Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-08-27
2002-05-28
Dawson, Glenn K. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S020000, C604S891100, C128S898000
Reexamination Certificate
active
06394994
ABSTRACT:
FIELD OF INVENTION
The present invention is generally related to drug delivery and more specifically to iontophoretic delivery of a medicament.
BACKGROUND
Iontophoretic delivery of a medicament is accomplished by application of a voltage to a medicament loaded reservoir-electrode, sufficient to maintain a current between the medicament loaded reservoir-electrode and a return electrode (another electrode) applied to a patient's skin so that an ionic form of the desired medicament is delivered to the patient.
An iontophoretic device loaded with a medicament, from a pharmaceutical point of view, may be considered as analogous to a tablet, a passive transdermal patch or a pre-filled syringe, i.e., a unit dose of the particular medicament for delivery into a single patient. Like the tablet, the transdermal patch or the pre-filled syringe, iontophoretic devices are a product of a multi-step manufacturing process. Accordingly, a concern of the manufacturer and the practitioner administering the dose of the medicament to the patient is: “Does the device, (tablet, passive transdermal patch or syringe) actually contain and is it capable of delivering the correct amount of the medicament?”
In the case of tablets, there are weight variation, content uniformity, dissolution tests and drug release tests. These tests have evolved into well-accepted methods and are published in the United States Pharmacopoeia. For a tablet, if the tablet weight is substantially uniform, the formulation that is used to prepare the tablet is correct and well mixed and the tablet disintegrates and releases the medicament, there can be a fair assurance that any individual tablet administered to a patient provides the desired dosage. For tablets, drug release tests are based on measuring the release of the medicament by diffusion into a medium under controlled conditions. For passive transdermal patches, which have the same drug release mechanism as oral dosage forms, the above standard tests have been modified and adapted to measure drug release.
An iontophoretic device presents a considerably more complex problem for analysis of drug release. While the test procedures described above and manufacturing controls can provide assurances that the formulation for the iontophoretic device is correct, well mixed and accurately applied to the device, the literature methods for measuring medicament release in tablets and passive transdermal devices are not suitable for study of iontophoretic drug delivery that depends upon ion migration in the presence of an electric field for drug transport. Ultimately it is necessary to determine if the iontophoretic device is capable of actually delivering the desired dose of the medicament under conditions indicative of the device's performance in actual use.
A published report by Lloyd, et al. from Transdermal Administration, A Case Study, Iontophoresis, March 1997 discloses an in vitro drug release test for commercial transdermal iontophoretic electrodes that the authors state is analogous to drug release tests used to evaluate passive drug release from commercial transdermal systems. In this paper, the authors relate the use of a glass double-sided diffusion cell containing a receptor solution that receives a delivery of lidocaine from an iontophoretic device. The authors relate that a difficulty they overcome in their method is discrimination between passive (diffusive) delivery of the medicament and the electrically driven iontophoretic delivery. The drug containing electrode is applied to polyvinylpyrollidone (PVP) coated polycarbonate microporous membrane on one side of the diffusion cell, with a return electrode applied to the other side of the diffusion cell. A current is generated through the cell and the concentration of the drug in the receptor solution is determined by an appropriate analytical method. The purpose of the PVP coated microporous membrane is to reduce the diffusional transport of the lidocaine from the reservoir-electrode into the receptor solution. The authors relate that their method provides ratios between 1.5:1 and 5:1 active iontophoretic delivery to passive diffusive delivery for the lidocaine present in their device in their test system into a diffusion cell containing aqueous sodium chloride as a receptor solution. The authors reported that the PVP coated porous membrane they used was the only membrane that was satisfactory, the other membranes, such as ion exchange membranes, either were unable to discriminate between active and passive delivery or were too resistive to allow an electric current to pass. The test as described in the paper required up to 120 minutes for each sample and the authors themselves state that there are many unresolved questions to be answered before a statistically valid test suitable for routine use is available.
The art of iontophoresis devices would be advanced if a rapid and reliably repeatable test were available. Such a method is disclosed hereinbelow.
SUMMARY
A method for testing the ability of an iontophoretic reservoir-electrode to deliver a medicament includes providing an iontophoretic reservoir-electrode. The reservoir-electrode includes a suitable electrical connection and a reservoir containing at least one ionized medicament. The method includes providing another suitable electrode. The method further includes providing a separation medium having the property of allowing a transport thereinto of the at least one ionized medicament under the influence of an applied electric current flowing therethrough compared to a transport of the ionized medicament thereinto in the absence of the applied electric current in a ratio greater than one. The method then includes placing the contact surface of the reservoir-electrode containing the ionized medicament in electrical contact with the separation medium and placing the separation medium in electrical contact with the another electrode. The method then includes applying a sufficient electrical potential between the iontophoretic reservoir-electrode containing the at least one ionized medicament and the another electrode so that a preselected current flows through the separation medium for a preselected time thereby transporting at least a portion of the at least one ionized medicament into the separation medium and determining an amount of the at least one ionized medicament in the separation medium.
The method of the invention provides differentiation between electrically driven (iontophoretic) and passive (diffusive) transport of the medicament, making it well suited as a test method for iontophoretic devices. The method of the invention is rapid and simple to practice. The method of the invention utilizes readily available and stable separation media as a sampling device in a simulated use condition. The ionized medicament is delivered to the separation medium by a preselected current and the amount determined. The method is compatible with a variety of assay methods. In one embodiment, the method allows a practitioner to apply a sufficient potential across the separation medium to cause a higher current than would be acceptable to deliver a particular medicament to a patient to transport the medicament into the separation medium. This higher rate of transport, available in the method of the invention, of the ionized medicament into the separation medium facilitates assay of multiple samples of reservoir-electrodes by minimizing the time required to prepare a series of individual samples for analysis. The ability to use the higher rate of transport has the additional benefit of facilitating the differentiation between the active (electrically driven) transport and the passive (diffusive) transport of the medicaments. Further, the method is applicable to iontophoretic devices having various shapes, sizes, and configurations of the active medicament charged reservoir-electrode and the return electrode without complicated and possibly confounding modifications to the device being tested. Additionally, the use of the separation medium as a sampling devi
Chabala Elena N.
Eliash Bruce M.
Jain Uday K.
Keusch Preston
Li Lue Huai
Dawson Glenn K.
Kirkpatrick & Lockhart LLP
Maynard Jennifer
Vyteris, Inc.
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