Note: Descriptions are shown in the official language in which they were submitted.
ARC 1621 CIP 1 1
IONTOPHORETIC DELIVERY DEVICE
TECHNICAL FIELD
s This invent ion relates to a device for delivering an agent
transdermally or transmucosally by iontophoresis. More
particularly, this invention relates to an electrically powered
iontophoretic delivery device which can deliver a drug from both
the anodic and catholic electrodes simultaneously.
io
BACKGROUND ART
Iontophoresis, according to Dorland°s Illustrated Medical
Dictionary, is defined to be "the introduction, by means of
is electric current, of ions of soluble salts into the tissues of the
body for therapeutic purposes." Iontophoretic devices have been
known since the early 1900's. British patent specification No.
410,009 (1934) describes an iontophoretic device which overcame
one of the disadvantages of such early devices known to the art at
zo that time, namely the requirement of a special low tension (low
voltage) source of current which meant that the patient needed to
be irr~nobilized near such source. The device of that British
specification was made by forming a galvanic cell from the
electrodes and the material containing the medicament or drug to
zs be delivered transdermally. The galvanic cell produced the
current necessary for iontophoretically delivering the medicament.
This ambulatory device thus permitted iontophoretic drug delivery
with substantially less interference with the patient's daily
activities.
ao
More recently, a number of United States patents have issued
in the iontophoresis field, indicating a renewed interest in this
mode of drug delivery. For example, U.S. Patent No. 3,991,755
issued to Ilernon et al; U.S. Patent No. 4,141,359 issued to
35 Jacobsen et al; U.S. Patent No. 4,398,545 issued to Wilson; and
204994
ARC 1621 CIP 1 2
U.S. Patent ~o. 4,250,878 issued to Jacobsen disclose examples of
iontophoretic devices and some applications thereof. The
iontophoresis process has been found to be useful in the
transdermal administration of medicaments or drugs including
s lidocaine hydrochloride, hydrocortisone, fluoride, penicillin,
dexamethasone sodium phosphate, insulin and many other drugs.
Perhaps the most common use of iontophoresis is in diagnosing
cystic fibrosis by delivering pilocarpine salts iontophoretically.
The piiocarpine stimulates sweat production; the sweat is
io collected and analyzed for its chloride content to detect the
presence of the disease.
In presently known iontophoretic devices, at least two
electrodes are used. Both of these electrodes are disposed so as
is to be in intimate electrical contact with some portion of the skin
of the body. One electrode, called the active or donor electrode,
is the electrode from which the ionic substance, medicament, drug
precursor or drug is delivered into the body by iontophoresis.
The other electrode, called the counter or return electrode,
zo serves to close the electrical circuit through the body. In
conjunction with the patient's skin contacted by the electrodes,
the circuit is completed by connection of the electrodes to a
source of electrical energy, e.g., a battery. For example, if the
ionic substance to be delivered into the body is positively
2s charged (i.e., a can on), then the anode will be the active
electrode and the cathode will serve to complete the circuit. If
the ionic substance to be delivered is negatively charged (i.e.,
an anion), then the cathode will be the active electrode and the
anode will be the counter electrode.
It is also known that iontophoretic delivery devices can be
used to deliver an uncharged drug or agent into the body. This is
accomplished by a process called electroosmosis. Electroosmosis
is the transdermal flux of a liquid solvent (e. g., the liquid
3s solvent containing the uncharged drug or agent) which is induced
~a4~~94
ARC 1621 CIP 1 3
by the presence of an electric field imposed across the skin by
the donor electrode. As used herein, the terms "iontophoresis"
and "iontophoretic" refer to (1) the delivery of charged drugs or
agents by electromigration, (2) the delivery of uncharged drugs or
s agents by the process of electroosmosis, (3) the delivery of
charged drugs or agents by the combined processes of
electromigration and electroosmosis, and/or (4) the delivery of a
mixture of charged and uncharged drugs or agents by the combined
processes of electromigration and electroosmosis.
1D
Furthermore, existing iontophoresis devices generally
require a reservoir or source of the beneficial agent (which is
preferably an ionized or ionizable agent or a precursor of such
agent) to be iontophoretically delivered into the body. Examples
is of such reservoirs or sources of ionized or ionizable agents
include a pouch as described in the previously mentioned Jacobsen
U.S. Patent No. 4,250,878, or a pre-formed gel body as described
in Webster U.S. Patent No. 4,383,529 and Ariura et al. U.S. Patent
No. 4,474,570. Such drug reservoirs are electrically connected to
zo the anode or the cathode of an iontophoresis device to provide a
fixed or renewable source of one or more desired agents.
Most typically, the drug and electrolyte reservoir layers of
iontophoretic delivery devices have been formed of hydrophilic
2s polymers. See for example, Ariura et al, U.S. Patent 4,474,570;
Webster U.S. Patent 4,383,529 and Sasaki U.S. Patent 4,764,164.
There are several reasons for using hydrophilic polymers. First,
water is the preferred solvent for ionizing many drug salts.
Secondly, hydrophilic polymer components (i.e., the drug reservoir
ao in the donor electrode and the electrolyte reservoir in the
counter electrode) can be hydrated while attached to the body by
absorbing water from the skin (i.e., through transepidermal water
loss or sweat) or from a mucosal membrane (e. g., by absorbing
saliva in the case of oral mucosal membranes). Once hydrated, the
35 device begins to deliver ionized agent to the body. This enables
2042994
ARC 1621 CIP 1 4
the drug reservoir to be manufactured in a dry state, giving the
device a longer shelf life.
DISCLOSURE OF THE INVENTION
It is an object of this invention to provide an improved
iontophoretic delivery device and method of using same.
It is another object of this invention to provide an
io iontophoretic delivery device which can deliver the same agent
from both electrodes simultaneously.
These and other objects are met by an electrically powered
iontophoretic delivery device which is adapted for placement on a
is body surface for iontophoretically delivering an agent
therethrough. The device includes a first electrode, a means for
electrically connecting the first electrode to a source of
electrical power, and a first agent reservoir electrically
connected to the first electrode. The first agent reservoir
Zo contains a portion of the agent to be delivered through the body
surface.
The device also includes a second electrode, means for
electrically connecting the second electrode to the source of
2s electrical power, and a second agent reservoir electrically
connected to the second electrode. The second agent reservoir
contains a portion of the agent to be delivered through the body
surface.
ao The agent delivered by the device has an isoelectric point
at a specified pH. The first agent reservoir has a pH above the
specified pH which renders at least a portion of the agent in the
first agent reservoir negatively charged. The second agent
reservoir has a pH below the specified pH which renders at least a
35 portion of the agent in the second agent reservoir positively charged.
CA 02042994 2002-11-20
67696-181
In this way, a portion of the agent in the first
agent reservoir has a net negative charge in solution and
therefore is delivered from the first agent reservoir by
electromigration. Simultaneously, a portion of the agent in
5 the second agent reservoir has a net positive charge in
solution and likewise is delivered from the second agent
reservoir by electromigration.
Also provided is a method of iontophoretically
delivering an agent through a body surface from such a
delivery device. The method includes the steps of:
adjusting the pH of the first agent reservoir to a
pH above the specified pH;
adjusting the pH of the second agent reservoir to
a pH below the specified pH; and
placing the first and second agent reservoirs in
agent transmitting relation to the body surface.
According to one aspect of the present invention,
there is provided an iontophoretic delivery device adapted
for placement on a body surface for iontophoretic delivery
of an agent therethrough, the device comprising:
a first electrode, means for electrically
connecting the first electrode to a source of electrical
power, and a first agent reservoir electrically connected to
the first electrode, the first agent reservoir containing a
portion of the agent to be delivered through the body
surface; and
a second electrode, means for electrically
CA 02042994 2002-11-20
67696-181
5a
connecting the second electrode to the source of electrical
power, and a second agent reservoir electrically connected
to the second electrode, the second agent reservoir
containing a portion of the agent to be delivered through
the body surface,
wherein the agent has an isoelectric point at a
specified pH; the first agent reservoir has a pH above the
specified pH and hence the agent in the first reservoir has
a net negative charge in a solution; and the second agent
reservoir has a pH below the specified pH, and hence the
agent in the second reservoir has a net positive charge in a
solution,
whereby the agent can be delivered simultaneously
from both the first and second agent reservoirs through the
body surface by electromigration, and
wherein at least about 10% of the agent in the
first agent reservoir has a net negative charge in solution,
and at least about 10% in the agent in the second agent
reservoir has a net positive charge in solution.
According to another aspect of the present
invention, there is provided a method of operating a
delivery device having a first electrode electrically
connected to a first agent reservoir containing an agent
having an isoelectric point at a specified pH, and a second
electrode electrically connected to a second agent reservoir
containing the agent, the first and second electrodes being
electrically connected to a source of electrical power, the
delivery device being for iontophoretically delivering the
agent through a body surface, the method comprising:
CA 02042994 2002-11-20
67696-181
5b
adjusting the pH of the first agent reservoir to a
pH above the specified pH so that the agent in the first
reservoir has a net negative charge in a solution;
adjusting the pH of the second agent reservoir to
a pH below the specified pH so that the agent in the second
reservoir has a net positive charge in a solution; and
placing the first and second agent reservoirs in
agent transmitting relation to the body surface,
whereby the delivery device is caused to
simultaneously deliver the agent from both the first and
second agent reservoirs through the body surface by
electromigration,
wherein the pH of the first agent reservoir is
adjusted to a pH wherein at least about 10% of the agent in
the first agent reservoir has a net negative charge in
solution and a pH of the second agent reservoir is adjusted
to a pH wherein at least about 10% of the agent in the
second agent reservoir has a net positive charge in
solution.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic view of an iontophoretic
drug delivery device according to the present invention;
Figure 2 is a schematic view of another embodiment
of an iontophoretic delivery device according to the present
invention;
Figure 3 is a schematic view of another embodiment
of an iontophoretic delivery device which is described in
Example I; and
CA 02042994 2002-11-20
67696-181
5c
Figure 4 is a schematic view of another embodiment
of an iontophoretic delivery device according to the present
invention.
ARC 1621 CIP 1 6
MODES FOR CARRYING OUT THE INVENTION
Figure 1 is a schematic view of an iontophoretic delivery
device 10 for delivering a beneficial agent through a body surface
s 22. Body surface 22 is typically intact skin or a mucosal
membrane. Iontophoretic delivery device 10 includes a pair of
electrodes 11 and 12 which are composed of dissimilar
electrochemical couples and which therefore form a galvanic
couple. Typical materials for delivering an agent into the body
io include a zinc electrode 11 and a silver/silver chloride counter
electrode 12. A Zn-Ag/AgCI galvanic couple provides an electrical
potential of about 1 volt. The device also includes agent
reservoirs 14 and 16 which contain the beneficial agent to be
iontophoretically delivered by device 10. The reservoirs 14 and
is 16 are separated by an insulator 18. Insulator 18 is comprised of
a material which is impermeable to the passage of ions and
electrical current. The device has a backing layer 13 made of an
electrically insulating material of the type commonly used in
transdermal delivery systems (e.g., ethylene vinyl acetate or
zo polyethylene terephthalate). The device is adhered to the body
surface 22 by means of a peripheral adhesive layer 15. Suitable
adhesives include, without limitation, polyisobutylene/mineral oil
and silicone adhesives. The device 10 normally includes a
strippable release liner, not shown, which is removed before
is placing the device on body surface 22.
Figure 2 illustrates a device 20 having an adhesive overlay
23 and a power source 17. The device 20 also has a strippable
release liner 28 which is removed dust before placement of device
so 20 on the body. Power source 17 is typically one or more
batteries.
Figure 4 illustrates one example of a preferred
iontophoretic delivery device 40. Device 40 has a top layer 41
ss which contains an electrical power supply (e.g., a battery or a
2~4~9~4
ARC 1621 CIP 1 7
series of batteries) as well as optional control circuitry such as
a current controller (e. g., a resistor or a transistor-based
current control circuit), an on/off switch, and/or a
microprocessor adapted to control the current output of the power
s source over time.
Device 40 also includes electrode assembly 48 and electrode
assembly 49. Electrode assemblies 48 and 49 are separated from
one another by electrical insulator 18. Electrode 11 is
io positioned adjacent drug reservoir 14 while electrode 12 is
positioned adjacent drug reservoir 16. Electrodes 11 and 12 may
be formed from metal foils (e. g., silver or zinc), or a polymer
matrix loaded with metal powder, powdered graphite, carbon fibers,
or any other suitable electrically conductive material. Most
is preferably, the anodic electrode is comprised of an oxidizable
metal such as silver or zinc and the cathodic electrode is
comprised of a reducible material such as silver chloride.
Reservoirs 14 and 16 can be polymeric matrices or gel matrices.
Insulator 18 is composed of a non-electrical conducting and non-
2o ion-conducting material which acts as a barrier to prevent short-
circuiting of the device 40. Insulator 18 can be an air gap, a
non-ion-conducting polymer or adhesive or other suitable barrier
to ion flow. The device 40 is adhered to the skin by means of
ion-conducting adhesive layers 45 and 46. The device 40 also
2s includes a strippable release liner 28 which is removed just prior
to application to the skin.
Generally, the combined skin-contacting area of electrode
assemblies 48 and 49 can range from about 1 cmZ to greater than
ao Z00 cmz, but typically will range from about 5 to 50 cm2.
When the device 40 is in storage, no current flows because
the device forms an open circuit. When the device 40 is placed on
the skin or mucosal membrane of a patient and reservoirs 14 and
35 16, and layers 45 and 46, become sufficiently hydrated to allow
ARC 1621 CIP 1 8
conduction of ions therethrough, the circuit between the
electrodes is closed and the power source begins to deliver
current through the device and through the body of the patient.
Electrical current flowing through the conductive portions of the
s device 40 (i.e., those portions used to connect the power source
to the electrodes) is carried by electrons (electronic
conduction), while current flowing through the hydrated portions
of the device 40 (e.g., the agent reservoirs 14 and 16 and the
ion-conducting adhesive layers 45 and 46) is carried by ions
io (ionic conduction). In order for current to flow through the
device, it is necessary for electrical charge to be transferred
from the power source in layer 41 to chemical species in solution
in reservoirs 14 and 16 by means of oxidation and reduction charge
transfer reactions at the surface of the electrodes 11 and 12 as
is is known in the art.
In accordance with the present invention, at least one of
agent reservoirs 14 and 16 is formulated to have a pH above the
isoelectric point of the agent while the other agent reservoir is
2o formulated to have a pH below the isoelectric point of the agent.
Specifically, the pH of the agent reservoir which is electrically
connected to the catholic electrode should be kept at a pH above
the isoelectric point for the agent while the pH of the agent
reservoir which is electrically connected to the anodic electrade
zs should be kept at a pH below the isoelectric point for the agent.
In this way, electromigration (i.e., delivery of charged agent
ions through the action of an electrical field) is maximized.
The pH of agent reservoirs 14 and 16 can be ad3usted using
ao techniques well known to those skilled in the art. For example,
appropriate acids, bases and/or buffering agents may be added to
reservoirs 14 and 16 in order to maintain the desired pH. Either
inorganic acids or organic acids can be used to lower the pH in
the anodic agent reservoir. Suitable organic acids include acetic
ss acid and succinic acid. Suitable inorganic acids include
2~429~4
ARC 1621 CIP 1 9
hydrochloric acid, sulfuric acid, and nitric acid. Of these,
hydrochloric acid is most preferred. In general, only relatively
small amounts of acid, usually less than 1 wt% of the agent
reservoir (on a dry weight basis) are necessary to achieve the
s desired low pH. For the cathodic agent reservoir, bases such as
NaOH, LiOH, NaZC03, Na3AS04, sodium borate, disodium tartarate and
Na3P04 are suitable to raise the pH level of the agent reservoir.
Of these, sodium hydroxide is most preferred to raise the pH to
the desired level.
io
In the most preferred embodiment, the agent in the anodic
agent reservoir is a salt formed by reacting the agent with an
acid, e.g., reacting the agent with hydrochloric acid to form the
hydrochloride salt of the agent. Such a salt will naturally
i5 buffer the pH of the anodic agent reservoir to a level below the
isoelectric point of the agent. Similarly, the agent in the
cathodic agent reservoir is most preferably a salt formed by
reacting the agent with a base, e.g., reacting the agent with
sodium hydroxide to form the sodium salt of the agent. Such a
2o salt will naturally buffer the pH of the cathodic agent reservoir
to a level above the isoelectric point of the agent. In this
embodiment, it is unnecessary to separately add an acid or base to
the drug reservoir since the agent salt itself acts to modify the
pH of the drug reservoir to the appropriate level.
In accordance with the present invention, the pH of the
anodic agent reservoir is preferably adjusted to a point
sufficiently above the isoelectric pH to insure that at least
about 10%, more preferably at least about 25% and most preferably
ao at least about 50% of the agent has a net negative charge.
Similarly, the pH in the cathodic agent reservoir is preferably
adjusted to a pH sufficiently lower than the isoelectric pH to
insure that at least about 10%, more preferably at least about 25%
and most preferably at least about 50% of the agent in the
reservoir has a net positive charge. The actual reservoir pH
2~4~99~
ARC 1621 CIP 1 10
level, as well as the difference between the reservoir pH and the
isoelectric pH, will vary depending upon the particular agent
being delivered. Those skilled in the art can easily determine
the optimum pH for each reservoir using routine experimentation
s starting with a pH of at least 1 pH unit, and preferably at least
2 pH units, removed from the isoelectric point.
As an alternative to the side-by-side alignment of the
electrode assemblies 48 and 49, and the insulator 18 shown in
to Figure 4, the electrode assemblies can be concentrically aligned
with one electrode assembly positioned centrally and surrounded by
the insulator 18 and the other electrode assembly. The concentric
alignment of the electrode assemblies can be circular, elliptical,
rectangular or any of a variety of geometric configurations.
The agent reservoirs 14 and 16 can be formed by blending the
desired drug, acid or base, and other component(s), with the
polymer by melt blending, solvent casting or extrusion, for
example. The drug loading in the polymer matrix is generally
2o about 10 to 60 wtfo, although drug loadings outside this range may
also be used.
Suitable polymers for use as the matrix of reservoirs 14 and
16 include, without limitation, hydrophobic polymers such as
z5 polyethylene, polypropylene, polyisoprenes and polyalkenes,
rubbers such as polyisobutylene, copolymers such as Kraton~,
polyvinylacetate, ethylene vinyl acetate copolymers, polyamides
including nylons, polyurethanes, polyvinylchloride, cellulose
acetate, cellulose acetate butyrate, ethylcellulose, cellulose
ao acetate, and blends thereof; and hydrophilic polymers such as
hydrogels, polyvinylpyrrolidones, polyethylene oxides, Polyox~,
Polyox~ blended with polyacrylic acid or Carbopol~, cellulose
derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl
cellulose, hydroxyprapyl cellulose, pectin, starch, guar gum,
ss locust bean gum, and the like, along with blends thereof.
2042~~4
ARC 1621 CIP 1 11
The adhesive properties of the reservoirs 14 and 16 may be
enhanced by adding a resinous tackifier. This is especially
important when using a non-tacky polymeric matrix. Examples of
suitable tackifiers include products sold under the trademarks
s Staybelite Ester #5 and #10, Regal-Rez and Piccotac, all sold by
Hercules, Inc. of Wilmington, DE. Additionally, the matrix may
contain a rheological agent, suitable examples of which include
mineral oil and silica.
io In addition to the drug, the reservoirs 14 and 16 may also
contain other conventional materials such as buffers, dyes,
pigments, inert fillers, and other excipients.
The electronic layer 41 of device 40 optionally includes a
is control circuit. The control circuit may take the form of an on-
off switch for "on-demand" drug delivery (e. g., on-demand delivery
of an analgesic for pain control), 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
20 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 current
from device 40 since a constant current level ensures that the
drug or agent is delivered through the skin at a constant rate.
Zs The current level can be controlled by a variety of known means,
for example, a resistor or a field effect transistor or a current
limiting diode. The control circuit may also include a microchip
which can be programmed to control the dosage of beneficial agent,
or even to respond to sensor signals in order to regulate the
ao dosage to maintain a predetermined dosage regimen. A relatively
simple controller or microprocessor can control the current as a
function of time, and if desired, generate complex current
waveforms such as pulses or sinusoidal waves. In addition, the
control circuit may employ a bio-feedback system which monitors a
35 biosignal, provides an assessment of the therapy, and adjusts the
2~4~9~~
ARC 1621 CIP 1 12
drug delivery accordingly. A typical example is the monitoring of
the blood sugar level for controlled administration of insulin to
a diabetic patient.
s As used herein, the expression "agent" can mean a drug or
other beneficial therapeutic agent which can be delivered to a
living organism to produce a desired, usually beneficial, effect
and which has an isoelectric point. An agent having an
isoelectric point can be made to carry (i) a net positive charge
io when in solution at a pH below the isoelectric point of the agent,
and (ii) a net negative charge when in solution at a pH above the
isoelectric point of the agent. In general, this includes
therapeutic agents in all of the major therapeutic areas
including, but not limited to, anti-infectives including
is antibiotics such as ampicillin, amoxicillin, vancomycin,
benzylpenicillin novocaine salt, 6-aminopenicillin acid,
penicillamine disulfide, sulfadiazine, sulfamerizine and
amphotericin B, antiviral agents such as vidarabine, analgesics
and analgesic combinations, anesthetics, anorexics, antiarthritics
zo such as aminosulfonic acids, antiasthmatic agents,
anticonvulsants, antidepressants such as aztreonam, antidiabetic
agents such as insulin, antidiarrheals, antihistamines,
anti-inflammatory agents such as baclofin, antimigraine
preparations, antimotion sickness preparations, antinauseants,
zs antineoplastics, antiparkinsonism drugs such as 1-dopa,
antipruritics, antipsychotics such as benperidol, antipyretics,
antispasmodics including gastrointestinal and urinary
antispasmodics, anticholinergics, sympathomimetrics, xanthine
derivatives, cardiovascular preparations including calcium channel
so blockers and ACE inhibitors such as moexipril, beta-blockers,
antiarrythmics, antihypertensives, diuretics, vasodilators
including general, coronary, peripheral and cerebral vasodilators,
central nervous system stimulants, cough and cold preparations,
decongestants, diagnostics, hormones such as liothyronine and
as thyroxine, hypnotics, immunosuppressives, muscle relaxants,
2~~~~~~
ARC 1621 CIP 1 13
parasympatholytics, parasympathomimetrics, proteins, peptides,
psychostimulants, sedatives and tranquilizers.
The invention is particularly useful in the controlled
s delivery of amino acids, polypeptides and proteins. These
macromolecular substances have isoelectric paints and typically
have a molecular weight of at least about 300 daltons, and more
typically a molecular weight in the range of about 300 to X0,000
daltons. Specific examples of amino acids, polypeptides and
io proteins in this size range include, without limitation,
adenosine, alcohol dehydrogenases, aprotinin, avidin, arginine,
riboflavin, LHRH, LHRH analogs such as busere7in, gonadorelin,
naphrelin and leuprolide, GHRH, insulin, insulin-like growth
factors, heparin, calcitonin, calmodulin, carbonic anhydrases,
is granulocyte colony stimulating factors, cytochrome C, endorphin,
TRH, NT-36 (chemical name: N~[[(s)-4-oxo-2-azetidinyl]carbonyl]-
L-histidyl-L-prolinamide), liprecin, pituitary hormones (e. g.,
HGH, HMG, HCG, desmopressin acetate, etc.), follicle luteoids,
aANF, growth factor releasing factor (GFRF), ~MSH, somatostatin,
2o bradykinin, somatotropin, platelet-derived growth factor,
asparaginase, bleomycin sulfate, chymopapain, cholecystokinin,
chorionic gonadotropin, corticotropin (ACTH), erythropoietin,
epidermal growth factors, epoprostenol (platelet aggregation
inhibitor), ferredoxin, glucagon, hyaluronidase, interferon,
2s interleukin-2, lactalbumin, lactoglobulin, lysozyme, menotropins
(urofollitropin (FSH) and LH), myoglobin, myokinase, ovalbumin,
oxytocin, pepsin, ribonuclease A, streptokinase, tissue
plasminogen activator, urokinase, vasopressin, ACTH analogs, ANP,
ANP clearance inhibitors, angiotensins, angiotensin II
ao antagonists, antidiuretic hormone agonists, antidiuretic hormone
antagonists, bradykinin antagonists, CD4, ceredase, CSF's,
enkephalins, FAB fragments, IgE peptide suppressors, IGF-1,
neurotrophic factors, parathyroid hormone and agonists,
parathyroid hormone antagonists, prostaglandin antagonists,
35 pentigetide, protein C, protein S, renin inhibitors, thymosin
2~4~~~~
ARC 1621 CIP 1 14
alpha-1, thrombolytics, TNF, vaccines, vasopressin, vasopressin
antagonist analogs, alpha-1 anti-trypsin (recombinant). It is
most preferable to use a water soluble salt of the drug or agent
to be delivered.
The invention is also useful in the controlled delivery of
compounds having at least one positively charged function and at
least one negatively charged function, such as amphoteric
compounds and zwitter ionic compounds. Amino acids are one
io example of zwitter ionic compounds. Amino acids have the general
formula:
R-CH-COON.
is NHZ
The carboxylic acid function carries a negative charge at low pH's
but carries no charge at high pH's. The amino group on the other
hand carries a positive charge at high pH's and no charge at low
2o pH's. Depending upon the particular acid and base groups in the
agent molecule, the agent is likely to have a pH range surrounding
the isoelectric point, within which pH range the agent is
substantially neutral, i.e., it carries no net charge in solution.
The pH of the agent reservoir is adjusted to be either above or
2s below this "neutral" range.
Other suitable agents are compounds which have both at least
one acid function (which is negatively charged) and at least one
base function (which is positively charged) in the molecule.
so Examples of suitable negatively charged functional groups include
organic acids such as carboxylic acids, sulphates, phosphates,
nitrates, phosphonates, sulphites, perchlorates and chlorates.
Most preferred are the organic acid functional groups. Examples
of suitable organic acid groups include formic, acetic, citric,
as succinic, malefic, lactic, butyric, propionic and valeric acid
groups. Examples of suitable positively charged functional groups
include amino groups, including primary, secondary, tertiary and
2Q42994
ARC 1621 CIP 1 15
quaternary amine groups, sulphonium groups and phosphines. Of
these, the amines are clearly preferred.
Having thus generally described our invention, the following
s examples will illustrate preferred embodiments thereof.
EXAMPLE I
An electrotransport device for transdermal delivery of 1-
io dope (pI of about 6) has the configuration of device 30
illustrated in Figure 3 and is made of the following materials.
The first electrode reservoir 14 is a self-adhering karaya gum
composition containing 1-dope formulated at a pH about 3.5 below
the isoelectric point. The second electrode reservoir 16 is a
is self-adhering karaya gum composition containing 1-dope formulated
at a pH of about 7.5 above the isoelectric point. In this manner,
both reservoirs 14 and 16 act as donors and deliver 1-dope to the
body surface. To form a galvanic couple capable of supplying
enough power to run the device, the electrode 11 is composed of Zn
zo while the electrode 12 is composed of Ag/AgCI. Insulator 18 is
composed of ethylene vinyl acetate having a vinyl acetate content
of 40% (EYA 40) and backing member 13 is composed of polyethylene
terephthalate/EVA.
25 EXAMPLE II
An iontophoretic delivery device for delivering baclofin (pI
of about 6) from both the anodic and cathodic drug reservoirs has
the configuration illustrated in Figure 4. The anodic electrode
ao is a silver foil laminated to a polymeric drug reservoir
containing baclofin. The anodic drug reservoir comprises on a dry
weight basis: 20 wt~ of polyisobutylene (PIB) having a molecular
weight of 1,200,000 (sold by Exxon Carp. of Irving, Texas), 20 wt~o
of PIB having a molecular weight of 35,000 (sold by Exxon Corp. of
as Irving, Texas), 25 wt~o of polyvinylpyrrolidone, (PVP-XL 10 sold by
ARC 1621 CIP 1 16
GAF Corp. of Wayne, New Jersey) having a degree of cross-linking
of 10%, and 35 wtfo of baclofin HC1. Baclofin HCl is prepared by
reacting baclofin with hydrochloric acid and subsequently drying
the salt in accordance with known procedures. The pH of the
s anodic drug reservoir is below the isoelectric point of baciofin.
The catholic electrode is comprised of a sheet of sintered
silver chloride laminated to a polymeric drug reservoir containing
baclofin. The catholic drug reservoir comprises on a dry weight
i~ basis: 20 wt% PIB having a molecular weight of 1,200,000, 20 wt/o
of PIB having a molecular weight of 35,000, 25fo wt% of PVP-XL 10,
and 35 wt% of sadium baclofin. Sodium baclofin is prepared by
reacting baclofin with sodium hydroxide and subsequently drying
the salt in accordance with known procedures. The catholic drug
is reservoir has a pH above the isoelectric point of baclofin.
The power source and control circuitry of the electronic
layer produce a current density of 100 NA/cm2. The device
operates to deliver baclofin from both the anodic drug reservoir
zo and the catholic drug reservoir. The baclofin which is delivered
from the anodic drug reservoir (low pH) is positively charged
while the baclofin which is delivered from the catholic drug
reservoir (high pH) is negatively charged.
2s EXAMPLE III
An iontophoretic delivery device for delivering insulin from
both the anodic drug reservoir and the catholic drug reservoir has
the configuration illustrated in Figure 4. The electrodes of the
3o device have the same composition as described in Example 2. The
anodic drug reservoir comprises 25 wtfo PIB having a molecular
weight of 1,200,000, 25 wt% PIB having a molecular weight of
35,000, 25 wt% PVP-XL 10, 24.7 wt% of insulin and 0.3 wt% succinic
acid. The pH of the anodic drug reservoir is about 3Ø
ARC 1621 CIP 1 17
The cathodic drug reservoir has the same composition as the
anodic drug reservoir except in place of succinic acid, the
cathodic drug reservoir contains 0.3 wt9~ Na3P04. The cathodic
drug reservoir has a pH of about 10.
The device has a power source and control circuitry
sufficient to produce a current density of 100 pA/cmz. The device
operates to deliver insulin from both the anodic drug reservoir
and the cathodic drug reservoir simultaneously. The insulin which
io is delivered from the anodic drug reservoir (pH of about 3.0) is
positively charged while the insulin which is delivered from the
cathodic drug reservoir (pH of about 10) is negatively charged.
Having thus generally described our invention and described
is in detail certain preferred embodiments thereof, it will be
readily apparent that various modifications to the invention may
be made by workers skilled in the art without departing from the
scope of this invention and which is limited only by the following
claims.
