Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2000-06-30
2003-10-07
Bennett, Henry (Department: 3743)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S020000, C424S449000
Reexamination Certificate
active
06629968
ABSTRACT:
FIELD OF THE INVENTION
The present invention is generally related to transdermal drug delivery and more particularly to a reservoir-electrode for iontophoresis that has enhanced stability properties.
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.
Shelf storage stability problems for many of the iontophoresis devices reported in the literature require that the medicament be stored separately from the reservoir-electrode until immediately prior to use. Iontophoretic delivery of medicaments is recognized as desirable for many medicaments, but it is not widely used because no devices are commercially available that meet all of the needs of the potential user population. An important requirement for a product to enjoy widespread usage is shelf storage stability. In an iontophoretic drug delivery system, one needs to be concerned not only with the drug stability, but also the stability of the delivery device and any interaction between the several components.
If a drug product is not stable under normal shelf storage conditions, it is unlikely to be a successfully commercial product because the short shelf life limits the products utility to most potential users as most of the product's useful life is exhausted during the time required for manufacturing and the distribution process. Thus, determination of shelf storage stability is an important part of a drug product's regulatory approval process. If there are difficulties with storage stability, regulatory approval may be withheld. Often, in iontophoretic devices the reservoir-electrode also is maintained in a dry (unhydrated) condition prior to use also because of the tendency of the active electrode material to undergo physical and chemical changes during shelf storage. Many drugs are not particularly stable to ambient conditions as the free base compound and as a result are formulated as salts that may react unfavorably with electrodes in iontophoretic devices. The need to store the several components separately has limited the use of iontophoretic devices, since in order to use the device, the reservoir-electrode needs to be charged with the medicament and hydrated either by a practitioner or user immediately prior to use.
Several United States Patents disclose devices that attempt to overcome the problem of shelf storage stability and facilitate the preparation of the device for use. U.S. Pat. No. 5,320,598 discloses a dry-state iontophoretic drug delivery device that has drug and electrolyte reservoirs that are initially in a non-hydrated condition. The device has a liquid containing pouch or breakable capsules that contain water or other liquid, the liquid being releasable by disrupting the liquid containers prior to use. Commercial manufacture of a device utilizing this disclosure would be complex.
U.S. Pat. No 5,385,543 also discloses a dry-state iontophoretic drug delivery device that has drug and electrolyte reservoirs. The disclosed device includes a backing layer with at least one passageway therethrough that allows the introduction of water or other liquids into the drug and electrolyte reservoirs prior to use followed by joining the reservoirs to the electrodes. The patent teaches that by joining the reservoirs to the electrodes after hydration, delamination problems are reduced.
No commercial products utilizing the technology disclosed either in the '598 or the '543 patents have been produced.
A different approach to the shelf storage stability problem is disclosed in U.S. Pat. No. 5,817,044. In this disclosure, the device is divided or otherwise separated into at least two portions, with one portion containing the electrode reservoir and the other containing the drug reservoir, which may include a medication in a dry form. In this disclosure, the user causes the two portions to come into electrical conducting contact with one another to at least partially hydrate one of the reservoirs, by either folding the device to bring the two portions into contact with one another or by removing a barrier dividing the two portions. While this device seems to be somewhat easier to use than the devices disclosed in the above patents, there currently is no commercial device that utilizes this disclosure.
International Application WO 98/208869 discloses an iontophoretic device for delivery of epinephrine and lidocaine HCl. The disclosed device includes materials that deter microbial growth and anti-oxidants to enhance the stability of epinephrine. While this disclosure recognizes the need for shelf storage stability and addresses the problem of epinephrine stability by including anti-oxidants, there is no recognition of the need to prevent corrosion of the electrodes during manufacture and shelf storage. Again, there is no commercial product based on the information in this disclosure.
A commercial iontophoretic device for delivery of lidocaine and epinephrine is provided under the tradename “Numby Stuff” by the Iomed Corp., Salt Lake City, Utah. The “Numby Stuff” device kit includes a vial sealed with a rubber septum containing a trademarked “Iontocaine” solution that includes Lidocaine HCl 2% and Epinephrine 1:100,000 that is used for charging the “Phoresor” system immediately prior to use. The “Numby Stuff” device lists U.S. Pat. Nos. 4,752,285; 5,374,241; 4,416,274; 5,135,477; and 5,415,628 that describe aspects of the device. None of these patents disclose a medicament-charged iontophoretic device with a useful shelf life. The patents are directed toward aspects of the delivery process and reservoir-electrode design. While these disclosures do potentially address the problem of keeping the medicament stable by isolating it from moisture, oxidation or from other components of the device, there is the problem, not previously recognized in the literature, corrosion of the active electrode during manufacture and storage. This problem is best understood by considering an electrochemical cell consisting of the silver/silver chloride electrode system commonly used in iontophoretic devices. In the cell considered, the Ag/AgCl electrode can be surround by solution of different chloride ion concentrations (Cl
1
and Cl
2
. The electrode reaction is illustrated by
Ag+Cl
−
=AgCl+e
−
.
The Nernst equation describing this cell is
&Dgr;E
0
=RT
F ln[Cl
1
]/[Cl
2
].
The Nernst equation illustrates that a chloride concentration gradient ([Cl
1
] not equal to [Cl
2
]) results in an open circuit potential, commonly called a concentration potential, that results in corrosion.
&Dgr;E
0
=open circuit potential as the concentration of Cl
−
moves away from unit concentration or activity.
Based on the Nernst equation's dependency on the log of the chloride ion concentration, the effect on the open circuit potential is about 60 millivolts (mV) per decade (10
1
) in concentration of chloride ion. Silver/silver chloride electrodes are the most common iontophoretic electrodes, and these electrodes require chloride ion to function. Most iontophoretic medicaments are provided as the hydrochloride salt and are added to the reservoir at some point prior to use. The practical effect of this phenomenon is, since the log of zero is infinity, that when chloride ion is added to the device before use, before the concentration of chloride ion can fully equilibrate, there is likely already some corrosive damage to the patch due to concentration differentials. Thus, there is often some corrosive damage to the reservoir-electrode interface almost immediately upon the addition of chloride ion containing constituents to the reservoir. Additionally, if the chloride ion addition is non-uniform, some corrosive conversion of silver to silv
Carey Kevin John
Eliash Bruce M.
Falevich Vitaly
Jain Uday K.
Keusch Preston
Ferko Kathryn
Kirkpatrick & Lockhart LLP
Vyteris, Inc.
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