Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2000-10-27
2003-04-22
Lazarus, Ira S. (Department: 3749)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S019000, C604S021000, C604S890100, C604S501000
Reexamination Certificate
active
06553255
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to the use of iontophoresis for permeant transport and, more specifically, to a method and device capable of reducing variability in the iontophoretic process by the use of a background co-ion that minimizes changes in the permeant flux and reduces inter-tissue variability.
BACKGROUND
Iontophoresis is commonly defined as the introduction of a compound or composition into the body or across a tissue by means of an electric current although; recently reverse iontophoresis has been used to non-invasively withdraw analytes (e.g. glucose) through the patient's skin for analysis. In practice, transdermal iontophoresis is a non-invasive method of enhancing the passage of drugs or other compounds across the skin or mucosal tissue. Unfortunately, most iontophoretic methods cannot provide a constant flux at constant current, likely due to time-dependent changes in the porosity (permeability) of the skin, changes in the surface charge density, and changes in the effective pore size of the pathways in skin during the course of iontophoresis. The inability to adequately predict and control permeant transport has severely limited clinician, patient, industry, and regulatory authority acceptance of iontophoresis as a viable drug delivery or analyte extraction option.
Systems for transporting ionized substances through the skin have been known for some time. British Patent Specification No. 410,009 (1934) describes an iontophoretic delivery device that overcame one of the disadvantages of the early devices, namely, the need to immobilize a patient near a source of electric current. The device was made by forming a galvanic cell which itself produced the current necessary for iontophoretic delivery from the electrodes and the material containing the drug to be delivered. Unlike previous iontophoretic delivery systems, the device allowed the patient to move around during drug delivery and thus minimized interference with the patient's daily activities.
In present iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some area of the body surface, i.e., skin or mucosal tissue. In iontophoretic drug delivery, one electrode, called the active or donor electrode, is the electrode from which the drug is delivered into the body. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode, completing the circuit. If the ionic substance to be delivered is negatively charged, then the cathode will be the active electrode and the anode will be the counter electrode.
In analyte extraction, the electrode that receives the analyte from the body can be termed the receiver electrode and the second electrode can be termed the indifferent or return electrode. If the substance being extracted from the body is a cation (positively charged), the receiver electrode will be the cathode. Conversely, if the extracted substance is an anion, the anode will be the receiver electrode. If, however, the extracted substance is uncharged, the receiver electrode will be the cathode because of the direction of electroosmotic flux in the direction of anode to cathode under physiological conditions.
In conjunction with the patient's skin, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery, and usually to circuitry capable of controlling current passing through the device.
Iontophoretic drug delivery devices also generally include a reservoir or source of the drug that is to be delivered into the body. Iontophoretic analyte extraction devices include a reservoir for collection of the analyte. Examples of such reservoirs or sources include a pouch, as described in Jacobsen, U.S. Pat. No. 4,250,878, a pre-formed gel body, as disclosed in Webster, U.S. Pat. No. 4,382,529 and Ariura et al. U.S. Pat. No. 4,474,570, a receptacle containing a liquid solution, as disclosed in Sanderson, et al., U.S. Pat. No. 4,722,726, a wetable woven or non-woven fabric, a sponge material, or any combination thereof. Such reservoirs are connected to the anode or the cathode of an iontophoretic device to provide a fixed or renewable source of one or more desired agents.
It is known that during direct current (DC) iontophoresis, the applied current causes pores in the skin cells to form (electroporation) and enlarge resulting in reduced electrical resistance. In addition, the direct current changes the net charge density of the pores. See, for example, U.S. Pat. No. 5,374,242 to Haak et al. and U.S. Pat. No. 5,019,034 to Weaver et al. Electroporation does not itself affect permeant transport but merely prepares the tissue thereby treated, for delivery of a drug by any of a number of techniques, one of which is iontophoresis.
In existing iontophoresis devices, the amount of agent transported across the tissue through these pores, generally referred to as the “flux”, varies with time during the course of a typical iontophoresis procedure. Serious variability in the permeant flux exists during the first one to two hours of the application. The flux drift can then stabilize or continue to change depending on the permeant transported, the current profile, excipients present in the formulation, and the status of the biological membrane through which transport occurs. Intra- and inter-patient variability is also a major concern in iontophoretic devices, due to differences in the pores from one area of tissue to the next or from one patient to the next. In addition, different regions of a patient's skin or skin between different patients respond differently to the electrical current, with some skin changing more than others. Some of the factors influencing the change in pore size are the patient's age, level of hydration of the stratum corneum, previous damage, follicular density, or other unknown factors.
The variability in permeant flux during iontophoresis is the main complication accompanying pore induction (electroporation) in human skin at low to moderate voltages. Since the amount of material (e.g., drug delivery or analyte extraction) transported across skin varies with time, varies among patients, and varies from day-to-day in the same patient, controlled and predictable permeant transport using iontophoresis has heretofore not been possible.
As stated in U.S. Pat. No. 5,983,130 to Phipps et al., it has been recognized in the art that “competitive” ionic species having the same charge (i.e., the same sign) as the drug ions being delivered by electrotransport compete with the permeant ion for the electrical current and therefore have a negative impact on electrotransport efficiency. For example, Untereker et al., U.S. Pat. No. 5,135,477 and Petelenz et al., U.S. Pat. No. 4,752,285 state that competitive ionic species are electrochemically generated at both the anode and cathode of an electrotransport delivery device and present methods for reducing the negative effects of these competitive ionic species using cation permeants in the form of salts.
In addition, formulation excipients can provide extraneous competing ions. Some devices employ sodium chloride as a chloride source to control the migration of silver ions formed at a silver foil cathode. U.S. Pat. No. 6,049,733 to Phipps et al. teaches the use of supplementary chloride ion sources in the form of high molecular weight chloride resins in the donor reservoir of a transdermal electrotransport device. The resins are highly effective at providing sufficient chloride to capture the competitive silver ion and prevent their migration, yet because of the high molecular weight of the resin cation, the resin cation is effectively immobile and hence cannot compete with the permeant for transport through the body surface.
Higuchi William I.
Li Kevin
Miller David J.
ACiont Inc.
Lazarus Ira S.
Nguyen Tu Cam
Reed & Eberle LLP
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