Thin polymer film drug reservoirs

The present invention relates to hydratable drug reservoir films for electrotransport drug delivery devices and to electrotransport drug delivery systems containing the hydratable drug reservoirs and to methods for manufacturing and using such systems. The hydratable reservoir films according to this invention are easily manufacturable and rapidly imbibe water and/or drug solution with good water retention and stability.

TECHNICAL FIELD
 The present invention relates to transdermal drug delivery. More
 particularly and without limitation, the present invention relates to thin
 film, anhydrous, hydratable drug reservoir materials useful as a drug
 reservoir material for transdermal drug delivery devices. The present
 invention relates to transdermal drug delivery systems containing the
 hydratable drug reservoirs and to methods for manufacturing and using such
 systems.
 BACKGROUND OF THE INVENTION
 Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is
 defined to be "the introduction, by means of electric current, of ions of
 soluble salts into the tissues of the body for therapeutic purposes."
 lontophoretic devices have been known since the early 1900's. British
 patent specification No. 410,009 (1934) describes an iontophoretic device
 which overcame one of the disadvantages of such early devices known to the
 art at that time, namely the requirement of a special low tension (low
 voltage) source of current which meant that the patient needed to be
 immobilized near such source. The device of the British patent
 specification was made by forming a galvanic cell from the electrodes and
 the material containing the medicament or drug to be delivered
 transdermally. The galvanic cell produced the current necessary for
 iontophoretically delivering the medicament. This ambulatory device thus
 permitted iontophoretic drug delivery with substantially less interference
 with the patient's daily activity.
 More recently, a number of United States patents have issued in the
 electrolytic transdermal delivery field, indicating a renewed interest in
 this mode of drug delivery. For example, U.S. Pat. No. 3,991,755 issued to
 Vernon et al., U.S. Pat. No. 4,141,359 issued to Jacobsen et al., U.S.
 Pat. No. 4,398,545 issued to Wilson, and U.S. Pat. No. 4,250,878 issued to
 Jacobsen disclose examples of iontophoretic devices and some applications
 thereof. The iontophoresis process has been found to be useful in the
 transdermal administration of medicaments or drugs including lidocaine
 hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium
 phosphate, insulin and many other drugs. Perhaps the most common use of
 iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine
 salts iontophoretically. The pilocarpine stimulates sweat production; the
 sweat is then collected and analyzed for its chloride content to detect
 the presence of the disease.
 In presently known iontophoretic devices, at least two electrodes are used.
 Both of these electrodes are disposed so as to be in intimate electrical
 contact with some portion of the skin of the body. One electrode, called
 the active or donor electrode, is the electrode from which the ionic
 substance, medicament, drug precursor or drug is delivered into the body
 by iontophoresis. The other electrode, called the counter or return
 electrode, serves to close the electrical circuit through the body. In
 conjunction with the patient's skin contacted by the electrodes, the
 circuit is completed by connection of the electrodes to a source of
 electrical energy, e.g., a battery. For example, if the ionic substance to
 be delivered into the body is positively charged (i.e., a cation), then
 the anode will be the active electrode and the cathode will serve to
 complete the circuit. If the ionic substance to be delivered is negatively
 charged (i.e. an anion), then the cathode will be the active electrode and
 the anode will be the counter electrode.
 Alternatively, both the anode and cathode may be used to deliver drugs of
 opposite charge into the body. In such a case, both electrodes are
 considered to be active or donor electrodes. For example, the anode can
 deliver a positively charged ionic substance into the body while the
 cathode can deliver a negatively charged ionic substance into the body.
 It is also known that iontophoretic delivery devices can be used to deliver
 an uncharged drug or agent into the body. This is accomplished by a
 process called electroosmosis. Transdermal delivery of neutral compounds
 by the phenomenon of electroosmosis is described by Hermann Rein in
 Zeitschrift fur Biologie, Bd. 8 1, pp 125-140 (1924) and the transdermal
 delivery of non-ionic polypeptides by the phenomenon of electroosmosis is
 described in Sibalis et al., U.S. Pat. Nos. 4,878,892 and 4,940,456.
 Electroosmosis is the transdermal flux of a liquid solvent (e.g., the
 liquid solvent containing the uncharged drug or agent) which is induced by
 the presence of an electric field imposed across the skin by the donor
 electrode. Similarly, electrophoresis is the transdermal flux of both the
 solute and the liquid solvent in an electric field. As used herein, the
 terms "electrotransport" and "electrolytic transdermal delivery" encompass
 both the delivery of charged ions as well as the delivery of uncharged
 molecules by the associated phenomenons of iontophoresis, electroosmosis,
 and electrophoresis.
 Electrotransport delivery devices generally require a reservoir or source
 of the beneficial agent (which is preferably an ionized or ionizable agent
 or a precursor of such agent) to be iontophoretically delivered or
 introduced into the body. Examples of such reservoirs or sources of
 ionized or ionizable agents include a pouch or cavity as described in the
 previously mentioned Jacobsen, U.S. Pat. No. 4,250,878, a porous sponge or
 pad as disclosed in Jacobsen et al., U.S. Pat. No. 4,141,359, or a
 preformed gel body as described in Webster, U.S. Pat. No. 4,383,529, and
 Ariura et al., U.S. Pat. No. 4,474,570. Such drug reservoirs are
 electrically connected to the anode or the cathode of an electrotransport
 device to provide a fixed or renewable source of one or more desired
 agents.
 Electrotransport delivery devices which are attachable at a skin surface
 and rely on electrolyte fluids to establish electrical contact with such
 skin surfaces can be divided into at least two categories. The first
 category includes those devices which are prepackaged with the liquid
 electrolyte contained in the electrode receptacle. The second type of
 device uses dry-state electrodes whose receptacles or reservoirs are
 customarily filled with liquid drug/electrolyte immediately prior to
 application to the body. With both types of devices, the user currently
 experiences numerous problems which make their use both inconvenient and
 problematic.
 With respect to the prefilled device, storage is a major concern. Many
 drugs have poor stability when in solution. Accordingly, the shelf life of
 prefilled iontophoretic drug delivery devices with such drug solutions is
 unacceptably short. Corrosion of the electrodes and other electrical
 components is also a potential problem with prefilled devices. For
 example, the return electrode assembly will usually contain an electrolyte
 salt such as sodium chloride which over time can cause corrosion of
 metallic and other electrically conductive materials in the electrode
 assembly. Leakage is another serious problem with prefilled iontophoretic
 drug delivery devices. Leakage of drug or electrolyte from the electrode
 receptacle can result in an inoperative or defective state. Furthermore,
 such prefilled devices are difficult to apply because the protective seal
 which covers the electrode opening and retains the fluid within the
 receptacle cavity must be removed prior to application on the skin. After
 removal of this protective seal, spillage often occurs in attempting to
 place the electrode on the skin. Such spillage impairs the desired
 adhesive contact of the electrode to the skin and also voids a portion of
 the receptacle cavity. The consequent loss of drug or electrolyte fluid
 tends to disrupt electrical contact with the electrode plate contained
 therein and otherwise disrupts the preferred uniform potential gradient to
 be applied.
 Although dry-state electrodes have numerous advantages in ease of storage,
 several problems remain. For example, the drug and electrolyte receptacles
 of such a device are conventionally filled through an opening prior to
 application of the device to the patient's skin. Therefore, the same
 problem of spillage and loss of drug or electrolyte upon application
 occurs as with the pre-filled electrode.
 Frequently, such electrodes are not well structured to develop the proper
 uniform current flow required in iontophoresis applications. Such
 nonuniform current flow may result from the occurrence of air pockets
 within the receptacle cavity at the skin surface. Such effects are
 particularly troublesome in electrolytic transdermal delivery
 applications, where a nonuniform current distribution may result in
 excessive skin irritation or "burning".
 Hydrogels have been particularly favored for use as the drug reservoir
 matrix and electrolyte reservoir matrix in electrotransport delivery
 devices, in part due to their high equilibrium water content and their
 ability to absorb water from the body. In addition, hydrogels tend to have
 good biocompatibility with the skin and with mucosal membranes. However,
 since many drugs and certain electrode components are unstable in the
 presence of water, electrotransport drug delivery devices having a drug
 reservoir formed of a prehydrated hydrogel may also have unacceptably
 short shelf life. In particular, certain therapeutic agents have a limited
 shelf life at ambient temperature in an aqueous environment. Notable
 examples are insulin and prostaglandin sodium salt (PGE.sub.1).
 One proposed solution to the drug stability problem is to use hydrophilic
 polymer drug and electrolyte reservoirs which are in a substantially dry
 or anhydrous state, i.e. in a non-hydrated condition. The drug and/or
 electrolyte can be dry blended with the hydrophilic polymer and then cast
 or extruded to form a non-hydrated, though hydratable, drug or electrolyte
 containing reservoir. Alternative methods also involve the evaporation of
 water and/or solvent from solution or emulsion polymers to form a dry
 polymer film. This process is energy intensive, however, and requires a
 large capital investment for equipment.
 In addition, the prior art non-hydrated hydrophilic polymer components must
 first absorb sufficient quantities of water from the body before the
 device can operate to deliver drug. This delay makes many devices unsuited
 for their intended purpose. For example, when using an iontophoretic
 delivery device to apply a local anesthetic in preparation for a minor
 surgery (e.g. surgical removal of a mole), the surgeon and the patient
 must wait until the drug and electrolyte reservoirs of the delivery device
 become sufficiently hydrated before the anesthetic is delivered in
 sufficient quantities to induce anesthesia. Similar delays are encountered
 with other drugs.
 In response to these difficulties, Konno et al., in U.S. Pat. No.
 4,842,577, disclose in FIG. 4 an electrotransport device having a
 substantially non-hydrated drug containing layer or membrane filter and a
 separate water reservoir which is initially sealed, using a foil sheet,
 from the drug containing portions of the electrode. Unfortunately, this
 electrode design is not only difficult to manufacture but also is subject
 to severe handling restriction. In particular, there is a tendency for the
 foil seal to be inadvertently broken during manufacture, packaging, and
 handling of the electrode. This can have particularly drastic consequences
 especially when the seal is broken during manufacture of the device. Once
 the seal is broken, water is wicked into the drug-containing reservoir
 which can cause degradation of the drug and/or other components before the
 device is ever used.
 Hydratable iontophoretic devices are known in the electrotransport art as
 disclosed in U.S. Pat. Nos. 5,158,537, 5,310,404, and 5,385,543, which are
 hereby incorporated in their entirety by reference. The reservoirs of
 these devices are preferably composed, at least in part, of a hydrophilic,
 natural or synthetic polymer material. Reservoir materials including
 low-substituted hydroxy propyl cellulose and hydrogels such as
 polyhydroxyethyl methacrylate are disclosed. The reservoir matrix may also
 include a hydrophobic polymer such as polyurethanes in order to enhance
 lamination of the reservoir to adjacent layers. Preferred hydroxypropyl
 cellulose and hydrophilic polyurethane compositions are not disclosed.
 Additionally, WO 92/20324 discloses polyurethane hydrogel compositions for
 iontophoretic drug delivery. These polyurethane hydrogel compositions are
 prepared by dissolving an isocyanate-capped oxyalkylene-based polymer in a
 first solvent which comprises an anhydrous aprotic organic solvent to give
 a prepolymer solution. The prepolymer solution is then mixed with a second
 solvent which comprises water and optionally a water-miscible organic
 solvent to give a hydrogel forming mixture, which is then allowed to cure
 to give a hydrogel matrix. The hydrogels may alternately be prepared by
 mixing the isocyanate-capped oxyalkylene-based prepolymer in a total
 solvent comprising water and a water-miscible organic solvent to give the
 hydrogel forming mixture. Additional hydratable drug reservoirs for
 iontophoretic drug delivery devices are disclosed in U.S. Pat. Nos.
 5,087,242 and 5,328,455, which are hereby incorporated in their entirety
 by reference.
 The hydrophilic polymer components of the hydratable reservoir materials of
 the prior art typically require an extensive cure step to process the
 polymers which typically involves high temperatures. Heat sensitive drugs
 and/or excipients can not be processed at such high temperatures without
 degradation. Furthermore, such processing requires additional dispensing,
 casting and/or curing equipment.
 Another disadvantage of using non-hydrated hydrophilic polymer components
 is that they have a tendency to delaminate from other parts of the
 electrode assembly during hydration. For example, when utilizing a drug
 reservoir matrix or an electrolyte reservoir matrix composed of a
 hydrophilic polymer, the matrix begins to swell as it absorbs water from
 the skin. In the case of hydrogels, the swelling is quite pronounced.
 Typically, the drug or electrolyte reservoir is in either direct contact,
 or contact through a thin layer of an ionically conductive adhesive, with
 an electrode. Typically, the electrode is composed of metal (e.g., a metal
 foil or a thin layer of metal deposited on a backing layer) or a
 hydrophobic polymer containing a conductive filler (e.g., a hydrophobic
 polymer loaded with carbon fibers and/or metal particles). Unlike the
 hydrophilic drug and electrolyte reservoirs, the electrodes do not absorb
 water and do not swell. The different swelling properties of the
 hydrophilic reservoirs and the electrodes results in shearing along their
 contact surfaces. In severe cases, the shearing can result in the complete
 loss of electrical contact between the electrode and the drug/electrolyte
 reservoir resulting in an inoperable device.
 Thus, there remains a need for an easily manufacturable, anhydrous drug
 reservoir with an extended shelf life that can be manufactured at lower
 temperatures and which rapidly imbibes water and/or drug solution with
 good water retention and stability.
 SUMMARY OF THE INVENTION
 Accordingly, it is an aspect of the present invention to provide an
 electrotransport drug delivery device with drug containing electrode
 components which are manufactured in an initially free non-hydrated
 condition but which can be quickly hydrated during processing with stable
 drugs or hydrated by the end-user with unstable drugs prior to placement
 on the body.
 It is another aspect of this invention to provide a hydratable drug
 reservoir material for an electrotransport device that can be processed at
 temperatures sufficient for melt-mixing heat sensitive drugs and/or
 excipients without causing degradation thereof.
 It is another aspect of this invention to provide drug reservoir films for
 electrotransport drug delivery devices that are flexible and conformable
 to skin or other body tissue in order to make intimate contact therewith.
 It is yet another aspect of this invention to provide hydratable drug
 reservoir films for electrotransport drug delivery devices which overcome
 the problems associated with the prior art hydratable drug reservoirs.
 These and other aspects of the present invention will be apparent from the
 drawings and detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION
 According to the present invention, hydratable films are provided which are
 particularly well suited as the drug reservoir for an electrotransport
 drug delivery device. The films of the invention are flexible and
 conformable and quickly imbibe a hydrating liquid and/or drug solution.
 The films can retain drug solution for periods of up to 2 years without
 syneresis and loss of stability. Drug solution can be imbibed into the
 film during processing and the resulting gel or swollen film used as a
 drug reservoir in an electrotransport device, or the drug can be
 incorporated into the film as a solid or liquid component during
 processing then made part of the electrotransport device in which the
 end-user imbibes a calculated amount of water or water-excipient mixture
 to form the drug reservoir just prior to activation. According to another
 embodiment, devices are manufactured without any drug solution, which is
 then imbibed into the drug reservoir just prior to use.
 With reference to the drawings, electrotransport delivery device 10
 includes a donor electrode assembly 12 and a counter electrode assembly
 14. The donor electrode assembly 12 and the counter electrode assembly 14
 are physically attached to an insulator 16 and form a single
 self-contained unit. Insulator 16 prevents the electrode assemblies 12 and
 14 from short circuiting the body by preventing electrical and/or ion
 transport between the electrode assemblies 12 and 14. Electrode assemblies
 12 and 14 are connected in series, by appropriate electrical conductors as
 known in the art such as metal foils, wires, printed circuits, or
 electrically conductive films (not shown), with an electrical power
 source. The power source and the electrical conductors are schematically
 shown as layer 18. The power source used to power device 10 is typically
 one or more low voltage batteries. A water impermeable backing layer 20
 may preferably cover layer 18 with its associated electrical components.
 The donor electrode assembly 12 typically includes an electrode layer 22
 and a reservoir layer 24 containing the beneficial agent to be
 iontophoretically delivered by device 10. A rate controlling membrane
 layer 26 may optionally be positioned between the reservoir layer 24 and
 the body surface for preventing the delivery of agent to the body surface
 when the device is turned off. Counter electrode assembly 14 contacts the
 body surface at a location spaced apart from electrode assembly 12.
 Counter electrode assembly 14 includes an electrode layer 28 and a
 reservoir layer 30. Device 10 may be adhered to the body surface by means
 of ion-conducting adhesive layers 32, 34. As an alternative to the
 ion-conducting adhesive layers 32, 34 shown in FIG. 1, device 10 may be
 adhered to the body surface using an adhesive overlay. Any of the
 conventional adhesive overlays used to secure passive transdermal delivery
 devices to the skin may be used in the present invention.
 When used in connection with the reservoir 24 or the electrode assembly 12,
 the term "agent" refers to beneficial agents, such as drugs, within the
 class which can be delivered through body surfaces. The expression "drug"
 is intended to have a broad interpretation as any therapeutically active
 substance which is delivered to a living organism to produce a desired,
 usually beneficial effect. In general, this includes therapeutic agents in
 all of the major therapeutic areas including, but not limited to,
 anti-infectives such as antibiotics and antiviral agents, analgesics and
 analgesic combinations, anesthetics, anorexics, antiarthritics,
 antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic
 agents, antidiarrheals, antihistamines, anti-inflammatory agents,
 antimigraine preparations, antimotion sickness preparations,
 antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,
 antipsychotics, antipyretics, antispasmodics, including gastrointestinal
 and urinary, anticholinergics, sympathomimetrics, xanthine derivatives,
 cardiovascular preparations including calcium channel blockers,
 beta-blockers, antiarrythmics, antihypertensives, diuretics,
 vasodiloators, including general, coronary, peripheral and cerebral,
 central nervous system stimulants, cough and cold preparations,
 decongestants, diagnostics, hormones, hypnotics, immunosuppressives,
 muscle relaxants, parasympatholytics, parasympathomimetrics, proteins,
 peptides, psychostimulants, sedatives and tranquilizers.
 The present electrotransport delivery system is particularly useful in the
 controlled delivery of peptides, polypeptides, proteins, macromolecules
 and other drugs which have a tendency to be unstable, hydrolyzed,
 oxidized, denatured or otherwise degraded in the presence of the liquid,
 such as water, which is necessary to conduct iontophoresis. For example,
 drugs containing either an ester bond (i.e., steroids) or an amide bond
 (i.e., peptides) may be hydrolyzed in water. Specific examples of drugs
 which can become degraded in the presence of water include catechols, such
 as apomorphine and epinephrine, salbutamol, sulfhydryls such as captopril,
 niphedipine and peptides such as VIP and insulin. Examples of other
 peptides and proteins which may be delivered using the device of the
 present invention are set forth with particularity in U.S. Pat. No.
 5,158,537 issued to Haak et al., and assigned to the present assignee, the
 entire contents of which are hereby incorporated by reference. Preferred
 agents for electrotransport delivery according to this invention include
 fentanyl, LHRH and analogs thereof, and insulin.
 When the device 10 is in storage, no current flows because the device does
 not form a closed circuit. When the device is activated and placed on the
 skin or mucosal membrane of a patient and the electrode assemblies 12 and
 14 are sufficiently hydrated to allow ions to flow through the various
 layers of the electrode assemblies, the circuit between the electrodes is
 closed and the power source begins to deliver current through the device
 and through the body of the patient. The donor and counter electrode
 assemblies 12 and 14 normally include a strippable release liner (not
 shown) which is removed prior to application of the electrode assemblies
 to the body surface. In certain instances, it may also be desirable for
 the delivery of the beneficial agent through the device 10 to be
 controlled by the user through a user-actuated switch (not shown).
 In accordance with the present invention, the donor reservoir 24 is an
 anhydrous hydrophilic polymer film containing a therapeutic agent. The
 reservoir is maintained in a dry state for storage, and then hydrated when
 ready for use. Hydration of the hydrophilic reservoir film may occur in
 any known manner, as described in further detail below and as described in
 the above-cited patents.
 The films according to this invention are thin, flexible, and conformable
 to provide intimate contact with a body surface, are capable of rapid
 hydration and also are able to release an agent from the reservoir at
 rates sufficient to achieve therapeutically effective transdermal fluxes
 of agent. The compositional ranges of the polymers used to make the films
 of this invention enable this unexpected combination of properties.
 The films of this invention are manufactured from hydrophilic base polymers
 and optional excipients such as hygroscopic additives to improve the
 kinetics of drug solution and/or water absorption, and/or plasticizers to
 aid in melt processing as well as rendering the film more flexible after
 being imbibed with the drug solution. The films do not need to be
 cross-linked although cross-linking is possible. The hydratable reservoir
 films according to this invention must absorb at least 1.5 times,
 preferably about 4-25 times their weight in water while maintaining their
 mechanical properties.
 According to a particularly preferred embodiment, the films comprise a
 shear modulus, G' (0.1 Hz), within the range of about 1-100 kPa,
 preferably 1-20 kPa, when at about 400% hydration in order to provide
 desired flexibility and conformability. The films according to this
 embodiment are capable of absorbing about 400-800% of their weight in
 water, preferably about 500-700%, within about 30 minutes, preferably
 within about 20 minutes, and most preferably within about 1 minute.
 Preferably, the base polymer for the films are hydrophilic polyurethanes
 or hydroxypropyl cellulose (HPC). Most preferably, the films are
 polyurethane films based on diisocyanate/polyglycol and glycol linkages
 wherein the glycol is polyethylene glycol.
 No additives are necessary for the preferred polyurethane films in order to
 attain the desired rate of absorption and flexibility. Preferred
 polyurethane films according to this invention are polyurethanes made by
 reacting polyethylene glycol with diisocyanates and butanediol and include
 Tecogel.RTM. polyurethanes manufactured by Thermedics of Woburn, Mass.,
 such as Tecogel-500 and Tecogel-2000 series. The relative amount of
 polyethylene glycol to the other components is adjusted to between 60-95%,
 preferably about 70-90% of the total weight of the dry matrix. According
 to another embodiment, a blend of polyethylene oxide and polyethylene
 glycol with the polyurethane is used in the same ratios.
 Other hydrophilic polymers, such as polypropylene oxide and polyethylene
 oxide, either singly or in any possible combination with polyethylene
 glycol, can be used in place of the polyethylene glycol alone, when
 synthesizing the polyurethane.
 For the HPC films of this invention, additives are necessary to render the
 HPC film flexible and absorbent. Preferably, the hydratable HPC films
 according to this invention comprise (by weight %) 50-90% HPC such as
 Klucel.RTM. HF grade from Aqualon, 10-30% silica gel or Sephadex.RTM., and
 5-30% plasticizer, such as glycerin, propylene glycol, or polyethylene
 glycol, for example.
 According to another preferred embodiment, at least one scrim layer
 comprised of a hydrophilic material is added to at least one surface of
 the hydratable film layer. According to this embodiment, a scrim layer may
 be placed on either surface of the hydratable film layer, or interposed
 between two hydratable film layers. Alternately, multiple repeating layers
 of hydratable film and scrim layers may be used according to this
 embodiment such as to form, for example, an assembly comprising hydratable
 film/scrim/hydratable film/scrim/hydratable film. The reservoir assemblies
 according to this embodiment provide additional mechanical integrity
 and/or increased hydration rates. Additionally, the scrim layer provides a
 surface which may be laminated to an electrode. According to this
 embodiment, the water absorption kinetics can be increased to less than a
 few minutes, preferably less than 1 minute. The scrim is a hydrophilic
 material including, but not limited to, non-woven cloths or fabric
 materials such as Rayon.RTM., Rayon.RTM./Polyester blends, or polyvinyl
 alcohol foams.
 The present invention is also directed to methods for manufacturing devices
 comprising the drug reservoir films according to this invention. According
 to one embodiment, drug solution can be imbibed into the film during
 processing. The formation of the hydrophilic therapeutic drug/polymer
 reservoir films in accordance with this embodiment of the present
 invention includes the dissolution of the therapeutic agent in aqueous
 media or a water/organic solvent mixture in order to obtain a low
 viscosity solution. A suitable solvent would include water, ethanol,
 isopropanol or a combination of water and an organic solvent. The drug
 solution may be prepared at ambient or less than ambient temperature for
 thermally sensitive molecules. In addition, the drug solutions may be
 mixed with relatively low shear mixing equipment which substantially
 prevents degradation of shear sensitive molecules.
 Once prepared, the solution of the therapeutic agent is applied to the
 surface of a selected hydrophilic polymer film. Hydrophilic within the
 terms of the present invention includes all polymers having a liquid
 absorption rate of generally 1-10 .mu.l/cm.sup.2 /sec or greater. The film
 would be unwound from a roll and die-cut into the appropriate size and
 shape. Drug solution would then be dispensed onto the film on-line. After
 a suitable time period for absorption of the drug solution into the film
 (maximum of 10-20 minutes), the film would be covered with a liner and
 then proceed to the next step. No end-user intervention is required.
 According to another embodiment, drug is incorporated into the film as a
 solid and/or liquid component during processing and subsequently made part
 of an electrotransport device. The end-user then imbibes a preselected
 amount of water or water/excipient mixture to hydrate the film just prior
 to use. According to this embodiment, agent is first dispersed and/or
 dissolved in the drug reservoir material by mixing and thereafter the film
 is extruded. In this embodiment, the manufacturer or end-user then adds
 sufficient water (or other suitable hydrating liquid) to make a swollen
 drug/polymer mixture for intimate contact to the skin. Alternatively, the
 end-user can incorporate drug solution in place of the hydrating liquid,
 in which case the device is provided initially free of agent. Other
 sources of a hydrating material could of course also be used in the
 present invention, such as, for example, a liquid pouch as described in
 U.S. Pat. No. 5,158,537 or a liquid passageway as described in U.S. Pat.
 No. 5,385,543, the contents of both of which are hereby incorporated by
 reference.
 The solution may be applied to the hydrophilic polymer film using a variety
 of techniques including spraying, BioDot or any other type of micrometer
 dispensing, dipping, volumetric metering, or other suitable coating
 technology. Low viscosity liquids, such as the therapeutic agent solution,
 are easily and reproducibly dispensed with a volumetric metering pump.
 The overall size of the anhydrous films will of course vary dependent upon
 the therapeutic agent and the amount thereof contained therein, but
 generally, anhydrous films on the order of 1 to 12 cm.sup.2 will be cut
 for placement into the appropriate reservoirs of the electrotransport
 system.
 Thus, the preparation of the therapeutic agent/hydrophilic polymer film
 affords a dry polymer matrix which enhances the storage stability of drug
 molecules that do not possess long term stability in an aqueous
 environment. In the anhydrous state, the polymer matrix has an extended
 shelf life and is not subject to the disadvantages and problems
 encountered with the storage of water sensitive therapeutic agents.
 The therapeutic agent/hydrophilic membrane of the present invention is very
 thin, generally on the order of two to sixty mils, (50.8 microns to 1524
 microns), more preferably 6 to 30 mils (152.4 microns to 762 microns). The
 rate of hydration obtained in the present invention is therefore rapid.
 Thus, the electrotransport of the therapeutic agent is not delayed as in
 the prior art devices. The hydrated membrane also remains firmly adhered
 to the hydrogel, which is partially due to the dimensional stability of
 the hydrated film. According to the embodiments wherein a scrim layer is
 used, the combined thickness of the hydratable film layer(s) and scrim
 layer is about 2-60 mils (50.8 microns to 1524 microns), preferably 6-30
 mils (152.4 microns to 762 microns).
 EXAMPLE 1
 In vitro studies were conducted in 2 compartment electrotransport cells.
 Each cell consisted of a donor housing thick enough to contain the swollen
 hydrogel and a 450 .mu.l receptor compartment fitted with circular
 polypropylene grid to prevent bowing of the skin into the receptor
 compartment. The anode electrode was silver foil, and the cathode
 electrode was silver chloride/PIB composite. To determine if holes or
 tears were present in the human cadaver epidermis, an initial sample was
 collected after an equilibration time without applied current and analyzed
 by HPLC. A cell was designated a leaker if drug was present in the passive
 time point receptor sample. The flow rate of receptor buffer was 250
 .mu.l/hr, and vials collecting the receptor solution (1:10 dilution of
 Dulbeco's phosphate saline buffer) were changed every 1.92 hours by a
 fraction which was maintained at 4.degree. C.
 5/16+L " diameter discs of hydrogel (Tecogel 1000S, Thermedics, Woburn
 Mass.) at a thickness of 20 mils (508 mcirons) were die-cut and weighed.
 The discs were then placed in the donor housing and hydrated with 2.5
 times their weight in drug solution. The LHRH drug solution had a
 concentration of 15 mM. The fentanyl solutions were made with sufficient
 fentanyl HCl to yield a final drug concentration in the hydrogel of 2 wt
 %. After sitting 10 minutes, a PET liner was applied to the housing to
 prevent further evaporation. The discs were allowed to hydrate
 approximately 30 minutes before conducting the flux tests.
 Since LHRH and fentanyl are positively charged in the pH range studied (pH
 5-8 for LHRH, pH 4-6.5 for fentanyl), only anodic drive experiments were
 performed; i.e. electrical current was applied such that the donor was
 anodically polarized with respect to the receptor. All studies were
 performed at 32.degree. C. maintained by aluminum heat blocks and
 controllers with at least three replications per condition. Each cell was
 connected in series to a constant current source set to obtain a current
 density of 100 .mu.A/cm.sup.2, and the voltage drop across the cell was
 measured and recorded every 20 minutes.
 The flux results for LHRH and fentanyl are shown in FIG. 2.
 While the invention has been described in detail with reference to the
 preferred embodiments thereof, it will be apparent to one skilled in the
 art that various changes and modifications can be made and equivalents
 employed, without departing from the present invention.