Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
2000-11-27
2003-07-08
Lazarus, Ira S. (Department: 3749)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
C604S030000, C604S036000, C604S289000
Reexamination Certificate
active
06591133
ABSTRACT:
TECHNICAL FIELD
The present invention relates to apparatus and methods for delivering drugs and other beneficial agents. More specifically, the present invention relates to apparatus and methods for subcutaneous, transdermal, intravenous, and intramuscular delivery of drugs and other beneficial agents to a subject.
BACKGROUND
In an effort to improve the convenience of drug delivery, provide accurate dosing, and improve efficacy, various invasive and non-invasive drug delivery systems have been devised. The many techniques for delivering drugs include direct injection into body tissues, oral administration, intravenous administration, and transdermal delivery through the skin. As used herein, transdermal delivery means introduction of drugs or other beneficial agents through, or by way of, the skin. Except in the case of transdermal delivery, the above-mentioned drug delivery systems typically provide for systemic administration of drugs in that the drug is delivered throughout the body by the bloodstream. In the case of transdermal delivery, passive diffusion and active transport mechanisms can be used for more localized delivery of drugs into the tissues.
Each type of drug delivery system has its own advantages over the various other delivery technologies. Most recently, transdermal drug delivery has been shown to offer particular promise for a number of reasons. As an alternative to medicines administered orally, transdermal drug delivery avoids the “first-pass” metabolism of the liver, allowing for relatively lower doses and more controlled delivery of conventional forms of certain drugs. In contrast to the direct injection of drugs, transdermal drug delivery allows for continuous and convenient drug administration over an extended time period. Transdermal delivery techniques can, in some applications, allow a subject unrestricted mobility, a benefit not afforded by many intravenous drug administration systems.
The low permeability of the outer surface of mammalian (including human) skin, however, provides a formidable barrier to the transdermal administration of drugs at therapeutic levels. The skin's outermost layer, the epidermis, acts as the primary resistive barrier to drug diffusion. The epidermis can be most basically described as an avascular layer of stratified squamous keratinised epithelium sitting on a basement membrane. The epithelium can be sub-divided into four primary layers from the base to the free surface. The most resistive layer of the epidermis forms a superficial water-resistant protective layer called the stratum corneum. The stratum corneum is composed of layers of dead tissue, essentially consisting of flattened cells filled with cross-linked keratin together with an extracellular matrix made up of lipids arranged largely in bilayers. Underlying the stratum corneum are the further layers of the epidermis, generally comprising three layers commonly identified as the stratum granulosum, stratum spinosum, and stratum basale. These further layers of the epidermis are followed by the dermis, which contains two layers, the papillary dermis and the reticular dermis.
One class of techniques for overcoming the resistive barriers imposed by intact skin is assisted diffusion of a drug through the epidermis by “electrotransport” processes. Using the principles of electrotransport, a direct electrical current or an electrical potential gradient is used to actively transport the drug transcutaneously into the body. The composition of the stratum corneum, however, is such that its innate resistance to the flow of electrons is relatively high in comparison to other underlying body tissue (e.g., the further layers of the epidermis and the blood vessels therein).
Electrotransport processes are presently used in a wide variety of therapeutic drug delivery applications. One method of using electrotransport for transdermal drug delivery is known as “iontophoresis.” In iontophoresis, the diffusion of an ionized drug (e.g., salts of a pharmaceutical or other drug which, when dissolved, form charged ions) across the stratum corneum and into the dermal layers a skin surface is enhanced by the direct application of a mild electrical potential to the skin. Typically, the permeation rate (or “flux”) of the ionized drug compound will be directly proportional to the strength of the applied electric current. A second type of electrotransport process called “electroosmosis,” involving the transdermal flux of a liquid solvent containing an uncharged drug or pharmaceutical agent, has been recognized as a means for delivery of an uncharged drug or agent into the body. Electroosmosis, in which the solvent convectively moves through a “charged pore” in response to the preferential passage of counter ions, can be induced by the presence of an electric field imposed across the skin by the active electrode of an iontophoretic device. A third type of electrotransport is known as “electroporation.” Electroporation can be used for drug or other agent transport by altering lipid bilayer permeability through the formation of transiently existing pores in the skin membranes.
At any given time during electrically assisted drug or agent delivery, more than one of these electrotransport processes may be occurring simultaneously to some extent.
As illustrated by
FIG. 1
, a typical iontophoretic system
16
, similar to the iontophoretic system disclosed in U.S. Pat. No. 5,618,265 to Meyers et al., involves the placement of two oppositely charged “donor and counter” electrodes (an anode and a cathode)
18
,
20
on a subject's skin surface
30
at or around a tissue region selected for therapeutic application. A reservoir
22
containing the ionized drug to be delivered is placed under the electrode bearing the same charge as the drug (the “donor electrode”). Thus, in anodal iontophoresis, as is shown in
FIG. 1
, a positively charged drug is placed under the positively charged anode electrode
18
. Conversely, if the ionized drug to be delivered were negatively charged, then the negative electrode (cathode)
20
would be the active electrode under which the ionized drug would be placed. An ion-conducting adhesive
28
may be situated under each electrode
18
,
20
for stabilization of the electrodes. Electrolytes are typically added-to the solution containing the ionized drug so that current can be easily conducted. A selectively permeable membrane (not shown) may further be placed under the active electrode
18
to allow for selective flow of particular types of charged and uncharged species into skin surface
30
. A voltage source
24
, typically a battery, supplies direct electric current by conductive wires
26
extending to the electrodes. At electrodes
18
,
20
, the current is converted to an ionic current by a series of oxidation-reduction reactions.
To activate the system, electrodes
18
,
20
are spaced apart from one another on skin surface
30
where skin surface
30
acts as a conductor to complete the electrical circuit of iontophoretic system
16
. Upon activation of iontophoretic system
16
, the charged drug is repelled by active electrode
18
into the skin
30
(as indicated by the arrows), thereby initiating drug transport by electrostatic repulsion, ionic conduction, and other cooperating electrotransport processes.
Representative iontophoretic systems are disclosed in U.S. Pat. No. 5,618,265 to Myers et al. and U.S. Pat. Nos. 5,647,844 and 4,927,408 to Haak et al. Other patents discussing a variety of iontophoresis systems, iontophoresis electrodes, and/or methods of iontophoretically administering medicament ions include U.S. Pat. Nos. 4,744,787 to Phipps et al., U.S. Pat. No. 4,752,285 to Petelenz et al., U.S. Pat. No. 4,820,263 to Spevak et al., U.S. Pat. No. 4,886,489 to Jacobsen et al., U.S. Pat. No. 4,973,303 to Johnson et al., and U.S. Pat. No. 5,125,894 to Phipps et al.
Modern galvanic transdermal delivery systems have been disclosed in U.S. Pat. No. 5,618,265 to Myers et al. and U.S. Pat. Nos. 5,647,844 and U.S. Pat. No. 4,927,408 to Haak et al. Myers e
Lazarus Ira S.
Microlin LLC
Ragonese Andrea M.
LandOfFree
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