United States Patent:  6,049,733

Assignee:  ALZA Corporation (Mountain View, CA)

Filed:  September 26, 1997

An electrotransport apparatus using dispersed ion exchange material (19,83) is disclosed. The ion exchange material (19,83) may be dispersed in either the donor electrode assembly (10), the counter electrode assembly (10) or both electrode assemblies. The dispersed ion exchange material (83) comprises mobile ionic species (84-2) and substantially immobile ionic species (P). The dispersed ion exchange material (83, 84-2) interacts with competitive species (86) generated during electrotransport to render those species substantially immobile (87). Electrotransport devices exhibiting reduced polarization are also disclosed.

DISCLOSURE OF THE INVENTION

The present invention derives from the discovery that a discrete layer, membrane, ion mobility inhibiting means or zone is not necessary to the enhancement of electrotransport drug or agent delivery. In particular, this invention relates to the incorporation of ion exchange materials which, in one aspect, provide a means of rendering competitive ions substantially immobile, and in another aspect provide a means of facilitating an electrochemical reaction where no competitive species are generated.

In one aspect, the present invention is an electrode assembly for an electrotransport delivery device comprising an electrode and at least one distributed or dispersed ion exchange material. An ion exchange material of this invention comprises mobile ionic species and substantially immobile ionic species. In one practice, the ion exchange material or ion exchange macromolecule is uniformly or homogeneously dispersed in the drug reservoir. In a less preferred practice, the ion exchange material is uniformly dispersed within an "in-line" skin contact adhesive, which adhesive is placed between the drug or salt (counter) reservoir and the patient's skin and which helps secure the reservoir to the patient. In a more preferred practice, the electrode, itself, will be a composite structure comprising an electronically conductive composition and an ion exchange material.

The mobile ionic species chosen will be of a type which interacts with a competitive species generated during operation of the electrotransport device so as to render the competitive species substantially immobile or otherwise making it substantially non-responsive to external electromotive forces. A suitable ion exchange material is generally substantially insoluble in the medium in which it is dispersed. Generally, this means the ion exchange material will be substantially insoluble in (1) the liquid solvent used to "hydrate" the reservoir matrix (most typically, the reservoir matrix is hydrated with water due to its excellent biocompatability) and (2) the polymer of the electrode, reservoir or adhesive matrix. More preferably, the ion exchange material has a minimal water soluble fraction since any low molecular weight water soluble fraction has the potential to be undesirably delivered into the patient by electrotransport. The water soluble fraction of any ion exchange material can be determined by washing the resin in water and calculating the weight loss of the material. Preferably, the ion exchange material has a water soluble fraction of less than about 0.1 wt % and most preferably less than about 0.001 wt %. The ion exchange material, while dispersed within a reservoir, may be in direct and intimate contact with an electrode or current distributing member. The ion exchange material described herein may be located essentially anywhere within ion conducting portions of the electrotransport device, provided most or all competitive ionic species generated during operation of the device interact with the mobile ionic species of the ion exchange material before they reach the skin surface of the agent recipient and thereby become immobilized. While the ion exchange material may be dispersed within any ion-conducting portion or portions of the electrotransport device, it is preferred to place the dispersed ion exchange material as far away from the patient body surface-contacting portions of the device as is possible. Thus, the ion exchange material is least preferably dispersed in a layer of skin-contacting adhesive positioned between the drug reservoir and the skin, is more preferably dispersed in the drug reservoir, and is most preferably dispersed in the current distribution elements (ie, the electrodes) of the device.

When a sacrificial electrode is chosen to deliver a positively charged drug ion, D⁺, (and assuming all other factors such as concentration are equal), the competitive ions generated at the anode in the oxidative process, will be positively charged metal ions. The ion exchange material is chosen in view of the competitive ion(s) generated with the express intent of rendering the positively charged competitive ion(s) immobile or at least substantially non-responsive to electromotive forces or electromigration tendencies. Thus an electrode assembly of this invention, by inclusion of a dispersed ion exchange material, will effectively reduce iontophoretic delivery of oxidatively produced ions which compete with the drug or agent to be delivered. This increases the efficiency associated with delivery of the drug or other beneficial agent. It is a further advantage of this invention that the cations generated during operation of the device, particularly metal cations, may have an undesirable toxicity. Prevention of such toxic species from reaching the skin, and the attendant reduction in possible toxicity due, eg, to the presence of metal cations, is a particular advantage of this invention. A further advantage of this invention is the reduction of the drug degradation processes which metal cations sometimes cause.

In a further practice of this invention, the above ion exchange material or materials are selected to provide some other desired property to the electrode structure or component in which it is dispersed. For example, the ion exchange material may provide hydrophilicity or other desirable property to the assembly component in which it is dispersed.

In yet another practice of this invention, the ion exchange material may be uniformly dispersed or distributed throughout each of several individual ion conducting portions of the electrode assembly. This approach tends to reduce the overall electrode thickness, to reduce polarization, and enhance drug or agent delivery efficiency of this device.

The terms "immobile" or "immobilized" are used extensively herein. Those terms are to be broadly construed to mean any of the physicochemical processes or interactions which produce or generate a species which does not compete with the drug ion (or which can migrate only to a limited extent), because of size or charge state in response to an electromotive force. Specifically, and without limitation, the physicochemical processes or "interactions" intended by this terminology include deposition, precipitation, neutralization, intercalation, association, complexation or chelation. The net effect of the interaction, "capture", or "binding" process is to render the competitive species substantially immobile. This interaction can occur within or in the vicinity of the ion exchange material or the ion exchange material may provide a source of mobile species which interact with the competitive species outside or far from the ion exchange material, as long as the competitive species generated is essentially prevented from migrating into the body surface. While irreversible interactions are preferred, reversible interactions may also be adequate provided that the mobility or concentrations of the reversibly-held, unwanted, competitive species is reduced substantially below the mobility or concentration of the agent to be delivered. Preferably, the transport number of the competitive species is less than 50%, more preferably less than 1%, of the transport number of the active agent being delivered when the device of the present invention is in operation.

The term "ion exchange material" is used extensively herein. This term is also to be broadly construed to mean essentially any material comprising mobile ionic species and substantially immobile ionic species where the immobile ionic species has the same charge state as the drug or agent but has sufficient mass, size, or molecular weight so as to reduce substantially its mobility in response to an applied electromotive force. It is to be understood, however, that most species will have at least some mobility in response to electromotive forces. Other terms used to describe the immobile ionic species which comprises a part of the ion exchange material include polymer, copolymer, oligomer, ionomer, polyelectrolyte, resin, colloid, micelle, particle and the like. An ion exchange material of this invention may be synthetic or natural.

While the ion exchange material used herein will generally be primarily organic in composition (ie, hydrocarbon-based) it is within the contemplation of this invention that the ion exchange material may be primarily inorganic in composition (eg, a ceramic composition). Generally speaking, the immobile ionic species will have a number average molecular weight in the range of at least about ten times greater than the molecular weight of the drug or agent to be delivered by electrotransport. A preferred polymeric immobile ionic species would be crosslinked and thereby rendered substantially insoluble in water.

Much of the above discussion relates to the class of electrochemical reactions where competitive ionic species are generated. As is noted above, there is a second class of reactions where no competitive ionic species are generated. In this later class of reactions, the dispersed ion exchange material will provide at least one of the reactants. By providing reactant (in part or in their entirety) the ion exchange material enhances the likelihood of occurrence of the reaction (or reactions) where no competitive ions are generated. Illustrating this, to facilitate electrotransport of an anionic drug D^-, the ion exchange material would provide a mobile cation which is reduced at the cathode as is suggested by reactions 9 and 12, above. These reduction reactions would be catalyzed at the surface of the cathode.

In the case where the cathode is an intercalation material (eg, M_x-1 WO₃ or conductive polymers like those suggested by Miller et al U.S. Pat. No. 4,585,652), then the ion exchange material would provide ionic species capable of participating in the intercalation reaction. For example, if the cathode were sodium tungstate in a partially oxidized state, then the ion exchange material would provide a source of sodium ion or other cation capable of being intercalated into the cathode structure during operation of the device, as indicated by reaction 10 above.

As a third example, the ion exchange material may provide an ionic species, opposite in charge state to the drug in its ionic form, which is not reduced at the cathode nor intercalated into the cathode, but instead is a reactant critical to the formation of a noncompetitive product. This type of scenario is suggested by reaction 11 above. In this case, the ion exchange material is a source of hydronium ion, H₃ O⁺. Ion exchange materials with mobile hydronium ions have been employed in the prior art as buffering agents (eg, Sanderson U.S. Pat. No. 4,722,726 to counteract the effect on reservoir pH due to generation of hydroxyl ion at the cathode (eg, via the reaction H₂ O+e^- .fwdarw.1/2H₂ +OH^-). In contrast, this example of the invention utilizes an ion exchange material as a source of hydronium ion which facilitates the formation of a noncompetitive species (eg, H₃ O⁺ +OH^- .fwdarw.H₂ O).

The above examples of this invention have focused on anodic and cathodic reactions. Anodic reactions were selected to illustrate the use of on exchange materials for the "capture" of competitive ions generated at the node. Cathodic reactions were used to illustrate the use of ion exchange materials for the "facilitation" of reactions, which generate no competitive ions. This was done to simplify the discussion and is not intended to restrict the use of ion exchange materials for one purpose or the other to a particular type of electrode, ie, anode or cathode. Ion exchange materials can be used for either purpose at either electrode, as appropriate for the particular drug to be delivered. In addition, the principles illustrated above can be used in conjunction with the counter electrode of the device to prevent generation or delivery of toxic or otherwise "unwanted" species into or out of the counter electrode reservoir whether or not such species are "competitive" as the term is used herein.

A "composite electrode structure", "composite drug reservoir", "composite electrode" or "composite material" as those terms are used herein mean that the reservoir, electrode, material or structure comprises at least two physically or chemically distinct phases. The ion exchange material comprises one phase which would be dispersed within one or more other materials or phases. Because the ion exchange material is dispersed within the composite structure in accordance with this invention (ie, there is no discrete layer, membrane or highly-concentrated zone of ion exchange material), ion migration is not required to occur through the ion exchange material. In a preferred practice, the ion exchange material is commingled with the electroactive substance thereby generating a composite electrode structure, or less preferably is commingled with the drug substance within the drug reservoir thereby generating a "composite" drug reservoir structure.

Put another way, an ion exchange material of this invention is not present as a discrete or continuous structure (eg, a membrane or layer), which separates one component of the device from another. Instead, the ion exchange material is distributed, within and throughout the electrode, the drug reservoir, the skin adhesive or other structure (or each structure) of the electrotransport system. Generally speaking, dispersed ion exchange materials are particulate, having a major dimension in the range of about 0.1 to 1200 microns. Particle sizes in the upper half of this range (eg, about 600 to 1200 microns) are preferred from the standpoint of optimizing electrotransport drug flux. Particle sizes at the lower end of this range (eg, about 1 to 600 microns and most preferably in the range of about 5 to 150 microns) are preferred from the standpoint of ease of processing and manufacturability. The ion exchange material, to be effective, must be in a drug or agent-transmitting relationship in the system. This means the material, regardless of where it is located, must be able to interact with the drug or agent flux during electrotransport.

The term "distributed" as used herein is not necessarily intended to mean "uniformly distributed", within the device structure. The term "distributed" means that the ion exchange material is sufficiently dispersed, whether particles, grains, pellets, colloids, or micelles, so that ionic polarization due to size selectivity or charge selectivity within the operant portion of the device, is substantially avoided.

Claim 1 of 30 Claims

1. An electrotransport device having one or more ion conducting regions comprising:

a donor electrode assembly including an electrode and a donor reservoir containing an active agent,

a counter electrode assembly including an electrode,

means for maintaining the device in ion transmitting relationship with a body surface or membrane;

a source of electrical power adapted to be electrically connected to the donor and counter electrode assemblies; and

particulate means for substantially immobilizing competitive ions located in at least one of the ion conducting regions, wherein said competitive ions are generated within at least one of the electrode assemblies during operation of the device and said particulate means comprises an ion exchange material distributed in at least one of said electrodes in order to form a composite electrode structure comprising an electronically conductive composition and an ion exchange material, said ion exchange material comprising a mobile ionic species and a substantially immobile ionic species, the mobile ionic species being interactive with said competitive ions so that said competitive ions are rendered substantially less mobile or less responsive to electromotive force generated by the device.

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