Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2002-07-22
2003-12-09
Jacyna, J. Casimer (Department: 3751)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S174000, C604S501000
Reexamination Certificate
active
06662044
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates in general to devices for enhancing the local delivery of drugs, pharmaceuticals, plasmids, genes, and other agents into the tissues or cells of the living body. In particular, the present invention relates to patch-based devices which provide an electrical driving force that can increase the rate of migration of drugs and other therapeutic agents out of a polymer matrix into body tissues and cells using iontophoresis only, electroporation only, or combined iontophoresis and electroporation. The two procedures may be applied sequentially in any order without removing or repositioning the device.
BACKGROUND OF THE INVENTION
Many different treatment agents, such as medicines, are generally administered to the body by various methods, such as topical application, oral ingestion, intravascular, intramuscular or parenteral injection and, less commonly, by aerosol insufflation and transdermal iontophoresis and electroporation. In all of these treatments there is an immediate dilution effect greatly reducing the concentration to which the target tissues or cells are exposed. Also, medicines administered by these systems may be more vulnerable to processes such as metabolic degradation, inactivation by binding to plasma proteins or accelerated clearance from the body. These processes adversely affect the drug's concentration and residence time in the target tissues and reduce its therapeutic efficacy.
Most of the above modes of drug administration also expose non-target tissues, i.e. those that do not require treatment, to the action of the drugs, with the consequent risk of serious side effects. It is this risk towards non-target tissues that reduces a drug's efficacy by restricting systemic concentrations to a threshold level above which the side effects would become unacceptable.
Local drug delivery procedures can obviate some of the metabolic breakdown, early clearance and side effect problems affecting efficacy by presenting therapeutic concentrations of a drug only to the target site, minimizing effects upon non-target tissues. The reduction in quantity of a drug required can also result in lower treatment costs.
Recognition of the advantages for local delivery strategies has stimulated the development of a number of catheter-based and patch-based delivery devices which apply drugs directly to the body tissues at certain locations, often to sites that would be otherwise inaccessible without surgery. However, if the specific target for an agent is intracellular, simple local application of the drug, followed by its passive diffusion into tissues, does not facilitate movement of the drug across cell surface membrane barriers into cytoplasmic compartments. Diffusion away from the target cells occurs and high extracellular concentrations are rarely sustained long enough to mediate significant passage into the cells. Some drugs penetrate intact cell membranes by diffusion very poorly and may require specific carriers or bulk transport by a phagocytic or pinocytic mechanism to penetrate the cell membrane. However, these natural transport systems operate poorly, or not at all, when the tissues are affected by disease.
Iontophoretic catheters and patches have been explored in some animal angioplasty studies to provide an electrical driving force for movement of a drug into tissues. This technique requires that the agent to be delivered carries an electrical charge under the local physiological pH conditions. While iontophoresis appears to enhance the delivery of drugs into body tissues, it has been shown in transdermal iontophoresis (“TDI”), that the migration of drugs through skin predominantly occurs via extracellular pathways (sweat glands and hair follicle channels) where the current densities are much higher than elsewhere. This preferential channel movement may be favorable towards providing high drug concentrations in the skin capillary bed and onward into the circulation. However, if it is a feature of other tissues, such as blood vessels and other organ surfaces, the delivery of drugs to cellular targets will be of low efficacy.
Additionally, these iontophoretic patches are only used for transdermal applications. These patches typically use an adhesive to adhere the device to the skin while iontophoresis is used to cause the migration of the drugs. Uses of the device on internal tissues or on the eye are not possible as the adhesive will not effectively hold the device, or may be detrimental to the surface to be treated.
Additionally, the transdermal patches have only a set amount of medicament that may be delivered before the patch must be removed and recharged or replaced, limiting the possible uses of the device.
Accordingly, what is needed are devices for delivering treatment agents to specific locations, especially intracellular locations, in a safe and effective manner. These devices would deliver the agents such that effective amounts may be delivered without endangering tissues or cells in non-target areas. Additionally, the devices would be capable of being placed inside the body and held in place while also being capable of having additional medicament be added to the device to permit the patch to be used for an indefinite period of time without the need to be removed and/or replaced.
SUMMARY OF THE INVENTION
The present invention is directed to devices for enhancing the local delivery of treatment agents into the tissues or cells of the living body. These devices are designed to target certain tissue and cell locations and deliver the treatment agents directly to those locations, while mininiizing any effects on non-targeted tissues and cells. Additionally, these devices are designed to be placed inside the body and held in place while also being designed to be used for an indefinite period of time without the need to be removed and/or replaced.
In particular, the present invention relates to patch-based devices which provide an electrical driving force that can increase the rate of migration of drugs and other therapeutic agents out of a polymer matrix or other carrier mechanism into body tissues and cells using iontophoresis only, electroporation only, or combined iontophoresis and electroporation. A preferable approach may be for electroporation to be applied to permeabilize the cells after pre-iontophoresis of the agent into the tissues. Preferably, the device is able to perform the two procedures sequentially without repositioning of the device. The patch is designed to maintain a high concentration of drug in the tissue extracellular spaces (e.g. by iontophoresis) such that the subsequent creation of transient pores in cell surface membranes by electroporation pulses results in greatly improved intracellular delivery of the treatment agent.
Alternatively where a tissue, organ or solid tumor has an impenetrable margin or denser peripheral zone inhibitory to iontophoretic migration, the patch may be used to first to perturb such barrier regions with electroporation pulses to facilitate diffusion or iontophoretic migration of the drug into the interior of the tissue. Intracellular penetration may then be enhanced by the application of electroporation pulses. Such a protocol may be particularly advantageous for the delivery of larger molecular weight agents, antibody fragments and gene constructs.
One mode of intracellular targeting, which is particularly applicable to therapeutic agents that do not readily pass through cell membranes, is electroporation. In electroporation, cell membranes can be rendered transiently permeable by the application of electrical fields of short pulse width (microseconds to milliseconds). With appropriate parameters, including time, sequence of pulse, pulse width and field strength, the cell membranes will reseal to their former structural and functional integrity.
The present invention is particularly applicable to the local delivery of drugs during interventional cardiology procedures such as angioplasty and stent implantation. Other applications include use during open
Brown, III Charles L.
Crawford Neville
GMP Drug Delivery, Inc.
Jacyna J. Casimer
Sutherland & Asbill & Brennan LLP
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