MXPA01004370A - Electrotransport device including a compatible antimicrobial agent - Google Patents

Abstract

A transdermal electrotransport drug delivery device (10) having an anode, a cathode and a source of electrical power electrically connected to the anode and the cathode. The cathode includes a cathodic electrode (24) and a cathodic reservoir (28) comprised of a housing composed of a polymeric material and an aqueous medium in contact with the housing. The aqueous medium includes i) a drug or an electrolyte salt or a mixture thereof and ii) a cetylpyridinium salt in an amount sufficient to inhibit microbial growth in the aqueous medium. The polymeric material is compatible with the cetylpyridinium salt. A process is also provided wherein when electric current flows from the source of electrical power so that the drug is transdermally deliveredto the patient by electrotransport from the anodic reservoir, the cetylpyridinium salt is not transdermally delivered to the patient by electrotransport from the cathodic reservoir.

Description

ELECTROTRANSPORTE DEVICE THAT INCLUDES A COMPATIBLE ANTIMICROBIAL AGENT BACKGROUND OF THE INVENTION A. Field of the Invention The present invention relates to a transdermal electrotransport delivery device that includes a cathode vessel containing an antimicrobial agent that is compatible with the cathode vessel material. The present invention further relates to a process for transdermally delivering a drug to a patient by electrotransport from a drug delivery device and a process for preparing a transdermal electrotransport delivery device.

B. Description of the Prior Art Transdermal drug delivery, by diffusion through the epidermis, offers improvements over more traditional delivery methods, such as subcutaneous injections and oral delivery. Transdermal drug delivery also avoids the hepatic first pass effect found with oral drug delivery. As used in the past, the term "transdermal" delivery broadly encompasses the delivery of an agent through a body surface, such as skin, mucosa, nails or other body surfaces (e.g., a surface of an organ) of an animal.

The skin functions as the primary barrier to transdermal penetration of materials in the body and represents the body's main resistance to the transdermal delivery of beneficial agents such as drugs. To date, efforts have focused on reducing the physical resistance or improving the permeability of the skin for drug delivery by passive diffusion. Various methods have been tried to increase the rate of transdermal flow of drugs, most notably by the use of chemical flow improvers. Other approaches to increasing the rates of transdermal drug supplies include the use of alternative sources of energy, such as electric power and ultrasonic energy. The electrically assisted transdermal supply is also referred to as electric transport. As used herein, the term "electrotransport" generally refers to the delivery of a beneficial agent (i.e., a drug) through a membrane, such as skin, mucous membrane, nails or other bodily surfaces that are induced. or help by applying an electric potential. For example, a beneficial agent can be introduced into the systemic circulation of a human body by electrotransport delivery through the skin. A widely used electrotransport process, referred to as electromigration (also called iontophoresis), involves the electrically induced transport of charged ions. Another type of electrotransport, referred to as electroosmosis, involves the flow of a liquid, whose liquid contains the agent to be delivered, under the influence of an electric field. Yet another type of electrotransport process, referred to as electroporation, involves the formation of transiently existing pores in a biological membrane by the application of an electric field. An agent can be delivered transdermally either passively (i.e., without electrical assistance) or actively (i.e., under the influence of an electrical potential). However, in any given electrotransport process, more than one of these processes, including at least some "passive" diffusion, can occur simultaneously to a certain degree. According to the foregoing, as used herein, the term "electrotransport" is given in its broadest possible interpretation in order to include the electrically induced or improved transport of at least one agent, which can be charged, without charge or a mixture thereof, whatever the specific mechanism or mechanisms by which the agent is actually transported. The electrotransport delivery device uses at least two electrodes that are in electrical contact with a certain portion of the skin, nails, mucous membrane or other surface of the body. An electrode, commonly called the "donor" electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically called the "counter" electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, ie, a cation, then the anodic electrode is the donor electrode, while the cathode electrode is the counter electrode serving to complete the circuit. Alternatively, if an agent is charged in a negative manner, ie, an anion, the cathode electrode is the donor electrode and the anodic electrode is the counter electrode. Additionally, both electrodes, anodic and cathodic, can be considered donor electrodes if both anionic and cationic agent ions are to be delivered, or the dissolved agents without charge. In addition, the electrotransport delivery devices require at least one container or source of the beneficial agent to be delivered to the body. Examples of such donor containers include a pouch or cavity, a porous sponge or pad and a hydrophilic polymer or gel matrix. Such donor vessels are electrically connected to, and placed between, the anodic or cathode electrodes and the body surface, in order to provide a fixed or renewable source of one or more beneficial agents. The electrotransport devices also have a source of electrical energy such as one or more batteries. Typically, at any time, a pole of a power source is electrically connected to the counter electrode. Since it has been demonstrated that the speed of electrotransport delivery of drugs is roughly proportional to the electrical current applied by the device, many electrotransport devices typically have an electrical controller that controls the voltage and / or current applied through the electrodes. , thus regulating the speed of drug delivery. These control circuits use a variety of electrical components to control the amplitude, polarity, synchronization, waveform configuration, etc. of the electric current and / or voltage supplied by the power source. See, for example, McNichosI et al. , Patent of E.U. 5,047,007. In the U.S. Patent 5,169,384 of Bosniak et al. An iontophoretic and variable temperature device is described for application to the body of a patient. The device can selectively apply or withdraw the thermal energy from portions of a body of a patient as well as iontophoretically administer a compound. In various embodiments, the device is configured to be applied to the face or knee of a patient. In a further development of electrotransport devices, hydrogels have been particularly favored for use as drug matrices and electrolyte vessel, in part, due to the fact that water is the preferred liquid solvent to be used in the electrotransport supply of electrotransport. drugs due to their excellent biocompatibility compared to other liquid solvents such as alcohols and glycols. Hydrogels have a high water balance content and can absorb water quickly. In addition, hydrogels tend to have good biocompatibility with the skin and mucous membranes. The electrotransport supply devices are prepared, shipped and stored (or stored, shipped and stored), prescribed and then used. As a result, the devices must have components that have a long shelf life that in some cases must comply with regulatory requirements. For example, the US Food and Drug Administration. It has requirements of useful life in deposit of from six to eighteen months for some materials. A complicating factor in obtaining a long shelf life is that the aqueous environment in the electrode vessels provides an excellent means for the development of microorganisms. According to the above, an antimicrobial agent can be incorporated into the aqueous medium of the electrode vessels to inhibit the proliferation of microorganisms. Several antimicrobial agents have been used in different environments. Known antimicrobial agents (sometimes referred to as biocides) include chlorinated hydrocarbons, organometallic, halogen releasing compounds, metal salts, organic sulfur compounds, quaternary ammonium compounds and phenolics. Illustrative compounds include sorbic acid, benzoic acid, methyl paraben and cetylpyridinium chloride. For example, the U.S. Patent. No. 5,434,144 discloses topical compositions, several of which include methyl paraben or cetylpyridinium salt. In the context of electrotransport devices, the US Patent. No. 5,668,120 discloses in column 8, lines 16-21, that condoms, such as methyl paraben and cetylpyridinium chloride, can optionally be included in the liquid carrier of the iontophoresis medium and several of the examples of the patent include such compounds. In addition, the Patents of E.U. Nos. 4,585,652 and 5,788,666 disclose that cetylpyridinium chloride can be administered by iontophoresis while the US Patent. No. 5,298,017 describes several different types of materials that can be administered by electrotransport.

BRIEF DESCRIPTION OF THE INVENTION It has been discovered that various antimicrobial agents are absorbed in the polymeric material that constitutes the housing containing the aqueous medium, thus reducing the effectiveness of the antimicrobial agent in the aqueous medium. It has also been determined that the efficacy of the antimicrobial agent can be maintained by preventing the transdermal delivery of the antimicrobial agent to a patient by electrotransport while a drug is delivered to the patient by electrotransport. Accordingly, an aspect of the present invention relates to a transdermal electrotransport drug delivery device comprising an anode, a cathode and a power source electrically connected to the anode and the cathode, the cathode including an electrode cathode and a cathodic vessel comprised of a housing composed of a polymeric material and an aqueous medium in contact with the housing, said aqueous medium comprised of i) a drug or an electrolyte salt or a mixture thereof and ii) a salt of cetylpyridinium in an amount sufficient to inhibit microbial growth in the aqueous medium wherein said polymeric material is compatible with the cetylpyridinium salt. In a further aspect, the present invention relates to a process for transdermally delivering a drug to a patient by electrotransport of a drug delivery device comprised of an anode, a cathode and a power source electrically connected to the anode and the cathode , the anode including an anode electrode and an anode container containing a drug and the cathode including a cathode electrode and a cathode vessel composed of a polymeric material and containing an aqueous medium comprised of i) an electrolyte salt and ii) a salt of cetylpyridinium in an amount sufficient to inhibit microbial growth in the aqueous medium, said polymeric material being compatible with the cetylpyridinium salt, said process comprising the proportion of electrical current coming from the electrical energy source in order for the drug to be delivered transdermally to the patient by electrotra nsport from the anodic vessel and so that the cetylpyridinium salt is not delivered transdermally to the patient by electrotransport from the cathode vessel. In yet a further aspect, the present invention relates to a process for preparing a transdermal electrotransport drug delivery device. The process comprises the preparation of an aqueous medium comprised of i) a drug or an electrolyte salt or a mixture thereof and ii) a cetylpyridinium salt in an amount sufficient to inhibit microbial growth in the aqueous medium; and the placement of the aqueous medium in the cathode vessel of a device comprised of an anode, a cathode and a power source electrically connected to the anode and the cathode, the cathode including a cathode electrode and a cathode vessel comprised of a housing composed of a polymeric material whereby the aqueous medium is in contact with the cathodic vessel housing and wherein said polymeric material is selected in order to be compatible with the cetylpyridinium salt.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an enlarged perspective view of a drug electrotransport delivery device according to an embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT As noted above, one aspect of the present invention relates to a transdermal electrotransport drug delivery device that is designed to deliver a drug to a patient through the skin or a mucous membrane. The transdermal electrotransport drug delivery device is comprised of an anode, a cathode and a power source electrically connected to the anode and the cathode, the cathode including a cathode electrode and a cathode vessel comprised of a housing composed of a polymeric material and an aqueous medium in contact with the housing, said aqueous medium comprising i) a drug or an electrolyte salt or a mixture thereof and ii) a cetylpyridinium salt in an amount sufficient to prevent microbial growth in the aqueous medium and said polymeric material being compatible with the cetylpyridinium salt. The cetylpyridinium salt used in the present invention is a highly effective antimicrobial agent and can eliminate or at least inhibit the development of various microorganisms, both bacteria and fungi. The antimicrobial efficacy in the cathode vessel is especially pronounced in view of a pH range of from about 3 to about 7.5, preferably from about 3.5 to about 6.5, which occurs in the aqueous medium of the cathode vessel and, at lower levels of these pH ranges, it can itself provide a certain level of antibacterial activity. The cetylpyridinium salt is present in an amount sufficient to inhibit microbial growth in the aqueous medium. In general, the aqueous medium contains at least about 0.005% by weight of the cetylpyridinium salt. More specifically, the aqueous medium contains from about 0.005% to about 2% by weight of the cetylpyridinium salt and preferably contains from about 0.01% to about 1% by weight of the cetylpyridinium salt. When calculating the weight of the aqueous medium, the amount of the gel matrix is not included (to the extent that it occurs). The cetylpyridinium salt may be a cetylpyridinium halide salt or a mixture thereof. The cetylpyridinium salt is preferably a cetylpyridinium halide salt and cetylpyridinium chloride is especially preferred. The cetipyridinium salt can be used in the cathode vessel of substantially any transdermal electrotransport delivery device. In general, an electrotransport device provides the transdermal delivery of the drug by electrically inducing or improving the transport of the drug in a form that can be loaded, uncharged, or a mixture of both, whatever the specific mechanism or mechanisms by the which the drug is transported. Electrotransport is based on the electrical potential to increase the flow or rate of delivery of the drug as compared to passive (ie, non-electrically assisted) transdermal delivery systems that deliver a drug through the skin solely by diffusion. A particularly applicable mechanism is through iontophoresis, where the drug is administered in a charged (ionized) form. As discussed further above, when the drug is to be administered as a cation, the drug is originally presented in an anodic container of the drug delivery device. On the other hand, when the drug is to be administered as an anion, the drug is originally presented in a cathode container of the drug delivery device. It is also possible to have drugs in both cationic and anionic forms, which are supplied simultaneously from the anodic vessel and cathode vessel, respectively. Any drug that can be delivered transdermally by electrotransport can be used with the present invention, including, without limitation, anti-infectives such as antibiotics and antiviral agents.; analgesics such as fentanyl, sufentanil and buprenorphine and analgesic combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents such as terbutaline; anti-convulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine preparations; preparations for antimovement diseases such as scopolamine and ondansetron; antinausea; antineoplastic; antiparkinsonism drugs; antipruritics; antipsychotic; antipyretics; antipasmodics including gastrointestinal and urinary; anticholinergic; sympathomimetics; xanthine derivatives; Cardiovascular preparations that include calcium channel blockers such as nifedipine; beta-agonists such as dobutamine and ritodrine; beta blockers; antiarrhythmics; antihypertensives such as atenolol; ACE inhibitors such as ranitidine; diuretics; vasodilators including general, coronary, peripheral and cerebral; stimulators of the central nervous system; preparations for cough and cold; decongestants; diagnostics; hormones such as parathyroid hormones; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; parasimpatomimetric; prostaglandins; proteins; peptides; psychostimulants; sedatives and tranquilizers. The most specific drugs include baclofen, beclomethasone, betamethasone, buspirone, cromolyn sodium, diltiazem, doxazosin, droperidol, encainide, fentanyl, hydrocortisone, indomethacin, acetoprofen, lidocaine, methotrexate, metoclopramide, miconazole, midazolam, micardipine, piroxicam, prazosin, scopolamine , sufentanil, terbutaline, testosterone, tetrcaine and verpamil. The present invention is also useful in the controlled delivery of peptides, polypeptides, proteins or other macromolecules difficult to deliver transdermally or transmucosally due to their size. These macromolecular substances typically have a molecular weight of at least about 300 daltons and more typically a molecular weight in the range of about 300 to 40,000 daltons. Examples of peptides and proteins that can be delivered by use of the device of the present invention include, without limitation, LHRH, LHRH analogues such as buserelin, goserelin, gonadorelin, naphrelin, naturetin, leuprolide, GHRH, GHRF, insulin, insulinotropin, heparin, calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name; N - [[(s) -4-oxo-2-azetidinyl] carbonyl] L-histidyl-L-prolinamide], liprecin, pituitary hormones (by example, HGH, HMG, HCG, desmopressin acetate), follicular luteosides, α-ANF, growth factor release factor (GFRF), β-MSH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor, asparaginase, bleomycin sulfate, chemopapain, cholecystokinin, cryonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet addition inhibitor), glucagon, hirulog, hyaluronidase, interferon, interleukin-2, meno-tropines (urofollitropin (FSH) and LH) , oxytocin na, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analogs, ANP, ANP elimination inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradikinin antagonists, CD4, ceredasa , CSF'S, enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors, colony stimulation factors, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, pentigetide, protein C, protein S, inhibitors of renin, alpha-1 thymosin, thrombolytics, TNF, vaccines, vasopressin antagonist analogs, alpha-1 antitrypsin (recombinant), and TGF-beta. Particularly preferred drugs that can be delivered by the device and process of the present invention are fentanyl and sufentanil, which are synthetic opiates that are characterized by their rapid analgesic effect and their short duration of action. They are extremely powerful and are estimated to be 80 and 800 times, respectively, more potent than morphine. Both drugs are amine compounds and therefore are weak bases whose main fraction is in cationic form in an aqueous acidic medium. When fentanyl or sufentanil is used as the drug to be administered from the anodic vessel, the cathode vessel is typically substantially free of drugs. Examples of transdermal electrotransport delivery devices of fentanyl and sufentanil are described in WO 96/39222; WO 96/39223; and WO96 / 39224, the descriptions of which are incorporated by reference. When fentanyl is used in the device, it is typically used in the form of acid addition salt, particularly the chloride salt, and the initial concentration in the aqueous medium of the anodic vessel (i.e., before any drug is administered to the patient). ) is from about 10 to about 50 mg / ml, preferably from about 20 to about 55 mg / ml based on the number of moles of fentanyl salt contained in the donor vessel, not the equivalent number of moles of fentanyl-free base. In addition, the concentration is based on the volume of the liquid solvent, not the total volume of the container. In other words, the concentration does not include the volume of the container that is represented by the container matrix (e.g., the hydrogel or other matrix material). In the context of the present invention, fentanyl is preferred over sufentanil. At a concentration of at least 5.7 mg / mL in the substantially neutral pH environment of the anodic vessel, fentanyl can provide antimicrobial properties against microorganisms such as S. aureus, E. coli, P. aeruginosa, B. pumilus spores and C. albicans At this concentration, fentanyl also inhibits the growth of other microorganisms, such as A. niger and is deadly for this fungus at concentrations of the order of 22.7 mg / mL. Accordingly, when fentanyl or a drug with similar antimicrobial properties is used as the drug to be administered to the patient from the anodic container, the anodic container need not contain a separate antimicrobial agent. The cathode electrode and the anode electrode are comprised of electrically conductive material such as a metal. For example, the electrodes can be formed from a sheet of metal, a metal screen, on metal deposited or painted on a suitable support or by lamination, evaporation of the film or by mixing the electrically conductive material in a polymer binder matrix. Examples of suitable electrically conductive materials include carbon, graphite, silver, zinc, aluminum, platinum, stainless steel, gold and titanium. For example, as noted above, the anodic electrode can be composed of silver, which can also be oxidized electrochemically. The cathode electrode can be composed of electrochemically reducible carbon and silver chloride. Silver is preferred over other metals because of its relatively low toxicity in mammals. Silver chloride is preferred because the electrochemical reduction reaction occurring at the cathode (AgCl + e "- Ag + CI") produces chloride ions that are prevalent and non-toxic in most animals. Alternatively, the electrodes can be formed from a polymer matrix containing a known conductive filler material such as a metallic powder, graphite powder, carbon fibers or other electrically conductive filler material. The polymer based electrodes can be made by mixing the conductive filler material in a polymer matrix, preferably a mixture of hydrophilic and hydrophobic polymers. Hydrophobic polymers provide structural integrity, while hydrophilic polymers can improve ion transport. For example, the zinc powder, the silver powder, the carbon powder, the carbon fibers and mixtures thereof can be mixed in a hydrophobic polymer matrix, the preferred amount of conductive filler material being within the range of about 30 to about 90 volume percent, with the balance being matrix polymer or other inert additives. The source of electrical energy electrically connected to the anode and the cathode can be of any variety. For example, if the electrodes, accountant and donor, are of dissimilar materials or have different average cellular reactions, it is possible that the system generates its own electrical energy. Typical materials that provide a galvanic couple include a zinc donor electrode and a silver chloride counter electrode. Such a combination will produce a potential of approximately one volt. When a galvanic couple is used, the donor electrode and the counter electrode are integral portions of the generation process in poivo. Such a galvanic pair powder system, absent certain control means, is activated automatically when the tissue and / or body fluids form a complete circuit with the system. There are numerous other examples of galvanic couple systems, potentially useful in the present invention. In some cases it may be necessary to increase the energy supplied by the galvanic electrode pair. This can be done with the use of a separate power source. Such an energy source is typically a battery or plurality of batteries, connected in series or in parallel, and placed between the cathode electrode and the anode electrode in such a way that one electrode is connected to one pole of the power source and the other electrode it connects to the opposite pole. Commonly, one or more 3-volt cellular button batteries are suitable for energizing electrotransport devices. A preferred battery is a 3 volt lithium button cell battery. The power source may include electronic circuitry to control the operation of the electrotransport device. In this way, the power source may include circuitry designed to allow the patient to manually turn the system on and off, such as with a demand medication regimen, or turn the system on and off at a desired periodicity, for example, to adjust the natural or circadian patterns of the body. In addition, the control means can limit the number of doses that can be administered to the patient. A relatively simple controller or microprocessor could control the current as a function of time or could generate complex current waveforms such as pulses or sine waves. The control circuitry may also include a biosensor and a certain type of feedback system that monitors biosignals, provides a determination of the therapy, and adjusts the drug delivery accordingly. A typical example is the monitoring of the level of sugar in the blood for the controlled administration of insulin. The aqueous medium in the cathode vessel, as well as also the aqueous medium typically found in the anodic vessel, can be any material adapted to absorb and contain a sufficient amount of liquid therein in order to allow the transport of the agent through the medium. of it by electrotransport. For example, gauzes, bearings or sponges composed of cotton or other absorbent fabric, both natural and synthetic, can be used. More preferably, the aqueous medium is composed, at least in part, of one or more hydrophilic polymers. Hydrophilic polymers are typically preferred because water is the preferred ionic transport medium and hydrophilic polymers have a relatively high water balance content. More preferably, the aqueous medium in the containers are polymer matrices composed, at least in part, of hydrophilic polymer. Insoluble hydrophilic polymer matrices are preferred over soluble hydrophilic polymers in view of their structural properties (e.g., less swelling after absorbing water). The aqueous medium can be a gel wherein the gel is formed of a hydrophilic polymer that is soluble or insoluble in water. Such polymers can be mixed with the components in any proportion, but preferably represent from a small percentage to about 50 percent by weight of the container. The polymers can be linear or degraded. Suitable hydrophilic polymers include copolyesters such as HYTREL® (DuPont De Nemours &; Co., Wilmington, Del.), Polyvinylpyrrolidones, polyvinyl alcohol, polyethylene oxides such as POLYOX (Union Carbide Corp.), CARBOPOL® (BF Goodrich of Akron, Ohio), polyoxyethylene blends or polyethylene glycols with polyacrylic acid such as POLYOX® mixed with CARBOPOL®, polyacrylamide, KLUCEL®, degraded dextran such as SEPHADEX® (Pharmacia Fine Chemicals, AB, Uppsala, Sweden), WATER LOCK® (Grain Processing Corp., Muscatine, Iowa) which is a polymer of starch poly-graft (sodium acrylate-co-acrylamide), cellulose derivatives such as hydroxyethyl cellulose, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose and degraded Na-carboxymethylcellulose such as Ac-DiSol (FMC Corp., Philadelphia, Pa. ), hydrogels such as polyhydroxyethyl methacrylate (National Patent Development Corp.), natural gums, chitosan, pectin, starch, guar gum, locust bean gum and the like, together with mixtures thereof. Of these, polyvinyl alcohols are preferred in an amount ranging from about 5 to about 35% by weight, preferably from about 19 to about 23% by weight of the contents of the container. This list is merely exemplary of the materials suitable for use in this invention. Other suitable hydrophilic polymers can be found in J.R. Scott & W.J. Roff, Handbook of Common Polymers (CRC Press, 1971), which is incorporated herein by reference. Optionally, a hydrophobic polymer may be present to improve the structural integrity. Preferably, the hydrophobic polymer can be fused to heat, in order to improve the lamination of adjacent layers. Suitable hydrophobic polymers include, but are not limited to, polyisobutylenes, polyethylene, polypropylene, polyisoprene and polyalkenes, rubbers, copolymers such as KRATON®, polyvinylacetate, ethylene vinyl acetate copolymers, polyamides such as nylons, polyurethanes, polyvinylchloride, acrylic or methacrylic resins. such as polymers of esters of acrylic or methacrylic acid with alcohols such as n-butanol, 1-methyl pentanol, 2-methyl pentanol, 3-methyl pentanol, 2-ethyl butanol isooctanol, n-decanol, alone or copolymerized with ethylenically non-monomers saturated such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides, N-tert-butylacrylamide, itaconic acid, N-branched alkylmaleamic acids, wherein the alkyl group has 10- 24 carbon atoms, glycol diacrylates, and mixtures thereof. Most of the aforementioned hydrophobic polymers can be fused to heat. However, the materials used in the cathode vessel should be selected so that they are compatible with the cetylpyridinium salt. The medium in the containers, anodic and cathodic, can be formed by mixing the desired drug, the electrolyte, or other component (s), with an inert polymer by processes such as melt blending, solvent melting or extrusion. Typically, the medium of the anodic container contains a drug to be delivered, while the medium of the cathode container contains an electrolyte, this is typically a biocompatible salt such as sodium chloride and the cetylpyridinium salt. The presence of the cetylpyridinium salt in the cathode vessel is advantageous because, after ionization, the cetylpyridinium cation is not delivered to the patient by electrotransport when electric current is provided in the device. In addition to the drug and the electrolyte, the anodic and cathodic containers may also contain other conventional materials such as inert fillers and the like. For example, the cathode vessel can contain from about 0.01 to about 1.0% by weight of an electrolyte salt, such as sodium chloride, from about 0.1 to about 1.0% by weight of citric acid or a comparable material and from about 0J to about 1.0% by weight of trisodium citrate dihydrate or a comparable material wherein citric acid and trisodium citrate dihydrate function as a regulatory system. In addition to a cationic drug, water and hydrogel, the anodic vessel may contain flow improvers as described in the U.S. Patent. No. 5,023,085, regulators as described in the U.S. Patent. No. 5,624,415, halide resins as described in WO 95/27530 and other known excipients. Specific additional components include sodium EDTA in an amount of from about 0.01 to about 1.0% by weight or L-histidine or HCl of L-histidine in an amount of from about 0J to about 2.5% by weight. In addition, as described in the US Patents. Nos. 5,080,646 and 5,147,296, one or more speed controlling membranes can be placed between the donor container and the body surface to control the rate at which the agent is delivered or limit the delivery of the passive agent when the energy source is located. in a "shutdown" mode. Reference is now made to Figure 1 illustrating an exemplary electrotransport device that can be used in accordance with the present invention. Figure 1 shows an enlarged perspective view of an electrotransport device 10 having an activation switch in the form of a push button switch 12 and a deployment in the form of a light emitting diode (LED) 14. device 10 comprises an upper housing 16, a circuit panel assembly 18, a lower housing 20, an anode electrode 22, cathode electrode 24, anode container 26, cathode holder 28 and skin compatible adhesive 30. Upper housing 16 has side flaps 15 that help to hold the device 10 on the skin of a patient. The upper housing 16 is preferably composed of an injection moldable elastomer (e.g., ethylene vinyl acetate). The printed circuit board assembly 18 comprises an integrated circuit 19 coupled to discrete electrical components 40 and a battery 32. The printed circuit board assembly 18 is attached to the housing 16 by posts (not shown) passing through openings 13a and 13b, the ends of the posts heating / melting in order to heat weld the circuit board assembly 18 to the housing 16. The lower housing 20 is joined to the upper housing 16 by means of adhesive 30, the upper surface 34 adhering to the same. adhesive 30 to both the lower housing 20 and the upper housing 16, including the lower surfaces of the fins 15. On the underside of the printed circuit board assembly 18 (battery) is shown (partially) a battery 32, which is preferably a cellular battery of button and more preferably a lithium cell. Other types of batteries can also be used to energize the device 10. The circuit outputs (not shown in Figure 1) of the circuit panel assembly 18 make electrical contact with the electrodes 24 and 22 through the openings 23, 23 ' in the depressions 25, 25 'formed in the lower housing, by means of electrically conductive adhesive strips 42, 42'. The electrodes 22 and 24, in turn, are in direct, mechanical and electrical contact, with the upper sides 44 ', 44 of the containers 26 and 28. The upper sides 46', 46 of the containers 26, 28 contact the patient's skin through the openings 29 ', 29 in the adhesive 30. After the depression of the push-button switch 12, the electronic circuitry in the circuit board assembly 18 supplies a predetermined DC current to the electrodes / vessels 22, 26 and 24, 28 during a delivery interval of predetermined length, for example, of about 10-20 minutes. Preferably, the device transmits to the user a visual and / or audible confirmation of the start of the drug delivery interval, or bolus, by means of a LED 14 starting to light and / or an audible sound signal coming from, for example, a bell". The analgesic drug, for example, fentanyl or sufentanil, is then delivered through the skin of the patient, for example, on the arm, during the predetermined delivery interval. In practice, a user receives feedback at the start of the drug delivery interval by visual cues (LED 14 starts to light) and / or audible (a beep from a "ringer"). The anodic electrode 22 is preferably comprised of silver and the cathode electrode 24 is preferably comprised of carbon and silver chloride charged to a polymer matrix material such as polyisobutylene. Both containers 26 and 28 are preferably composed of polymer hydrogel materials as described herein. The electrodes 22, 24 and the containers 26, 28 are retained by the lower housing 20. For the salts of fentanyl and sufentanil, the anodic container 26 in the "donor" container containing the drug and the cathode holder 28 contains a biocompatible electrolyte. and the cetylpyridinium salt. If the electrode material is composed of materials that can absorb the cetylpyridinium salt, an ion exchange membrane can be located between the electrode 24 and the container 28. Thus, for example, an anion exchange membrane (not shown in FIG. Figure 1), such as an anion exchange membrane SYBRON® or RAIPORE®, can be located between the cathode electrode 24 and the cathode vessel 28 so that the cetylpyridinium cations do not penetrate through such a membrane and therefore do not contact the cathodic electrode. The push button switch 12, the electronic circuitry in the circuit board assembly 18 and the battery 32 are adhesively "sealed" between the upper housing 16 and the lower housing 20. The upper housing 16 is preferably composed of rubber or other elastomeric material. The lower housing 20 is composed of polymeric sheet material that can be easily molded to form deprens 25, 25 'and cut to form openings 23, 23'. The lower housing, particularly the portions containing the anode container 26 and the cathode holder 28, is composed of a polymeric material. The polymeric material is compatible with the cetylpyridinium salt so that the cetylpyridinium salt is not substantially absorbed in the polymeric material. Suitable polymeric materials include polyethylene terephthalate, polyethylene terephthalate modified with cyclohexane dimethylol (referred to as polyethylene terephthalate glycol or PETG) which makes the polymer more amorphous, polypropylene and mixtures thereof. Preferred polymeric materials are polyethylene terephthalate and PETG, both of which are commercially available and more PETG is preferred. A suitable PETG is available from Easan Chemical Products, Inc. under the designation copolyester of PETG 6763 KODAR®. The assembled device 10 is preferably water resistant (i.e., splash-proof and more preferably waterproof.) The system has a low profile that easily molds to the body thus allowing freedom of movement in and around the site. The anodic container of the drug 26 and the cathode container 28 are located on the side that contacts the skin of the device 10 and are sufficiently separated to prevent an accidental electric short during normal handling and use. to the patient's body surface (for example, the skin) by means of a peripheral adhesive 30 having an upper side 34 and a side in contact with the body 36. The adhesive side 36 has adhesive properties which ensure that the device 10 remains in place in the body during the activity user's normal and still allows for his reasonable withdrawal after the predetermined period of use (for example, 24 hours). The upper adhesive side 34 adheres to the lower housing 20 and retains the electrodes and drug containers within the depressions of the housing 25, 25 ', as well as retains the lower housing 20 secured to the upper housing 16.

The device is also normally provided with a separation liner (not shown) that is initially clamped to the side that contacts the body 36 of the adhesive 30 and is removed before being attached to the patient. The release coating is typically ethylene terephthalate of siliconized polyethylene so that the cetylpyridinium salt is also compatible with this material. The push button switch 12 is located on the upper side of the device 10 and is easily operated through the clothes. A double pressure of the push button switch 12 within a short period of time, eg, three seconds, is preferably used to activate the device 10 for drug delivery, thus minimizing the likelihood of inadvertent actuation of the device 10. After Upon activating the switch, an audible alarm signals the start of drug delivery, at which time the circuit delivers a predetermined level of DC current to the electrodes / vessels during a predetermined delivery interval (e.g., 10 minutes). The LED 14 remains "on" throughout the entire supply range, indicating that the device 10 is in an active mode of drug delivery. The battery preferably has sufficient capacity to continuously energize the device 10 at the predetermined level of DC current for the entire period of use (eg, 24 hours). The integrated circuit 19 can be designed so that a predetermined amount of drug is delivered to the patient for a predetermined time and then ceases to operate until the switch is activated again and that after a predetermined number of doses have been administered, no no additional supply is possible despite the presence of additional drug in the donor container. The cathodic container material is selected so as to be compatible with the cetylpyridinium salt so that the antimicrobial efficacy of the cetylpyridinium salt within the container can be maintained even for a prolonged period, such as may be encountered during shipping and storage or storage, shipping and storage before using the transdermal electrotransport drug delivery device. This means that the material containing the aqueous medium of the cathode vessel, such as the lower housing of the device illustrated in Figure 1, is selected such that it does not absorb substantial amounts of the cetylpyridinium salt which would reduce its effectiveness in the cathode vessel. . Such material can also be used for the release coating (not shown) which is typically placed on the contacting surface of the body 36 of the peripheral adhesive 30. As used in the context of the present invention, the term "compatible" means that the material will not absorb a substantial amount of cetylpyridinium salt from the aqueous medium after storage. To determine whether a polymeric material is compatible with the cetylpyridinium salt, one can prepare an aqueous solution of the cetylpyridinium salt at a concentration of OJ mg / ml, immerse a sample of the polymeric material for four weeks at 25 ° C and determine the amount of cetylpyridinium salt that was absorbed by the polymeric material by HPLC. If the absorbed amount of cetylpyridinium salt is less than 0.25 mg per gram of polymeric material, preferably less than 0.10 mg per gram of the polymeric material, more preferably less than 0.025 mg per gram of the polymeric material, the polymeric material can be considered compatible with the cetylpyridinium salt. As indicated above, suitable polymeric materials that can be used to form the cathode vessel include polyethylene terephthalate, polyethylene terephthalate modified with cyclohexane dimethylol, polypropylene, and mixtures thereof. Preferably, the material is polyethylene terephthalate or polyethylene terephthalate modified with cyclohexane dimethylol. The polymeric materials can be formed into the desired shape (e.g., the shape of the bottom housing) by hot molding or any other suitable technique. The aqueous medium to be contained in the anodic vessel can be prepared according to any conventional technique. For example, when the aqueous medium is a hydrogel formulation, it may be composed of from about 10 to about 30% by weight of polyvinyl alcohol, from about 0.1 to about 0.4% by weight of regulator and the desired amount of drugs, such as salt of fentanyl or sufentanil, particularly the hydrochloride salt. The rest is water and other conventional ingredients. The hydrogel formulation can be prepared by mixing all the ingredients, including the fentanyl or sufentanil salt, in a single vessel at an elevated temperature of from about 90 to about 95 ° C for at least about 0.5 hours. The hot mixture is then emptied into a foam mold and stored at a freezing temperature of about -35 ° C for a period of time (e.g., overnight) sufficient to degrade the polyvinyl alcohol. After heating to room temperature, a highly viscous elastomeric gel suitable for placement in the anodic container of the transdermal electrotransport delivery device is obtained. The aqueous medium to be contained in the cathode vessel can also be prepared according to any conventional technique. For example, when the aqueous medium is a hydrogel formulation, it can be composed of from about 10 to about 30% by weight of polyvinyl alcohol and ingredients, such as sodium chloride, trisodium citrate, citric acid and the cetylpyridinium salt in the previously described quantities, the rest being water. The hydrogel formulation can be prepared by mixing all the ingredients and using the described process with respect to the preparation of the hydrogel formulation used in the anodic vessel. The various aspects of the present invention can be understood from the following examples and comparative examples. However, it should be understood that the present invention is not limited by the representative embodiments shown in the examples.

EXAMPLE 1 To illustrate the antimicrobial efficacy of the cetylpyridinium salt of the present invention, hydrogel cathodic formulations were prepared containing 0.01%, 0.02% and 0.03% cetylpyridinium chloride with three bacterial species, one species of yeast, one species of mold (these microorganisms are specified for the Antimicrobial Preservative Effectiveness Test) and a kind of environmental mold. All percentages in this example are percent by weight unless noted otherwise. The viability of the inoculation in the cathodic hydrogels was tested according to an Antimicrobial Effectiveness Test, which is generated in relation to and according to those methods described in the Pharmacopoeia of E. U. 23 < 51 > Antimicrobial Preservatives-Effectiveness; British Pharmacopoeia (BP) Appendix XVI C Efficacy of Antimicrobial Preservation; and European Pharmacopoeia (EP) VIII.15 Efficacy of Antimicrobial Preservation. The microorganisms used were the following: Bacteria Staphylococcus aureus ATCC 6538 Escherichia coli ATCC 8739 Pseudomonas aeruginosa ATCC 9027 Yeast Candida albicans ATCC 10231 Mold Aspergillus niger ATCC 16404 Environmental isolated Cladosporium species (environmental isolate) The formulations used in the tests are the following: Samples of the hydrogel formulation of the Formulation 1 by adding in a glass beaker, coated, 250 mL, 80.28 g USP purified water; OJ O g of sodium chloride, USP; 0.37 g of trisodium citrate; 0.24 g of citric acid and 0.01 g of cetylpyridinium chloride. The resulting mixture was stirred for 5 to 10 minutes with a glass stirring rod and the salts were completely dissolved. Rinsed polyvinyl alcohol, 19.00 g, was added to the beaker and a rubber stopper equipped with a thermowelded thermometer and a glass stirring rod with a Delrin blade were inserted into the beaker mouth. The mixture was heated to 90 to 95 ° C while stirring and held at that temperature for about 60 minutes. The hot polyvinyl alcohol solution was cooled to about 60 ° C and transferred to a 60 mL polypropylene syringe. The polypropylene syringe and its contents were placed in an aluminum block heater previously heated to 60 ° C and distributed in a 2.0 cm2 PETG cathode housing containing the silver chloride / polyisobutylene / carbon black electrode. Natural gas and electrically conductive adhesive tape, such as a pressure sensitive tape composed of polyisobutylene and natural gas carbon black. The filled PETG housing was covered with a polyethylene terephthalate (PET) release coating and the samples were placed in a freezer at -35 ° C for approximately 24 hours. The frozen hydrogels were allowed to warm to room temperature to provide a cathode hydrogel containing cetylpyridinium chloride as an antimicrobial additive. The pH of the cathode hydrogel was 4.5. Samples of the hydrogel formulations of Formulations 2 and 3 are prepared by using the same technique except that the percentages of each of the components was as given in the previous table. The following media were used in the tests: Trypticase Soy Agar (TSA) w / Lecithin and Polysorbate 80, Difco Code No. 0553-17-2 or Dextrose Sabouraud Agar equivalent (SDA), Difco Code No. 0305-17 -3 or equivalent Tripticase Soy Agar (TSA), BBL 1 1043 or Phosphate Regulator equivalent, BBL No. 1 1544 or equivalent with the additional 0.1% Polysorbate 80, BBL No. 1 1925 or equivalent Standard Inoculation Preparation Inoculation suspensions were made for each of the six test organisms, according to a standard procedure and only cultures with less than five steps were used. The suspensions were adjusted to approximately 1.0 x 108 colony forming units (CFU) / ml, according to a standard procedure. Immediately prior to inoculation, inoculation concentrations were confirmed by the Emptying Plate Method (see the description provided in the EU Pharmacopoeia 1995 and the publication Biology of Microorganisms, 3rd Ed. 1979, the contents of which are incorporated for reference). The Emptying Plate Method used Trypticase Soy Agar (TSA) for bacteria and Sabouraud Dextrose Agar (SDA) for yeast and mold. The TSA plates were incubated at 30-35 ° C for 48-72 hours. The SDA plates inoculated with A. niger were incubated at 20-25 ° C for 3 days. SDA plates inoculated with C. albincans and Cladosporium species were incubated at 20-25 ° C for 5-7 days. After incubation, the colonies were enumerated. The average colonies counted between the triplicated plates were multiplied by the dilution factor to obtain the number of organisms per system.

Sample Examination Procedure To examine the samples, the protective release liners were removed from the reservoirs under aseptic conditions. Each hydrogel formulation was inoculated with 6DL of the microorganism suspension (approximately 6.0 x 10 CFU / housing). Immediately after inoculation, the release coating was replaced and the inoculated housing was returned to the original package, which was sealed by the use of a thermal sealant. The liberated packages containing the inoculated housings were incubated at 20-25 ° C. Three inoculated hosts reproduced at 0 hours and 2, 7, 14, 21 and 28 days after inoculation were analyzed. This procedure was repeated for each of the six microorganisms examined. In order to evaluate the samples, each hydrogel was analyzed by first removing it from the package and the housing, placing it in a screw cap tube containing 5.4 mL of Phosphate Regulator with 0.1% Polysorbate 80. Each tube swirled for 2 minutes. Using the Emptying Plate Method, serial dilutions of the extract were plated on TSA with Lecithin and Polysorbate 80 for all bacteria, and on SDA for yeast and mold. The plates were then incubated and enumerated in the manner discussed above. The results of the tests established in Tables 1 -3 indicate that cathodic hydrogel formulations containing 0.01%, 0.02% and 0.03% cetylpyridinium chloride comply with antimicrobial preservative efficacy requirements, as established in the Microbiological Tests < 51 > of the Pharmacopoeia of E.U. 23 Antimicrobial Preservatives-Effectiveness are: 1) concentrations of viable bacteria are reduced by a minimum of 3 logarithms after 14 days with no increase after this, and 2) viable yeast concentrations and molds remain at or below the concentrations initials throughout the entire 28-day study. At all three concentrations of cetylpyridinium chloride, the viable microbial counts of all bacteria and test yeasts were reduced on day 2 of the study, to less than the lowest detectable levels of the assay which is 10 CFU / housing. At a concentration of 0.03% CPC, viable mold counts were also reduced to less than 10 CFU / housing on Day 2 of the study. At a concentration of 0.02% CPC, less than 0.1% of A. niger survived on Day 2; and Cladosporium species were reduced to less than 10 CFU / lodging. At a concentration of 0.01% CPC, A. niger was reduced to less than 10 CFU / housing; and Cladosporium species were reduced to less than 0.1% on Day 14. Further analysis of the experimental results indicates that the cathodic hydrogel formulations containing 0.01%, 0.02% and 0.03% cetylpyridinium chloride also satisfy the antimicrobial preservative requirements for topical preparations as established in the British Pharmacopoeia, which are: 1) the viable bacterial count was reduced to a minimum of three logarithms at the time point of 48 hours without recovery of the test bacteria the daytime point of time 7 or after it; and 2) the fungal count was reduced by a minimum of two logarithms at the time point of day 14 without increase of the test fungi at the time point of day 28. In addition, the cathodic hydrogel formulations containing 0.1%, 0.02% and 0.03% cetylpyridinium chloride also satisfy the antimicrobial preservative requirements for topical preparations as set out in Criterion A of the European Pharmacopoeia, which are: 1) the viable bacterial count was reduced by at least two logarithms in the time points of Day 2 and Day 7, respectively, with no increase after this; and 2) the viable fungal count was reduced by a minimum of two logarithms at the Day 14 time point without an increase in the test fungi at the Day 28 time point.

TABLE 1 Formulation: USP Purified Water (80.28%), rinsed polyvinyl alcohol (19.00%), sodium chloride,. USP (0.10%), trisodium citrate (0.37%), citric acid, USP (0.24%), cetylpyridinium chloride (0.01%)? oo Initial Sample Concentration: the baseline value to determine all subsequent changes in the concentration of the organism at various time points. CCFU: colony forming units d. Time 0: Platelet count immediately after inoculation. This count is not representative of the concentration of inoculation due to the possible immediate action of the antimicrobial. ß Environmental Isolation: Isolated from cathodic hydrogels without antimicrobial fN / A: Not applicable TABLE 1 (Cont.) Formulation: USP Purified Water (80.28%), rinsed polyvinyl alcohol (19.00%), sodium chloride, USP (0.10%), trisodium citrate 5 (0.37%), citric acid, USP (0.24%), cetylpyridinium chloride ( 0.01%) Initial Sample Concentration: the baseline value to determine all subsequent changes in the concentration of the organism at various time points 10 c CFU: colony forming units dHora 0: Platelet count immediately after inoculation. This count is not representative of the concentration of inoculation 15 due to the possible immediate action of the antimicrobial Environmental Isolation: Isolated cathodic hydrogels without antimicrobial fN / A: Not applicable TABLE 2 Formulation: USP Purified Water (80.27%), rinsed polyvinyl alcohol (19.00%), sodium chloride, • USP (0.10%), trisodium citrate (0.37%), citric acid, USP (0.24%), cetylpyridinium chloride ( 0.02%) oi Initial Sample Concentration: the baseline value to determine all subsequent changes in the concentration of the organism at various time points. CCFU: colony forming units d. Time 0: Platelet count immediately after inoculation. This count is not representative of the concentration of inoculation due to the possible immediate action of the antimicrobial. Insulated Environmental: Isolated cathodic hydrogels without antimicrobial fN / A: Not applicable TABLE 2 (Cont.) Formulation: USP Purified Water (80.27%), rinsed polyvinyl alcohol (19.00%), sodium chloride, USP (0.10%), trisodium citrate 5 (0.37%), citric acid, USP (0.24%), cetylpyridinium chloride ( 0.02%) Initial Sample Concentration: the baseline value to determine all subsequent changes in the concentration of the organism at various time points 10 c CFU: colony forming units dHora 0: Platelet count immediately after inoculation. This count is not representative of the concentration of inoculation 15 due to the possible immediate action of the antimicrobial Environmental Isolation: Isolated cathodic hydrogels without antimicrobial fN / A: Not applicable TABLE 3 Formulation: USP Purified Water (80.26%), rinsed polyvinyl alcohol (19.00%), sodium chloride, • USP (0.10%), trisodium citrate (0.37%), citric acid, USP (0.24%), cetylpyridinium chloride ( 0.03%) faith i Initial Sample Concentration: the baseline value to determine all subsequent changes in the concentration of the organism at various time points CFU: colony forming units d Hour 0: Platelet count immediately after inoculation. This count is not representative of the concentration of inoculation due to the possible immediate action of the antimicrobial. Insulated Environmental: Isolated cathodic hydrogels without antimicrobial fN / A: Not applicable TABLE 3 (Cont.) CCFU: colony forming units dHora 0: Platelet count immediately after inoculation. This count is not representative of the concentration of inoculation due to the possible immediate action of the antimicrobial. Ambient Environmental: Isolated cathodic hydrogels without antimicrobial fN / A: Not applicable EXAMPLE 2 To further illustrate the antimicrobial efficacy of the cetylpyridinium salt of the present invention, cathodic hydrogel formulations containing 0.08% cetylpyridinium chloride were made with various microorganisms including bacteria, yeast and molds. The organisms used were S. aureus, E. coli, P. aeruginosa, C. albicans and A. niger as well as four environmental fungal isolates. The test methods followed were the same as those discussed above with respect to the U.S. Pharmacopoeia, the British Pharmacopoeia and the European Pharmacopoeia. The microorganisms used were the following: Bacteria S. aureus ATCC No. 6538 E. coli ATCC No. 8739 P. aeruginosa ATCC No. 9027 Yeast C. albicans ATCC No. 10231 Mold A. niger ATCC 16404 Isolated Environmental Penicillium species (isolated environmental) Cladosporium species (environmental isolate) Aspergillus species (environmental isolate) Cryptococcus albidus (environmental isolate) The formulation used in the test was as follows: Formulation 4: Purified water, USP (84.21%), PVOH rinsed (15.00%) , Citric Acid, USP (0.24%), Trisodium Citrate Dihydrate, USP (0.37%), Sodium Chloride, USP (0.10%), Cetylpyridinium Chloride (0.08%), pH 4.5. Samples of the formulation were prepared in a manner similar to the procedure set forth above for Example 1. The following media were used in the tests: Trypticase Soy Agar (TSA) with Lecithin and Polysorbate 80, BBL Code No. 431 1764 or equivalent Sabouraud Dextrose Agar (SDA), BBL Code No. 431 1584 or equivalent Soy Broth of Tripticasa (TSB), BBL Code No. 431 1768 or equivalent TS Saline Solution containing 0.05% Polysorbate 80 Fluid A (USP): 0.1% Bacto-Peptamine, Difco Code No. 0905-01 or equivalent Fluid D (USP) : 0.1% Bacto-Peptamine, Code Difco No. 0905-01 or equivalent 0.1% Polysorbate 80, Code Difco No. x257-07 or equivalent.

Standardization of Test Inoculation Microbial cultures were prepared as described in the Pharmacopoeias of E.U. , British and European. In particular, bacterial cultures were subcultured in TSB and incubated at 30-35 ° C for 18-24 hours. The yeast cultures (C. albicans and Cryptococcus albidus) were subcultured in TSB and incubated at 20-25 ° C for 48 hours while shaking (ventilated to obtain a higher concentration of the organism). After incubation, each suspension was rinsed by centrifugation at 10,000 rpm for 10 minutes at 4 ° C. The cultures were rinsed twice with sterile distilled water and the beads were resuspended in sterile water. The concentrations of the prepared suspension were determined turbidimetrically by reading the absorption value at the wavelength of 530 nm. The concentrations of the suspension were adjusted to produce approximately 108 colony forming units (CFU) per milliliter and were used immediately thereafter. The fungal spores (molds) were developed as described in the Pharmacopoeia of E.U. In particular, cultures of A. niger, Cladosporium species, Aspergillus species, and Penicillium species were grown on the surface of SDA plates at 20-25 ° C for 1 week or until heavy sporulation was obtained. After incubation, each fungal culture was harvested in sterile saline TS containing 0.05% polysorbate 80. The number of CFU / mL in the suspension was determined by the SDA Casting Method. The spore counts were adjusted to approximately 108 CFU per milliliter.

Examination Procedure In order to inoculate the samples, the following procedure was followed for all microorganisms. Using aseptic technique in a protected environment, thirty samples of hydrogel formulation were placed in 45 mm diameter Petri dishes (one gel per disc). The protective release coatings were removed from the gels and stored aseptically in Petri dishes. Each housing was inoculated with three aliquots of 3 μL of microorganism suspension (approximately 10 6 CFU / housing). The inoculation concentrations were determined by using the Emptying Plate Method at the beginning, at the middle and at the end of the inoculation procedure. Immediately after inoculation, Petri dishes containing inoculated lodges were placed in their lined original leaf sachets to protect the sample from light and moisture loss. The excess volume of air inside the leaf perforations was removed by gently pressing both sides of the leaf sack while ensuring that the sachets do not contact the inoculum on the surface of the hydrogels. The sachets were sealed by the use of a thermal sealant. After 24 hours, each pouch and sheet was cut open and the release coating was replaced on the inoculated surface of each sample (to stimulate the storage condition of the product) and the sachets were resealed with the thermal sealant. The liberated sachets containing the inoculated housings were stored at 20-25 ° C for a duration of 28 days. Five inoculated hosts were recovered per organism on days 2, 7, 14, 21 and 28 subsequent to inoculation. To analyze the housings, each of the five housings inoculated with release liners in place were removed from their pouches and placed in five threaded cap tubes each containing 20 mL of Fluid D (USP). The tubes with samples and release coatings were placed on a horizontal shaker and the contents were shaken at approximately 200 RPM for 30 minutes. The tubes were removed from the agitator and swirled at high speed for 1 minute. Serial dilutions of ten foldings were made for each tube and aliquots were cultivated by using the Emptying Plate Method with 20-30 mL of nutrient medium: TSA with lecithin and polysorbate 80 for bacteria and SDA for fungi. The bacterial cultures were incubated at 30-35 ° C for 48 hours and the fungal cultures were incubated at 20-25 ° C for 3-5 days. The results are summarized in Table 4. As can be determined from Table 4, viable bacterial counts for S. aureus, E. coli and P. aeruginosa and viable yeast counts for C. albicans and Cryptococcus albidus (environmental isolate ) on the surface of the inoculated samples were reduced to less than 10 CFU / housing, which is the maximum sensitivity of the test method, after 2 days of exposure and after that (a decrease of more than 4 logarithms). The viable mold counts for A. niger and the environmental isolates (Cladosporium species, Penicillium species and Aspergillus species) in the inoculated samples were reduced by more than 3 logarithms on day 2 and without increase on day 28. The results of the tests indicated that the cathodic hydrogel formulation containing 0.08% cetylpyridinium chloride meets the antimicrobial preservative efficacy requirements discussed above in the US Pharmacopoeias , British and European.

COMPARATIVE EXAMPLES For comparison purposes, Tables 5 and 6 provide the results of hydrogel samples (the formulations below each Table being described) without cetylpyridinium chloride over a period of twelve months. Fungi growth was observed in these formulations as shown in the Tables.

TABLE 4 Organism Exposure Time Day 0 Day 2 Day 7 Day 14 Day 21 Day 28 S. aurßus ATCC 6538 2.7 + 0.3x10 ° < 10"< 10 < 10 < 10 < 10 E. coli ATCC 8739 4.3 + 0.4x10c < 10 < 10 < 10 < 10 < 10 P aeruginosa ATCC 9027 1.1 + 0.2x10c < 10 < 10 < 10 < 10 < 10 C. albicans ATCC 10231 2.0 + 0.5x10 ° < 10 < 10 < 10 < 10 < 10 A. nigßr ATCC 16404 4.4 + 0.9x10"3.8 + 0.8x10 '0.8 + 1 .3x10p 2.9 + 0.9x10 6.2 + 2.9x10 8.6 + 2.4X101 Cladosporíum so 2.9 + 0.5x10"< 10 < 10 2.6 + 1 .1 x10 '2 + 4.5 < 10 Crytococcus albidus 2.4 + 0.1 x10 ° < 10 < 10 < 10 < 10 < 10 Pnicnicillium sp. 7.8+ 1 .4x10 ° < 10 «51 0 3.8 + 1 .8x10 0.8 + 0.8x10? < 10 Aspergillus sp. 2.6 + 0.8x10 ° < 10 < 10 1 .6 + 0.9x10 '2.2 + 1 .3x10? < 1 0 Formulation: Purified Water USP (84.21%), PVOH Rinsed (15.00%), Citric Acid, USP (0.24%) Trisodium Citrate (0.37%), Sodium Chloride, USP (0.10%), Cetilpiridinium Chloride (0.08%) " Concentrations of the Organism: colony forming units (CFU) / system ° Environmental isolates Maximum sensitivity of the test method TABLE 5 Formulation: Purified Water USP (87.29%), PVOH Rinsed (12.00%), Citric acid, USP (0.24%), Trisodium Citrate (0.37%), Sodium Chloride, USP (0.10%), PH 4.0 Fungal Concentrations: forming units of colonies (CFU) / system; n = 4 or 3 Maximum sensitivity of the test method dA Penicillium species at a level of 104 CFU was detected from one of the four units inoculated with A. niger ATCC 16404 ^ or eA Penicillium species at a level of 105 CFU was detected of two of the four units and one species of Aspergillus at a level of 104 CFU was detected from the other two units inoculated with A. niger ATCC 16404 (no contaminants were detected in the re-examined samples) for an Aspergillus species (identical to the Aspergillus species above) at a level of 106 CFU was detected from one of the four units inoculated with C. albicans ATCC 10231 9A Penicillium species at a level of 104 CFU and one Aspergillus species (identical to the previous Aspergillus species) ) at a level of 102 CFU and Pink Yeast at a level of 103 CFU were detected from three of the four units inoculated with C. albicans ATCC 10231 A species of Penicillium at levels of 104 and 105 CFU were detected from two of the three units inoculated with A. niger ATCC 16404 A species of Penicillium at a level of 105 CFU was detected from one of the three units inoculated with A. niger ATCC 16404 TABLE 6 Formulation: Purified Water USP (87.29%), PVOH Rinsed (12.00%), Citric acid, USP (0.24%), Trisodium Citrate (0.37%), Sodium Chloride, USP (0.10%), PH 4.0 The yeast and species of Cladosporium were isolated from the processing environment. The esp. of Penicillium was isolated from the gel inoculated with A. niger ATCC 16404 in the previous experiment Fungal concentrations: colony forming units (CFU) / system; n = 3 except for the 6-month time point (n = 6) n cMolde blue (resembling the Penicillium species) at a level of 103 CFU was detected from one of the systems inoculated with Cladosporium species. Test method A fungal colony (identified as Sp. Cladosporium) was observed on the surface of one of the hydrogel units inoculated with Cladosporium species fTBD: EXAMPLE 3 To illustrate the compatibility of cetylpyridinium chloride with modified polyethylene terephthalate with cyclohexane dimethylol (obtained from Easan Chemical Products, Inc. under the designation co-polyester of KODAR® 6763 PETG) and using a compound cathode electrode, polyisobutylene compound, carbon and silver chloride, the following formulation was prepared in a hydrogel. TABLE 7 The hydrogel formulation was prepared by the addition of 84.2 g of purified water, USP, 0.24 g of citric acid, 0.37 g of trisodium citrate dihydrate, OJ Og of sodium chloride and 15.0 g of poly (vinyl alcohol) rinsed in a glass beaker, coated, 250 mL. A rubber stopper equipped with a nitrogen inlet, a powder addition tunnel, a thermowelded thermometer and a stainless steel stirrer shaft with a Delrin blade were inserted into the mouth of the beaker. The mixture was stirred (Arrow 850, speed setting = 1 to 2) while heating to 90-95 ° C and maintained at that temperature for 70 minutes. The buffer solution of poly (vinyl alcohol) citrate was cooled to 50 ° C and 0.075 g of cetylpyridinium chloride was added to the beaker. The mixture was stirred for 15 minutes and the cetylpyridinium chloride was completely dissolved. The polymer solution was transferred into a 60 mL polypropylene syringe which was preheated to 55 ° C with an aluminum block heater and distributed in the thermoformed bottom housings of the PETG material (which contained a compound cathode, composed of 29% by weight of polyisobutylene, 2.5% by weight of carbon and 68% by weight of silver chloride and having an area density of approximately 0.35 mg / cm2) with a Multicore solder paste distributor. The filled cathode hydrogel formation samples were covered with a siliconized polyethylene terephthalate release coating and the filled systems were stored in the freezer at -20 ° C for 18 hours and allowed to warm to room temperature over the top of the freezer. ia banking The degraded hydrogel formation samples, the polymeric material housing and the polyethylene terephthalate release coating were individually weighted and packaged in a sealed Surlyn sheet pouch. Samples of cathode hydrogel formation were removed from the leaf sachets after storage at 4o, 25o and 40oC for weeks 1, 4, 8, 12, 24 and 48. Samples of cathode hydrogel formulation were extracted with a mobile phase composed of 60% water / 40% acetonitrile and the content of cetylpyridinium chloride (CPC) was determined by HPLC analysis. The results of this test are established in Table 8 below. TABLE 8 To understand the previous results more completely, it is observed that the weight of the cathodic hydrogel is 0.64 g. Accordingly, the content of cetylpyridinium chloride (based on 0.075% by weight of CPC in the hydrogel) is 0.48 mg CPC / hydrogel corresponding to 0.75 mg CPC / g of hydrogel. After 48 weeks at 4o, 25 ° C and 40 ° C, the concentration of CPC in the cathode hydrogel decreases to 0.055% by weight, 0.053% by weight and 0.043% by weight, respectively. The CPC concentration in the cathode hydrogel formation after 48 weeks at 4 ° C, 25 ° C and 40 ° C was 0.55, 0.53, 0.43 mg CPC / g hydrogel. The amount of CPC lost for the cathode of the compound after 48 weeks at 4 °, 25 ° and 40 ° C was 0.20, 0.22 and 0.32 mg CPC / g of hydrogel, respectively. The cathode area of AgCl / PIB compound is 2.33 cm2. The amount of CPC lost after 48 weeks at 4 ° C, 25 ° C and 40 ° C based on contact with 1.0 cm2 of AgCl / PIB compound was calculated as 0.086, 0.094 and 0.137 mg CPC / g of composed of hydrogel / cm2, respectively. Subsequent extraction experiments showed that cetylpyridinium chloride was essentially lost at the compound cathode. As noted above, a potential solution to this situation is to provide an anion exge membrane, such as an anion exge membrane of SYBRON® or RAIPORE®, between the electrode and the container contents so that the cetylpyridinium cations do not penetrate through such a membrane and therefore do not contact the cathode electrode.

ABSORPTION DATA To illustrate the absorption of cetylpyridinium chloride and benzyl chloride by the addition of polymeric materials, two sets of solutions were prepared. A set of sample solutions was composed of 0.01% sodium chloride, 0.24% citric acid, 0.37% sodium citrate, 0.03% benzoic acid (BA) and 76% water. This gave a concentration of 397 μg BA / ml which is at the upper end of the test range in the experimental method for BA, but is one tenth of what is normally used in hydrogel formulations. The other set of sample solutions contained CPC dissolved in water at a concentration of 58J μg / m which is near the middle of the CPC assay range.

The following polymeric materials were examined: EXX-216 Polypropylene filled with TiO2 (obtained from Exxon Chemical EXX-210 Polypropylene (0.1 millimeters thick) ACLAR Laminate obtained from Techniplex consisting of 0.13 millimeters of polyvinyl chloride (PVC) /0.05 millimeters of polyethylene / 0.15 millimeters of ACLAR® (a fluorohalocarbon film) For the tests, 150 cm2 of test material was cut into small pieces and immersed in 50 ml of test solution.A sample of each material was prepared in a bottle of extraction of 100 ml glass for storage at 25 ° C and another for storage at 40 ° C. Because the PVC and ACLAR® sides of the trilaminate test material are expected to exhibit different properties, a second set was prepared of samples with two pieces of the ACLAR® laminated on a piece of electrically conductive adhesive tape so that only the ACLAR® side is exposed to the solution Since the electrically conductive adhesive tape could also absorb the antimicrobial agents, a control was prepared by sandwiching the tape between the microscopic divisions of the glass. Another control was simply the microscopic divisions of the glass. All samples exhibited the same proportion of test surface area in ml of the test solution. All tapes using the electrically conductive adhesive tape had approximately the same area of exposed tape per ml of solution. The prepared sample bottles were weighed and stored at 25 ° C and at 40 ° C for eight weeks. At t = 1 day, 1 week, 2 weeks, 4 weeks, 8 weeks, the samples were equilibrated at room temperature and weighed. Any sample that had lost more than 0.1 g during the previous storage period was returned to the appropriate weight by the addition of water before sampling. The samples were kept small to minimize the effect on the remaining time points. New weights were recorded before returning the samples to the cameras each time. At the end of the study, the sample pieces were removed from the solutions for visual observation. The results of the tests are given in Table 9. In the Table, "CLAR (clear)" refers to the pieces of the ACLAR sample completely immersed in the solution. "ACLAR (laminate)" refers to ACLAR laminated with electrically conductive adhesive tape so that only the ACLAR side is exposed. The same nomenclature was used with the examples of glass division. In addition, it is observed that the benzoic acid tests were finished after 4 weeks because no change in concentration had been detected for any of the samples at any temperature.

TABLE 9 CPC Solution 58.08 μg / ml # Material Temp T = 0 1 Day 1 Sem 2 Sem 4 Sem 8 Sem 1 Control 4C 4 58.08 56.87 56.13 54.33 55.58 55.68 2 Control 25C 25 58.08 56.94 57.25 55.29 56.20 55.29 3 Control 40C 40 58.08 56.94 57.32 56.50 56.50 56.80 57.40 4 EXX-210 (clear) 25C 25 58.08 54.00 56.61 54.80 56.28 54.28 00 EXX-210 (clear) 40C 40 58.08 53.17 51.80 54.68 53.14 54.92 6 EXX-216 (white) 25C 25 58.08 54.32 56.82 54.53 56.28 56.91 7 EXX-216 (white) 40C 40 58.08 55.10 56.08 56.26 55.43 52.94 8 CLARIFY (clean) 25C 25 58.08 63.62 55.65 56.77 67.17 56.50 9 CLARIFY (clean) 40C 40 58.08 54.22 57.90 54.83 56.25 53.89 10 ACLAR (laminate) 25C 25 58.08 57.40 57.17 57.02 56.60 55.86 1 1 ACLAR (laminate) 40C 40 58.08 57.17 57.68 58.53 52.79 50.99 1 2 Glass Divisions 40C 40 58.08 52.36 49.96 49.67 51 .57 48.61 13 Glass Divisions (Laminate) 40C 40 58.08 52.64 52.51 50.75 49.32 48.88 in oo Benzoic Acid Solution 397.25 μg g // mmll # Material emp T = 0 1 Day 1 Sem 2 Sem 4 Sem 1 Control 4C 4 397.25 396.96 399.35 397.62 399.01 2 Control 25C 25 397.25 397.26 398.32 398.65 401 .43 3 Control 40C 40 397.25 396.37 398.17 398.95 400.14 4 EXX-210 (clear) 25C 25 397.25 396.22 397.15 394.97 395.29 00 EXX-210 (clear) 40C 40 397.25 397.26 394.50 395.56 397.55 6 EXX-216 (white) 25C 25 397.25 395.48 396.12 396.59 396.58 7 EXX-216 ( white) 40C 40 397.25 396.22 396.22 396.26 397.33 396.91 8 ACLAR (clean) 25C 25 397.25 397.70 398.32 397.92 397.71 9 ACLAR (clean) 40C 40 397.25 398.30 397.59 397.77 400.79 10 ACLAR (laminate) 25C 25 397.25 398.30 397.00 398.65 396.74 1 1 ACLAR (laminate) ) 40C 40 397.25 397.55 396.70 397.92 396.42 12 Divisions of Glass 40C 40 397.25 400.97 398.91 399.83 399.17 1 3 Divisions of Glass (laminate) 40C 40 397.25 400.52 397.73 398.65 398.85 Table 2. Test Data From the results of the test and the visual observations, it is observed that all the CPC test materials showed some loss of CPC compared to the controls. The biggest losses were the control samples that contain the glass divisions. The results were similar for the glass with or without the electrically conductive adhesive tape. Additional absorption data for talc-filled polypropylene, PETG and siliconized PET release liner were obtained by the use of cathode solutions containing cetylpyridinium chloride (CPC). The solutions and samples are described as follows: Preparation of Cathode Solution - 1.0 mg / ml of CPC In a 1000 mL volumetric flask were added 1379 g of citric acid, 6,321 g of trisodium citrate dihydrate, 1149 g of chloride of citrate. sodium and 1.0 g of cetylpyridinium chloride. The flask was then filled to the mark with millipore water and stirred for about 15 minutes until all the salts dissolved completely. Preparation of Cathode Solution - 1.0 mg / ml CPC In a 500 mL volumetric flask, 50 mL of the 1.0 mg / mL CPC solution was added through a 50 mL pipette. The flask was then filled to the mark with millipore water and the contents were stirred until homogeneous. Preparation of Stuffed Polypropylene Samples with CPC / Talc The mixture of talcum-filled polypropylene sheet (available under the designation Proprint) was cut with a die in 2 cm2 disks. 24 discs were placed in each glass bottle. The weight of the 24 discs was approximately 1.0 grams. In each vial, 2 mL of the appropriate solution was measured through a repeating pipette. Eighteen samples were prepared per solution. The weight of all the bottles was recorded at t = 0. The samples were stored in an environmental chamber at 25 ° C. Preparation of CPC / PETG Samples In each bottle of 125 mL glass medium approximately 9.5 g of lower trilaminate blue housing was added. The accommodations were cut into small pieces to allow them to fit through the neck of the Leyden bottle. In each Leyden bottle, 16.6 mL of the appropriate CPC solution was then measured. Three samples of each concentration of the solution were prepared. The weight of the PETG placed in each sample was recorded at t = 0. The samples were then placed in a shaker at room temperature. Preparation of CPC / PET Samples In each bottle of 125 mL glass medium approximately 8.2 g of siliconized PET release coating was added. The release liner was cut into smaller pieces to ensure passage through the neck of the Leyden bottle. In each Leyden bottle, 16.6 mL of the appropriate CPC solution was then measured. Three samples of each concentration of the solution were prepared. The weight of the PET placed in each sample was recorded at t = 0. The samples were then placed in a shaker at room temperature.

Preparation of Control Solutions The original CPC solutions prepared for these compatibility studies were used as the control solutions. They were stored in volumetric glass flasks at room temperature. The CPC control solutions and the test samples were removed from the environmental chambers and the agitator for 24 hours, 1, 2, 4, 8 and 16 weeks. Proprint samples were weighed to determine if any loss of evaporative water had occurred. If this was the case, then water was added to the jar to equalize the weight at the previous time point. The PET and PETG samples were released and returned to the agitator after analysis, while the Proprint samples were discarded after each time point. The test solutions were sampled and analyzed for CPC content by HPLC analysis. The results are set forth in Tables 10 and 11 and represent the actual amount of CPC absorbed per gram of substrate. These values were determined when calculating the loss of CPC in mg / mL of solution. This value was multiplied by the total volume of the solution to obtain the total mg of the CPC loss. This was then divided by the total weight of the substrate in the sample to obtain the CPC loss in mg per gram of substrate.

TABLE 10 ma CPC absorbed per gram of Proprint TABLE 11 Negative values are due to the concentration of CPC greater than the concentration of t = 0.

Example 4 To illustrate the compatibility of cetylpyridinium chloride (CPC) with a cathode of silver / carbon chloride compound and other housing materials, a cathode hydrogel was prepared and examined. The cathode hydrogel was prepared by the addition of 3.0 g of L-histidine and 148.84 g of purified water, USP in a 250 mL coated glass beaker. A Teflon-coated magnetic pin bar was placed in the beaker and the L-histidine was completely dissolved. A pH electrode was placed in the aqueous solution of L-histidine and the pH was adjusted to pH = 4.5 by the drop drop of concentrated hydrochloric acid (1.968 g). Additional purified water, USP (8,032 g) was added to provide 200 g of the mixture. The magnetic pin bar was removed from the coated beaker and 38.0 g of rinsed poly (vinyl alcohol) was added to the beaker. A rubber stopper equipped with a thermocouple thermometer and a stainless steel agitation shaft with a Delrin blade was inserted into the mouth of the coated beaker. The mixture was stirred while heating to 90 ° C and maintained at that temperature for 70 minutes. The poly (vinyl alcohol) solution was cooled to 60 ° C and 0J 6 g of cetylpyridinium chloride was added to the coated beaker. The mixture was stirred for approximately 10 minutes and the cetylpyridinium chloride was completely dissolved. The solution was transferred to a 60 mL polypropylene syringe which was previously heated with an aluminum block heater at 60 ° C and distributed in lower housing composed of talc-filled polypropylene (available under the designation Proprint) with a distributor of best-selling pasta Multicore. The filled cathode hydrogel vessels were covered with a siliconized polyethylene terephthalate (PET) release coating and the filler systems were stored in a freezer at -20 ° C for 18 hours and allowed to warm at 4 ° C for 2 hours. hours and then allowed to warm to room temperature. The degraded hydrogel is removed from the hydrogel vessel and weighed to determine the initial weight. The initial pH of the cathode hydrogel was 4.53. The samples were individually sealed in a lined sheet sachet from Surlyn and stored at 40 ° C. At weeks 1, 4, 8, 12, 32 and 56, the hydrogels were removed from the lower housing and extracted with a mobile phase composed of 60% water / 40% acrylonitrile and the concentration of cetylpridinium chloride was determined by HPLC (AAM 1.443). The components of the lower housing were extracted separately to determine the amount of cetylpyridinium chloride that has diffused into them and the results are given in Table 12.

TABLE 12 Although the present invention has been described with respect to certain preferred embodiments, it is apparent that modifications and variations thereof may be made by those skilled in the art without departing from the scope of the invention as defined by the following claims.

Claims (26)

1. CLAIMS 1. A transdermal electrotransport drug delivery device comprised of an anode, a cathode and a power source electrically connected to the anode and the cathode, the cathode including a cathode electrode and a cathode vessel comprised of a housing composed of a polymeric material and an aqueous medium in contact with the housing, said aqueous medium comprising i) a drug or an electrolyte salt or a mixture thereof and ii) a cetylpyridinium salt in an amount sufficient to inhibit microbial growth in the aqueous medium in wherein said polymeric material is compatible with the cetylpyridinium salt.
2. 2. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the aqueous medium has a pH of from about 3 to about 7.5.
3. 3. The transdermal electrotransport drug delivery device according to claim 2, characterized in that the aqueous medium has a pH of from about 3.5 to about 6.5.
4. 4. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the aqueous medium includes a regulator.
5. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the polymeric material is selected from the group consisting of polyethylene terephthalate, polyethylene terephthalate modified with cyclohexane dimethylol, polypropylene and mixtures thereof.
6. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the cathode holder contains an aqueous medium of an electrolyte salt and is substantially free of drug.
7. The transdermal electrotransport drug delivery device according to claim 6, characterized in that the anode includes an anode electrode and an anode container containing a drug.
8. The transdermal electrotransport drug delivery device according to claim 7, characterized in that the anodic container contains fentanyl in a form that can be delivered when the current flows from the electric power source.
9. 9. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the cetylpyridinium salt is a halide salt.
10. 10. The transdermal electrotransport drug delivery device according to claim 9, characterized in that the cetylpyridinium halide salt is cetylpyridinium chloride. eleven .
11. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the aqueous medium contains at least about 0.005% by weight of the cetylpyridinium salt.
12. 12. The transdermal electrotransport drug delivery device according to claim 1, characterized in that the aqueous medium contains from about 0.005% to about 2% by weight of the cetylpyridinium salt.
13. The transdermal electrotransport drug delivery device according to claim 12, characterized in that the aqueous medium contains from about 0.01% to about 1% by weight of the cetylpyridinium salt.
14. The transdermal electrotransport drug delivery device according to claim 1, characterized in that it includes an anion exchange membrane between the cathode electrode and the cathode vessel.
15. 15. A process for transdermally delivering a drug to a patient by electrotransport from a drug delivery device comprised of an anode, a cathode and a power source electrically connected to the anode and the cathode, the anode including an anode electrode and a anodic container containing a drug and the cathode including a cathode electrode and a cathode vessel composed of a polymeric material and containing an aqueous medium comprised of i) an electrolyte salt and ii) a cetylpyridinium salt in an amount sufficient to inhibit growth microbial in the aqueous medium, said polymeric material being compatible with the cetylpyridinium salt, said process comprising the proportion of electric current coming from the electric power source in order that the drug is delivered transdermally to the patient by electrotransport from the anodic container and in order that the ions of cetylpyridinium are not delivered transdermally to the patient by electrotransport from the cathode vessel.
16. The process according to claim 15, characterized in that the drug is fentanyl in a form that can be delivered when the current flows from the source of electrical energy.
17. The process according to claim 15, characterized in that the aqueous medium is a hydrogel comprised of at least about 0.005% by weight of the cetylpyridinium salt.
18. 18. The process according to claim 17, characterized in that the hydrogel comprises from about 0.005% to about 2% by weight of the cetylpyridinium salt.
19. 19. The process according to claim 18, characterized in that the hydrogel comprises from about 0.01% to about 1% by weight of the cetylpyridinium salt.
20. The process according to claim 15, characterized in that the cetylpyridinium salt is cetylpyridinium chloride. twenty-one .
21. The process according to claim 15, characterized in that substantially no drug is supplied from the cathode vessel when the current flows from the source of electrical energy.
22. 22. The process according to claim 15, characterized in that the drug comprises fentanyl.
23. 23. A process for preparing a transdermal electrotransport drug delivery device, characterized in that it comprises the preparation of an aqueous medium comprised of i) a drug or an electrolyte salt or a mixture thereof and ii) a cetylpyridinium salt in an amount sufficient to inhibit microbial growth in the aqueous medium; and the placement of the aqueous medium in the cathode vessel of a device comprised of an anode, a cathode and a power source electrically connected to the anode and the cathode, the cathode including a cathode electrode and a cathode vessel comprised of a housing composed of a polymeric material by which the aqueous medium is in contact with the cathodic vessel housing and wherein said polymeric material is selected so as to be compatible with the cetylpyridinium salt.
24. The process according to claim 23, characterized in that the polymeric material is selected from the group consisting of polyethylene terephthalate, polyethylene terephthalate modified with cyclohexane dimethylol, polypropylene and mixtures thereof.
25. 25. The process according to claim 23, characterized in that the aqueous medium is substantially free of drugs.
26. 26. The process according to claim 23, characterized in that the cetylpyridinium salt is a halide salt.