Patent Application
20070066934
The present invention relates generally to the electrokinetic mass transfer of substances into and/or extracting substances from tissue and particularly to apparatus and methods for delivering substances, e.g., a medicament to a treatment site.
Electrokinetic delivery of medicaments for applying medication locally through an individual's skin is known. One type of an electrokinetic delivery mechanism is iontophoresis, i.e. the application of an electric field to the skin to enhance the skin's permeability and to deliver various ionic agents, e.g., ions of soluble salts or other drugs into the skin. In certain situations, iontophoretic transdermal or transmucosal delivery techniques have obviated the need for hypodermic injection for many medicaments, thereby eliminating the concomitant problem of trauma, pain and risk of infection to the individual. Other types of electrokinetic delivery mechanisms include electroosmosis, electroporation, electromigration, electrophoresis, and endosmosis, any or all of which are generally known as electrotransport, electromolecular transport or iontophoretic methods.
In recent years, various mechanisms for electrokinetically delivering a substance, e.g., a medicament to a treatment site include, for example, a finger mounted electrokinetic delivery system for self-administration of medicaments as disclosed in U.S. Pat. No. 6,792,306, of common assignee herewith, the disclosure of which is incorporated herein by reference. That system includes a power source, active and ground electrodes and a medicament containing matrix whereby, upon application of the active electrode to the treatment site, an electrical circuit is established from the power source, through the medicament or a conductive carrier therefor, the treatment site, the individual's body and the ground electrode to drive the medicament into the treatment site. Other electrokinetic delivery mechanisms are set forth in U.S. Pat. No. 6,895,271, issued May 17, 2005; U.S. Pat. No. 6,735,470, issued May 11, 2004; U.S. Pat. No. 6,477,410, issued Nov. 5, 2002 and U.S. Reissue Pat. No. RE 37796, re-issued Jul. 23, 2002, the disclosures of which are also incorporated herein by reference.
While those systems have been found to be efficacious, it will be appreciated that an individual's skin is formed of many different layers e.g. the Epidermis and the Dermis, both of which overlie the subcutaneous cellular tissue and each of which are, in turn, formed of various sub-layers. Of particular significance is the epidermis which is non-vascular and consists of stratified epithelium including the stratum corneum with various underlying sub-layers. These layers offer various electrical resistances to penetration of electrokinetically driven substances through the skin to a targeted layer. For example, the outer stratum corneum layer, offers very high electrical resistance to electrokinetic delivery of a substance through that layer into the underlying sub-layers. High electrical resistance impedes the electrokinetic delivery of the substance to the targeted site. The amount of medicament delivered across an individual's skin is dependent, in part, upon current density. As the area of iontophoretic treatment expands, total current increases to maintain the prescribed current density. For example, if a current density of 250 μA/cm2 is prescribed for delivery of a specific medicament and the area of the iontophoretic delivery system is 4 cm2, total current will be 4×250 μA or 1 mA. If the area of the iontophoretic delivery system is increased to 100 cm2, total current would have to be 25 mA to maintain current density. Administration of this level of current presents a potential risk of damaging the patient's skin.
A further significant problem for electrokinetically driving substances through the skin includes the use of multi-channel electrodes, i.e., an array of individualized electrodes, each connected to a discrete donor site of medicament thereby creating individually controlled electric fields for larger area electrokinetic application of the medicament to the skin. For example, when a multi-channel electrode device is placed in contact with the skin in the presence of a conductive liquid, e.g., the medicament or a conductive gel and the liquid crosses over between electrodes, a short circuit may occur that compromises the multi-channel device. If a unified field is created and if there is an area of low resistance, there is the likelihood that the current will be channeled into that low resistance area, possibly burning the individual's skin. This has been a limiting factor in large area electrokinetic application of substances through an individual's skin. Consequently, there is a need to provide systems and methods for facilitating electrokinetic penetration of larger areas of an individual's skin in a manner which is not adversely affected by high electrically resistant layers of the skin while minimizing or eliminating short circuiting of the current as the substance is transported electrokinetically through the skin to the targeted site.
In accordance with example embodiments of the present invention, there are provided systems and methods for penetrating a high electrically resistant layer(s) of the skin, e.g., the stratum corneum to create an electrical connection directly between the active electrode through the drug-filled matrix into the targeted site, e.g., the epidermal layer, bypassing the high resistant skin layer. It will be appreciated that the epidermal layer of the skin below the stratum corneum has a high fluid content that is also conductive which provides a much larger receptor area for the supplied substance as compared with higher electrically resistant layers, such as the stratum corneum. To penetrate one or more high electrically resistant layers to supply medicament to a targeted underlying layer or layers, a pad or applicator is provided having a surface array of needles, preferably micro-needles along one side or face of the applicator. The needles are carried by a non-conductive membrane of the applicator and project from the membrane a distance sufficient to penetrate the high electrically resistant layer(s), upon application of the applicator to the individual's skin. Because of the very high density of the needles, preferably micro-needles, numerous low electrically resistant areas are created by perforating the high electrically resistant layer(s). That is, the needles form a multiplicity of channels i.e., micro-channels through the more highly electrically resistant layer(s). The needles in effect create channels in the skin. The length and density of the needles as well as the thickness or diameter of the needles including the diameter of the orifices through the needles can be varied depending upon the location of the targeted treatment site underlying the skin surface. The needles may be formed of a non-conductive material, e.g., a plastic material or may be formed of metal material coated with a non-conductive material. The needles can be monolithic with well-defined orifices for delivery of actives or fused particulates (sintered) that provide a porous needle with a tortuous network of many liquid transport paths in a more tortuous design. Such sintered material avoids the problem of needle coring of stratum-corneum tissue that occludes the fluid passages. It is understood that such material would include filaments, particles, staple fibers, wires or other forms of needle material that is joined under pressure to create a porous needle structure. Needles may also be made of conductive materials and coated with nonconductive layers. The needles may also be made of non-conductive intermetallic glasses. The needles may also be formed of bioresorbable polymers containing drugs or other active ingredients molecularly dissolved or dispersed as a separate phase. The active ingredient is delivered to the skin electrokinetically as the needle polymer is eroded and/or solubilized by interstitial fluid within the skin. Polymers such as polylactic acid, polyglycolic acid, copolymers of poly(lactide-glycolide), polyorthoesters, polyvinylalcohol and others, as well as natural products such as sugars, starches and graft copolymers of these. The opposite side of the pad from the needles may comprise a conductive membrane in contact with an active electrode and a power supply.
The micro-needles may be attached to a flexible substrate to provide a compliant system for skin interface. Micro-needles may not penetrate the epidermis to the full extent of needle height due to the compliant nature of the stratum-corneum and dermal underlayers. Additionally, skin is a viscoelastomer that relaxes mechanically under load. This causes the substrate to move away from the needle during puncture. One means for improving the consistency of puncture by needle arrays is to impose an upward movement of the skin using an iontophoretic patch. The patch may include a rigid boundary surrounding an array of micro-needles enabling, upon application, the skin surrounded by the boundary to present itself, i.e., become proud of skin adjacent the patch, to the micro-needle array. In another embodiment, to provide skin penetration, the arrays of micro-needles are attached to a slightly concave-shaped elastomeric backing attached to the iontophoretic patch and acts as a suction cup. Upon actuation by the user, the target skin area is pilled into the concavity and against the micro-needles attached to the more rigid backing material. Micro-needles are thus allowed to penetrate the skin without interference from the more compliant dermal layers below.
The system also includes a device containing the active and ground electrodes and a power supply. Preferably, the applicator and the device are separable from one another whereby the applicator is disposable and the device may be reused with a fresh applicator. Alternatively, the device and applicator may constitute an integrated disposable or reusable unit.
In another embodiment hereof, groups of the applicators may be provided, for example, on sheet material whereby the applicators are separable, e.g., by perforation lines through the sheet. Thus, the involved area of the applicator overlying the treatment site can be varied in size. A multi-channel electrode array is therefor coupled to the applicators whereby the area coverage of the applicators can be personalized to the size of the targeted treatment site. It will be appreciated that the shape of the applicators can vary, e.g., circular, rectilinear, hexagonal or any other shape. In this manner, the needles provide multiple very low electrically resistant pathways through the high electrically resistant layer(s) enabling, for example a micro-processor to drive via the multi-channel electrode array the medicament or a carrier therefor disposed in a matrix within the applicator through the skin to apply the medicament directly to the targeted treatment site.
As noted previously, the applicator containing the needles may be combined with a delivery device. For example, the finger mounted devices disclosed in U.S. Pat. Nos. 6,792,306 and 6,735,470, may be provided with applicators containing needles of selected sizes and configurations to penetrate through the high electrically resistant layers of the skin to supply medicament to the targeted treatment site. Alternatively, the device disclosed in U.S. Pat. No. RE37796, may likewise use applicators of the type described herein. In all instances, by forming a multiplicity of low electrically resistant perforations or pathways through the higher electrically resistant layer or layers of the skin, the substance can be driven from the supply matrix through the needles directly to the targeted treatment site bypassing the high electrically resistant skin layer(s).
Advantages of using the present delivery system include the capacity to increase the quantity of the substance delivered by reducing the resistance to penetration of the substance through the skin. The provision of multiple pathways, e.g., micropores enables delivery of an array of drugs, e.g., large molecules such as peptides, liposomes encapsulating hydrophobic drugs, or other encapsulated drug formulations not currently deliverable by electokinetic processes, particularly iontophoresis. Further, by controlling the length of the needles, the substance may be delivered to selective targeted sites at different skin depths. For example, if just the stratum corneum is penetrated, the underlying layers of the epidermis are used as a substance reservoir with that area being loaded with the substance bypassing the stratum corneum and enabling administration of the substance. Further penetration by the needles enables proximity to the blood supply enabling systemic administration of substances making the electrokinetic process appropriate for delivery of systemic drugs. Also, by locating the substance supply close to the blood supply, the substance can clear its entry points quickly enabling substance delivery on a more continuous basis.
In a preferred embodiment of the present invention, there is provided a device for delivering a medicament to a treatment site underlying an electrically resistant layer of an individual's skin, comprising an applicator for overlying the treatment site and the electrically resistant skin layer, the applicator having a plurality of needles projecting from a first surface thereof for penetrating the electrically resistant layer of the individual's skin, the needles and the surface being formed of a non-electrically conductive material; a matrix carried by the applicator for containing the medicament or the medicament and an electrical carrier therefor, the needles having one or more orifices in communication with the medicament or the medicament and the electrical carrier therefor contained in the matrix and opening at locations spaced from the matrix for delivering the medicament to the treatment site; the applicator having a second surface formed of electrically conductive material.
In a further preferred embodiment, there is provided a system for delivering a medicament to a treatment site underlying an electrically resistant layer of an individual's skin, comprising an applicator for overlying the treatment site and the electrically resistant skin layer, the applicator having a plurality of needles projecting from one side thereof for penetrating the electrically resistant layer of the individual's skin; a matrix carried by the applicator for containing the medicament or the medicament and an electrical carrier therefor, the needles having one or more orifices in communication with the medicament or the medicament and the electrical carrier therefor contained in the matrix and opening at locations spaced from the matrix for delivering the medicament to the treatment site; a first electrode for electrical connection with a power source; whereby, upon application of the applicator to the individual's skin overlying the treatment site and connection to the power source and a second electrode for electrical connection with the power source enabling completion of an electrical circuit through the first electrode, the medicament or the electrical carrier therefor, a portion of the individual's body, the second electrode and the power source, the system enables an electrical current to flow for electrokinetically driving the medicament or the medicament and the electrical carrier therefor through the needle orifices into the treatment site bypassing the electrically resistant layer of the individual's skin.
In a still further preferred embodiment, there is provided a system for delivering a medicament to a treatment site underlying an electrically resistant layer of an individual's skin, comprising a power source; an applicator for overlying the treatment site and the electrically resistant skin layer, the applicator having a plurality of needles projecting from one side thereof for penetrating the electrically resistant layer of the individual's skin; a matrix carried by said applicator for containing the medicament or the medicament and an electrical carrier therefor, the needles having one or more orifices in communication with the medicament or the medicament and the electrical carrier therefor contained in the matrix and opening at locations spaced from the matrix for delivering the medicament to the treatment site; a first electrode carried by the applicator in electrical connection with the power source; a second electrode in electrical connection with the power source; whereby, upon application of the applicator to the individual's skin overlying the treatment site and electrical connection to the power source and a second electrode for electrical connection with the power source enabling completion of an electrical circuit through the first electrode, the medicament or the electrical carrier therefor, a portion of the individual's body, the second electrode and the power source, the system enables an electrical current to flow to electrokinetically drive the medicament or the medicament and the electrical carrier therefor through the needle orifices into the treatment site bypassing the electrically resistant layer of the individual's skin.
Another preferred embodiment of the present invention includes a system for delivering a medicament to a treatment site underlying an electrically resistant layer of an individual's skin, comprising a sheet of discrete applicators selectively separable from one another enabling one or more of the applicators to overlie the treatment site and the electrically resistant skin layer, each applicator having a plurality of needles projecting from one side thereof for penetrating the electrically resistant layer of the individual's skin; a matrix carried by each applicator for containing the medicament or the medicament and an electrical carrier therefor, the needles of each applicator having one or more orifices in communication with the medicament or the medicament and the electrical carrier therefor contained in the matrix and opening at locations spaced from the matrix for delivering the medicament to the treatment site; a first electrode carried by each applicator for electrical connection with a power source; whereby, upon application of one or more of the applicators to the individual's skin overlying the treatment site and connection to the power source and a second electrode in electrical connection with the power source enabling completion of an electrical circuit through the first one or more electrodes, the medicament or the electrical carrier therefor of the one or more applicators, a portion of the individual's body, the second electrode and the power source, the system enables an electrical current to flow for electrokinetically driving the medicament or the medicament and the electrical carrier therefor through the needle orifices of the one or more applicators into the treatment site bypassing the electrically resistant layer of the individual's skin.
In a still further embodiment hereof, there is provided a method for delivering medicament to a treatment site underlying an electrically resistant layer of an individual's skin, comprising the steps of applying a plurality of micro-needles to the individual's skin to penetrate the electrically resistant layer of the individual's skin; and electrokinetically driving the medicament or the medicament and an electrical carrier therefor through the micro-needles into the treatment site bypassing the electrically resistant layer of the individual's skin.
Referring to the drawings, particularly to
The applicator 11 includes a multiplicity of needles 14, preferably micro-needles projecting from one side of the housing 12. The needles 14 are carried by, and penetrate through, a non-conductive impermeable, preferably hydrophobic membrane 16 along the face of the applicator which is to be applied in overlying relation to the skin and hence the treatment site. By preferably using a hydrophobic membrane, movement of liquid at the interface is resisted and which otherwise might act to bridge individual channels. The non-conductive impermeable membrane 16 has edges along the margins of the applicator which are likewise non-conductive and impermeable. The opposite face of the applicator 11 is formed of a conductive membrane 18. A drug-filled matrix 15 is sandwiched between the impermeable membrane 16 and the conductive membrane 18, so that the matrix and drug contained within are contiguous with the bases of the needles 14 and particularly the orifices through the needles are described below. A first or active electrode 20 is illustrated in electrical contact with the conductive membrane 18 and with a power supply 22. Also connected to the power supply is a second or ground electrode 24 for application to another part of the individual's body spaced from the targeted treatment site. The ground electrode 24 completes the electrical circuit for the electrokinetic delivery of the medicament to the targeted treatment site as described below.
The needles 14 are preferably micro-needles formed of a non-conductive material, such as a thermoplastic material, e.g., a polycarbonate, polyester, polymethylacrylate or other materials sufficiently rigid to penetrate the skin when applied to the skin. The micro-needles may also be formed of thermoset materials, such as epoxy, polyurethane and silicones. The micro-needles may also be formed of metal materials coated both externally and internally with a non-conductive material, such as a thermoplastic and which may be polymeric in nature or inorganic, such as oxide layers. The micro-needles 14 have a density in the range of about 1-1000 needles per cm2, and preferably in a range of about 150-250 needles per cm2. The height of the needles 14 projecting from the non-conductive membrane 16 may lie within a range of 100 to 800 microns. The micro-needles are preferably conically or pyramidally shaped and have a height equal to about twice the diameter of the base. The base can be nominally one-half the height to about twice the height Thus, for example, a needle 400 microns in height may have a base of about 200 microns. For the same needle, the orifice through the needle may have a diameter in a range of 25-200 microns. The micro-needles may also have a constant width throughout their length in contrast to the preferred conical or pyramidal shape. Thus, each micro-needle may have less than one millimeter in length, be useful to penetrate the uppermost layers of tissue such as the stratum corneum of human skin, may contain one or more conduits for passage of liquids between interstitial regions of the tissue and a medical or drug-delivery device may be comprised of or coated with nonconductive materials to allow for electrokinetic transport of ions through the micro-needle.
Referring to
In
In an illustrative embodiment of the invention, for example, for supplying medicament to a targeted treatment site underlying one or more layers, e.g., the stratum corneum of the skin, an applicator is selected having needles 14 of appropriate size and configuration, e.g., length, width, orifice depth and orifice size, to penetrate the stratum corneum with the tip of each needle being exposed in the targeted layer. Thus, the targeted layer could be any sub-layer under the stratum corneum, i.e., any layer of the epidermis or layers of the dermis or below. For example and referring to
To provide broader area coverage for the medicament, and simultaneously to avoid the problems of short-circuiting the electrical current through current pathways of least resistance, a plurality of applicators 11 may be provided, e.g., in sheet form. The applicators are separable to provide groups of applicators for selected area coverage. The area coverage of the applicators 11 is aggregated as dictated by the area of the treatment site and the areas of the individual applicators 11 themselves. Referring to
Although the example embodiment uses a microprocessor to control currents supplied to the electrodes, other types of processing may be used such as application specific integrated circuits, programmable logic arrays, and the like.
Referring to
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While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
