Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2~~fl~~~~
ELECTRICAL TRANSDERMAL DRUG APPLICATOR WITH
COUNTERACTOR AND METHOD OF DRUG DELIVERY
_BACKGROUND OF THE INVENTION
This invention relates generally to an electrical
transdermal drug device delivering a drug to the patient for
systemic distribution by blood flow using principles of
electrokinetic phenomena, such as electrophoresis and
electroosmosis, and more particularly to an electrical
transdermal drug applicator delivering counteracting substances
locally to the patient's skin and/or electrically inducing the
skin to produce endogenous compounds which extend the period of
therapeutic drug delivery and thereby increase usefulness of the
drug applicator. Reference to or disclosure of devices for
transdermal delivery of drugs by application of electrical
current through the skin of a person or animal are shown in the
following United States patents:
385,556 4,243,052
486,902 4,325,367
588,479 4,367,745
2,493,155 4,419,019
2,267,162 4,474,570
2,784,715 4,406,658
3,163,166 4,314,554
3,289,671
4,166,457
3,547,107 4,239,052
3,677,268 4,290,878
4,008,721 4,164,226
4,141,359 4,362,645
4,239,046 4,273,135
The following foreign patents refer to ar disclose
transdermal drug delivery devices:
EPA No. 0060452
DE No. 290202183
DE No. 3225748
EPA No. 0058920
UK No. 2104388
Thus, it is evident, that transdermal delivery of drugs by
application of an electrical current is not unknown. Yet, except
for experimental and developmental purposes, such electrical
transdermal drug applicators are not presently commercially
available for use by medical professionals or by individuals.
A problem with transdermal patches, especially electrically
powered patches, is that such devices ex.:~ibit a rate of drug
delivery which decays with passage of time despite a steady state
condition for the applied electrical current and steady state
drug concentrations within the drug reservoir of the device.
This phenomenon has been reported in scientific journals, for
example, an article, IN VIVO TRANSDERMAL DELIVERY OF INSULIN,
Chien et al Annals of New York~Academ of Sciences
y . pages 38-47
(1987).
Therein, changes in blood glucose level are recorded versus
time after insulin is delivered transdermally to laboratory
animals, using an electrical current. Several parameters are
varied. For example, it is reported that a pulsed DC current has
a greater and more enduring effect in reducing-: blood glucose
levels in laboratory animals,~than does a pure continuous DC
2
20fi0~~ t~
current. The actual quantity of insulin, which is delivered, is
not measured. Rather, the effect of the drug in reducing blood
glucose levels is measured. It is found that one repetition rate
of DC pulses is more effective than another pulse repetition rate
in reducing blood glucose levels measured both in magnitude and
time duration. A square waveform provided better results than
did a sinusoidal waveform or a trapezoidal waveform.
The authors of the paper analogize the skin electrically
with resistances and capacitance in parallel as an equivalent
circuit. They theorize that the DC current charges the
capacitance of the skin which, once charged, can accept no more
current and accordingly limits drug delivery. Using DC pulses
rather than steady state current allows time for the skin
capacitance to discharge, such that on the next pulse, additional
current, capacitor charging, and drug delivery can occur.
However, an anomalous situation arises when at a favorable
pulse repetition rate, and with the same current delivery level
as in prior tests, the duty cycle is varied: It would be
expected that the greater the duty cycle, that is, the greater
the current ON time versus the current OFF time ratio, the
greater amount of insulin would be delivered transdermally and
the measured effects on blood glucose level would be
correspondingly more favorable and more enduring. Contrary to
expectations, as the duty cycle increases from a one-to-one ratio
toward an eight-to-one ratio, the reduction in~'blood
[ glucose
3
2~~~~~
level becomes less, rather than more, although duration of this
reduction is somewhat extended.
In summary, application of current over a longer period of
time, that is, consumption of more energy for delivering drugs
transdermally, results in what appears to be less delivery of
drug as measured by the effect on blood glucose level.
That publication graphically illustrates the problem with
prior art transdermal drug applicators and delivery methods using
electrical current to carry drugs through the skin, that is, the
effectiveness of the delivered drug is insufficient in duration
of effect and the rate of drug delivery falls off as the
delivering current is continuously applied over extended periods
of time.
What is needed is an electrical transdernaal drug applicator
and method which provide enhanced drug delivery to the patient
with regard to quantity of systemically delivered drug and
duration of drug effectiveness.
SUMMARY OF THE INVENTION
Generally speaking, in accordance with the invention, an
electrical transdermal drug applicator having enhanced drug flow
to the bloodstream of the subject is provided. The applicator,
in addition to delivering a primary drug into. a subject s
circulatory system for therapeutic purposes, delivers from a
4
reservoir a non-therapeutic counteracting agent to the skin of
the patient which induces flow enhancement and allows delivery of
the primary drug systemically over a longer period of time and in
greater quantity than heretofore appeared possible using electric
current. Construction of the electrical transdermal drug
applicator with electrochemical flow enhancement by introduction
of a counteracting agent to the skin and/or specific electrical
wave shapes is based on applicant's appraisal of known phenomena
as described above.
However, charging of skin capacitance is not considered to
be the primary factor in reducing drug delivery capability as
current application time and magnitude of current are increased.
The efficiency of administration of insulin may be partially
vitiated by adsorption and degradation within the skin tissues or
by restricted blood circulation in the skin. The passage of
current and/or dissociated water ions and/or certain drugs
through the human skin causes a series of events related to
reduction in magnitude of negative net surface charge exhibited
by living mammalian cells. A, most important consequence of
reduction in magnitude of the negative charge on the cells is
triggering of an avalanche-like coagulation process which forms
thrombi, that is, blood clotting, which in turn stops blood flow
through capillaries. Passage of current from a transdermal
applicator tends to reduce the negative charge on cells of the
skin proximate the applicator reservoir, where drugs- are
delivered, causing blood clotting in the capillaries which not
~~~~~v~
only stops local blood flow, but also stops drug flow into the
circulatory system of the subject. A drug transdermally
delivered locally is not effective systemically when the
capillaries of the skin contain coagulated blood.
In addition, especially in the anodic (+) region of current
delivery through the skin, an immediate contraction of small
blood vessels, especially arteries, takes place causing a
complete interruption of blood flow to said vessels. Thus, as
with blood clotting, contraction of the small blood vessels
prevents drugs delivered through the skin by the transdermal
applicator from being delivered into the circulatory system.
Electroosmosis, which is an important factor in delivery of
drugs from the applicator reservoir through the skin and into the
blood circulation system, is affected by the existence of fixed
negative charges on the cellular walls within the skin. A
reduction of such net negative charge, as caused by passage of
even small electric currents or of the water ions through the
skin, inhibits electroosmosis.
Blood clotting, blood vessel contraction, and reduced
electroosmotic effects, as described above, can combine
synergistically to slow down or completely stop system
transdermal delivery of primary drugs, especially from
electrically powered transdermal applicators. This occurs even
when the drug is successfully transferred from the applicator
through the skin into the local skin tissue.
6
To counteract the current or drug induced loss of negative
charge on the cellular walls within the skin, the electrical
transdermal drug applicator with electrochemical flow
enhancement, in accordance with the invention, delivers into the
skin, in addition to the primary drug having therapeutic purpose,
counteractive substances known to increase the negative charge on
cell surfaces.
A negative charge on cell surfaces is generally accepted as
a fundamental factor in preventing the clotting of blood on that
surface. Negative charge (Coulombic repulsion) is also
considered to be part of the mechanism for the coagulation of
platelets. Additionally, overcoming negative charge is also
believed to be a crucial aspect of fibrin formation, part of the
avalanche of reactions in the clotting of blood (thrombosis).
Without being bound by theory, for the reasons given above, it is
known at a minimum, that providing a negative charge on natural
or artificial surfaces in contact with animal blood helps prevent
clotting or thrombosis.
One may add to the negative charge on a cell surface by
reaction with or adsorption of anionic moieties compatible with
animal cells such as salicylates, nitrates, methylcarboxylates,
sulfonates, chlorosulfonates, phosphonates, gluconates, maleates,
citrates, phthalates, or sulfates. These moieties bonded to or
adsorbed on a cell surface inhibit adherence of animal blood,
maintain the fluidity of animal blood, and help prevent clotting
of blood in motion.
7
Specific drugs known as anticoagulants, antiplatelets, or
antifibrotics also are negatively charged and are illustrated in
the Table. Among these are heparin (a mixture containing
mucosaccharide sulfonates), salicylates, protamine sulfate,
potassium aminobenzoate, and nitroprusside - a source of sodium
nitrate. Not only are these substances direct action drugs, they
are also agents for increasing the negative charge on cell
surfaces and artificial surfaces in contact with animal blood.
The chemicals may be chemically bonded to, adsorbed to, or
absorbed in the surface. .
Another class of entities for increasing the negative charge
on cell surfaces or acting to inhibit either platelet formation
or coagulation of animal blood are natural substances produced by
the metabolism of the animal or man. Among these natural
biochemical factors are: prostacyclin, thrombomodulin, Ecto-
ADPase, urokinase, tissue plasminogin activators (TPA),
streptokinase, antithrombin III, protein C, protein S,
prostaglandins I2 and El, sulfated glycosaminoglycans, N-
acetylcysteine with nitroglycerin, nicoumalone, phosphatidyl
inositol, hydrophilic gangiioside GM-1, cyclic GMP,
S-nitrothiols, dodecapeptide gamma F1B, 400-411, and guanosine
31,51-monophosphate, their metabolic precursors and reaction
products.
Additional natural vasodilators are kinins and histamines.
Such substances, if included in the reservoir of the
transdermal drug delivery applicator, move through the skin and
8
react with the cells at the same time that the primary
therapeutic drug is delivered through the skin. By maintaining a
more negative condition of charge on cell surfaces, blockage of
flow through local blood vessels is reduced or prevented,
allowing drugs delivered transdermally to be further delivered
into the systemic flow. Generally, the counteractive substance
has no therapeutic value, although in special instances a
substance may serve a dual purpose.
Maintaining a more negative condition of charge on cell
surfaces could be achieved simultaneously and/or alternatively by
precharging the cell surface with a negative charge prior to
electroosmo~ic drug delivery in cases where such delivery takes
place from the positive drug reservoir. The precharging and the
discharging voltage levels are monitored and maintained within
preset limits by electronic means.
In situations where one polarity of voltage delivers the
primary drug and the opposite polarity delivers the counteractive
substance, arrangements can be made for simultaneous delivery of
both substances, or alternatively, alternating delivery can be
provided.
To prevent formation of thrombi of platelets, that is, blood
coagulation, adjacent the applicator/skin interface,
antithrombotic agents are delivered from the applicator
reservoir, either as a preconditioner or during drug delivery or
alternately. Such counteractive substances would include, for
example, heparin or aspirin. To counteract contraction or
9
i
constriction of blood vessels adjacent the applicator interface,
vasodilators can be used in the reservoir. Nitroglycerin is one
such dilator. Alternatively or concomitantly, specific
electrical pulses, such as square wave pulses of ~.4 ms and a
frequency of 80 Hz at an intensity which could produce a tingling
sensation may be used for repetitive periods of up to two hours a
day to maintain vasodilation.
Accordingly, it is an object of the invention to provide an
improved transdermal drug applicator and method which provide
enhancement of drug flow into the system of the subject by means
of delivery of counteractive agents.
Another object of the invention is to provide an improved .
transdermal drug applicator and method which provide, in addition
to the primary therapeutic drug, a counteractor which works to
make local cell charges relatively more negative.
Yet another object of the invention is to provide an
improved transdermal drug applicator and method which enhance
flow of primary therapeutic drug through the skin by addition of
a vasodilator in the applicator reservoir.
A further object of the invention is to provide an improved
transdermal drug applicator and method which provide an
anticoagulant in the primary drug reservoir for delivery with the
primary drug into the skin of the user.
Another object of the invention is to provide an improved
transdert~al drug applicator and method which captures mobile ions
such as H+ and OH" and thereby prevents such ions from reaching
7.0
the skin tissues and causing production of thrombi, vaso-
constriction arid extreme changes of the cellular negative charge.
A still further object of the invention is to provide an
improved transdermal drug applicator and method for the
stimulation and systemic release of endogenous substances which
have a natural therapeutic effect.
Still other objects and advantages of the invention will in
part be obvious and will in part be apparent from the
specification.
The invention accordingly comprises the several steps and
the relation of one or more of such steps with respect to each of
the others, and the apparatus embodying features of construction,
combinations of elements and arrangement of parts which are
adapted to effect such steps, all as exemplified in the following
detailed disclosure, and the scope of the invention will be
indicated in the claims.
ERIEF DESCRIPTION OF THE DRAWINGS
For a fuller understanding of the invention, reference is
had to the following description taken in connection with the
accompanying drawings, in which:
Figure 1 is a cross-section of human skin showing pathways
for transdermal drug delivery in accordance with the invention.
11
' 2~~~~~~
Figure 2 is an electrical transdermal drug applicator in
accordance with the invention including a single reservoir
holding both a.primary drug and a counteractor.
Figure 3 is an electrical transdermal drug applicator in
accordance with the invention including a parallel arrangement of
reservoirs; one holding a primary drug; the others holding a
counteractor.
Figure 4 is an electrical transdermal drug applicator in
accordance with the invention including two reservoirs
electrically in series.
Figures 5-8 illustrate alternative arrangements of
reservoirs and circuitry in accordance w~.th the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
With reference to the Figure 2, an electrical transdermal
drug applicator 10 in accordance with the invention includes a
reservoir 12 containing a primary drug 14 and a counteractor 16,
both being dispersed in a suspension, for example, a gel 18 as
disclosed in any of the above-referenced patents by the inventor
here (as examples). A surface 20 of the reservoir 12 rests
against the surface 22, of the user's skin 23 and is maintained in
position, Eor example, by an adhesive (not shown). An electrode
24 connects to another surface 26 of the reservoir 12 and this in
turn is connected to a DC source 28 by way of-:an electrical
current conditioner 30. and a single pole switch 32. The other
12
rw 2~~~~~4
terminal of the DC source 28 connects to the skin surface 22 by
way of a return electrode 36 which directly contacts the skin and
is maintained in position, for example, by an adhesive (not
shown). A single pole switch 34 is intermediate the electrode 36
and the DC source 28.
As discussed more fully hereinafter, the counteractor 16
acts locally on the blood vessels, for example, blood
capillaries, whereas, as described in the Sibalis patents cited
above, the primary drug is delivered systemically into the body's
circulatory system.
It should be understood that the skin 23 is illustrated in
Figures 1, 2 with simplified representations and the electrical
transdermal drug applicator is also shown schematically in Figure
2 as a generic representation of such a device. More detailed
descriptions may be found in the above-cited references by the
inventor in this application. It suffices here to state that the
gel 18 and the primary drug 14 and counteractor 16 are contained
in the reservoir 12 in a manner to prevent leakage of the
substances. Also, there is no short-circuit of electrical
current across the skin surface 22 directly to the electrode 36.
When the switches 32, 34 are closed as illustrated, a
positive potential appears on the electrode 24 and a negative
potential on the electrode 36 causing a current to flow from the
source 28 through the current conditioner 30, the electrode 24,
reservoir 12 and skin surface 22 in series. A DC current flows
within the skin 23 as indicated by the arrow 38, then back
13 '
1
through the skin surface 22 to the return electrode 36, and then
back through switch 34 to the negative terminal of the DC source
28. The positive potential of the source 28 applied to the
electrode 24 and the electrical current drive the primary drug 14
and the counteractor 16 through the interface between the
reservoir 12 and the skin surface 22.
In Figure 1, the human skin 23 is represented in simplified
construction as including an outer layer, the epidermis 42, which
is broken by hair follicles 44 and sweat ducts 46, and at greater
depth blood capillaries 40, glands, etc. In electrical
transdermal drug applicators, it is known that small quantities
of the drug pass directly through the epidermis 42 as indicated
by the arrows 43 but also the drug 14 enters the skin with
relative ease through the hair follicles 44 and sweat ducts 46
which act as shunts. Having entered into the skin, the drug 14
is disseminated to the systemic circulatory system by
electrokinetic processes, for example, electrophoresis,
electroosmosis, iontophoresis, etc. With certain drugs and
counteractors it may be desirable to pick skin areas with greater
or lesser densities of hair follicles and sweat ducts for
application of the transdermal applicator 10 thereto.
Where a reversed polarity from that described in Figure 2 is
required to drive the primary drug 14 and counteractor 16 into
the skin tissues, the switches 32, 34 in Figure 2 are moved to
the positions indicated with broken lines, whereby a negative
14
potential is applied to the electrode 24 and a positive potential
is applied to the return electrode 36.
Where the primary drug 14 and the counteractor 16 require
opposite polarities of voltage to cause the substances to enter
into the skin, an alternating DC potential is applied by
periodically changing the positions of the switches 32, 34 such
that the potentials on the electrodes 24, 36 are periodically
reversed. The timing of the switches 32, 34 in each alternating
position is based upon the drug 14 and counteractor 16 which are
being used. Equal driving times or unequal driving times can be
provided as best suited for the substances 14, 16.
Further, in recognition of the work reported by Chien et al
as discussed above, it may be desirable, in the process of drug
delivery, to incorporate time periods wherein no potential is
applied to the electrodes 24, 36 and, it may be desirable during
those periods of no driving potential, to apply a short circuit
between the electrodes 24, 36 such that charges, if any, built up
within the skin during the driving periods may be readily
discharged. The switch 48, shown with broken lines in Figure 2,
is connected between the electrodes 24, 36 and when closed
provides the desired short circuit.
Tn electrical transdermal drug applicators in accordance
with the invention, wherein a complex operational cycle is
desirable, including (for examples) polarity reversals, periods
without driving potential, periods of electrode short-
circuiting, etcetera, a controller 50, also shoran in broken lines
2~~~'~~t~
in Figure 2, is used to automatically regulate opening and
closing of the switches 32-35, 37, 48 in desired programs.
It should be understood that whereas the power source 28 is
indicated in Figure ~ and in the other Figures for the sake of
illustration, as a DC battery, the power source may include
circuitry for converting potential from a DC battery to voltages
of controlled magnitude with regulated current delivery: the
electrodes not being connected directly to the DC battery but to
the output of the voltage generating circuitry. Additionally,
the switches which are schematically represented in Figure X as
electro-mechanical switches can be solid state switches,
especially when considering the very low current flows which are
frequently involved in electrical transdermal drug applicators as
indicated in the patents of the present inventor cited above.
Thus complex operational cycles of an applicator in accordance
with the invention may be automatically controlled by a
microchip.
The counteractors 16, which~are added to the reservoir 12,
can operate wfthin the skin to accomplish one or more effects
which tend to maintain blood circulation in the skin area
adjacent the transdermal drug applicator 10, such that the
primary drug 14, which enters the skin, is carried,away by the
bloodstream into systemic circulation for therapeuxic purposes.
Broadly speaking, the counteractors 16 can include vasodilators
which operate by relaxing the muscles surrounding the blood
vessel walls, including capillary walls, such that a greater flow
16
area and easier blood flow is possible. A counteractor 16 may
fall in the category of antithrombosis agents in that they work
to reduce platelet accumulation and blood clotting'in the blood
vessels, in particular the capillaries, in the area where the
drug applicator 10 is applied. A single counteractor which
performs both functions may be used in the reservoir 12 or a
plurality of counteractors which in combination perfona both
functions, or a counteractor which performs only one such
function may be used in the reservoir 12. Also, the counteractor
16 may be a substance which when introduced into the skin induces
the body to produce substances which delay, inhibit, or eliminate
blood coagulation or aid in dilating the blood vessels to improve
blood circulation. The primary drug and counteractor may be
variants of the same substance which do not interact
pharmacologically, e.g. nitroglycerine and isosorbide dinitrate.
The counteractive substance can be part of the primary drug
ro
molecule. Especially sulfonated, phospho~lated and carboxylated
groups attached to the primary drug molecules may be effective in
providing a desired increase of the negative charge
characteristics of the cellular walls where the applicator is
attached.
Substances known to be unsuitable for systemic transdermal
delivery as a primary drug with intended therapeutic benefit may
be the preferred counteractor as the drug s action will be
limited to the target area of applicator attachment and the
counteractor will not be available to produce. any systemic
17 .
effects. Thus, such application of substances as counteractors
is entirely opposed to prior teachings where it may be indicated
that no therapeutic utility for these materials is present in
transdermal applicators. The counteractors are formulated to
function only as topical agents. For example, if nitrates are
used, e.g. nitroglycerin, the flux rate of the counteractor may
be adjusted so as not to produce any detectable blood serum level
of the counteractor suLstance, while at the applicator site blood
circulation is improved. There is no or negligible systemic
effect or pharmacological effect. More specifically, the
counteractive substance will be formulated for negligible
transdermal delivery when its use is limited only to the
counteractive function. The counteractive substance could be of
a nature which selectively allows its delivery through the
stratus corneum, such as nitroglycerin, whereas the
electrokinetic main drug delivery takes place via the skin
shunts, perspiration and sebaceous ducts. In such a case the
stratum corneum would function as a depot for the counteractive
substance even though the counteractive substance previously
contained in said applicator reservoir is exhausted from the
applicator.
Known vasodilators which may be used as counteractors, and
knot~;n antithrombosis substances which also may be used as
counteractors 16 and substances which may serve as both blood
vessel dilators and also act to reduce or -eliminate blood
coagulation, are set forth herein below.
18
CARDIOVASCULAR DRUGS VASODILATORS
TRADE NAME GENERIC (;TRIVIAL NAME
Cerespan - papaverine hydrochloride
Cyclospasmol - cyclandelate
Ethatab - ethaverine hydrochloride
Lipo-Nicin - mixture of six agents: nicotinic
acid, niacinamide, ascorbic acid,
thiamine HC1, riboflavin,
pyridoxine
Pavabid - papaverine hydrochloride
Theo-24 - theophylline
Vasodilan - isoxsuprine hydrochloride
Cardilate - erythrityl tetranitrate
~~E N~ GENERIC
TRIVIAL) NAME
Iso-bid - isosorbide dinitrate
Isordil - isosorbide dinitrate
Nitro-Bid - nitroglycerine
Nitroglyn - nitroglycerine
Nitrol (ointment) nitroglycerine (ointment)
-
Nitrospan - nitroglycerine
Nitrostat - nitroglycerine/polyethylene glycol
Peritrate - pentaerythritol tetranitrate
Persantine - dipyridamole
8orbitrate - isosorbide dinitrate
19
r
TRADE NAME rENERIC fTRrvrAr~i N~
Tridil - nitroglycerine
Arlidin - nylidrin hydrochloride
Aprosoline HC1 - hydralazine hydrochloride
l~rfonad - trimethaphan camsylate
Dibenzyline - phenoxybenzamine hydrochloride
Esimil - guanethidine sulfate/hydrochioride
Hyperstat - diazooxide
Ismelin - guanethidine monosulfate
roniten - minoxidil
Nico-400 - nitroglycerine
Priscoline HC1 - talazoline hydrochloride
Serpasil - reserpine
NTICOAGULANTS
Calciparine - ca~.cium heparin
Coumadin - sodium warfarin (propanol-2
clathrate)
Heparin, Na - sodium heparin
Protamine sulfate - protamine sulfate
A~1TIFIBROTICS systemic
Potaba - potassium aminobenzoate
ao
~~~~~~i~
ANTIPLATELET
Aspirin - salicylates, such as
salicylic acid, its derivatives
and salts thereof.
OTHER
flavoroids (such as riboflavin)
and their phenolic breakdown
products or compounds.
calcitonin gene related peptide
(CGRP)
nitroprusside
prostacylin
streptokinase
Activase recombinant alteplase
While the above listings are by no means complete, they are
nevertheless representative of various categories of drugs or
agents which may be suitable in the practice of the invention.
Moreover, the present invention contemplates the use of any
counteractors which have the specific characteristics and produce
the effects desired as have been described in the present
application.
Figure 3 illustrates an alternative embodiment of an
electrical transdermal drug applicator 10' in accordance with the
invention, wherein the primary drug 14 is contained in a first
reservoir 12' and the counteractor 16 is contained in the
reservoirs 12 " . In each reservoir, the substances are suspended
21
~~~~~9~~
in a gel 18. Electrodes 24, 52 are connected in parallel to
receive current from the DC power source 28 by way of the
electrical current conditioner 30. As illustrated, current flows
from the battery 28 through the current conditioner 30 to the
electrodes 24, 52, through the associated reservoirs 12°, 12 "
and through the surface 22 of the skin 23. The current flows
(arrows 38) within the skin to the return electrode 36 and then
back to the DC power source 28.
To suit a particular primary drug 14 and counteractor 16,
provision for switching the polarity of the DC source 28 may be
provided as indicated in Figure 2, and a shorting circuit
connecting all electrodes 24, 52 directly to the return electrode
36 by way of a switch 48 may also be included. By operation of
switches 33, 35, 37, reservoirs may be selectively inactivated
while the other reservoirs continue to function. A controller 50
may be used to control the switches 32, 34, 48 (see Figure 2)
When periodic cycling is involved in operation of the transdermal
drug applicator 10'.
Figure 4 illustrates another alternative embodiment of an
electrical transdermal drug applicator 10'°. In this
configuration, the reservoir 12' is connected to one terminal of
the DC source 28, whereas the reservoir 12 " is connected to the
other terminal of the DC power source 28. Thereby, opposite
polarities are always present on the two reservoirs 12', 12 " .
This is advantageous when the primary drug 14 is delivered
through the skin's surface 22 by one electrical potential and the
22
counteractor 16 is delivered through the skin surface 22 by the
opposite potential. In this way, both the drug 14 and
counteractor 16 can be continuously and concurrently delivered if
desired.
A shorting circuit between the electrodes 24, 52 including
the switch 48 may be used to remove charge, if any, from the skin
during periods when the voltage is not applied. A controller 50
may be used with the configuration of Figure 4 as described above
to control ON/OFF periods, periods when the short circuit through
the switch 48 is desired, etc. A return electrode 36 (broken
lines) may be used to eliminate the reservoir 12' from the
circuit when a switch 39 is closed while switches 47, 54 are open
while switch 48 is also open. In this way, delivery of the
counteractor substance 16 to the skin may continue while delivery
from the reservoir 12' of the primary drug 14 is discontinued.
Similarly, the return electrode 36 can be used to eliminate
counteractor reservoir 12 " when it is desired to deliver the
drug 14 while interrupting delivery of the counteractor 16. In
this case the switch 47 is closed, switches 38, 48, 49 are open
and switch 54 is closed.
The electrical transdermal drug applicator 10 of Figure 2
was described as containing a drug and a counteractor in
suspension, for example, a gel. However, it should be understood
that in alternative embodiments of an electrical transdermal drug
applicator in accordance with the invention, the reservoir may be
in the form of a matrix, liquid, paste, etc. as suits the
23
particular substances in use. Also, Figure 2 illustrates a
generally random and equal distribution of drug 14 and
counteractor 16 within the reservoir 12. It should be understood
that the reservoir may contain a predominance of one substance
over the other. The distribution of materials may not be uniform
or randomized. The drug 14 may be in one layer, whereas a
counteractor 16 may be in another ~ayer, the layers being at
different distances from the skin surface 22. As dictated by the
particular application, either the drug 14 or counteractor 16
layer may be closer to the skin surface. Such layers may
themselves combine several substances which can be in varying
proportions as suits the particular construction with drug 14 and
counteractor 16 in each layer. The layers may be of different
thicknesses such that one layer may act as a flow inhibitor of
materials from the other layer. There may be several layers each
of counteractors and drugs and these layers may be alternated in
their stacking within a reservoir.
In an exemplary embodiment of the invention, blockage of the
capillaries and stratum corneum of the skin may be avoided or
inhibited by sub-therapeutic dosages of an active vasodilator
such as nitroglycerin. For example, a therapeutic ointment at 2%
concentration is available from the W.H. Rorer Co. (Fort
Washington, Penna 19034) under the tradename NITROL ointment.
Since it is known that nitroglycerine relaxes smooth muscles,
principally in the smaller blood vessels thus dilating arterioles
and capillaries, it may be advantageous to topically apply sub-
24
i ~~~~~.'.~4
therapeutic doses of about 0.001 to about 0.2% nitroglycerine
ointments to the skin, when employing an otherwise .conventional
transdermal applicator, such as described in the applicant's own
earlier issued U.S. Patents. Thus a counteractor layer is at the
skin surface: the primary drug passes through this layer before
entering the skin. If desired, the body of the ointment may
preferably be a hydrophilic polymer, such as polyvinyl
pyrrolidone or neutralized polyacrylic acid and the like in order
not to interfere with the hydrophilic adhesive which may be
employed in the transdermal applicator.
In another exemplary embodiment, one may utilize a
stabilized vasodilator in order to restrict blockage
counteraction to the region of the patient's body where the
transdermal applicator of the invention is located. This may be
achieved by the use of a polymer stabilizer for a vasodilator,
such as nitroglycerine. One such polymer stabilizer is
polyethylene glycal, but other stabilizers having like properties
may also be suitable in the practice of the invention. As is
known, a polyethylene glycol of molecular weight 3350 operates to
lower the migration of nitroglycerine, (see U.s. Patent
3,789,119). With the present invention, a higher molecular
weight would be preferred, for example of from about 5000 to
about 20,000 so as to localize the vasodilation of the very
region where the electrolytic patch of the invention is applied.
Of course, other suitable benign polymers with a molecular weight
of from abut 3,000 to about 30,000 may be employed, depending on
their diffusion constant.
Figures 5-8 illustrate alternative embodiments in accordance
with the invention wherein the primary drug indicated in those
Figures with a D and the counteractive agent, indicated in those
Figures with a C, are located in individual reservoirs. In
Figure 5, counteractor reservoirs 60 alternate with drug
reservoirs 62 in the direction of current flow indicated by the
arrows 64 when an applicator 66 is attached to the skin surface
22. For the sake of example, the reservoirs are connected in
parallel schematically to one terminal of an electrical control
unit 68 and current flows from the reservoirs 60, 62 through the
skin surface 22 and within the skin to the return electrode 70
indicated in Figure 5 by the letter R. The skin to which the
applicator 66 is attached receives the primary drug from the
reservoirs 62, while at the same time a current passing through a
counteractor reservoir 60 from the upstream direction (left to
right in Figure 5) delivers the counteractive substance and acts
as a preconditioner to the blood vessels in the area of the drug
reservoirs 62. The counteractive substance and the primary drug
axe thereby simultaneously active in the same region of skin.
The Figures 5-8 are schematic. Any electrical control, such
as polarity reversal, ON/OFF voltage application, electrode
short-circuiting, series arrangement of reservoirs, etc., as
described above in relation to Figures 2-4, can be applied
equally to the arrangements of Figures 5-8. Figures 6, 7 and 8
26
show applicators with separate drug D reservoirs and counteractor
C reservoirs. In each instance, the reservoirs may be
electrically connected such that the counteractor substance acts
as a preconditioner for the blood vessels in the area where the
drug reservoir is applied. With regard to Figures 5-8, it should
be understood that the relative positions of the primary drug
reservoirs D may be interchanged with the counteractive substance
reservoirs C as suits the particular substances which are in use.
Other configurations as shown in the above cited patents by the
inventor here, may also be adapted to utilize counteractors in
conjunction with primary drug delivery.
It will thus be seen that the objects set forth above, among
those made apparent from the preceding description, are
efficiently attained and, since certain changes may be made in
carrying out the above method and in the construction set forth
without departing from the spirit and scope of the invention, it
is intended that all matter contained in the above description
and shown in the accompanying drawings, shall be interpreted as
illustrative and not in a limiting sense.
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