct application (e.g., spreading), via an impregnated porous material or
object or
by spraying or misting. It will be appreciated that topical application of the
fluid to
the skin of the subject is typically less precise and, if not done carefully,
may
inadvertently cause an electrical connection between the electrodes directly
through
the conductive fluid such that the electric current and the mobilized ions
would not
~ 5 pass through the skin.
Accordingly, the retainers will vary in shape, size and method of dispensing
according to the quantity, application and location relevant to the treatment.
Shown
in Figures 2b-g are retainers in the form of a vessel 31 tube 32, jar 33, a
container
34, a dispenser 35 and an ampoule 36. It will be appreciated that the present
2o invention contemplates all such retainers as well as others in any shape,
size or
configuration that serve to retain the conductive fluid and dispense it for
use as
needed on either the electrodes or upon the skin of a subject.
Shown in Figure 2a is retainer 30 which is a separator. The use of the term
"separator" is intended to describe a retainer made of a porous non-conductive
25 material, such as a sponge, paper, etc., that serves to retain the
conductive fluid
therein. Separators offer advantages over other retainers in that they allow
precise
positioning of the conductive fluid, they are not messy, and they permit a
precise
dosage to be administered.
Fluid is retained in a separator in such a manner that objects that are in
3o contact with the separator are also in contact with the fluid contained
therein.
Accordingly, electrical contact may be made with the conductive fluid held
within a
separator by establishing physical contact between the electrode and the
separator.
14
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Separators are preferably designed and configured to fit between one or both
of electrodes 22 and 24 and the skin of the subject, thus providing a simple,
clean
and convenient electrode/skin interface through which electricity may flow via
the
conductive fluid to the area of treatment. As stated earlier, separators are
constructed so that their non-conductive structure does not impede the
electrical
contact between electrodes 22 or 24 and the conductive fluid therein. It is
understood that a separator will not be positioned such that it or its
contents create
an electrical contact between electrodes 22 and 24. Such positioning will form
an
electric circuit that does not include the skin of the subject and will
frustrate the
1o purpose of the electrical application.
Separators may be fabricated in the form of plugs, cartridges or tablets and
the like which are designed to be compatible with different shapes, sizes and
configurations of electrodes 22 and/or 24.
According to a preferred embodiment, retainer 30, in its embodiment as a
separator, is preferably a thin waferlike container, which may be of a desired
shape
to be compatible with both the area of treatment and the electrode in use.
Such
separators may preferably be protected by a thin film layer, which will be
peeled off
immediately prior to use.
Separators may be packaged for storage or use as may be compatible with
2o the preferred embodiment of the kit of the present invention. Separators
will
preferably be individually packaged in order to preserve shelf life and to
avoid
evaporation of the conducting fluid and/or to substance contained therein.
The use of the above described retainers, particularly separator 30, are
intended to render patch 10 extremely user friendly and almost foolproof in
its
employment. The wide variation in the designs and configurations of retainers
shown are for the purpose of the precise application of the conductive fluid
either on
the appropriate electrode or topically upon the skin of the subject. For
example, a
retainer in the form of tube 32 will permit the simple deposition of a dab of
conductive fluid precisely on the electrode. A retainer in the form of ampoule
36
will assure correct dosing of the medicament. Dispenser 35 will permit careful
and
accurate application of conductive fluid to the exact skin portion of the
subject. The
preferred embodiment of the invention will have separator 30 as the vehicle
for the
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
conductive fluid, which can be positioned with precision on either the
electrode or
on the skin of the subject.
It is appreciated that the precise positioning of the conductive fluid, either
upon the relevant electrode or upon the skin of the subject, is critical to
the effective
conduction of electric current through the skin of the subject. Accordingly,
the kit
comprising patch 10 and one or more of retainers 30 through 36 will preferably
also
contain any other implements, instruction, markings, aids or devices that will
serve
to assist a user to properly apply and position the conductive fluid as
required.
Several foolproof embodiments with respect to patch 10 of the present
1o invention are shown in Figures 3a-Sc. In the embodiment of Figures 3a-d, a
strip
100 is placed over the skin 102 and a conductive lotion, gel, cream or the
like 104 is
applied over the skin 102, such that upon removal of strip 100, two non-
contacting
zones 106 receptive of a patch 108 constructed and operative in accordance
with the
teachings of the present invention are formed and patch 108 is applied onto
the skin
15 102, such that the electrodes 110 thereof each being in contact with one of
zones 106
so as to avoid a shortcut.
In the embodiment of Figures 4a-d, a patterning device 200 having two
openings 201 is placed over the skin 202 and a conductive lotion, gel, cream
or the
like 204 is applied over the skin 202, such that upon removal of patterning
device
20 200, two non-contacting zones 206 receptive of a patch 208 constructed and
operative in accordance with the teachings of the present invention are formed
and
patch 208 is applied onto the skin 202, such that the electrodes 210 thereof
each
being in contact with one of zones 206, so as to avoid a shortcut.
In the embodiment of Figures Sa-c, a foldable patch 308 is placed, in its
25 folded configuration, over the skin 302 and a conductive lotion, gel, cream
or the
like 304 is applied over the skin 302 on both sides thereof, such that upon
flattening
patch 308, two non-contacting zones 306 receptive of patch 308 are formed and
patch 308 is contacting the skin 302, such that the electrodes 310 thereof
each being
in contact with one of zones 306, so as to avoid a shortcut.
3o Reference is now made to Figure 6 which shows an embodiment of patch 10
of the present invention in which electrode 22 is not integral to
electrochemical cell
14 but is connected by a conductive connector, hereinafter referred to as
connector
16
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
21. Components of patch 10 according to this embodiment of the invention and
which are similar to those described above, are not further described and are
identified by the same reference numerals as above. Connector 21 may be
printed or
may be of any conductive material known in the art. According to the
illustrated
embodiment, the retainer, which is a separator, is deposited on electrode 24
of
electrochemical cell 14. Thus, in this configuration, electrode 24 may be
referred to
as the medical electrode and electrode 22 as the conductive adhesive
electrode.
According to this embodiment, simultaneous contact with the skin of a subject
by
electrode 22 and separator 30 will form an electrical circuit which includes
the skin
of the subject as part of the conductive path. In this configuration,
electrochemical
cell 14 will produce an electric current which will be delivered through the
conductive fluid held by retainer 30 which is in contact with the skin. The
electric
current will pass through the skin thus mobilizing appropriately charged ions
or
molecules within the conductive fluid contained therein to pass through the
skin.
One purpose of patch 10 is to transdermally or intradermally deliver a
pharmaceutical substance, a cosmetic substance or a cosmeceutical substance.
As
used herein, the terms "transdermal" and "intradermal" and grammatical
variations
thereof, respectively refer to the delivery of a composition through/across
the skin or
into the skin. As used herein, the term "pharmaceutical" refers to therapeutic
and
2o anesthetic substances. Therapeutic, as used herein, is understood to
include any
substance serving to cure, heal, treat medically or preserve health.
Anesthetic, as
used herein, is understood to include any substance serving to cause a loss of
tactile
sensation, particularly pain. Such substances, in order to be delivered
electrically,
will preferably be in the form of charged molecules which will respond to an
electric
current. It is appreciated that any pharmaceutical substance, cosmetic
substance or
cosmeceutical substance may be delivered by the invention described herein, as
long
as the substance is charged or can be charged.
In cases where the substance is not naturally charged it is preferably
combined with a charging agent, or subjected to environmental conditions, such
as a
3o specific pH environment, which induces charge formation. Methods of
charging
molecules are well known in the art and as such no further description is
given
herein. In any case, it is to be understood that the substance to be delivered
may be
charged prior to or concomitant with its delivery.
17
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Therefore, where used herein the term "substance" refers to active substances
which are preferably in the form of charged ions or charged molecules and
which
are able to be electrically delivered transdermally or intradermally. In
general, this
includes therapeutic substances in all of the major therapeutic areas
including, but
not limited to, antiinfectives such as antibiotics and antiviral agents,
analgesics
including fentanyl, sufentanil, buprenorphine and analgesic combinations,
anesthetics, anorexics, antiarthritics, antiasthmatic agents such as
terbutaline,
anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals,
antihistamines,
antiinflammatory agents, antimigraine preparations, antimotion sickness,
1 o preparations such as scopolamine and ondansetron, antinauseants,
antineoplastics,
antiparkinsonism drugs, cardiostimulants such as dobutamine, antipruritics,
antipsychotics, antipyretics, antispasmodics, including gastrointestinal and
urinary,
anticholinergics, sympathornimetics, xanthine derivatives, cardiovascular
preparations including calcium channel blockers such as nifedipine, beta-
Mockers,
beta-agonists such as salbutamol and ritodrine, antiarrythmics,
antihypertensives
such as atenolol, ACE inhibitors, diuretics, vasodilators, including general,
coronary,
peripheral and cerebral, central nervous system stimulants, cough and cold
preparations, decongestants, diagnostics, hormones such as parathyroid
hormone,
growth hormone and insulin, hypnotics, immunosuppressives, muscle relaxants,
2o parasympatholytics, parasympathomimetics, anti-oxidants, nicotine,
prostaglandins,
psychostimulants, sedatives and tranquilizers. The invention is also useful
for the
delivery of cosmetic and cosmeceutical substances. Such substances, include,
for
example, skin acting anti-oxidants, such as caretenoids, ascorbic acid
(vitamin C)
and vitamin E, as well as other vitamin preparations and other anti-oxidants,
anti
wrinkling agents such as retinoids, including retinol (vitamin A alcohol),
alpha-hydroxic acids, beta-hydroxy acid, better known as salicylic acid,
combination-hydroxy acids and poly-hydroxy acids, and hydrolyzed and soluble
collagen and others, moisturizers such as hyaluronic acid and others,
anticellulite
agents such as aminophyllines and others, skin bleaching agents such as
retinoic
acid, hydroquinone and peroxides and others, botanical preparations such as
extracts
of aloe-vera, wild yam, hamamelitanin, ginseng, green tea and others.
It is understood that the invention may be used for delivery of a wide range
of dosages of the above listed and other substances over a desired duration of
time.
18
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
The delivery of the substance transdermally or intradermally preferably
occurs by a process of iontophoresis and/or electrophoresis. Iontophoresis
refers to
the-movement of ions caused by the application of an electrical potential.
Electrophoresis refers to the movement of charged colloidal particles or
macromolecules caused by the application of an electrical field. The electric
current
caused by the electric potential between electrodes 22 and 24 serves to
release the
charged substance from the conductive fluid and to deliver the molecules/ions
of the
charged substance from the conductive fluid and to deliver the molecules into
the
adjacent skin tissue. The charged substance within the conductive fluid, which
is
1o deposited between one or both of electrodes 22 and 24 and the skin of the
subject,
would be attracted to or repelled by electrode 22 and electrode 24 as
appropriate to
their charge. For example, if the substance is positively charged, electrode
22 would
repel the substance, thus mobilizing it into or through the skin. In this
configuration,
when current flows from positive electrode 22 in a direction toward the skin,
the
charged substance is driven across the conductive fluid/skin interface into
the skin.
It must be noted that reverse iontophoresis may also be used in a process of
transdermal or intradermal recovery of substances from the body. Such a
technique
employs the same electrical principles applied in reverse. Techniques of
transdermal, or intradermal recovery of substances are well known in the art.
2o The movement of substances transdermally or intradermally may also be
aided by a process of electroporation. Electroporation is typically carried
out by high
voltage pulses applied to a pair of electrodes which are applied to a tissue
surface.
The electric pulses cause the passing ions to perforate the tissue layer,
providing
new pathways for the passage of substances, both charged and not charged. It
must
be noted that electroporation does not deliver a charged substance, but rather
reduces
the resistance to passage of substances into the adjacent tissue. Because it
does not
provide a needed driving force, it is desirable that electroporation be
combined with
delivery techniques such as iontophoresis or electrophoresis in order to
achieve good
penetration.
3o Another preferred purpose of patch 10 is to promote wound healing, scar
reduction, scar prevention, tissue repair and/or tissue regeneration by direct
application of currents through the skin. Electric current has long been known
and
utilized therapeutically to force excitable cells (nerve, muscles and
receptors of
19
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
nerve ends) of the human body, by electrical stimuli externally supplied in
the form
of electrical pulses, to generate an electrical response, the so-called action
potentials.
These action potentials are cell-intrinsic electrical pulses with a defined
amplitude
and duration for the relevant cell type. For one nerve, for instance, a pulse
width of
about 1 ms and an amplitude of about 80 mV to 100 mV is typical. The cell
reverts to
its cell membrane voltage, which at rest, depending on cell type, has a value
between
60 mV and 120 mV. This voltage is caused by different ion concentrations in
the
extracellular and intracellular spaces separated by the cell membrane. More
positive
ions are found outside the cell. According to definition, the potential
outside the cell
1 o is set to 0 V, so that a negative potential is given in the cell.
In healthy humans, the action potentials are generated by the body itself and
utilized for information transfer and to trigger cellular processes.
In electrotherapy, therapeutic effects are induced by specific generation of
action potentials (defined number and at specific loci).
Apparatuses for electrotherapy use a plurality of various electrical currents,
or pulse forms. Aiming to choose the electrotherapy best suited for a specific
indication, the therapist should be able to revert to criteria of maximally
clear
definition. These criteria derive from the replies, to questions about the
effectiveness and tolerance of the various current form.
The spectrum of effects includes, e.g., the areas of pain alleviation,
stimulation of striated and nonstriated muscles, of influencing perfusion, the
detumescent mechanisms, of the areas of checking inflammatory processes and of
promoting regeneration (wounds, accelerated healing of bones, etc.,) The aim
in the
application should always be achieving the desired effect in the affected area
by
proper selection of the current form, either distal or, proximal to the
electrode or in
the depth of the body.
Basically, electrotherapeutic apparatuses are based on two stimulus current
methods, the polarity-dependent "polar stimulation principle" and the
polarity-independent "apolar stimulation principle".
3o Low-frequency alternating currents (LF current) ranging from 0 to 200 Hz
are used in the "polar stimulation principle". Hyperpolarization (rise in
membrane
voltage) occurs beneath the positive electrode, the anode, making the spacing
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
between the potential in the cell and the stimulus threshold greater. In
contrast, the
membrane voltage drops beneath the negative electrode, the cathode. As the
stimulus threshold is reached, the cell triggers automatically an action
potential.
Stimulant current apparatuses employ different pulse shapes in the
low-frequency spectrum of about >0 to 200 Hz (LF current). Applicable are,
e.g.,
the so-called delta currents, rectangular currents, diadynamic currents, high-
voltage
currents, ultrastimulant currents, faraday currents - to name but a few. Some
alternating currents have a direct current component, which additionally backs
the
polar effects.
l0 There are two frequency-dependent methods of using action potential's
therapeutically:
Functional imitation principle:
The number of action potentials generated by the excitable cell (e.g., nerve
or
muscle) for the performance of its tasks is ascertained. In therapy, the same
number
15 of pulses are then generated in the relevant cell by stimulation, thereby
backing the
cell in performing its tasks.
For instance, a stimulation frequency of up to 6 Hz is applied to generate up
to 6 individual contractions per second.
Fatigue principle:
2o In contrast, when forcing the cell (nerve or muscle) to generate action
potentials, by stimulation at higher frequency and appreciably more often than
the
cell would be required to do so to perform its tasks, it fatigues after a
short time.
The opposite effect occurs. The cell fatigue can be explained by energy-
consuming
processes in the formation of action potentials.
25 For instance, a sclerosed muscle can be relaxed according to this fatigue
principle by stimulating it with a "higher" frequency of, e.g., 100 Hz or 200
Hz.
To generate any action potentials at all, of course, the intensity must be
chosen sufficiently high to exceed the stimulus threshold. The level of
intensity to
be set depends on the following factors: the position (depth) of the cell to
be
3o stimulated in the tissue (distance from the electrode), the size of the
electrodes and
21
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
the tissue resistances in the region penetrated by the electric potential,
which, in
turn, is influenced by the parameters of the current form.
In practice, current form and electrode size are prescribed. To stimulate now
a group of cells at a certain distance from the electrode (for example, deep
in the
tissue), the current and/or voltage intensity continues to be increased until
action
potentials occur.
As the intensity increases, cells located deeper, and deeper, or cells ever
more distal from the electrodes, are being stimulated successively. With the
apolar
stimulation principle, only so-called medium-frequency alternating currents
(MF
1 o currents) without any direct current component are employed. Meant by MF
currents are sinusoidal alternating currents with a frequency of > 5 Hz to
100,000
Hz. A single cycle (alternating pulse) with sufficient intensity has a polar
effect
which is able to trigger an action potential in a nerve or muscle cell.
Often, a "summation effect" occurs. At increasing frequency, ever higher
15 intensities are needed too, in order to be able to trigger action
potentials in the cells.
Wyss has proved beyond doubt that the generation of action potentials with MF
pulses proceeds entirely independently of polar effects. This means that
wherever
the intensity and number of oscillations is sufficiently large, action
potentials will be
generated irrespective of the momentary polarity of the MF current (Wyss,
Oscar
20 A.M; Prinzipien der elektrischen Reizung, [Principle of Electrical
Stimulation],
Neujahrs-Blatt, published by the Natural Research Society in Zurich for the
year
1976, Kommissionsverlag Leeman AG, Zurich, 1976, 28-34).
MF pulses are applied at a low-frequency repetition rate of >0 to about 200
Hz and MF carrier frequencies of > 5 Hz to 100,000 Hz. In practice, this is
mostly a
25 sinusoidal, amplitude-modulated MF current (AM-MF current). The following
principles are in agreement with those described in conjunction with the
"polar
stimulation principle".
Functional -imitation principle:
In synchronism with the MF pulses (amplitude modulation), action potentials
30 occur in excitable cells. The cell is thereby induced to exercise its
natural functions,
which emanate from this frequency.
Fatigue principle:
22
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
To fatigue excitable cells, MF pulses with higher amplitudes are used.
As the current intensity rises, cells are stimulated successively that are
located deeper and deeper (more distal from the electrodes).
Along with an increasing the frequency, more intensity is needed to generate
action potentials.
On the basis of the medium-frequency alternating current, the following
additional options of therapy are given:
When stimulating with (constant-amplitude) MF current of sufficient
intensity, an action potential is generated first. With MF current that flows
for a
to longer time, the decaying flank of the action potential remains at the
depolarization
level (permanent depolarization), which amounts to about one-half of
equilibrium
potential. Upon shutting the NM current off, the membrane voltage drops then,
delayed, to the level of equilibrium potential.
The following sub-items describe the therapeutic utilization of the permanent
15 depolarization.
Pain alleviation and influencing perfusion:
High intensities which, depending on the properties of the region being
treated, range at the tolerance limit cause a blocking of nerve transmission
paths, due
to the permanent depolarization. This genuine nerve block (proof established
by
20 BOWMAN, Bruce R., 1981, dissertation E. K. University of LJubljana, Rancho
Los
Amigos Hospital, Downey, Calif, U.S.A.) is utilized, e.g., for pain blocking
in
phantom-limb pains or for stellatum block in blood flow disorders.
Muscular contraction:
Muscle training in voluntary innervation insufficiency and muscle distention.
25 With the nerve muscle apparatus intact, the striated muscle (skeletal
muscle)
is stimulated directly by permanent depolarization. This results in muscle
contraction, which is used, e.g., in voluntary innervation insufficiency of
the
muscles or to stretch the antagonists of spastic muscles. During treatment,
the,
intensity should be interrupted by pauses in short intervals. The intensity
also may
3o be increased and decreased between 100% and about 50% of the adjusted
value.
23
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Generating strong muscle contraction forces:
Very strong muscle contractions may be induced without fatigue phenomena.
In tetanic contraction, which can be induced with stimulation current of about
SO Hz
and up, a rapid decrease of the muscle contraction force occurs contrarily,
due to
fatigue of the myokinetic units.
Cell division:
Wound healing and accelerated bone healing:
Permanent depolarization induces cell division in healthy cells. Wound
healing may be promoted thereby, bone healing accelerated in fractures.
Moreover,
1 o MF currents induce under the effect of the electrical alternating field
reciprocal
movement (shaking effect) of charged molecules in the current penetrated
tissue,
accompanied by rotation movements of the charged molecule shares. Achieved
thereby is a greater probability of a "correct" meeting position of enzyme and
substrate, which in metabolic processes interact chemically (metabolic
facilitation).
15 This shaking effect tends to level differences in concentration, in that
diffusion
processes which on account of existing concentration gradients proceed in
certain
directions are accelerated due to the kinetic energy that is additionally
imparted (MF
iontophoresis, inhibition of inflammation, alleviation of pain).
The shaking effect is especially effective at high intensities.
2o Distribution of inflammatory and pain mediators:
Inhibition of inflammation and alleviation of pain:
In painful, inflammatory processes a high concentration of inflammatory and
pain mediators is regularly found in the diseased tissue. This high
concentration is
reduced (dispersed) by the shaking effect. Caused by high current intensities,
the
25 "shaking intensity" - the same as the frequency - is of great significance
for the
therapeutic effects (Hans-Jurgens, May, Elektrische Differential-Therapie
[Electrical
Differential Therapy], Karlsruhe 1990).
Influencing of metabolism (diffusion, mitochondria, cyclic AMP):
Facilitation and promotion of metabolic processes:
3o As described above, the biochemical metabolic processes are facilitated.
24
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Also in penetrating cell cultures with MF current it has been found that the
number of mitochondria ("energy plants" of the cells) and their size increase
significantly.
The concentration of an important messenger substance of the cell, the cyclic
AMP, can also be influenced by alternating current, depending on MF current
and/or
voltage (Dertinger, 1989, Kemforschungszentrum Karlsruhe, Nagy Nemectron
GmbH Karlsruhe).
Furthermore, a painless and strong muscle contraction can be induced with
MF currents.
The so-called "threshold dissociation" occurs from 8 kHz, that is, the
threshold amperage for muscle contraction goes below that of the sensible
threshold
(Edel, H.: Fibel der Elektrodiagnostik and Elektrotherapie [Primer of
Electrodiagnostics and Electrotherapy, Muller & Steinicke Munchen 1983, p.
193).
Strong muscle contractions can be induced without pain. Viewed
therapeutically,
15 threshold dissociation is of particular interest in utilizing the
reversible process of
muscle contraction, which is caused by the permanent depolarization of the MF
current.
Due to the high intensities of the MF current, heat is generated in the
current-penetrated tissue. But a prerequisite is that the patient not be
discomforted
2o by exceeding the thresholds (sensation, muscle, tolerance, pain).
Analogous to the improvement of the metabolic processes, also an
iontophoresis can be accomplished with MF current, i.e., the administration of
medications with the aid of current through the skin into the body. Owing to
the
physical circumstances, iontophoresis with MF current requires a longer
treatment
25 time and higher intensities as compared to galvanic current.
As described above and found insofar also in the pertaining trade 5 literature
(refer to book "Elektrische Differential-Therapie" [Electrical Differential
Therapy]
by A. Hansjuorgens and H. U. May, 1990; Nemectron GmbH, Karlsruhe), the prior
electrotherapeutic apparatuses employ, depending on diagnosis, low-frequency
3o currents or amplitude-modulated medium-frequency currents at frequencies >0
to
200 Hz or medium-frequency currents at a frequency of >S Hz to 100,000 Hz,
each
with constant amplitude (intensity).
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Because any one and more of the above uses is anticipated for dermal patch
of the present invention, patch 10 preferably includes electrical circuitry
for
controlling the level or duration of current produced by electrochemical cell
14.
Such circuitry may take the form of an on-off switch for "on-demand" drug
delivery
(e.g., patient controlled delivery of an analgesic for pain relief), a timer,
a fixed or
variable electrical resistor, a controller which automatically turns the
device on and
off at some desired periodicity to match the natural or circadian patterns of
the body,
or other more sophisticated electronic control devices known in the art. For
example, it may be desirable to deliver a predetermined constant level of
electric
1 o current since a constant current level ensures a constant rate of
substance delivery.
The level of current can be controlled by a variety of known means, for
example, a
resistor or a simple circuit that employs a resistor and a field effect
transistor. The
circuitry may also include an integrated circuit which could be designed to
control
the dosage of active agent delivered, or even to respond to sensor signals in
order to
regulate the dosage to maintain a predetermined dosage regimen. A relatively
simple circuit can control the current as a function of time, and if desired,
generate
complex current waveforms such as pulses or sinusoidal waves as is further
described above. In addition, the circuitry may employ a bio-feedback system
which monitors a biosignal, provides an assessment of the therapy, and adjusts
the
2o active agent delivery accordingly. A typical example is the monitoring of
the blood
sugar level for controlled administration of insulin to a diabetic patient. A
simple
yet important use of a controlling circuit is the avoidance of heat buildup
and
resultant tissue damage. It is understood that the delivery of ions causes
heat due to
the movement of the ions and that the greater the delivery, the greater will
be the
heat buildup at the site of the delivery. As such, the current used for
treatment could
be patient-controlled such that a balance may be found between maximizing the
delivery of substance and minimizing the discomfort of temperature increase.
A kit according to the present invention will therefore include a dermal
patch-for the transdermal and/or intradermal delivery of at least one
substance, and
at least one retainer for retaining the substances) away from the patch prior
to use.
This construction allows the versatile use of substances/dosages with a single
dermal
patch.
26
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
A method of transdermal or intradermal delivery of at least one substance
according to the present invention is hence effected by (a) topically applying
a
conductive fluid containing the substance onto a skin portion of the subject
and/or
depositing the conductive fluid containing the substance on at least one
electrode of
a dermal patch which, comprises an, electrochemical cell having at least two
electrodes positioned on one side of the dermal patch; (b) positioning the
dermal
patch such that the electrodes are in electrical contact with the skin portion
of the
subject; and (c) delivering an electric current through the conductive fluid
and the
skin portion so as to transdermally or intradermally deliver the substance.
to A method of introducing current and/or voltage to a skin portion of a
subject
according to the present invention is hence effected by (a) topically applying
a
conductive fluid onto a skin portion of the subject and/or depositing the
conductive
fluid on at least one electrode of a dermal patch which comprises an
electrochemical
cell having at least two electrodes positioned on one side of the dermal
patch; (b)
positioning the dermal patch such that the electrodes are in electrical
contact with
the skin portion of a subject; and (c) delivering an electric current through
the
conductive fluid so as to introduce current and/or voltage to the skin portion
of the
subj ect.
It is understood that the conductive fluid may be deposited onto one or both
2o electrodes either being retained within the retainer or by being: dispensed
from any
of the other retainers described. It is further understood that the above
applications
of the present invention may also be effected by topically applying the
conductive
fluid to the skin at the location that the electrode will be placed.
The present invention offers numerous advantages over existing patches
which inherently include substances to be transdermally or intradermally
delivered
as a single dermal patch can be used to deliver any number of different
substances/doses as long as it is powered, it need not be discarded as it is
never
depleted.
Additional objects, advantages, and novel features of the present a invention
will become apparent to one ordinarily skilled in the art upon examination of
the
following examples, which are not intended to be limiting. Additionally, each
of the
various embodiments and aspects of they present invention as delineated
27
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
hereinabove and as claimed in the claims section below finds experimental
support
in the following examples.
EXAMPLES
Reference is now made to the following examples, which together with the
above descriptions, illustrate the invention in a non limiting fashion.
Treatment of mild rosacea
Mild rosacea, characterized by redness of parts of the face and telangectasia,
is a common disorder, afflicting many individuals, mainly from the aging
l0 population. Unfortunately the treatments for mild rosacea are 5 limited.
Three patients with mild rosacea were enrolled in a pilot study, meting the
following inclusion criteria:
Patient has mild to moderate redness in both sides of the face; and
Patient is between 20 and 65 years of age.
15 The study objectives were to detect the therapeutic effects on the redness
phenomenon, during and following treatment and to detect side effects.
Each study subject received treatment of both sides of the face.
On one side of the face an "Active Patch", linked by thin cords to a power
supply so that the large part of the patch (Main Patch) was linked to the
Positive
2o pole of the power supply and the small part of the patch (Counter-Patch)
was linked
to the negative pole of the power supply.
A "Passive Patch", with same shape, without being connected to an electrical
source, was used on the other side of the face of each tested subject.
Each patch was coated by a Test Preparation (aqueous gel, containing witch
25 hazel extract). 0.4 ml of the Test Preparation was evenly applied onto the
Main
Patch and 0.1 ml to the Counter Patch, using a spatula. The patches were then
applied onto the skin of the study subjects for a 5 period of 7-20 minutes
(the
Treatment Period).
28
CA 02464301 2004-04-21
WO 03/035166 PCT/IL02/00848
Observations were taken immediately after removal of the patches and 10, 25
and 40 minutes thereafter, including subjective assessment by the patient and
blinded assessment by a trained observer. Photographs were taken prior to
treatment
and at all observation points.
In all three patients, there was a pronounced reduction in the degree of
redness and the extent of telangectasia at the Active Patch sites. This
improvement
was first observed immediately after patch removal and further documented for
the
rest of the observation period. The Passive Patch sites exhibited very slight
improvements, which were not considered by the patients or the observer as
1 o significant.
It is appreciated that certain features of the invention, which are, for
clarity,
described in the context of separate embodiments, may also be provided in
combination in a single embodiment. Conversely, various features of the
invention
which are, for brevity, described in the context of a single embodiment, may
also be
15 provided separately or in any suitable subcombination.
It will be appreciated by persons skilled in the art that the present
invention
is not limited to what has been particularly shown and described hereinabove.
Rather, the scope of the present invention is defined by the appended claims
and
includes both combinations and subcombinations of the various features
described
z0 hereinabove as well as variations and modifications thereof which would
occur to
persons skilled in the art upon reading the foregoing description.
Accordingly, it is
intended to embrace all such alternatives, modifications and variations that
fall
within the spirit and broad scope of the appended claims.
29
