Surgery – Means for introducing or removing material from body for... – Infrared – visible light – ultraviolet – x-ray or electrical...
Reexamination Certificate
1999-08-30
2003-03-11
Mendez, Manuel (Department: 3263)
Surgery
Means for introducing or removing material from body for...
Infrared, visible light, ultraviolet, x-ray or electrical...
Reexamination Certificate
active
06532386
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and devices for transporting molecules (e.g., active agents or interstitial fluid) across a barrier membrane (e.g., skin or mucosa).
BACKGROUND OF THE INVENTION
Transdermal and topical dosage forms have been widely prescribed for decades in the treatment of systemic diseases and local conditions such as those involved with the skin and underlying tissues. These drugs are typically “easy-to-deliver”, since they easily permeate through the skin or mucosal membrane at a high potency. Permeation of the drug across the skin or mucosal membrane is a result of the chemical potential gradient across the skin or mucosal membrane. Examples of “easy-to-deliver” drugs include nitroglycerin, scopolamine, nicotine, hydrocortisone, betamethasone, benzocaine and lidocaine.
Most drugs and biological active ingredients, however, do not meet the above criteria, and therefore, are categorized as “difficult-to-deliver” drugs. Examples of “difficult-to-deliver” drugs include insulin, vasopressin, erythropoietin, interferons, and growth hormone at its releasing factors. Typically, “difficult-to-deliver” drugs have high hydrophilicity and/or high molecular weight, such as polypeptides, proteins, and DNAs.
To increase skin permeation of these drugs, various chemical and physical permeation enhancing methods have been employed. Chemical permeation enhancing agents may be applied typically to increase transdermal delivery of drugs. An extensive review of chemical penetration enhancing agents is reported in Buyuktimkin et al., “Chemical Means of Transdermal Drug Permeation Enhancement”,
Transdermal and Topical Drug Delivery Systems,
Interpharm Press, Inc., 1997, pages
357-475. This method, however, is usually only effective for drugs having relatively low molecular weights (less than approximately
1000 daltons).
Electricity may also be employed to facilitate drug transport across the skin barrier by applying an electric potential gradient across the skin to facilitate drug transport. There are three types of electrically facilitated drug transport through the skin barrier, namely, iontophoresis, electro-osmosis and electroporation. In transdermal iontophoresis, an ionized drug migrates into the skin driven by an applied electric potential gradient. In electro-osmosis, a non-ionic or low-ionic drug is carried by a fluid which is driven across the skin by an applied electric potential gradient. Electroporation is the microscopic perforation of the skin barrier by extremely short pulses of high electric voltage and low current. These methods are described in Ying Sun, “Skin Absorption Enhancement by Physical Means: Heat, Ultrasound, and Electricity”,
Transdermal and Topical Drug Delivery Systems,
Interpharm Press, Inc., 1997, pages 327-355.
There is a continuing need for non-invasive or minimally invasive transdermal devices for delivering active agents, especially high molecular weight drugs, such as polypeptides and proteins. Due to the high cost of high molecular weight drugs, there is a need for highly efficient minimally invasive transdermal drug delivery systems which do not cause decomposition or deactivation of the drug. Additionally, transdermal delivery devices which continually or periodically administer an active agent through skin and mucosal membrane over a long period of time and do not irritate the skin and mucosal membrane are needed.
SUMMARY OF THE INVENTION
In one aspect, the invention features an apparatus for transporting a compound across a barrier membrane of a mammal, such as the skin or mucosa membrane of a human. The compound may be an active agent, such as a drug, for therapeutic purposes, or a biologic sample (e.g., a compound with the interstitial fluid of a mammal) for diagnostic purposes. The apparatus comprises a vessel having a membrane contacting surface, a reservoir for containing the compound, and an electrode. The membrane contacting surface contains a plurality of exposed blades with a channel adjacent to the blades. The width and/or thickness of each blade is tapered away from the membrane contacting surface (e.g., the width decreases as it moves from the membrane contacting surface toward the top or tip of the blade). The reservoir is in communication with the channels and the electrode.
In one embodiment, when the membrane contacting surface contacts a barrier membrane, such as stratum corneum, the blades disrupt the barrier membrane to create pathways through the barrier membrane. The active agents in the reservoir are then forced through the pathways by electrotransport, e.g., iontophoresis. In one embodiment, liposomal formulations may be delivered by this apparatus to efficiently mediate transfection of nucleic acids into the skin cells of the basal layer of the epidermis.
Another embodiment of the invention is a transdermal electrotrasport system comprising the aforementioned apparatus, a counter electrode, and a power source, such as an electronic control unit, electrically connected to the electrode of the apparatus and the counter electrode. To deliver the active agent by electrotransport (e.g., iontophoresis, electro-osmosis, reverse electro-osmosis, or electroporation), the membrane contacting surface of the apparatus and the counter electrode are contacted with the barrier membrane of an mammal and an electrical current is applied (e.g., from the electrode, through the barrier membrane, and to the counter electrode). For example, during iontophoresis, the electrical current causes the ionized active agents, and to a lesser extent non-ionized active agents, including liposome-encapsulated active agents, in the reservoir of the apparatus to flow through the channels of the apparatus into the mammal.
In another aspect, the present invention features a method for transporting an active agent across a barrier membrane of a mammal is provided comprising penetrating the barrier membrane with a plurality of blades spaced at predetermined intervals without substantially penetrating the dermis under the barrier membrane to form pathways through the barrier membrane and applying an electrical current through the mammal to cause an active agent to flow into or out of the mammal through the pathways. Each blade is tapered toward the top of the blade.
Other features and advantages of the present invention will be apparent from the brief description of the drawings, from the detailed description of the invention, and from the claims
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Niemiec Susan M.
Oakeson Ralph W.
Sun Ying
Wang Jonas C. T.
Wisniewski Stephen J.
Johnson & Johnson Consumer Companies Inc.
McGowan William E.
Mendez Manuel
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