Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2001-02-13
2003-01-28
Derakshani, Philippe (Department: 3754)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C108S051300
Reexamination Certificate
active
06512950
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the field of drug delivery and more particularly to methods of transport of agents such as pharmaceutically active agents across tissues, including transport 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 for many tissues renders it difficult to move agents across a body surface. Permeability in many tissues is low because cell membranes are generally composed of lipid bilayers that are relatively impermeable to ionized and uncharged polar species. For example, transport of agents across skin has proved difficult in part because the outer layer of skin termed the stratum corneum consists of tightly packed cells with intercellular lipids which severely impede passage of substances through this barrier.
Oral administration of drugs remains the most common method of drug delivery because the cells lining the intestine tend to be quite permeable and because oral ingestion is generally accepted by patients. This approach, however, has a variety of shortcomings including degradation of the agent within the gut, the inability to apply a driving force, and local gastrointestinal irritation.
Iontophoresis is an alternative approach that can be utilized to deliver agents across a tissue by the application of an electrical current. In practice, iontophoretic methods generally involve positioning an electrode that includes some type of reservoir or absorbent pad that contains the agent to be transferred on the tissue through which delivery is to occur. Another electrode that typically does not include the agent but contains, or is coated with, a conductive gel is also placed in contact with the tissue to complete the electrical circuit.
Application of a voltage between the two electrodes and across the tissue generates a current that causes the ionized agent to move towards the electrode of opposite charge, thereby driving the agent through the tissue. Neutral agents can also be transported, albeit less effectively than ionized agents, via electroosmosis. lontophoresis induces the formation and/or enlargement of pores within tissues, which in turn increase tissue permeability to ionic and polar agents and drive these agents through such pores. When the tissue is skin, the agent penetrates the stratum corneum and passes into the dermo-epidermal layer. The innermost portion of the dermis 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 circulatory system.
A majority of the 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 clinicians, patients and government regulators. One shortcoming of constant-current DC is that the rate of drug delivery changes with the passage of time, even though a constant current is applied. The inability to provide a constant flux at constant current is possibly 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 pose significant problems in effectively controlling the transdermal delivery of drugs by iontophoresis. It is generally observed that with constant-current DC methods the transference number (fraction of total current carried by a particular charged species) for the bioactive agent increases with time over the course of a typical iontophoresis procedure. This variability in transference number means that the amount of agent transported across a tissue varies with time and cannot be controlled 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 systems, transport is accompanied by water hydrolysis that causes significant pH shifts in the bulk solution and gas formation at the surface of the electrodes. In particular, protons form at the anode while hydroxide ions form at the cathode. Such pH shifts may result in electrochemical bums that can cause tissue damage. In addition, gas formation interferes with the contact, and hence the electrical conduction between the electrode and tissue surface.
Various strategies have been tested to address these problems, including using different waveforms 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 drug delivery. However, many DC pulsed methods suffer from at least some of the same general problems as the constant-current DC methods.
Illustrative of a general pulsed DC method is U.S. Pat. No. 5,019,034 to Weaver et al. Weaver et al. discuss methods that utilize a series of short DC pulses to induce electroporation, in particular a state referred to as reversible electrical breakdown. Various forces can then be utilized to effectuate transport of an agent across a tissue. Once electroporation is established, the nature of the DC pulses (e.g., pulse duration, shape and frequency) is maintained until transfer is complete. U.S. Pat. No. 5,391,195 to Van Groningen discusses a method that uses a pulsed direct current with a frequency of at least 1 kHz and having a duty cycle of at least 80%. Such a signal is asserted to increase the efficiency of transport. Methods employing DC signals and methods designed to monitor the level of current such that a relatively stable current is applied and are discussed in 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. For example, U.S. Pat. No. 5,968,006 to Hoffman discusses a system in which one electrode assembly is used to generate a pulsed DC signal to induce pores in a patient's skin. A second electrode assembly generates a low voltage continuous electric field of sufficient magnitude to affect transport of molecules through the electroporated region. Each of the foregoing patents, are limited in that they discuss only the use of direct current to perform iontophoresis. These patents also do not discuss how to maintain a substantially constant electrical state in the electroporated region of the tissue in order to maintain constant transference numbers, and hence constant flux, for the agent(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 particle. 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 [reverse pulse of an alternating current] would result in an inverse effect to the positive pulse, thereby reducing the efficiency of treatment.”
Nonetheless, certain investigators have discussed the use of AC signals for specific purposes in conducting iontophoresis. For example, several patents
Higuchi William I.
Li S. Kevin
Song Yang
Zhu Honggang
Derakshani Philippe
Townsend and Townsend / and Crew LLP
University of Utah Research Foundation
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