Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2002-05-03
2004-10-05
Bockelman, Mark (Department: 3762)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
Reexamination Certificate
active
06801804
ABSTRACT:
TECHNICAL FIELD
The invention relates generally to a device and method for monitoring and controlling the iontophoretic transport of a compound through a localized region of an individual's body tissue. In particular, the invention employs a novel reference electrode, in conjunction with at least one of two iontophoretic electrodes, to monitor and control the electrical resistance of the tissue at the localized region. The invention is particularly useful when there is a need to precisely control the administration of a compound to, or the extraction of a compound from a body tissue, such as in the administration or monitoring of a therapeutic drug or glucose, for example.
BACKGROUND
Iontophoresis involves the transport of a compound across a body tissue under the influence of an electrical current. In practice, two iontophoretic electrodes are placed on a body tissue, typically the skin or mucosa, in order to complete a circuit. At least one of the electrodes is considered to be an active iontophoretic electrode, while the other may be considered as a return, inactive, or indifferent electrode. Compound transport across the tissue occurs when a current is applied to the electrodes through the tissue. Compound transport may occur as a result of a direct electrical field effect (e.g., electrophoresis), an indirect electrical field effect (e.g., electroosmosis), electrically induced pore formation (electroporation), or a combination of any of the foregoing.
Iontophoretic techniques have been used to deliver compounds to, or extract compounds from, body tissues of a patient. When iontophoresis is used to deliver a compound to the tissue, an active iontophoretic electrode is provided with a reservoir containing the compound to be delivered, as well as optional additional compounds that may serve to enhance iontophoretic delivery. For example, U.S. Pat. No. 6,248,349 to Suzuki et al. describes an iontophoretic electrode in combination with an interface capable of making contact with the skin that effectively holds a drug and humectant mixture. The humectant is described as improving iontophoretic drug delivery by controlling the concentration of the drug at the delivery site. Similarly, when iontophoresis is used to extract a compound from the tissue, the active iontophoretic electrode may be provided with a reservoir for collecting the extracted compound. Further, additional compounds may be added to the receiving reservoir to enhance iontophoretic extraction. Once extracted, the compound may be analyzed using sensors, processors, and algorithms known in the art. See U.S. Pat. Nos. 6,139,1718; 6,144,869; 6,180,416; 6,201,979; 6,233,471; 6,284,126; and 6,326,160.
In some instances, the process of iontophoresis can cause irritation, sensitization, and pain at the application site. The effects of the electrical current on sensitization have been investigated in various attempts to develop iontophoretic methods that are capable of maintaining the electrical current and/or potential at a comfortable level. It has been found that the degree of irritation, sensitization, and/or pain is directly proportional to the applied current or voltage. Thus, there is a need to apply iontophoretic current at a level that is effective to transport compounds of interest at a desired rate but that does not cause tissue irritation, sensitization, and/or pain.
A majority of the known iontophoretic methods employ a constant direct current (DC) iontophoretic signal and suffer from a number of shortcomings as a consequence. It is generally believed that the constant driving force provided by the DC current will produce a constant, unwavering permeant flux. It has been observed, however, that a constant current DC signal does not result in constant flux. The constant DC causes the electrical resistance of the tissue to change as a result of variations in tissue porosity, pore surface charge density, and effective pore size over the course of treatment. As a result, the amount of compound transported across a tissue varies with time and cannot be controlled, monitored, or predicted effectively. The inability to control analyte flux during iontophoresis has proven to be a major constraint to the marketing and regulatory success of iontophoretic products.
In addition, iontophoretic techniques that employ a constant DC signal can result in the formation of unwanted byproducts. For example, the application of a constant direct current to a tissue can result in water hydrolysis at the treatment site, causing protons to accumulate at the anode and hydroxide ions to accumulate at the cathode. The resulting shift in pH at the electrodes may cause tissue irritation and/or damage. In extreme cases, this resulting electrolysis causes gas formation at the interface between the active electrode and tissue in contact with it. As a consequence, interfacial electrical resistance may be altered as well. The highly mobile hydrogen and hydroxide ion byproducts of water hydrolysis competes against the permeant for the electrical current, thereby decreasing permeant transport efficiencies.
As a whole, the overarching problem associated with DC iontophoretic systems is their high degree of variability. A number of attempts have been made to overcome the problems associated with constant DC signals by using pulsed DC signals and signals of different waveforms. In theory, pulsed DC signals improve iontophoretic delivery by allowing skin capacitance to discharge, thereby dissipating accumulative pore charging and the resulting formation of electropotential barriers. This capacitance discharge is thought to permit more controlled current flow and agent transport. In some instances, employing pulsed DC signals may involve switching the polarity of electrodes between the pulses. See U.S. Pat. No. 5,771,890 to Tamada. In practice, however, many DC pulsed methods suffer from at least some of the same general drawbacks as the constant current DC methods.
Iontophoretic methods that use alternating current (AC) signals, with or without a DC offset, have exhibited improved performance for both compound delivery and extraction. The premise of AC constant conductance iontophoresis is that molecular transport across a tissue is directly proportional to the tissue's conductivity and inversely related to the tissue's resistivity. The conductance of the membrane is a direct measure of the ease of passage of molecules and ions, but in particular, sodium and chloride ions. It has been found that, at constant current levels, the molecular transport though a membrane is related to the conductance of the membrane. AC iontophoretic methods are described in U.S. patent application Ser. No. 09/783,138, entitled “Methods for Delivering Agents Using Alternating Current,” filed on Feb. 13, 2001, corresponding to International Patent Publication No. WO 01/60449. AC iontophoretic methods are also described in U.S. patent application Ser. No. 09/783,696, entitled “Methods for Extracting Substances Using Alternating Current,” filed on Feb. 13, 2001, corresponding to International Patent Publication No. WO 01/60448.
In order to reduce the energy requirements needed to effect iontophoretic transport, it has been discovered that application of a barrier-modifying substance (also referred to herein as a “barrier-modifying agent” or “barrier modifier”) to the body tissue, either prior to or during AC iontophoresis, lowers the potential voltage difference needed to achieve electroporation. As discussed in U.S. patent application Ser. No. 10/014,741, entitled “Method of Increasing the Battery Life of an Alternating Current Iontophoresis Device Using a Barrier-Modifying Agent,” filed on Dec. 10, 2001, the use of such barrier modifiers makes it possible to maintain the rate at which a compound of interest can be transported through a body tissue at lower electrical voltage levels. This reduction in applied voltage ultimately results in increased battery life, extended treatment duration, decreased treatment cost, and increased patient comfort.
In order to
Hastings Matthew S.
Higuchi William I.
Li Kevin
Miller David J.
Aciont, Inc.
Bockelman Mark
Reed & Eberle LLP
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