Layered rate controlling membranes for use in an electrotransport device

The disclosed invention relates to an improved electrotransport device. The improvement relates to a membrane assembly including a low porosity membrane adhered or sealed to one or two high porosity membranes. The high porosity membranes protect the low porosity membrane from being damaged by components or contaminates on the body surface and/or in the drug reservoir which can lead to undesirable passive flux and/or insufficient iontophoretic flux. As a result, the electrotransport device having the membrane assembly more reliably, precisely, and accurately delivers drug and/or therapeutic agent through the body surface by electrotransport.

FIELD OF INVENTION 
This invention relates to electrotransport devices to deliver drugs and 
therapeutic agents to a patient. The invention also relates to rate 
controlling membranes for use in electrotransport devices. 
BACKGROUND OF THE INVENTION 
Electrotransport devices and transdermal patches are drug delivery systems 
that are capable of satisfying many needs facing the health care industry. 
For example, attempts have been made to control and increase the rate of 
delivery, reduce drug and agent degradation, and reduce the risk of 
infection. However, such goals have become more difficult to reach as the 
molecular size of the drugs and therapeutic agents to be delivered 
increases. Such drugs and agents include peptides, polypeptides and 
proteins. 
An electrotransport device generally includes at least two electrodes and a 
source of electrical power. Each electrode is in electrical communication 
and physical contact with some portion of the skin, nails, mucus membrane 
or other membrane surface of the body. One electrode is generally referred 
to as the active or donor electrode, and the other electrode is referred 
to as the counter or return electrode. The donor electrode also includes a 
donor reservoir which contains the drug or therapeutic agent to be 
delivered, and the counter electrode includes a counter reservoir that 
generally contains an electrolyte. In combination, the electrodes close 
the electrical circuit through the patients body surface. 
The drug or therapeutic agent is a charged molecule, or ion, that is 
carried through the body surface by applied current. The charge of the 
drug or agent determines whether the donor electrode is the cathode or 
anode. For example, the donor electrode is the anode when the drug is 
positively charged, and the counter electrode is the cathode. 
Alternatively, the donor electrode is the cathode when the drug is 
negatively charged, and the counter electrode is the anode. 
The reservoirs are generally in the form of a pouch, a cavity, a porous 
sponge or pad, or a pre-formed gel or polymer composite body. The donor 
reservoir is in electrical communication with the respective electrode. 
Semipermeable membranes typically have a limited number of minute pores to 
control the rate of drug delivery. 
Known electrotransport devices may also include a semipermeable membrane 
that controls the rate of drug delivery. The membrane is located between 
the donor reservoir and the body surface. The membrane is also in 
electrical and ion-transmitting communication with the donor reservoir and 
the body surface. Membranes are also used in the counter reservoir to 
control passive delivery of a drug or therapeutic agent. 
However, there may be a need for a semipermeable membrane that more 
accurately and precisely controls passive drug/agent flux. Prior membranes 
were disadvantaged in that membranes having small pore size (about 0.09 
micron diameter) and low porosity (about 4.times.10.sup.5 pathways per 
cm.sup.2 or 0.003% by volume) prevented passive flux, but failed to allow 
therapeutically sufficient current after lamination and assembly. Prior 
devices are also disadvantaged in that the membrane can be damaged or 
compromised by oils and other contaminants from the skin or drug reservoir 
during operation of the device. The contamination may cause occlusions in 
the membrane that affect the rate of drug delivery. For example, if the 
membrane loses resistance, the drug may passively flux into the body 
surface at significant levels. Membranes may also have excessive 
resistance that hampers drug delivery reducing efficacy and depleting the 
electrical power source. Such losses of control over the rate of drug 
delivery are acutely disadvantageous where the drug is an analgesic, such 
as an opioid. 
Membrane pores may also be deleteriously affected when the membrane is 
contacted with the body surface. Body oils, dirt particulates and other 
contaminates on the skin are transferred to the semipermeable membrane 
clogging pores in the membrane. Hydrophobic components in the donor and/or 
counter reservoirs may also clog membrane pores or cause occlusions. Such 
damage to the semipermeable membrane compromises control, precision and 
accuracy of the drug delivery rate. 
Prior devices are further disadvantageous because the membrane pores may be 
altered when the membrane is affixed to the donor and/or counter 
reservoir. Semipermeable membranes are affixed using adhesives and/or 
laminates under heat and/or pressure that can cause occlusions in and 
deformation of the membrane pores. Such damage deleteriously affects the 
passive and/or iontophoretic flux of the drug/agent. 
SUMMARY OF THE INVENTION 
The present invention is advantageous over such prior devices because, 
among other reasons, a semipermeable membrane assembly is employed. The 
present membrane assembly, which is for use only in an electrotransport 
device, is substantially unaffected by skin oils and other contaminants or 
by hydrophobic components in the reservoir. The present invention also 
includes a method of attaching the membrane to the reservoir without the 
problems associated with affixing it with adhesives and laminates under 
heat and pressure. 
Another advantage of the present invention is that, as shown in the 
preferred embodiments, the low porosity membrane is structurally supported 
by the one or more, preferably two, high porosity protective layers. In 
addition, the present membrane assembly achieves steady state drug 
delivery faster than comparable conventional electrotransport systems. For 
example, the present membrane assembly will generally be less flux 
resistant than a comparable single low porosity layer having similar 
thickness and structural integrity. As a result, the present invention 
increases structural integrity without substantially affecting the time 
needed to achieve steady state drug delivery/flux. 
Another aspect of the invention is a method of reducing occlusive effects 
in a rate-controlling membrane caused by body oils, adhesives, particulate 
contaminates and/or hydrophobic components. Such occlusions may 
deleteriously affect or compromise the passive flux of such membranes in 
an electrotransport device. 
Still another aspect of the invention is an electrotransport device 
including a rate-controlling membrane assembly positioned between the 
donor reservoir and the body surface. The assembly includes a low porosity 
layer adjacent the reservoir and a high porosity layer positioned between 
the low porosity layer and the body surface. In another aspect of the 
invention, the high pososity layer is adjacent the donor reservoir, and 
the low porosity layer is positioned between the high porosity layer and 
the body surface. 
Yet another aspect of the invention is an electrotransport device including 
a second high porosity protective layer whereby the low porosity layer is 
sandwiched between the high porosity layers. The high porosity membrane(s) 
may be affixed to the device and/or low porosity membrane by lamination 
without substantially altering the porosity of the low porosity, 
rate-controlling layer. As such, a significant amount of pore occlusion 
may be tolerated when the membrane assembly is affixed to the donor 
reservoir. As a result, the precision and accuracy of the low porosity 
layer is not significantly compromised. The high porosity layer protects 
the low porosity layer from exposure to body oils and particulate 
contaminates causing occlusions and other damage. 
Preferably, the high porosity membranes of the present invention have a 
porosity sufficient to permit a drug delivery rate substantially greater 
than the therapeutic drug delivery rate. More preferably, the porosity is 
greater than or equal to about 10%, and even more preferably, greater than 
or equal to about 20%. 
Preferably, the low porosity, rate-controlling membranes of the present 
invention have a porosity sufficiently low to permit a drug delivery rate 
substantially equal to a therapeutic drug delivery rate. More preferably, 
the porosity is less than or equal to about 1%, and even more preferably, 
less than or equal to about 0.1%. 
Yet another aspect of the invention is a method of making a low and high 
porosity membrane for use in assembling the membrane assembly. For 
example, the membrane may be made by lithographically depositing a film on 
a preformed low porosity substrate. Preferably, the low or high porosity 
membranes are photolithographically formed on either major opposing 
surface of an appropriate pre-formed substrate, low or high porosity. The 
high porosity membranes may be affixed to the low porosity membrane by 
using adhesives or by applying pressure and/or heat seals. Preferably, 
substantially only the periphery of the high porosity membrane is 
adhesively affixed or laminated. Preferably, the low porosity membrane is 
sandwiched between the high porosity layers protecting the low porosity 
layer from damage.

DETAILED DESCRIPTION OF THE INVENTION 
One preferred embodiment of the invention relates to a rate-controlling 
membrane assembly for use in an electrotransport device. The membrane 
assembly is designed and assembled in an electrotransport device to 
improve the accuracy and precision of the drug and/or therapeutic agent 
flux. The accuracy and precision of the flux is improved by having the 
assembly include high and low porosity layers. In one embodiment, a high 
porosity layer is positioned between the donor reservoir and the low 
porosity layer which is adjacent to the body surface. 
The high porosity layer has a porosity sufficiently high before assembly or 
operation that, upon acquiring pore occlusions, the high porosity layer is 
more porous than the low porosity layer. Such occlusions may be caused 
during assembly by adhesives or laminates, or exposure to contaminates 
during assembly or operation. As a result, the drug/agent delivery rate is 
substantially unaffected by damage to the high porosity membrane during 
assembly or operation of the electrotransport device. 
In another preferred embodiment of the invention, a rate-controlling 
membrane assembly includes a high porosity membrane positioned between the 
low porosity layer and the body surface. The high porosity layer has a 
porosity sufficiently high before assembly or operation that, upon 
acquiring pore occlusions or damage during assembly or operation of the 
device, the high porosity layer is more porous than the low porosity 
layer. The high porosity layer protects the low porosity layer from being 
compromised. For example, the high porosity layer may be damaged by oils 
or particulate contaminates on the body surface. Occlusions may form 
and/or pores may be clogged or otherwise obstructed. Such damage may also 
occur when the membrane are affixed and assembled. 
In another preferred embodiment of the invention, a rate-controlling 
membrane assembly includes a first high porosity membrane positioned 
between a low porosity membrane and the body surface and a second high 
porosity membrane positioned between the low porosity membrane and the 
donor reservoir. As a result, the low porosity membrane is protected from 
ingredients and contaminants in the drug/agent reservoir and from oils and 
particulate contaminants on the body surface. The low porosity membrane is 
also protected from adhesives and laminates during assembly. 
Preferably, the rate-controlling membrane assembly employs two high 
porosity membranes protecting a low porosity membrane. The assembly more 
accurately and reliably delivers drugs and/or therapeutic agents at a more 
precise flux. As in the other embodiments, the high porosity layers have a 
porosity sufficiently high before assembly or operation that, upon 
acquiring pore occlusions or damage during assembly or operation of the 
device, each high porosity layer is more porous than the low porosity 
layer. 
In a preferred embodiment of the invention, as shown in FIG. 1, an 
electrotransport device 10 includes a donor electrode 12 and a counter 
electrode 14. The donor and counter electrodes 12,14 are positioned 
adjacent to the donor and counter reservoirs 16,18 respectively. The donor 
reservoir 16 contains the drug or agent to be delivered, and the counter 
reservoir 18 contains a biocompatible electrolytic salt. Alternatively, 
drug and/or therapeutic agent may be delivered from the donor and counter 
electrodes simultaneously or in an alternating manner. In that case, a 
rate-controlling membrane assembly is employed in conjunction with the 
counter electrode and reservoir. 
An insulator 20 separates the donor electrode 12 and donor reservoir 16 
from the counter electrode 14 and counter reservoir (which is optional). 
The insulator 20 prevents direct ion or electron transport between the 
donor electrode 12 or reservoir 16 and the counter electrode 14 or 
reservoir 18. The insulator 20 prevents the device 10 from 
short-circuiting. The insulator 20 may be made from a material 
sufficiently impermeable to water and ions to ensure agent ion transport 
through the body surface 100,200,300. Preferably, the insulator 20 is made 
from polyisobutylenes or ethylene vinyl acetate or a material capable of 
forming sufficiently strong bonds with the polymeric reservoirs to achieve 
structural integrity. 
As shown in FIG. 1, the electrotransport device 10 also includes a backing 
layer 22 constructed from an electrically insulating or non-conducting 
material. A power source 24 supplies electrical power to the electrodes 
12,14. The power source 24 comprises a battery, which can include without 
limitation, thin film and lithium batteries; and a controller for 
regulating the flow of electricity. The controller comprises various 
electronic circuits for regulating the flow of electricity, such 
electronic components including without limitation a microprocessor. The 
backing layer 22 is preferably made from a material having negligible 
electrical conductivity insulating the device 10. The backing layer 22 
prevents short-circuits due to external moisture and structurally supports 
the adjacent components of the device 10. 
The electrodes 12,14 are constructed of an electrically conductive material 
such as a metal. Preferably, the electrodes 12,14 are made from foil or 
screen, or they are made using a chemical process, such as deposition, 
painting/coating, calendaring, film evaporation, or by embedding metal 
powder in a binder matrix. Exemplary metals include silver, zinc, silver 
chloride, aluminum, platinum, stainless steel, gold and titanium. The most 
preferred embodiment includes an anodic electrode made of silver and a 
cathodic electrode made of silver chloride. 
The electrodes 12,14 may also be constructed from a conductive filler 
dispersed in a polymer matrix. For example, the conductive filler is 
preferably powdered graphite, carbon fibers, or other fillers known in the 
electrode art. The polymer matrix is preferably a hydrophobic polymer 
known in the electrode art to minimize any interaction or reaction with 
any water that may be present in the respective reservoir. The counter and 
donor electrodes 12,14 may be constructed from dissimilar metals or have 
different half cell reactions. The electrodes 12,14 may also generate at 
least a portion of the required electrical power. An exemplary galvanic 
couple is the silver silver chloride electrode assembly where the standard 
electrochemical reactions and respective reduction potentials are known in 
the art. For example, see the CRC Handbook of Physics and Chemistry, 67th 
Edition, pages D151-D158 (1987), which is incorporated herein by 
reference. 
The electrotransport device 10 also includes electronic control circuitry 
(not shown) connected to opposite poles of the power source 24. The power 
source 24 is preferably a 3 volt lithium button cell battery or a thin 
film battery. An adhesive layer 28, preferably peripherally, adheres the 
device 10 to the body surface 100. The device 10 may also include a 
removable liner (not shown) that protects the adhesive layer 28 until the 
device 10 is applied to the body surface and engaged into operation. 
The donor and counter reservoirs 16,18 may be capable of adsorbing and 
containing a composition suitable for iontophoretic delivery. For example, 
the reservoir may be a gauze, pad or sponge constructed from cotton or 
other natural or synthetic adsorbent fabric or material. Preferably, the 
reservoirs 16,18 also include a hydrophilic polymer and a water medium. 
More preferably, the reservoirs 16,18 include a solid polymer matrix 
composed, in part, of a structurally significant, insoluble hydrophilic 
polymer. 
A matrix containing the agent to be delivered may be crosslinked (such as a 
silastic matrix) or prefabricated and sorbed with the drug solution (such 
as with using cellulose, woven fiber, pads or sponges as the matrix). 
Alternatively, the reservoirs 16,18 may include a gel matrix, such as a 
hydrophilic polymer swellable or soluble in water. Blends of the mentioned 
polymers may also be used. The polymers may also be linear or crosslinked. 
Preferably, the total polymer content in the reservoir is between about 2% 
and 50% by weight. Suitable hydrophilic polymers include those mentioned 
herein with respect to the membrane layers. 
Alternatively, the reservoirs 16,18 may include a hydrophobic polymer to 
enhance structural rigidity. Preferably, the hydrophobic polymer is heat 
fusible to enhance lamination of the reservoirs 16,18 to the insulator 20 
or other adjacent components. Exemplary hydrophobic polymers include those 
mentioned herein with respect to the membrane layers. 
The matrices may be a polymeric matrix structure made by blending the drug 
agent or electrolyte (and other components) with an inert polymer. The 
donor reservoir 16 contains the drug agent to be delivered and the counter 
reservoir 18 contains an electrolyte, such as a water soluble 
biocompatible salt. Preferably, the reservoir composition includes about 
25-90% by weight of the matrix. A hydrophobic polymer may also be included 
to maintain an open pore (or microporous) polymer structure facilitating 
agent flux. 
The reservoirs 16,18 may also contain at least one optional material 
including dyes, pigments, inert fillers, and/or a rheological agent (such 
as mineral oil and silica). The counter reservoir 18 may also contain at 
least one optional component including alkali metal salts (such as NaCl), 
alkaline earth metal salts (such as chlorides, sulfates, nitrates, 
carbonates or phosphates thereof), organic salts (such as ascorbates, 
citrates or acetates), electrolytes containing redox species (such as 
Cu.sup.2+, Fe.sup.2+, Fe.sup.3+, quinone, hydroquinone, Ag.sup.1+, and 
(IO.sub.3).sup.1-, and other biocompatible salts and buffers. More 
preferably, the electrolytic salt is sodium chloride to enhance 
biocompatibility. 
A low porosity membrane 30 is positioned between the donor reservoir 16 and 
the body surface 100. A high porosity membrane 31 is located between the 
low porosity membrane 30 and a donor reservoir 16. Pores are distributed 
substantially uniformly throughout the entire thickness of the membranes 
30,31 and extend from surface to surface. The electrotransport device 10 
may be used to transfer drug and/or therapeutic agent through the body 
surface 100. 
The surface area of contact where drug is transmitted may range from about 
1-200 cm.sup.2. More preferably, the area is in the range of about 2-30 
cm.sup.2. The lower end of the area range may be limited by the strength 
of available power sources and the desired flux rate, whereas the upper 
end is limited by the amount of body surface available, by the 
availability of continuous adhesion given the contours of the body, and by 
patient comfort. 
The electrotransport device 10 also includes a controller (not shown) that 
is preferably adapted and configured to permit a patient to activate and 
deactivate the device 10. The controller may also be programmed with an 
on-demand medication regime or programmed to automatically activate and 
deactivate periodically to, for example, match the natural or circadian 
patterns of the body. Preferably, a microprocessor controls the current as 
a function of time and/or generates current waveforms, such as pulses, 
sinusoidal, ramp up, ramp down, spikes, etc. 
The structural components of the present invention may be melt blended, 
solvent cast or extruded by methods generally known in the art. 
Shown in FIG. 2 is another preferred embodiment of the present invention. 
The electrotransport device 10 includes a high porosity membrane 44 
positioned between a low porosity, rate-controlling membrane 42 and the 
body surface 200. Preferably, the high porosity membrane has a porosity 
sufficient to permit a drug delivery rate substantially greater than the 
therapeutic drug delivery rate. More preferably, the porosity is greater 
than or equal to about 10%, and even more preferably, greater than or 
equal to about 20%. Preferably, the low porosity, rate-controlling 
membrane 42 has a porosity sufficiently low to permit a drug delivery rate 
substantially equal to a therapeutic drug delivery rate. More preferably, 
the porosity is less than or equal to about 1%, and even more preferably, 
less than or equal to about 0.1%. The high porosity layer 44 protects the 
low porosity layer 42 from oils and particulate contaminates on the body 
surface 200. Layer 44 also protects the layer 42 from ion-transmitting 
adhesive when the assembly 40 is affixed to the body surface 200. 
Shown in FIG. 3 is another preferred embodiment of the invention including 
two high porosity layers 52,56. Membrane 52 is located between the low 
porosity membrane 54 and the donor or counter reservoir 16,18. The other 
high porosity membrane 56 is located between the low porosity membrane 54 
and the body surface 300. Preferably, the high porosity layer 56 has a 
porosity greater than or equal to about 10%, and more preferably, greater 
than or equal to about 20%. The membrane 56 protects the low porosity 
membrane 54 from occluding or being otherwise damaged. Such damage may be 
caused by oils, particulates or other contaminates transferred from the 
body surface. 
The layer 56 also protects the membrane 54 from ion-transmitting adhesive 
that may be coated onto the layer 56 when the assembly 50 is affixed to 
the body surface 300. As a result, the risk of clogged pores, occlusions 
and other damage affecting delivery rate are significantly reduced or 
eliminated. The high porosity membrane 52 protects the low porosity 
membrane 54 from components and/or contaminates in the donor and/or 
counter reservoirs 16,18. 
Shown in FIG. 4 is another preferred embodiment of the invention. The 
rate-controlling membrane assembly 60 is preferably affixed to the device 
10 by laminating along its periphery 68. The assembly 60 includes a low 
porosity layer 64 positioned between two sealed high porosity layers 62,66 
that are affixed along their periphery 68 by heat and/or pressure fusion. 
The low porosity layer 64 is thereby secured between the outer layers 
62,66. 
The high porosity membranes of the present invention have preferred pore 
sizes, size distributions and spatial distributions. For example, 
preferably, the pores in the high porosity membrane are sufficiently 
distributed spatially to avoid any significantly uneven agent/drug 
delivery. Preferably, pore dimensions in the high porosity layer are 
sufficiently large to permit a drug delivery rate in excess of a 
therapeutic drug delivery rate. Preferably, the size distribution of the 
pores is sufficiently narrow to permit a sufficiently even and therapeutic 
drug delivery rate. 
The rate-controlling, low porosity membrane of the present invention also 
has preferred pore sizes, size distributions, and spatial distributions. 
Preferably, the pore size of the pores in the low porosity membrane is 
sufficiently large to substantially permit a therapeutic drug delivery 
rate and sufficiently small to prevent any significant passive drug or 
agent delivery. Preferably, the size distribution of the pores in the low 
porosity layer is sufficiently narrow to prevent significantly uneven drug 
flux. Preferably, the spatial distribution of the pores in the low 
porosity layer is sufficiently even to prevent significantly uneven drug 
flux. 
Preferably, the widest average segment of the pore openings in the low 
porosity membrane is between about 1 millimeter and the molecular size of 
the drug or agent being delivered. The shape of the pores are, preferably, 
substantially cylindrical in shape having an average radii between about 
0.01 microns and the molecular size of the drug or agent being delivered, 
and more preferably, between about 0.01 and 5 microns, and even more 
preferably, between about 0.01 and 200 microns. Preferably, in the high 
porosity layer membrane, the average pore radii or the widest average 
segment of the pore openings is greater than 5 microns. 
Preferably, the membrane assembly of the present invention is made by a 
lithographic process capable of high accuracy and precision in terms of 
porosity and pore distribution, uniformity, size, shape and dimension. One 
preferred method of making the low porosity membrane is to coat a low 
porosity substrate with a resistive or energy-sensitive material. A high 
porosity substrate may be used to form the high porosity membrane. 
Alternatively, pores may be formed by laser drilling. 
The resistive material is cured by exposure to an appropriate energy 
source. The membrane is removed from the substrate by applying a solvent 
to uncured resistive material shielded from the energy source. The solvent 
treatment step is also referred to as chemical etching. A preformed mask 
may be used to shield a preselected portion of the resistive material. 
Exemplary lithographic methods include electron beam lithography, xray 
lithography, and ion-beam lithography. More preferably, photolithography 
is used to make the low and high porosity membrane layers of the present 
invention. Other lithographic processes usable in the present invention 
include those disclosed in "Encyclopedia of Polymer Science and 
Engineering," Kirk Othmer's, vol. 11 (1988), which is incorporated, in 
relevant part, herein by reference. 
Preferably, the membrane layers of the present invention is made from an 
energy-sensitive or resistive material. For example, when a lithographic 
method is employed, positive and negative image resist materials are 
preferably used. Such material are disclosed in the "Encyclopedia of 
Polymer Science and Engineering," vol. 9, pages 97-139 (1987), which is 
incorporated herein by reference. 
Exemplary materials include hydrophilic and hydrophobic polymers. Exemplary 
hydrophilic polymer include ,copolyesters (such as HYDREL.TM. from DuPont 
De Nemours & Co., Wilmington, Del.), polyvinylpyrrolidones, polyvinyl 
alcohols, polyethylene oxides (such as POLYOX.TM. from Union Carbide 
Corp.), CARBOPOL.TM. from BF Goodrich of Akron, Ohio, blends of 
polyethylene oxides or polyethylene glycols with polyacrylic acid (such as 
POLYOX.TM. blended with CARBOPOL.TM.), polyacrylamides, KLUCEL.TM., 
crosslinked dextran (such as SEPHADEX from Pharmacia Fine Chemicals, AB of 
Uppsala, Sweden), starch grafted poly(sodium acrylate-co-acrylamides (such 
as WATER LOCK.TM. from Grain Processing Corp. of Muscatine, Iowa), 
cellulose derivatives (such as hydroxyethyl celluloses, 
hydroxypropylmethyl celluloses, low-substituted hydroxypropyl celluloses, 
and crosslinked sodium carboxymethyl celluloses such as Ac-Di-Sol from FMC 
Corp. of Philadelphia, Pa), hydrogels (such as polyhydroxylethyl 
methacrylates available from National Patent Development Corp.), natural 
gums, chitosans, pectins, starches, guar gums, locust bean gums, blends 
and combinations thereof, and equivalent materials thereof. Other suitable 
materials are disclosed in "Handbook of Common Polymers," J. R. Scott & W. 
J. Roff, (CRC Press, 1971), which is incorporated, in relevant part, 
herein by reference. 
Exemplary hydrophobic polymers for use in making the high and/or low 
porosity membranes of the present invention include polycarbonates, 
polyisobutylenes, polyethylenes, polypropylenes, polyisoprenes, 
polyalkenes, rubbers, KRATON.TM., polyvinylacetates, ethylene vinyl 
acetate copolymers, polyamides, nylons, polyurethanes, polyvinylchlorides; 
acrylic or methacrylic acid esters of an alcohol such as n-butanol, 
1-methyl pentanol, 2-methyl pentanol, 3-methyl pentanol, 2-ethyl butanol, 
iso-octanol, n-decanol, and combinations thereof; such acrylic or 
methacrylic acid esters of an alcohol copolymerized with one or more 
ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, 
acrylamides, methacrylamides, n-alkoxymethyl acrylamides, n-alkoxymethyl 
methacrylamides, n-tert-butylacrylamides, itaconic acid, n-branched alkyl 
maleamic acids having 10-24 carbons in the alkyl group, glycol 
diacrylates, and mixtures and combinations thereof. It is also preferred 
that the hydrophobic or hydrophilic polymer used to make the low and/or 
high porosity membrane be heat fusible. 
In addition to such materials, the rate-controlling, low porosity membrane 
is preferably made from a polycarbonate or nylon resin. Preferably, the 
low porosity membrane made from polycarbonate has a pore size of about 
0.01 to 14 microns and a pore density of about 6.times.10.sup.8 to 
1.times.10.sup.5 pores/cm.sup.2. Preferably, the low porosity membrane 
made from nylon has a pore size of about 0.22 to 5.0 microns and a pore 
density of about 1.times.10.sup.3 to 1.times.10.sup.6 pores/cm.sup.2, and 
more preferably about about 1.times.10.sup.3 to 1.times.10.sup.4 
pores/cm.sup.2. 
An exemplary embodiment includes a three layer membrane assembly including 
a low porosity membrane made from nylon located between two high porosity 
membranes made from polycarbonate. The low porosity membrane has a pore 
size of about 1.0 micron, and the high porosity layers have a pore size of 
about 5.0 microns. The low and high porosity membranes preferably have 
substantially the same pore density, pore size distribution, and pore 
spatial distribution. The periphery of the polycarbonate membranes may be 
sealed with an adhesive, or more preferably, by applying heat and pressure 
laminating the outer layers. 
For example, as is known in the art, the low porosity membrane may be made 
by gamma irridiating a polycarbonate membrane. The irridiated membrane is 
then chemically etched with, for example, sodium hydroxide, as is known in 
the art. 
The electrotransport device of the present invention is used to deliver a 
therapeutic agent and/or drug to the body surface of a patient, such as 
skin, mucosa or nails. For a given set of operating parameters (e.g. 
porosity, electrical current, contact area, molecular size, flux rate, 
etc.), the drug or agent is present in the reservoir in a concentration 
sufficient to deliver a therapeutic amount or concentration through the 
skin. 
As used herein, "agent" is to be given its broadest reasonable 
interpretation in the art and includes drugs that produce desirable and 
generally beneficial effects. For example, "agent" includes therapeutic 
compounds and molecules from all therapeutic categories including, but not 
limited to, anti-infectives (such as antibiotics and antivirals), 
analgesics (such as fentanyl, sufentanil, buprenorphine, and analgesic 
combinations), anesthetics, antiarthritics, antiasthmatics (such as 
terbutaline), anticonvulsants, antidepressants, antidiabetics, 
antidiarrheals, antihistamines, anti-inflammatories, antimigranes, 
antimotion sickness preparations (such as scopolamine and ondansetron), 
antineoplastics, antiparkinsonisms, antipruritics, antipsychotics, 
antipyretics, antispasmodics (including gastrointestinal and urinary), 
anticholinergics, sympathomimetrics, xanthine and derivatives thereof, 
cardiovascular preparations (including calcium channel blockers such as 
nifedipine, beta-agonists (such as dobutamine and ritodrine), beta 
blockers, antiarrythmics, antihypertensives (such as atenolol), ACE 
inhibitors (such as lisinopril), diuretics, vasodilators (including 
general, coronary, peripheral and cerebral), central nervous system 
stimulants, cough and cold preparations, decongestants, diagnostics, 
hormones (such as parathyroid hormones), hypnotics, immunosuppressives, 
muscle relaxants, parasympatholytics, parasympathomimetrics, 
prostaglandins, proteins, peptides, psychostimulants, sedatives and 
tranquilizers. 
More preferably, the electrotransport device of the present invention 
delivers drugs and/or agents including baclofen, beclomethasone, 
betamethasone, buspirone, cromolyn sodium, diltiazem, doxazosin, 
droperidol, encainide, fentanyl, hydrocortisone, indomethacin, ketoprofen, 
lidocaine, methotrexate, metoclopramide, miconazole, midazolam, 
nicardipine, piroxicam, prazosin, scopolamine, sufentanil, terbutaline, 
testosterone, tetracaine and verapamil. 
In an exemplary embodiment, the electrotransport device of the present 
invention also delivers peptides, polypeptides, proteins and other 
macromolecules. Such molecules are known in the art to be difficult to 
deliver transdermally or transmucosally due to their size. For example, 
such molecules may have molecular weights in the range of 300-40,000 
daltons and include, but not limited to, LHRH and analogs thereof (such as 
buserelin, gosserelin, gonadorelin, naphrelin and leuprolide), GHRH, GHRF, 
insulin, insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH, 
NT-36 or N[[(s)-4-oxo-2-azetidinyl]carbonyl]L-histidyl-L-prolinamide], 
liprecin, pituitary hormones (such as HGH, HMG, HCG, desmopressin 
acetate), follicile luteoids, .alpha.-ANF, growth factor releasing factor 
(GFRF), .beta.-MSH, somatostatin, bradykinin, somatotropin, 
platelet-derived growth factor, asparaginase, bleomycin sulfate, 
chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin 
(ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), 
glucagon, hirulog, hyaluronidase, interferon, interleukin-2, menotropins 
(such as urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue 
plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analogs, 
ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic 
hormone agonists, antidiuretic hormone antagonists, bradykinin 
antagonists, CD4, ceredase, CSF's, enkephalins, FAB fragments, IgE peptide 
suppressors, IGF-1, neurotrophic factors, colony stimulating factors, 
parathyroid hormone and agonists, parathyroid hormone antagonists, 
prostaglandin antagonists, pentigetide, protein C, protein S, renin 
inhibitors, thymosin alpha-1 antitrypsin (recombinant), and TGF-beta. 
The electrotransport device of the present invention is particularly 
advantageous for delivering high potency drugs and drugs having dangerous 
side effects, such as narcotics. For example, the present membrane 
assembly can prevent or significantly reduce the risk of overdosing 
(inadvertent or intentional) by eliminating or substantially reducing 
passive flux of the drug or agent. 
As shown in FIG. 5, the membrane assembly 60 may be sealed with an adhesive 
along peripheral interface 68. An adhesive is particularly preferred when 
the membranes do not heat/pressure seal well or when the membranes do not 
self-adhere. Preferred adhesives include STAYBELITE.TM. ester Nos. 5 and 
10; or, REGAL-REZ.TM. or PICCOTAC.TM. available from Hercules Corporation 
of New Jersey. 
As shown in FIG. 5, the membrane assembly 60 may also be sealed by 
employing upper and lower high porosity membranes 62,66 that are 
self-adhering along the peripheral surface interface 68. When sealed, the 
low porosity membrane 64 is contained within the high porosity membranes 
62,66. Preferred self-adhering materials include polystyrenebutadiene, 
poly(styrene-isoprene-styrene) block copolymers, polyisobutylene 
copolymers, and the polymers disclosed in U.S. Pat. Nos. 4,391,278; 
4,474,570; and 4,702,732, which are incorporated herein by reference. 
Having generally described the invention and described in detail the 
preferred embodiments thereof, it will be readily apparent that the 
invention may be modified or equivalents substituted thereof without 
departing from the scope of the invention.