Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1998-06-26
2001-11-27
Bockelman, Mark (Department: 3762)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C424S449000
Reexamination Certificate
active
06324424
ABSTRACT:
TECHNICAL FIELD
This invention relates to electrotransport agent delivery devices, compositions, and methods. More particularly, this invention relates to methods of reducing skin irritation during transdermal electrotransport agent delivery.
BACKGROUND ART
The term “electrotransport” as used herein refers generally to the delivery of an agent (eg, a drug) through a membrane, such as skin, mucous membrane, or nails, which delivery is induced by application of an electrical potential. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of a human body by electrotransport delivery through the skin. A widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Another type of electrotransport, electroosmosis, involves the flow of a liquid, which liquid contains the agent to be delivered, under the influence of an electric field. Still another type of electrotransport process, electroporation, involves the formation of transiently-existing pores in a biological membrane by the application of an electric field, through which pores an agent can be delivered either passively (ie, without electrical assistance) or actively (ie, under the influence of an electric potential). However, in any given electrotransport process, more than one of these processes may be occurring simultaneously to a certain extent.
Accordingly, “electrotransport”, as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture thereof, regardless of the specific mechanism or mechanisms by which the agent actually is transported.
Electrotransport devices generally use at least two electrodes which are in electrical contact with some portion of the skin, nails, mucous membrane, or other surface of the body. One electrode, commonly referred to as the “donor” or “active” electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically termed the “counter” or “return” electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, ie a cation, then the anode will be the active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if an agent is negatively charged, ie an anion, the cathode will be the donor electrode. Additionally, both the anode and cathode may be considered donor electrodes if both anionic and cationic agent ions are to be delivered.
Furthermore, electrotransport delivery systems generally require at least one reservoir or source of the agent to be delivered to the body. Examples of such donor reservoirs include a pouch or cavity, a porous sponge or pad, and a hydrophilic polymer or a gel matrix. Such donor reservoirs are electrically connected to, and positioned between, the anode or cathode and the body surface, to provide a fixed or renewable source of one or more agents or drugs. Electrotransport devices also have an electrical power source such as one or more batteries. Typically, one pole of the power source is connected to the donor electrode, while the opposite pole is connected to the counter electrode. In addition, some electrotransport devices have an electrical controller which controls the current applied through the electrodes, thereby regulating the rate of agent delivery. Furthermore, passive flux control membranes, adhesives for maintaining device contact with a body surface, insulating members, and impermeable backing members are some other potential components of electrotransport devices.
Although the advantages of electrotransport delivery are numerous (eg, enhanced transmembrane flux of beneficial agents compared to passive, ie, non-electrically assisted flux; precise control of agent delivery, including patterned delivery, etc.), there are disadvantages under certain application conditions. One potential problem with electrotransport transdermal delivery is skin irritation. For instance, applying an electric current through skin under certain conditions has been known to cause skin irritation. See for example, “Skin Biological Issues in Electrically Enhanced Transdermal Delivery”, P. Ledger, Advanced Drug Delivery Reviews, Vol. 9 (1992), pp 289-307.
The prior art has recognized that the pH of the solution of the drug or agent being delivered (ie, the pH of the donor reservoir in an electrotransport device) can have an effect on skin irritation. According to “Structure-Transport Relationships in Transdermal lontophoresis” by Yoshida et al,
Ad. Drug Del. Rev
. (1992), 9, 239-264, the preferred pH range of the donor reservoir, for avoiding skin irritation is 3 to 8. Outside this pH range, according to this reference, irritation and/or damage of the stratum corneum can occur. Furthermore, previous disclosures relating to minimizing skin irritation from electrotransport devices have concentrated on the active or donor reservoir. However, electrotransport devices apply as much current through the counter electrode as through the donor electrode, and hence, skin irritation, erythema and/or damage due solely to application of electric current also occurs beneath the counter reservoir or counter electrode. In a typical electrotransport device, the area of device/skin contact beneath the counter reservoir is nearly equivalent to the area beneath the donor reservoir. Hence, skin erythema, irritation, and/or damage in the counter reservoir contact area may be similar in magnitude to that in the donor reservoir contact area.
DISCLOSURE OF THE INVENTION
Hence, it is an object of this invention to provide an apparatus and method by which tissue irritation may be reduced or eliminated during and after electrotransport of an agent through a body surface (eg, skin).
A further object of this invention is to improve patient compliance with electrotransport drug administration schedules by reducing or preventing skin irritation caused by transdermal electrotransport drug delivery.
Satisfaction of these objects and other advantages of this invention will become apparent from the electrotransport device and method of the present invention. The electrotransport device contains donor and counter reservoirs which are adapted to be placed in ion-transmitting relation with a body surface such as the skin or a mucosal membrane of an animal. The donor reservoir contains the drug to be delivered. The device includes a source of electrical power which can apply a voltage across the donor and counter reservoirs in order to apply a predetermined level of electric current therethrough and through said body surface. At least one of the reservoirs contains a solution of an anti-inflammatory agent selected from the group consisting of hydrocortisone, an ester of hydrocortisone and salts thereof. The flux of the anti-inflammatory agent is sufficient to reduce body surface irritation associated with said applied level of electric current. The flux of the anti-inflammatory agent necessary to reduce tissue irritation encountered with electrotransport drug delivery is typically in the range of about 0.03 to 10 &mgr;g/cm
2
·h, and preferably in the range of about 0.1 to 5 &mgr;g/cm
2
·h.
Preferably, the anti-inflammatory agent is hydrocortisone, hydrocortisone phosphate and/or hydrocortisone succinate, most preferably hydrocortisone. When the anti-inflammatory agent is hydrocortisone, the reservoir which contains the hydrocortisone preferably contains a liquid solvent selected from the group consisting of an alcohol, a glycerol, a glycol, a cyclodextrin, and an aqueous solution of a surfactant.
In another embodiment of the present invention, a method of reducing body surface (eg, skin) irritation during (eg, transdermal) electrotransport delivery of a drug is presented. The method involves placing the donor and counter reservoirs of an electrotransport delivery device in ion-transmitting relation with a body surface, the donor reservoir containing
Campbell Patricia S.
Cormier Michel J. N.
Ledger Philip W.
ALZA Corporation
Bates Owens J.
Bockelman Mark
Miller D. Byron
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