Note: Descriptions are shown in the official language in which they were submitted.
36698 PCT
IOM~OPHORE5IS DRUG DELIVE~Y SYSTE~
INTRODUCTION
This invention relates to drug delivery systems
and, more particularly, to systems wh~ch deliver
medications using iontophoresis techniques.
BACKGROUND OF THE INVENTION
Iontophoresis can be defined as the application of
drugs or medications in their ionic forms to the
~urface of tissues, e.g. to the surface of the skin.
An electric current of relatively low amplitude level,
as obtained from a voltage having a selected polarity
which is opposite to the polarity of charge of the
drug ions, is passed through the drug and the body
area of the patient into which the drug is to be
introduced thereby driving the oppositely charged drug
ions transdermally through the skin tissue
In applying such technique to a patient, an
electrode which contains the medication to be
introduced is normally positioned over the region of
the body which is to be treated and a second
electrode, which normally contains a conductive gel,
but no medication, i~ placed at the region of the
patient's body opposite thereto so as to form an
electric circuit with the current source for the
system. Application of a current producing voltage
across the electrodes provides a desired operating
current for causing the ionized molecules of the
medication to be transported transdermally into the
body portion where the medication can produce its
therapeutic effects.
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While iontophoresis as a method of administering
drugs has been known for many years, little efective
use has been made of the technique because the systems
purporting to utilize such methods have been too
cumbersome, inefficient, and/or c05tly to find a ready
market for them. Moreover, such systems do not permit
effective control of the drug d.e:Livery rate or provide
any effective safety control :~or the current level
which is used. Further, there tends to be a resistant
to the use thereof by some patients who may experience
traumatic effects from the actual or anticipated use
thereof. .
It is desira~le that an effective system be
devised in which the application of the drug dose and
the rate at which such dosage is applied can be readily
controlled and in which the probability of hiyh patient
drug compliance is increased. Such a system should be
one designed so as to provide the desired operation at
a reasonable cost and one which can be easily used by a
doctor, nurse, or even the patient himself or herself,
without fear of harm, of making a mistake, or of
causing the system to become inoperative.
BRIEF SUMMARY OF THE INVENTION
In accordance with one aspect of the invention
there is provided a transdermal medication delivery
system comprising means for retaining a medication in a
form such that it is capable of being electrically
charged, means for identifying the medication in said
medication retaining means, means for supplying a d-c
electrical current through said medication retaining
means at a selected body location of a patient to be
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treated when said medication is in its electrically
charged form, said medication retaining means and said
body location forming an electrical current path for
causing said medication to be delivered from said
medication retaining means to said body location
transdermally when said electrical current is so
supplied, current control means for controlling the
level of said electrical current in said current path,
said control means, said medication retaining means,
said ~ody location, and said electrical current
supplying means forming a closed loop during operation
whereby said current is supplied in a controlled manner
such that said current is generally maintained at a
substantially constant level while said medication is
being transdermally delivered to said body location and
whereby said delivery can be terminated if said current
level exceeds a selected maximum allowable level, and
said control means further includes time control means
responsive to said medication identifying means and to
the substantially constant level of said electrical
current for determining the treatment time over which
said medication is to be delivered and for
automatically terminating the delivery of said
medication at the expiration of said treatment time.
In accordance with another aspect of the invention
there is provided a medication electrode for use in an
iontophoresis medication delivery system for treating a
selected body location by applying a current through
said body location and said electrode in order to
introduce said medication into said selected body
location transdermally, said electrode comprising a
membrane layer formed of a matrix of a hydrophilic
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material containing non-ionized molecules of said
medication distributed throughout said matrix, a layer
of conductive material adhered to one said of said
membrane layer, a portion of said conductive material
being formed as a contact portion for connection to a
source of current, and adhesive material placed on
selected regions of the other side of said membrane
layer for permitting said electrode to be adhered to
the skin surface at said selected body location.
A system in accordance with the invention uses a
microprocessor having appropriate memory components,
programmable d-c power supply, means for sensing the
current level of pulses supplied therefrom, and
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suitable D/A and A/D interface units for providing a
closed loop control ~ystem during operation to control
the level of the current pul~e~ automatically at a
level celected as best for the patient to whom a
medication i~ to be delivered. The sy~tem is
controlled so that delivery can be terminated prior to
completion if the current level exceeds a
predetermined maximum allowable level.
The medication is supplied via an electrode in
which molecules of the medication in a non-charged
state are interspersed throughout a porous or
non-porous membrane. Just prior to delivery the
membrane is suitable moistened so as to cause such
non-charged molecules to be charged.
DESCRIPTION OF THE INVENTION
The invention can be described in more detail with
the help of the accompanying drawings wherein
FIG. 1 shows a block diagram of a system
representing an embodiment of the invention;
FIG. 2 shows a flow chart depicting the operation
of the embodiment of FIG. l;
FIG. 3 shows a perspective view of an embodiment
of the invention; and
FIG. 4, 4A, and 4B show various views o~ a
particular embodiment of a medication electrode that
can be used in the system of FIGS. 1 and 3.
FIG. 1 6hows a block diagram of an embodiment of a
system utilizing the techniques of the invention. The
system generally comprises three major components,
namely, a microprocessor unit 10, an analog/digital
interface unit 11, and a programmable power ~ource
12. The power source 12 supplies a voltage across the
load 13 so as to produce a current I through the
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load. The load as shown therein ~f~e~tiYely
represents the body portion of the patient through
which the current flows and the appropriate
electrodes, as discussed below, which are attached
thereto. The value of the current i~ monitored by a
suitable current sensing, or monitoring, resistor in
the power source unit 12, using well known techniques,
the value of the monitored current IR through the
resistor being continually supplied to the
microprocessor unit 10 through the analog-to-digital
(A/D) converter unit llA of an interface unit 11 for
appropriate processing, as discussed below. Digital
command signals C are supplied via a digital-to-analog
(D/A) converter unit llB of interface unit 11 to
provide analog signal commands for controlling the
voltage and, hence, the current output from
programmable power source 12.
The microprocessor unit also responds to an
appropriate card reader 16 which is used to identify
the particular medication which is to be applied to
the patient. Card reader 16 supplies, as by means of
a bar code on a medication card inserted therein, for
example, a coded identification of the medication to
the microprocessor unit, a~ discussed below. A
suitable memory system can include ROM and/or RAM
memory units, for example, which memory system i~ used
to store predetermined information which is required
with respect to a large variety of different
medications so that the microprocessor can perform the
~eces~ary processing for determining the required
treatment times for them. Memory 15 is also used to
store one or more application programs which can be
appropriately loaded into the microprocessor unit 1~
for use thereby. ~he microprocessor unit 10 further
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provides appropriate output signal6 which can be used
to control the programmable power source 12, or to
display information during treatment, for example,
concerning the status of the system on a suitable
display system 17. Microprocessor 10 can also supply
an output signal for use in actuating a suitable alarm
system 18, as discussed below.
The microprocessor unit can be implemented by
using any suitably selected microprocessor available
h to the art, such as the Intel ~odel 8048 microcomputer
available from Intel Corporation of Sunnyvale,
California, the treatment program microcode being
supplied, ~or example, to the microprocessor as ROM
microcode stored in the processor memory system 15.
~ he programmable power source 12 re6ponds to a
command received from the microprocessor, via D/A
converter llB, for providing voltage output pulses of
a desired DC voltage which can be selected within a
range from 0 to +150 volts DC, for exampl6, at a
selected pulse repetition rate or frequency, e.g. a
frequency within a range from about 2 KHz to about 50
KHz, and preferably at 50 KHz to avoid interference
with other equipment which may be in the vicinity. A
current sensing resistor (not shown) in power source
12 has a known resistance value, the monitored voltage
VR across such known resistance being interpreted by
the analog/digital interface unit to produce a digital
value IR representing the current through the load
13.
The microprocessor unit is suitably arranged to
fetch the desired treatment program from the memory 15
when treatment is to be initiated. The value of the
current during treatment can be displayed on the
display unit 17 so that the operator of the device can
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visually moni~or the curren~ level as the system is
performing it~ treatment operation.
In accordance therewith, a~ described with
reference to the flow chart of FIG. 2, when the power
is turned on all the registers of the microprocessor
are set to zero and the display unit di6plays the
instruction ~'Enter ~reatment Card.~ The user enters a
treatment card into a conventional card reader 16,
e.g. one which reads a bar code on the card. When the
bar code has been read correctly the microprocessor
responds thereto 60 as to identify the medication to
be administered and to display the name of the
medication 80 identified.
Once the medication ha~ been identified the us~r
i~ instructed to test the patient for sensitivity to
the current level which is to be used (at this time
the patient has been connected to the system via
appropriate electrodes as discussed below). The
sen~itivity test is performed by a sub-routine program
in which pulses of voltage are supplied from
programmable power source 12 80 as to produce pulses
of current through the load 13 which includes the body
portion of the patient to which the medication ls to
be administered and the electrodes at either side
thereof. Such current pulses are supplied at a
suitable selected frequency, e.g. preferably 50 Hz as
discussed abov~. The amplitude level of such current
pulses is increased in discrete steps at selected
intervals from a relatively low level, e.g. at 0~1
milliamperes (mA.), through incremental steps of 0.1
mA. each until the patient indicates to the operator
that he or she begins to feel a perceived sensation,
e.g., a tingling type of sensation, at which point the
operator can abort the test and note the value of the
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current at such maximum level which can be referred to
as Im. The level of perceived ~ensation is ~et
automatically as the operating current level,
identified as Io, ~o a value such that the current
level which is to be used during treatment to supply
the particular medication to the patient i8 equal to
the maximum current value, Im, less a selected fixed
current value. Thus, the operating current level for
drug delivery is at a value just below the current
level at which the patient has first perceived a
sensation. For example, in a particular embodiment
the constant current level for drug delivery during
treatment may be ~et at a value which is 0.2 mA below
the maximum current level which has been indicated by
the patient's response (i.e., Io = Im - 0.2). The
value of the operating current level is then
appropriately stored for use by the microprocessor in
controlling the dosage for the medication in
accordance with the treatment program.
When the operating current level has been set, the
microprocessor displays an indication to the user that
the system i6 ready for treatment. Based on the value
of the constant operating current level (Im - 0.2) mA
which has been selected for use and based on the
identification of the drug, the microprocessor
determines the time of treatment for the particular
drug involved, using preset treatment time and current
values for each expected medication, which values have
been previously stored in the memory 15 associated
with the microprocessor.
When the operator pushes a start switch to begin
treatment, the microprocessor performs tests to
determine if the start switch is closed and to
determine if there i5 electrical continuity through
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the power ~ource circuitry and the load. If both
conditions are satisfied the treatment begins. If
continuity 15 not present the power is shut oPf and
the operator i~ given the opportunity to check the
circuitry and electrical connections involved and to
make a determination as to whether treatment should or
should not be continued, a suitable display legend
(Continue or Abort?) being displayad on display unit
17 for such purpose. If treatment is to continue, the
user turns on the power and the above tests are
performed again. In accordance therewith the
microprocessor then causes the programmable power
source to supply pulses of voltage, at the desired 50
KHz frequency, so as to produce current pulses through
to the load, the amplitude levels of the current
pulses through the load being increased in incremental
steps, as before, until the amplitude of the current
reaches the operating current level Io. The
programmable power source then maintains the voltage
at such constant operating current level so as to
cause the desired current to be applied through the
load to deliver the drug transdermally to the patient.
The monitoring resistor in power source 12
continually monitors the value of the current level
and supplied such value to the microprocessor via D/A
converter llA. The overall system thereby forms a
closed loop whlch is used for maintaining the
amplitude of the current at the desired level. For
example, if such current level exceeds (Im -0.2) m~.
The microprocessor commands the programmable power
source to reduce the voltage amplitude of the pulses
until such current level is reached while, conversely,
if the current level drops below (Im -0.2) mA, the
microprocessor commands the power source to increase
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the voltage amplitude until ~uch current level is
reached.
As a safety feature, if the monitored current
level, for whatever reason, increases to a ~electad
value above the desired operating current level, for
example, to a value which is twice the operating
current level desired, i.e. 2 Io mA. (referred to as
the maximum allowable level), the microprocessor
automatically Rhuts off the ~yBtem 80 as to avoid any
tissue damage or pain which might result from the use
of an excessive current through the patient.
So long as the current level is maintained
substantially at the desired operating level Io, the
medication is delivered to the patient over a time
period which is equal to the previously calculated
time of treatment. The treatment time is displayed on
the display unit, such time display being continually
decreased as treatment proceeds so as to inform the
user of the time remaining for treatment. Such
process can be implemented, for example, by the use of
suitable and well known count-down circuitry (not
shown) which is activated when the dxug delivery
operation begins and counts down to zero by the end of
the treatment time. When the time left is zero, the
display screen indicates that the treatment has been
completed and the microprocessor provides a signal to
an alarm unit which then appropriately signals that
the treatment has been completed, using either a
visual and/or an audible alarm device. The user must
then 6hut off the alarm.
The flow chart of such a treatment program as
shown in FIG. 2 can be implemented by the
microprocessor unit as described above. Uæing such
flow chaxt, those having skill in the art can readily
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program any ~uitable microprocessor main program and
any required sub-routine program~ in order to perform
the deslred operation of the system as described.
A physical representation of an exemplary system
em~odying the above described invention i~ shown ln
FIG. 3. As can be seen therein, a plurality of
medication packages 20 each has imprinted thereon a
bar cod~ 21 which identifies the particular medication
that i~ so packaged therein. The portion of th~
package bearing the bar code can be inserted into an
appropriate bar code reader unit 22 within a housing
23 for reading the bar code and supplying the
information which has been read to a microprocessing
system which is also housed in housing unit 23 and
which includes a microprocessor board and an
appropriate memory board, or boards, as needed, as
well as suitable control switches 24 as required to
operate the microprocessing syst2m. Housing 23 also
includes appropriatc connector terminals 25 for
connection via cables 27 to various types of
electrodes 26 containing the desired medication, as
well as for connection to a suitable ground plane
electrode 28. The electrodes are encased in the
medication packages 20 so that when the bar code has
been read, the electrode containing the desired drug
can be removed therefrom and attached via snap clip 34
to one of the cables 27 for use by the system. The
drug containing el~ctrode can be of various ~hapes
which can be clipped to a cable connector, as
depicted, or it can be a specially designed electrode
permanently connected to a cable as shswn by electrode
26A, for example.
Housing unit 23 can also include a display unit 29
which may be in the form of a well known liquid
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crystal display, for example, for displaying
alpha-numeric information as supplied to it by the
microprocessor. Housing unit 23 al~o includes the
programmable power source 12 (not shown) which
supplied the current to the electrodes and the A/D and
D/A converter/interface circuitry (not shown)
discussed above with reference to FIG. 1. Such
components would be well known and readily available
to those in the art.
A particular embodiment of a suitable and novel
electrode for use in the system of FIGS. 1 and 3 is
depicted as electrode 30 shown in FIGS. 4, 4A and 4B.
The structure thereof comprises a medication layer 31
and an upper conductive foil layer 32 having a contact
tab 33 for contacting a snap clip 34 at the end of a
cable 27 such as shown in FIG. 3.
A layer 35 of adhesive material is positioned
around the periphery of layer 31 as shown in FIG. 4A.
A removable strip 36 is placed over the bottom surface
of the electrode 30, which layer when removed exposes
the lower surfaces of the adhesive layer 35 and the
medication layer 31 which are then positioned against
the skin of the body location to be treated for
adherence thereto. FIG. 4B shows diagramatically a
portion of the microstructure of medication layer 31
which comprises a hydrophilic membrane 37 which has
interspersed throughout its interior non-ionized
molecules 38 of a medication which is to be delivered
to the selected body location. Membrane 37 may in
some applications be formed as a relatively porous
membrane (as shown in FIG. 4B) to assist the migration
of the drug molecules therethrough. However, it need
not be porous in nature and for some medications such
migration will readily occur even if the porosity is
relatively low or substantially non-existent. For
example, a ~ypical non-~orous membrane can be
fabricated from a polyurethane material, one such
material being made and sold under the model
descrip~ion Ticoflex* by Thermedics, Inc. of Woburn,
Massachusetts for retaining a medication such as
tetracyclene, for example. A typical porous membrane
can be fabricated from a hydrophilic prepolymer
polyurethane, one such material being made and sold
under the model designation Hypol* 2002 by W. R.
Grace, Co. of Lexington, Massachusetts for retaining
a medication such as morphine, for example. Such
materials are ready available to the art.
Ground electrode 28 in FIG. 3 is of the type,
for example, made and sold by Minnesota Mining and
Manufacturing Co. of Minneapolis, Minnesota under the
Trade Mark "Red Devil" and is also adhered to the
patients' skin at the surface of the body location
opposite to that of the medication electrode by the
use of a suitable conductive adhesive normally with
the use of a conductive gel, as would be well known
in the art.
When the system is ready for delivery of the
medication, the exposed lower surface of the
electrode is moistened as by applying a few drops of
water thereto. Since the membrane is hydrophilic,
the water is quickly absorbed throughout the membrane
and converts the non-ionized molecules of the
medication therein to ionized form having a
particular predetermined polarity of charge depending
on the nature of the medication involved.
The desired current level through the load is
produced by power source 12 from a voltage across the
load which is selected to have a polarity opposite to
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that of the polarity of the charged ions of the
particular medication being used. Such polarity is
determined by the microproce6sor using pre-stored
information in memory 15 concerning the particular
medication in ~uestion. The molecular ions migrate
through membrane 37 and thence outwardly therefrom
into and through the skin of the patient as required.
The system described above can be u~ed for many
types of medication treatments and with the help of
certain sensed information, as provided by sensor
input from a variety of different sensing elements,
shown broadly as block 19 in FIG. 1, many advantageous
results can be achieved.
For example, in many treatments currently used, a
patient is provided with a medication, e.g~ a tablet,
a capsule, or other form of medication, which must be
ingested systemically a selected periodicity e.g. one
or more times daily. Such an approach, in order to be
effective, normally requires the dosage level to be
higher than necessary so as to assure that a
sufficient amount of the medication reaches the
location at which its therapeutic effect occurs, there
being a 10BS of medication effect as it works its way
through the patient' 8 system to the desired location.
Moreover, in some cases a patient' 9 need for the
medication varies and a more effective use thereof
would be to apply the medication only when the
patient's metabolic response indicates that medlcation
is required rather than to have the patient take the
medication on a constant periodic basis.
For example, patients suffering from hypertension
may need m,edication only when the patient's blood
pres~ure level is above specified limits. It has been
found that terhniques of photopleythamography using a
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light emitting diode (LED) element a~d a light
responsive sensor (photodiode) ~an provide a
determination of blood pressure levels. Hence a
LED/photodiode ~ensor system mounted adjacent a
patient~ skin can provide a sensed output which can
be supplied to the microprocessor 10 which in turn can
use a known algorithym to compute a sensed blood
pressure l~vel. The microprocessor can be arranged to
start treatment of a hypertension medication only when
the sensed blood pressure level exceeds a known
specified limit. Hence, the patient only receive~ the
medication when he or she needs it and receives it
transdermally rather than systematically at the
desired location. Accordingly, less medication (lower
dosages at lower intervals) is used by the patient and
side effects of the medication are reduced.
As a further example, diabetic patients who are
being treated with insulin may be subject to
hypoglycemia shock (due to an excessively low blood
sugar level). It i8 known that if the temperature and
electrical conductivity of a patient'~ skin are
determined and if the oxygen content of the patient's
blood is determined, a known algorithym can be used to
determine the patient's blood sugar content. Such
metabolic response can be determined using inputs from
appropriate sensors 80 that microprocessor 10 using
such a known algorithym can determine when a patient's
blood sugar content drops below a selected level so as
to then stop the insulin treatment transdermally.
Accordingly, the system of the invention can be used
to control the insulin dosage to apply it only when
needed, and to do 80 non-invasively as the patient's
metabolic responss it continually monitored.
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~ he application of pain killing drugs can also be
suitably monitored so a~ to avoid respiratory failure
which may occur if an excessive dosage thereof is
given to the patient, thus the patient's heart beat
rate can be monitored, as by using well known
capacitive sensors for monitoring pulse rates, and
supplied to the microprocessor so that if such rate
exceeds a selected level during the delivery of a pain
killing medication, such delivery can be stopped to
avoid drug overdose and the possibility of respiratory
arrest. Moreover, the microprocessor can also be
arranged 80 that the delivery of a pain killing
medication can be activated by the patient himself or
herself (as by pushing a start button). The
microprocessor can be further programmed so that the
patient cannot start a subsequent delivery until a
selected time period has elapsed from a previous
delivery in order to avoid an excessive dosage.
~urther, the microprocesor can be programmed so that
when a patient is in an extremely painful state, the
current level used for delivery can be set to an
oparating level initially which is much higher than
would normally be used (e.g. 2 Io) so that a bolus of
the medication can be delivered immediately. The
current is then subsequently set at a much lower level
than the normal operating level so that the remainder
of the medication is delivered at a much lower dosage
rate thereafter. Thus, a more immediate therapeutic
effect is achieved for a patient in pain distress.
Other programs for monitoring and controlling a
dosage delivery rate as well as for triggering or
aborting drug delivery can be devised by those in the
art using the system and method of the invention for
many other applications.
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While the particular embodimant of the invention
described above repre6ents a preferred embodiment at
thi~ time, modification~ thereof will occur to those
in the art within the spirit and scope of the
invention. Hence, the invention is not to be
construed as limited to the specific embodiment
described, except as defined by the appended clauses.
