Methods for extracting substances using alternating current

Details Methods for extracting substances using alternating current Methods for extracting substances using alternating current

2001-02-13

2002-12-17

Derakshani, Philippe (Department: 3754)

Surgery

Means for introducing or removing material from body for...

Infrared, visible light, ultraviolet, x-ray or electrical...

C128S869000

Reexamination Certificate

active

06496728

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to the field of substance extraction and detection from a subject's body utilizing electrical signals, including substances extracted by iontophoresis.
BACKGROUND OF THE INVENTION
The transport of various agents such as metabolites, drugs and nutrients across tissues is a function primarily of three factors: tissue permeability, the presence or absence of a driving force and the size of the area through which transport occurs. The lack of inherent permeability of many molecular permeants severely impedes the movement of permeants across a layer of tissue. Permeability in skin is low because the unique, tightly packed arrangement of cells in the membrane and the intercellular lipid matrix make the
stratum corneum
relatively impermeable, especially to polar and ionized species.
Iontophoresis is one method that has been explored as a way to effectuate transport of agents across a tissue. Such methods have been used primarily to deliver rather than extract agents through a tissue into the body (e.g., transdermal delivery of a drug). Iontophoresis is characterized by the application of an electrical current to enhance transport across a tissue by driving ionized agents through the membranes as a result of a direct electrical field effect (e.g., electrophoresis), electroosmosis, or through electrically induced pore formation (electroporation). In practice, iontophoretic methods generally involve positioning an electrode that includes some type of reservoir on the tissue through which delivery is to occur. The reservoir typically includes a solution or an absorbent pad that contains the substance to be transferred. This is called the active or drug electrode. Another electrode is also placed in contact with the tissue to allow for the completion of the electrical circuit. This is called the return, inactive, or indifferent electrode.
Application of a voltage between the two electrodes and across the tissue generates a current that causes the ionized agent of one charge to move towards the electrode of the opposite charge. In the standard configuration in which iontophoresis is used to deliver an agent, this current drives the agent in the reservoir at the active electrode through the tissue and into the body. Neutral agents can also be transported, albeit less effectively than ionized agents, via electroosmosis. The electric field also induces new pore formation on the tissue and increases its permeability. When the tissue is skin, the agent penetrates the
stratum corneum
and passes into the dermo-epidermal layer. The outermost portion of the dermis layer is typically referred to as the papillary layer and contains a network of capillaries from the vascular system. This network absorbs the agent and subsequently moves it to the main portion of the vascular system.
During analyte extraction, with the analyte traverses the membrane outward from the dermo-papillary layer to the surface of the
stratum corneum
under the influence of an electrical field. When iontophoresis is used to extract a substance from a body, the reservoir is the site at which the substance is collected. The current formed between the electrodes acts to extract the substance from the vascular network through the tissue and into the reservoir.
A majority of iontophoretic methods utilize constant-current DC signals to effectuate transport. There are several problems associated with such methods that have resulted in limited acceptance by regulatory authorities, clinicians, and patients. Literature and unpublished data from the inventors' laboratories suggest that one shortcoming of constant-current DC is the inability to achieve a constant flux at constant current due to time-dependent changes in tissue porosity, accompanying changes in pore surface charge density and effective pore size over the course of treatment. Such changes and the resulting flux variability pose significant problems in effectively controlling the transport (either delivery or extraction) of agents through a tissue by iontophoresis. It is generally known that with constant-current DC methods the transference number (fraction of total current carried by a particular charged species) for the bioactive agent changes with time over the course of a typical iontophoresis procedure. Thus, while application of the DC signal initially results in a state of electroporation, with time the properties of the pores change. This trend can be monitored by the changes in the tissue electrical resistance and/or the changes in the transference number with time during iontophoretic transport. This variability in transference number means that the amount of agent transported across a tissue varies with time and cannot be controlled, monitored, nor predicted effectively. Problems in controlling the extent of electroporation with constant-current DC methods also result in high inter- and intra-patient variability. Hence, not only does the amount of agent transported vary as a function of time, there is further day-to-day variation for the same individual, as well as variation from person to person.
Yet another problem is a function of byproducts formed during iontophoresis. With many direct current systems, transport is accompanied by water hydrolysis that causes significant pH shifts at the electrodes. In particular, protons accumulate at the anode while hydroxide ion accumulates at the cathode. Such pH shifts result in electrochemical bums that can cause tissue damage. In addition, water hydrolysis results in gas formation that interferes with the contact, and hence the electrical conduction, between the electrode components and tissue surface. The use of pure AC ameliorates water hydrolysis and subsequent problems with tissue irritation and gas formation.
Various strategies have been tested to address these problems, including the use of different wave-forms and pulsed DC signals rather than constant-current signals. It has been suggested that the use of pulsed DC signals should theoretically provide improved performance by allowing skin capacitance to discharge, thereby allowing for more controlled current flow and agent transport. However, many DC pulsed methods suffer from at least some of the same general problems as the constant-current DC methods.
The following U.S. patents are illustrative of general pulsed DC methods: U.S. Pat. No. 5,391,195 to Van Groningen; U.S. Pat. No. 4,931,046 to Newman; and U.S. Pat. No. 5,042,975 to Chien et al. Certain DC methods employ a combination of pulsed and continuous electric fields (see, e.g., U.S. Pat. No. 5,968,006 to Hofmann). Each of the foregoing patents, however, are limited in that they discuss only methods for delivering substances across a tissue into the body of an individual. These patents include no discussion of methods for extracting compounds from a body across a tissue. Furthermore, these patents only discuss the use of DC signals to perform iontophoresis; the patents include no discussion on how AC signals can be utilized to effectuate transport. In particular, these patents do not discuss how to maintain a substantially constant electrical state in order to maintain substantially constant levels of transport (e.g., a transference number) for the substance(s) being transported.
The iontophoretic literature on balance has taught against the utility of AC signals in conducting iontophoresis. It has been the belief of many of those skilled in the art that an AC signal lacks the necessary driving force to achieve effective iontophoretic transport; instead, the view has been that the driving force of an applied DC signal is required to transport a charged species. The bidirectional nature of an AC signal, led many to conclude that the use of an AC signal would result in inefficient transport at best, and perhaps no net transfer at all. For example, in U.S. Pat. No. 5,391,195 it is noted that “the negative pulse [of an alternating current] would result in an inverse effect to the positive pulse, thereby reducing the efficiency of

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