Awakenable iontophoretic/delivery device for reducing electrical sensation upon application thereof

An iontophoretic drug delivery device includes a controller normally being in an off or low power consumption state, and a patch including electrodes, a reservoir containing an ionizable drug for transcutaneous delivery to a patient and a return reservoir. The patch is removably and electrically connectable to the controller, and delivers the drug to patient when the patch is on the patient's skin and when the controller is switched from the off or low power consumption state to an operational state. This occurs when the patch is inserted into the controller. This feature preserves the battery of the controller. Upon patch insertion, the controller periodically changes from a non-current delivery state to a current delivery state for the predetermined period of time to deliver a pulse of current to the inserted patch. A current sensor within the controller measures the current delivered to the patch. The controller switches to the non-current delivering state if the amount of current drawn is less than a predetermined amount, and is therefore off the skin, and switches to the current delivering state otherwise. This feature prevents the build up of charge on the patch electrodes and the possibility of an uncomfortable electrical sensation.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention is in the field of iontophoresis. In particular, the 
invention relates to awakening an electronic controller of an 
iontophoretic delivery device by the insertion of a drug delivery patch 
into the controller. The invention is also directed to a controller that 
prevents an electrical sensation upon the application of the drug delivery 
patch to the skin of a patient. 
2. Description of Related Art 
Iontophoresis is the migration of ions when an electrical current is passed 
through a solution containing ionized species, usually the ionic form of a 
drug or other therapeutic agent. One particularly advantageous application 
of iontophoresis is the non-invasive transdermal delivery of ionized drugs 
into a patient. This is done by applying low levels of current to a patch 
placed on the patient's skin, which forces the ionized drugs contained in 
the patch through the patient's skin and into his or her bloodstream. 
Passive transdermal patches, such as those used to deliver nitroglycerin 
for angina pectoris, estradiol for hormone replacement, and nicotine to 
stop smoking, can only use a limited number of drugs because they work by 
diffusion. Iontophoresis advantageously expands the range of drugs 
available for transdermal delivery, including, for example, parenteral 
drugs (e.g., peptides). Further, because the amount of drug delivered is 
proportional to the amount of current applied, the drug delivery rate can 
be precisely controlled by controlling the current, unlike the passive 
transdermal patches. This allows for more rapid delivery (onset) and drug 
reduction (offset) in the patient. 
When compared to drug delivery by needle injection, iontophoresis has less 
physical and emotional trauma, pain and possibility of infection. 
Transdermal drug delivery by iontophoresis also avoids the risks and 
inconvenience of IV (intravenous) delivery. In addition, when compared to 
oral ingestion of drugs, drug delivery by iontophoresis puts the drug 
directly into the bloodstream, bypassing the GI tract, thus reducing 
side-effects such as drug loss, indigestion and stomach distress and 
eliminating the need for swallowing the drug. Iontophoresis also avoids 
drug loss due to hepatic first pass metabolism by the liver that occurs 
when drugs are ingested. 
Further, transdermal drug delivery by iontophoresis permits continuous 
delivery of drugs with a short half life and easy termination of drug 
delivery. Because iontophoresis is more convenient, there is a greater 
likelihood of patient compliance in taking the drug. Thus, for all of the 
above reasons, iontophoresis offers an alternative and effective method of 
drug delivery, and a especially useful method for children, the bedridden 
and the elderly. 
An iontophoretic drug delivery device typically includes a current source, 
such as a battery and current controller, and a patch. The patch includes 
an active reservoir and a return reservoir. The active reservoir contains 
the ionized drug, usually in a conductive gel. The return reservoir 
contains a saline gel and collects ions emanating from the patient's skin 
when the drug is being delivered into the patient's skin. 
The patch also has two electrodes, each arranged inside the active and 
return reservoirs to be in respective contact with the drug and saline. 
The anode, or positive, electrode and the cathode, or negative, electrode 
are respectively electrically connected to the anode and cathode of the 
current source by electrical conductors. Either the anode electrode or the 
cathode electrode is placed within the drug reservoir, depending on the 
charge of the ionized drug. This electrode is designated as the active 
electrode. The other electrode is placed within the return reservoir, and 
is designated as the return electrode. 
The active electrode has the same charge as the ionized drug to be 
delivered and the return electrode has a charge opposite the drug to be 
delivered. For example, if the drug to be delivered to the patient has a 
positive ionic charge, then the anode will be the active electrode and the 
cathode will be the return electrode. Alternatively, if the drug to be 
delivered has a negative ionic charge, then the active electrode will be 
the cathode and the return electrode will be the anode. When current from 
the current source is supplied to the active electrode, the drug ions 
migrate from the drug gel in the reservoir toward and through the skin of 
a patient. At the same time, oppositely-charged ions flow from the 
patient's skin into the saline solution of the return reservoir. Charge is 
transferred into the return electrode and back to the current source, 
completing the iontophoretic circuit. 
The electronic controller between the battery and the electrodes delivers 
the required current to the patch. The controller may control the output 
current so that drug delivery is accomplished at a constant or varying 
rate, or over a short, long or periodic time interval. These controllers 
generally require relatively complex electrical circuits, sometimes 
including microprocessors, to meet the above requirements. Conventional 
manually-operated mechanical switches have been used in controllers to 
disconnect the battery from the controller circuitry to prevent battery 
drain during device storage. See, for example, the switch disclosed in 
U.S. Pat. No. 4,808,152 (Sibalis). 
These controllers need to be switched on at the time they are placed on the 
body in order to begin operating. This represents a potential opportunity 
for error in drug delivery because the physician, nurse or patient may not 
remember to turn on the switch, and may also inadvertently turn off the 
switch before completion of the drug delivery cycle. In addition, in the 
case of a defective switch or a switch having poor electrical contact, 
there may be uncertainty concerning whether or not the device is actually 
delivering the therapeutic agent, or can uninterruptibly complete an 
entire drug delivery cycle. 
Moreover, in iontophoretic delivery devices that are switched on prior to 
placement on a patient, electric charge has the opportunity to build up on 
the electrodes. A mild, but discomforting electrical sensation may be felt 
by the patient upon placement of the patch onto the patient's skin from 
the discharge of built-up electric charge. Although not painful, this is 
likely to reduce compliance with a drug treatment program because the 
patient might be afraid to use the device in the future. 
In one iontophoretic device shown in U.S. Pat. No. 5,314,502 (McNichols et 
al.), the device, including activation circuitry and power generating 
circuitry, remains completely turned off until the patch is applied to the 
skin. At that time, the activation circuitry closes and the power 
generating circuitry is turned on, thereby activating the device. Because 
the skin acts as the switch, no conventional mechanical switch is 
required. Other touch-sensitive switches have been disclosed in U.S. Pat. 
No. 4,099,074 (Maeda et al.) and G.B. Patent 1,321,863 (Reichart). 
However, a problem may still exist because the device may be activated 
when in contact with a conductor other than a patient's skin. If the 
device is placed on a conductive surface, the device will be activated 
resulting in the unnecessary waste of the therapeutic drug, and generate 
uncertainty in its ability to deliver the entire drug dosage. Moreover, 
because the circuitry is completely turned off until the patch is applied 
to the skin, the device shown in McNichols et al. cannot perform 
self-testing prior to the application of the patch to the skin. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide an iontophoretic 
delivery device for delivering a drug to a patient that overcome the 
above-described problems. 
Another object of the invention is to provide a controller that is turned 
completely on by the insertion of a drug delivery patch into the 
controller. 
It is still another object of the present invention to provide a 
iontophoretic drug delivery device which does not require the use of 
conventional mechanical switches or touch-sensitive switches. 
In one aspect of the present invention, an iontophoretic drug delivery 
device is provided which includes a controller normally being in an off or 
low power consumption state, and a patch including electrodes, a reservoir 
containing an ionizable drug for transcutaneous delivery to a patient and 
a return reservoir. The patch is removably and electrically connectable to 
the controller, and delivers the drug to patient when the patch is on the 
patient's skin and when the controller is switched from the off or low 
power consumption state to an operational state. This occurs when the 
patch is electrically connected or inserted into the controller. This 
feature preserves the battery of the controller. 
It is yet another object of the present invention is to provide a 
iontophoretic drug delivery device for preventing or reducing the 
potentially uncomfortable electrical sensation felt by a patient upon 
application of a charged patch to the skin of a patient. 
In another aspect of the present invention, the controller periodically 
changes from a non-current delivery state to a current delivery state for 
the predetermined period of time to deliver a pulse of current to the 
inserted patch. A current sensor within the controller measures the 
current delivered to the patch. The controller switches to the non-current 
delivering state if the amount of current drawn is less than a 
predetermined amount, and is therefore off the skin, and switches to the 
current delivering state otherwise. This feature prevents the build up of 
charge on the patch electrodes and the possibility of an uncomfortable 
electrical sensation.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
First Embodiment 
One type of iontophoretic drug delivery device includes a separate, 
reusable controller 2, which can be removably and electrically connected 
to a patch 4 containing the drug, therapeutic agent or medicament, as 
shown in FIG. 1. The patch 4 is attached to the skin of the patient 6. The 
patch includes active electrode 8 and a return electrode 10, with the 
ionic drug gel 12 and active electrode 8 positioned within the active 
reservoir 14, and the saline or electrolyte gel 16 and return electrode 10 
positioned within the return reservoir 20. 
The iontophoretic drug delivery device also includes a controller 2 having 
a power supply 22 and electronic control circuitry 24, as shown in FIG. 2. 
The controller is electrically coupled to the patch 4 using electronic 
interconnectors 26, such as a printed flexible circuit, metal foils, 
wires, tabs or electrically conductive adhesives. The power supply 22 in 
combination with the electrodes 8 and 10 and the patient's body 6 
completes the circuit and generates an electric field across the body 
surface or skin on which the iontophoretic device is applied. The electric 
field causes the drug in the active reservoir 14 to be delivered into the 
body of the patient by iontophoresis. 
Patch 4 is generally a planar flexible member formed of, for example, a 
biocompatible material such as woven or non-woven textiles or polymers, or 
any other construction well-known in the art. The patch is attached to the 
patient's skin using adhesives or a strap or both. The patch includes an 
enlarged patch body 30, which includes the active and return reservoirs. 
The lower surface of the reservoirs are placed in contact with the skin, 
allowing the electrodes to be very close to the skin when the patch is 
mounted on the patient. Generally, a thin layer of the gel in the 
reservoirs will be between the skin and the electrodes. The electrodes are 
positioned so that an electrical current path is established between the 
electrodes 8 and 10 through the reservoirs and the patient's skin 16. 
Electrodes 8 and 10 are placed in conductive contact with reservoirs 12 and 
20, respectively, in a manner well-known in the iontophoretic drug 
delivery art. A direct current source may be connected to the electrodes 8 
and 10 so that the active electrode has the same charge polarity as the 
ionic drug 12. When current is passed through the active electrode 8 to 
the return electrode 10 through the skin 16, the ionic drug 12 contained 
the active reservoir 14 is delivered through the skin 16 and into the 
patient. 
The patch also includes an extending narrow tab 32, as also shown in FIG. 
4, substantially including the electrical connectors 26. The electrical 
connectors 26 may be one or more conductive paths extending from the 
electrodes 8 and 10 to exposed conductive pads 34 positioned on the 
marginal edge of the extended patch tab 32. The pads 34 are positioned for 
electrical connection with the controller when the extending patch tab 32 
is inserted into the controller 2, thereby providing the electrical 
connection between the patch electrodes and the controller. 
The controller housing 2 is generally rectangular or oval in shape, with 
rounded edges, and has an opening 36 in the front end to accommodate the 
inserted patch tab 32. The housing 2 also has a connection array 38 to 
which the electric circuits are electrically connected through electric 
conductors 27, and is preferably mounted with the electric circuits on a 
printed circuit board. The connection array may include plural, spaced 
apart electrical terminals 38a-38d to which the patch tab pads are 
electrically connected. Any suitable electrical interconnection device may 
be employed in accordance with the present invention. Further, it may be 
appreciated that the patch insertion and release mechanisms may take any 
known form, so long as the patch tab is capable of being mechanically and 
electrically connected to and disconnected from the controller. 
The controller 2 may include, but is not limited to, battery 22, 
microprocessor 40, EEPROM 46, a serial communication port 44 and current 
control circuit 42, as shown in FIG. 3. The microprocessor 40 provides 
signals to the current control circuit 42 to ensure that the required 
current is delivered by the current control circuit 42 to the connected 
patch through conductors 27 and 26 to electrodes 8 and 10 so that the 
correct amount of drug is delivered to the patient. The current control 
circuit 42 will produce from the battery 22 the required output current 
irrespective of the varying resistance and/or capacitance of the load 
(including the patient's skin, the impedance of which normally varies from 
patient to patient and which may change as iontophoresis takes place). 
Further, voltage from a sensor, such as a current sense resistor 48, is 
monitored by the current control circuit 42 to ensure that the amount of 
delivered current is constant. The current passing through the current 
sense resistor 48 is the amount of current actually being delivered 
through the iontophoretic patch and skin. If less or more than the 
required current is being delivered as indicated by the current sense 
resistor 48, the current control circuit 42 will adjust the current to the 
required level. 
It would be advantageous to keep the controller circuitry completely turned 
off, or almost completely turned off, until the patch is inserted before 
device is used, so that the battery is not unnecessarily drained. In the 
present invention, the controller circuitry is "awakened", that is, turned 
fully on, not by the manual operation of a conventional mechanical switch 
or touch sensitive switch, but instead by the connection or insertion of 
the patch tab into the controller. 
The controller may be kept completely turned off by (1) connecting one end 
of the battery 22 to one end of the controller circuitry 24, (2) 
connecting the other end of the battery 22 to one of the controller 
electrical terminals 38a, and (3) connecting the other end of the 
controller circuitry to another controller electrical terminal 38b, as 
shown in FIG. 4. Because the controller electrical terminals 38a and 38b 
are unconnected, the circuit is open, and the controller circuitry is 
completely off. 
When the patch is inserted into the controller in slot 36, an electrical 
jumper 37 within the patch electrically connects to each of the patch tab 
pads 34a and 34b, and thus to each of the controller electrical terminals 
38a and 38b. This closes the open circuit and thus connects the battery 22 
to the controller circuitry 24. The controller circuitry, including the 
microprocessor, turns on and is ready to deliver current to the patch. 
Second Embodiment 
Alternatively, the battery may be placed within the controller circuit so 
that the controller circuitry always has electrical power, but is almost 
completely turned off. That is, only a small portion of the controller 
circuitry will draw current from the battery, consuming, for example, on 
the average, only about 10 microamperes or less. In this embodiment, 
because current is being drawn at all times, the battery will drain over 
time. But since such a small amount of current is being drawn, it will 
take a very long time for the battery to drain, thus ensuring a long shelf 
life for the controller. Since the battery is connected to the circuitry 
in this embodiment, self-testing prior to the application of the patch to 
the patient could be performed if desired. 
In this embodiment, the controller contains one or more normally-closed 
switches. For example, the switches may comprise three metal spring 
switches 50a, 50b and 50c normally held against a grounded metal plate 52, 
as shown in FIG. 5. Each switch is respectively connected to one end of a 
pull-up resistor 54a, 54b and 54c and to one input of a two-input 
exclusive OR logic circuit 56a, 56b and 56c. The other end of the resistor 
is connected to signal line 58 from an independent pulse generator or 
clock 49. The other input of the exclusive OR circuits are respectively 
connected to registers 57a, 57b and 57c loaded with a logic "ZERO" value 
by the microprocessor when the microprocessor initially turns on upon 
initial battery insertion (the microprocessor then turns off or goes to 
sleep). Because the switches 50a-50c are normally closed to ground and the 
inputs of the exclusive OR circuits connected to the pull-up resistors are 
also normally at zero voltage, the outputs 59a, 59b and 59c of the 
exclusive OR circuits are all logic ZERO. 
The outputs 59a-59c may be combined in an "OR" circuit (not shown). The 
outputs 59a-59c, or the output of the "OR" circuit, serve as interrupts to 
turn on, or awaken, the microprocessor when any one of the outputs changes 
value from a logic ZERO to a logic ONE. (It will be appreciated that with 
known modifications the logic values "ZERO" and "ONE" may be reversed as 
required, and the above embodiment is not to be limited to any particular 
logic scheme.) 
Normally, the microprocessor is asleep, and because only the independent 
pulse generator 49 draws energy for only a brief interval of time each 
period, very little current will be drawn on the average. In particular, 
the pulse generator 49 generates a pulse on signal line 58 periodically, 
for example, once a second, the pulse itself having a short duration of, 
for example, one microsecond to one millisecond. The pulse is sent to each 
of the pull-up resistors 54a-54c, which are typically each about 1 
kiloohm. If any one of the spring switches 50a-50c are closed, the current 
flows to ground through that switch and thus no pulse is generated at the 
input of the respective exclusive OR circuit. Thus, if all of the spring 
switches are closed when the signal pulse is generated, all the outputs of 
the exclusive OR circuits will be at logic ZERO, and the microprocessor 
will remain asleep since no interrupt was generated. 
In this embodiment, the patch tab 62 is designed to have openings 60a and 
60b positioned so that when the patch tab 62 is slidably inserted into the 
controller, the openings 60 and 60b will be aligned with the area at which 
the switches 50a and 50b contact the metal grounding plate 52. Upon 
insertion into slot 36, the patch will force one or more of these 
normally-closed switches to remain open if there is no hole in the patch 
at the contact area of the switch, because the non-conducting patch tab 62 
will come between the switch and the grounding plate (in this example, 
switch 50c will be forced open). Upon the next pulse being applied to each 
of the pull-up resistors 54a-54c, for the switches that remain closed 
through the patch openings, the input to the exclusive OR circuits will 
still be a logic ZERO, and there will be no change in those exclusive OR 
circuit outputs (in this case, outputs 59a and 59b will remain logic 
ZERO). Thus, those exclusive OR outputs will not cause an interrupt. 
However, for those switch or switches that are now open, a pulse is 
generated at the input of the exclusive OR circuit, causing a pulse, or a 
logic ONE, at the output of those exclusive OR circuits (in this case, 
output 59c will be a logic ONE). This pulse at the exclusive OR output 
will interrupt and awake the microprocessor and enter its normal operating 
state. 
The microprocessor now examines both the exclusive OR outputs (which may be 
latched to preserve the logic ONE or ZERO outputs) and the positions of 
switches 50a-50c to confirm that a patch was actually inserted into the 
controller. If the microprocessor determines that the switch positions are 
opened or closed in accordance with the corresponding exclusive outputs 
59a-59c, the microprocessor concludes that the patch was inserted and 
allows the controller circuitry 24 to turn on. The controller 2 is now 
ready to deliver current to the attached patch 4. 
Otherwise, if there is a mismatch between the switch positions and the 
exclusive OR outputs, for example, the former are all closed while one or 
more of the latter are at logic ONE, the microprocessor determines that 
the patch was not inserted, that the interrupt was a false alarm, and 
returns to sleep. This could occur, for instance, if there was a brief 
opening and closing of one of the switches because of a jarring event, 
such as the controller being dropped, causing an exclusive OR output to 
become a logic ONE upon application of the pulse on signal line 58, thus 
erroneously awakening the microprocessor. In this case, the microprocessor 
and the controller circuitry remain turned off until an actual patch is 
connected. 
Accordingly, in the first and second embodiments, no operation of a 
conventional mechanical switch is required by either medical personnel or 
patients; they only need to insert the patch into the controller to power 
up the iontophoretic device. 
The second embodiment has another feature in that the microprocessor can 
decode the exclusive OR output circuits to determine which of the switches 
were opened by the inserted patch. By arranging the holes in the patch 
into certain patterns, various combinations of switches will be opened by 
the inserted patch. The switch openings are then decoded by the 
microprocessor to determine which patch was inserted. Accordingly, each 
kind of patch can be identified by the controller and this identifying 
information can be used by the microprocessor to determine the proper 
current delivery profile required for that patch. 
For example, in the controller shown in FIG. 5, one of 4 types of patches 
can be decoded according to the opening of the switches 50a and 50b. If 
switches 50a and 50b are both closed, then patch type A has been inserted; 
if switch 50a is open but switch 50b is closed, then patch type B has been 
inserted; if switch 50a is closed but switch 50b is open, then patch type 
C has been inserted, and if both switches 50a and 50b are open, then patch 
type D has been inserted. Of course, it will be appreciated that any 
number of patch types may be accommodated, depending on the number of 
switches used. 
Moreover, the microprocessor can monitor the switch positions or the 
exclusive OR outputs to determine that the patch has been removed. When 
the patch has been removed, the microprocessor and the controller 
circuitry can go asleep again until another patch is inserted and awakens 
them. 
Third Embodiment 
As explained above in the first and second embodiments, the insertion of a 
patch into a controller switches on the controller circuitry 24. 
Generally, current would now be delivered to the patch electrodes. Because 
the patch has not yet been applied to the skin, however, there may be a 
large build up of charge on the patch electrodes. The accumulated charge 
will quickly discharge when the patch is placed near or onto the skin, 
causing an uncomfortable electrical sensation. 
Although not harmful or painful to any great extent, these sensations may 
deter future use of the device by the patient, especially if the patient 
is a young child. Accordingly, elimination of these sensations is greatly 
desired to ensure a comfortable drug delivery. 
To prevent these sensations upon application of the patch to the skin, as 
little charge as possible should be allowed to build up on the patch. This 
is accomplished by keeping the powered-up controller in a non-current 
delivering mode until the patch is on the skin. Only at that time will the 
controller be allowed to deliver the required current to the patch. 
The controller periodically determines whether the patch is applied to the 
skin. Each second, for example, a rectangular-shaped pulse of current is 
delivered to the patch by the controller, as shown in FIG. 6A. The pulse 
has a short duration, for example, between one microsecond to a few 
milliseconds. The current sense resistor 48 measures how much of that 
current pulse was actually delivered to the load, indirectly measuring the 
load impedance. Alternatively, a sensor may measure the voltage across the 
load. 
As shown in FIG. 6B, if substantially no delivered current is measured, 
that is, the measured current is less than a predetermined threshold TH, 
then the load has a very high impedance, which probably means that the 
load is air and the patch is off the skin. The current control circuit is 
thus kept turned off to prevent charge from building up on the patch 
electrodes. 
If, however, the delivered current as measured by the current sense 
resistor crosses the predetermined threshold, as shown in FIG. 6C, then 
this load has a relatively low impedance compared to that of air, meaning 
that the patch may be on the skin. The current control circuit can now be 
turned on to begin current delivery. 
Because the presence of delivered current above the predetermined threshold 
may also result from a short-circuit, it is preferable to take additional 
samples to determine whether the patch is on skin or not. These samples 
may be longer in duration and/or occur more frequently. Moreover, if the 
current (or voltage) pulse measured by the current sense resistor has a 
time-decaying signature typical of skin, as shown in FIG. 6C, it is more 
likely than not that the patch is on skin, because if it was a 
short-circuit, the measured pulse would have substantially the same 
rectangular shape as the delivered pulse of FIG. 6A. 
Accordingly, since the current control circuit is kept turned off most of 
the time, very little charge will build up on the electrodes, and the 
possibility of an electrical sensation being felt by the patient is 
greatly reduced. Moreover, even in the unlikely event that enough charge 
has built up on the electrodes so that a discharge might occur, the 
sensation is likely to be so weak as to be unnoticeable by the patient. 
Of course, it will be appreciated that the invention may take forms other 
than those specifically described, and the scope of the invention is to be 
determined solely by the following claims.