MXPA00005761A - Device for enhancing transdermal agent flux - Google Patents

Abstract

A device (3) comprising a sheet number (6) having a plurality of microprotrusions (4) for penetrating the skin and a rigid support (15) contacting and extending across the sheet member (6) for transmitting an applied force evenly across the length and width of the sheet member (6) to reproducibly and reliably penetrate the skin with the microprotrusions (4).

Description

DEVICE TO INCREASE THE FLOW OF A TRANSDERMAL AGENT TECHNICAL FIELD The present invention relates to the delivery and sampling of a transdermal agent. More specifically, this invention relates to the delivery of transdermal agents, such as peptides and proteins, through the skin, as well as transdermal sampling of agents from the body, such as glucose, other body analytes and addictive substances such as alcohol and drugs. illicit BACKGROUND OF THE INVENTION Interest in the transdermal or percutaneous delivery of peptides and proteins to the human body continues to grow with the increasing number of medically useful peptides and proteins available in large quantities and in pure form. The transdermal delivery of peptides and proteins continues to face significant problems. In many cases, the rate of delivery or flow of polypeptides through the skin is insufficient to produce a desired therapeutic effect due to its large size / molecular weight and the resulting inability to pass through natural access routes (pores, follicles). hairy, etc.) through the skin. Further, the polypeptides and proteins are easily degradable during the penetration of the skin, before reaching their target cells. Likewise, the passive flow of small water-soluble molecules such as salts is limited. A method to increase the transdermal delivery of agents is based on the application of an electric current through the body surface, or "electrotransport". "Electrotransport" generally refers to the passage of a beneficial agent, for example, a drug or drug precursor, through a body surface such as the skin, mucous membranes, nails and the like. The transport of the agent is induced or increased by the application of an electrical potential which results in the application of an electric current that supplies or increases the supply of the agent. The electrotransport of agents through a body surface can be achieved in various ways. A widely used electrotransport process is iontophoresis, which involves the electrically induced transport of charged ions. Electrosurgery, another type of electrotransport procedure, involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, another type of electrotransport, involves the passage of an agent through the pores formed by applying a high voltage electrical impulse to a membrane. In many cases, more than one of these procedures can occur simultaneously and to a different extent. Accordingly, the term "electrotransport" is used in the present with its broadest interpretation, to include electrically induced transport or increased of at least one loaded or uncharged agent, or mixtures thereof, without considering the specific mechanism by which the agent is actually transported. The electrotransport supply generally increases the supply of the agent, in particular, the delivery rates of species with a high molecular weight (eg, polypeptides), relative to passive or non-electrically assisted transdermal delivery. However, additional increases in transdermal delivery rates and reductions in polypeptide degradation during transdermal delivery are highly desirable. A method for increasing the rate of delivery of the transdermal agents includes pretreating the skin with, or delivering together with the beneficial agent, a skin penetration enhancer. The term "penetration enhancer" is widely used herein to describe a substance which, when applied to a body surface through which the agent is delivered, increases its flow therethrough. The mechanism may involve a reduction of the electrical resistance of the body surface to the passage of the agent through the same, an increase in the selectivity of penetration and / or permeability of the body surface, the creation of hydrophilic access routes through the body surface and / or a reduction in the degradation of the agent (for example, degradation by skin enzymes). ) during electrotransport. There have been several attempts to mechanically deteriorate the skin in order to increase the transdermal flow, as in the U.S. Patent Nos. 3,814,097 issued to Ganderton et al., 5,279,544 issued to Gross et al., 5,250,023 issued to Lee et al., 3,964,482 issued to Gerstel et al., U.S. Patent No. Re 25,637 issued to Kravitz. et al. and PCT application WO 96/37155. Commonly these devices use tubular or cylindrical structures, although Gerstel describes the use of other forms to pierce the outer layer of the skin. The piercing elements described in these references generally extend perpendicularly from a flat, thin element, such as a pad or metal sheet. The flexible nature of the flat element and the tubular shape of the piercing elements result in a variety of deficiencies, such as manufacturing difficulties, bending of the flat element when pressure is applied to the upper part of the device, uneven penetration of the skin scarce punctures of the skin resulting in low transdermal flow and, for electrotransport, increased irritation due to the concentration of drug flow through fewer access routes. The skin piercing elements have also been commonly used in the field of vaccines. For example, the patent of E.U.A. Rosenthal 3,072,122 discloses vaccination sites pressed from a thin metal sheet. The stitches have a length of 1-4 mm which is long enough to cause bleeding. The metal sheet is installed on a plastic handle and provides enough stiffness to press the spots on the patient's skin. The points are typically covered with a dry antigenic substance to carry out vaccination or inoculation.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a suitable device for increasing transdermal flow. The device has microprotrusions that consistently and reliably penetrate a body surface (e.g., skin) to increase the supply or sampling of the transdermal agent. The device of the present invention can be easily manufactured in large volumes and at low cost. The device of the present invention can penetrate the stratum corneum of the skin with a plurality of microprotrusions to form access routes through which a substance such as a drug (i.e., supply) can be introduced or a substance can be removed. such as a body analyte (ie, sampling). An important advantage of the present invention is that the device ensures uniform penetration (i.e., generating access ways of the same size and depth) by the microprotrusions through the device. Moreover, the present invention reproducibly provides uniformity in penetration from patient to patient. In one aspect, the invention comprises a rigid structure which is in contact with and extends through a flexible device having a plurality of microprotrusions for piercing the skin. The structure Rigid transmits force applied in the upper part of the structure substantially uniformly through the flexible device and thereby transmits uniform displacement of the microprotrusions. This is achieved with a substantially lower dissipation of the application force in the compliant elements of the flexible device having the microprotrusions. The rigid structure provides secure transmission of a load applied externally to the microprotrusions for easier, more complete and reproducible skin penetration. The improved penetration of the skin by the microprotrusions due to the rigid structure is particularly beneficial to produce increased flow. The uniformly distributed displacement of the microprotrusions provides almost complete penetration through all the microprotrusions in order to produce a substantial number of agent access paths and electrical continuity (if electrotransport is used) with the skin for a continuous agent flow and reproducible through the skin. In an aspect of the invention, the flexible skin piercing device comprises a relatively thin sheet which in use is adapted to be placed in substantially parallel relationship to the body surface to be pierced. The sheet has a plurality of openings therethrough, which allow the agent to pass a deposit associated with the sheet (and typically placed on the surface of the sheet far from the body) and the holes punched in the body surface by means of of the microprotrusions. The sheet further has a plurality of microprotrusions (also referred to as micro-pallets) that extend approximately perpendicularly from one side of the sheet proximal to the body. In this aspect of the invention, a rigid support structure is in contact and extends through the sheet in order to impart additional structural rigidity thereto and more evenly distribute any force applied to the device for the purpose of displacing more uniformly the microprotrusions in (ie, pierce) the body surface. Optionally, although preferably, the rigid structure forms a gap for an agent deposit. The deposit can be filled with a deposit containing / taking sample agent. In a second aspect of the invention, the flexible skin piercing device comprises a relatively thin flexible sheet having a configuration defining a gap or space for supporting an agent-containing or agent-containing reservoir. In use, the sheet is placed in a relationship substantially perpendicular to the body surface to be perforated, so that the sheet has an edge contacting the body surface, said edge having a plurality of microprotrusions extending therein. In this aspect of the invention, a rigid support structure contacts and extends through the edge of the far sheet to the body in order to impart structural rigidity thereto and more evenly distribute any force applied to the device for to more uniformly displace the microprotrusions in (ie, pierce) the body surface.

The device of the present invention can be used in connection with agent delivery, agent sampling or both. In particular, the device of the present invention is used in connection with transdermal drug delivery, transdermal analyte sampling or both. Delivery devices for use with the present invention include, but are not limited to, electrotransport devices, passive devices, osmotic devices, and pressure operated devices. Sampling devices for use in the present invention include, but are not limited to, inverse electrotransport devices, passive devices, devices operated under negative pressure, and osmotic devices. The device of the present invention can be used repeatedly in order to maintain microcuts / micro-grooves on the body surface, which are created by the microprotrusions, open for extended periods during transdermal delivery or sampling. This can be easily accomplished by having the patient or other medical technician reapply pressure periodically next to the device far away from the skin, causing the microprotrusions to pierce the stratum corneum layer of the skin. This exceeds the potential closure of the slots initially cut due to the body's natural healing processes.

BRIEF DESCRIPTION OF THE DRAWINGS In the figures, similar reference numbers refer to similar elements in the different drawings. Figure 1 is an enlarged cross-sectional view of a rigid support and skin penetration element taken along the line 1-1 in Figure 2; Figure 2 is a view of the upper plane of the rigid support of Figure 1; Figure 3 is an enlarged perspective view of the base end of a skin penetration device with a connection means removed therefrom for clarity in accordance with an embodiment of the present invention; Figures 4, 6 and 7 are views of the upper plane of other embodiments of the rigid support; Figure 5 is a schematic perspective view of an alternate embodiment of the rigid support and skin penetration element; Figure 8 is a side view of another embodiment of a skin penetration support and element according to the present invention; Figure 9 is a top view of another embodiment of the support element of the present invention; Figure 10 is a schematic perspective view of another embodiment of the support of the present invention; Figure 11 is a schematic cross-sectional perspective view of another embodiment of the support of the present invention; Figure 12 is a perspective view of a handheld device having a support according to another embodiment of the present invention; Fig. 13 is a schematic perspective view of one embodiment of an electrotransport delivery / agent sampling system according to an embodiment of the present invention; Fig. 14 is a view of the lower plane of the electrotransport delivery / agent sampling system of Fig. 13; Figure 15 is an elevated view of the right side of the electrotransport delivery / sampling system of the agent of Figure 13; Figure 16 is a rear elevational view of the supply / sampling electrotransport system of the agent of Figure 13; Figure 17 is a cross-sectional view taken along the line 17-17 of the electrotransport assembly / supply agent sampling system of Figure 15; and Figure 18 is a cross-sectional diagram of a passive agent delivery / sampling system according to an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Referring in detail to the drawings, the device 2 of the present invention is generally shown in figure 1 which comprises a skin penetration sheet element 6 and a support element 15. The device 2 is used to increase the supply transdermal or sampling of an agent. The terms "substance", "agent" and "drug" are used interchangeably herein and include in their broadest sense physiologically or pharmacologically active substances to produce a localized or systemic effect or effects in mammals including humans and primates, birds, pets, competition or farm animals, or for administration in laboratory animals, such as mice, rats, guinea pigs and the like. These terms also include substances such as glucose, other body analytes found in the tissue, interstitial fluid and / or blood, alcohol, licit substances and illicit drugs, etc. which can be sampled through the skin. The main barrier to the transdermal flow of agents (eg, drugs to be delivered and analytes to be sampled) is the outer layer (i.e., stratum corneum). The internal division of the epidermis generally consists of three layers commonly identified as stratum granulosum, stratum of Malpighii, and stratum germinative. There is essentially little or no resistance to transport or to the absorption of an agent through the stratum granulosus, stratum of Malpighii, and stratum germinative. The device 2 comprises a rigid support element 15 and a compliant sheet element 6 (see Figure 3 in which the device 2 is in a reverse position to show the microprotrusions) having a plurality of microprotrusions 4 extending outwardly therefrom. . The device 2 is pressed against an area of skin through which the agent will be delivered or sampled transdermally. The microprotrusions 4 form thin grooves in the skin and penetrate at least through the stratum corneum so that the agent is driven through the skin with little or no resistance. Typically, microprotrusions penetrate the skin to a depth of up to 500 μm, more typically to a depth of 50 to 300 μm. The microprotrusions 4 may be micropalettes (Figures 1 and 3), pins (not shown), or any other variety of configurations for piercing the skin or body surface. The microprotrusions 4 penetrate the stratum corneum of the epidermis when pressure is applied to the upper part of the support element 15 to increase the administration of, or sampling of an agent through, a body surface. The term "body surface" as used herein, generally refers to the skin, mucous membranes and nails of an animal or human and to the external surface of a plant. The microprotrusions 4 penetrate the body surface to create good agent conduction from the system to the body, or vice versa. In the embodiments shown in Figures 1-3, the sheet member 6 is formed with a plurality of openings 8, each opening 8 having the minus a microprotrusion 4 along the periphery thereof. The microprotrusions 4 cut micro-strands in the stratum corneum, thereby increasing the transdermal flow of agent released or collected in the collecting tanks or containing agent 27 housed by the plurality of voids 7. The sheet member 6 may be composed of metal, silicon or plastic, although metals such as stainless steel and titanium are preferred. The sheet member 6 is generally compliant and flexible due to its relatively thin thickness. For example, when the sheet member 6 consists of a metal such as stainless steel or titanium, the sheet member 6 will typically have a thickness of only about 5 μm to about 100 μm, and more typically about 25 μm to about 50 μm. . According to the present invention, a rigid structural support element 15 having a stiffness superior to the sheet element 6 is placed along the sheet element 6 (figures 1 and 2). The support element 15 prevents deformation or bending of the sheet member 6 as the device 2 is applied to the body surface and as a downward force is applied (ie, directed towards the body surface that is perforated) in order to cause that microprotrusions 4 pierce the body surface. The support element 15 must be rigid enough to deviate less than 300 μm and preferably less than 50 μm, under manually applied pressure with finger or hand of the device 2 against the skin. The support element 15 can be a variety of configurations, for example, but not limited to the modalities shown in figures 1, 2, 4-8 and 13. In the embodiment shown in figures 1 and 2, the support element 15 is a rigid structure which forms a plurality of recesses 7, which extend through the thickness of the support element, the recesses 7 collectively house the reservoir 27 (Figure 1) to contain the agent that will be supplied or to receive the agent that will be taken as a sample. Between the recesses 7 there is a plurality of supports or transverse elements 5 which are in contact and extend across the width or length of the sheet element 6. The transverse elements 5 transmit force which is applied to the upper part of the device 3 of uniformly through the sheet element 6 so that each of the microprotrusions 4 are displaced (on the skin) in the same amount for more uniform penetration of the skin by the microprotrusions 4. When used with a transdermal electrotransport device , the sheet element 6 and / or support element 15 are preferably electrically insulated from the current conducting elements (for example, the electrodes) of the electrotransport device in order to avoid short circuit in the drug reservoir. This can be achieved by using electrically insulating and electrically non-conductive coatings or materials for the sheet member 6 and / or support element 15. Preferably, the support member 15 also has a low compression. Optimally, the support element 15 compresses a distance of less than 250 μm and preferably less than 50 μm, during device pressure manually applied with finger or hand against the skin. Preferably, the support member 15 will exhibit a combined flexibility and compression of less than about 250 μm during manually applied pressure of the device with the finger or hand against the skin. The support element 15 can be made of any material having the aforementioned high rigidity and preferably the aforementioned low compression. Suitable materials include metals, metal alloys, ceramics, glasses, rigid and reinforced plastics (for example, reinforced carbon fiber). Various embodiments of the support element are illustrated in Figures 2 and 4-13. In the modalities shown in figures 2, 4-7 and 13, the support element 15 consists of a peripheral wall 53 (for example, annular) having at least one transverse element 5 extending through the support element 15 so as to create a plurality of voids 7 which house the reservoir for the agent and for distributing a force applied uniformly through the sheet element 6 (ie, without bending or flexing the sheet 6). The transverse elements generally extend diagonally in FIGS. 4, 5, 6 and 13 through the volume bounded by the outer wall of the support element 15. Diagonal, as used herein, refers to describe embodiments other than transverse elements that join two vertices of a rectilinear figure that are not adjacent or passing through two non-adjacent edges of a polyhedron, as can be seen in the modalities shown in the figures. As can be seen, the transverse elements indicate oblique transverse elements (figure 6) and non-oblique transverse elements (figure 7) as well as honeycomb configurations (figure 2). The number of transverse elements depends on a variety of factors, for example, the relative structural integrity or flexibility of the sheet element 6 and the support element 15, the distance through the support element 15, the size of the contacting area with the skin of the agent reservoir and the volume of the agent reservoir. In general, when the sheet member 6 formed of very thin metal is used, the maximum distance between the adjacent transverse elements 5 in the support member 15 will not be more than about 4 times, and preferably not more than about 2 times, the distance between adjacent microprotrusions 4 in the sheet element 6. Figure 7 illustrates which support member 15 may consist of a plurality of internal annular walls 55 connected by the transverse elements 5 to the outer annular wall 53. Figure 5 illustrates a alternating mode of the sheet member 6 wherein the microprotrusions 4 extend outwardly from an end that makes contact with the body 49 of a thin sheet element 6. In this embodiment, the plane of the sheet member 6 is oriented in a relationship approximately perpendicular to the body surface during use. The sheet element 6 has a configuration of spiral which defines the voids 51 for supporting an agent-containing or agent-containing deposit (not shown in Figure 5). The twisting, bending (not shown) and curving (not shown) as well as other shapes can also be used to form the sheet member 6 from its generally planar state along its length to form a structure having a plurality. of holes 51. In a preferred embodiment, the recesses 51 are in communication with the recesses 7 of the support element 15. The surface of the support element 15 which is in contact with the side / edge of the reed element 6 remote from the The skin is generally shown as flat in FIGS. 1 and 5. However, preferably, the surface of the support element 15 which is in contact with the sheet element 6 has a convex or curved surface 54 (for example, of cylindrical shape). ) as best shown in Figure 8. The radius of curvature of the cylindrical or convex surface 54 is preferably more than about 5 cm, preferably more than about 10 cm. Figure 9 illustrates an alternate embodiment of the support element 15. In this embodiment, the support element 15 consists of a plurality of bands which have a wave shape and are oriented perpendicular to the plane of the sheet element 6. The sheet member 6 has the same configuration shown in Figure 3 with openings 8 therein and associated microprotrusions 4 (not shown in Figure 9). The corrugated strips 91, 93 are preferably fixed and joined at their points of contact 95, for example by welding in the case wherein the sheets 91, 93 are composed of metal or plastic. The corrugated configuration of the adjacent strips 91, 93 create gaps 97 therebetween to contain a suitable reservoir material. In this way, the height of the strips 91 and 93 will be regulated in part by the thickness of the reservoir material loaded in the recesses 97. FIG. 10 illustrates another embodiment of the support member 15. In this embodiment, the retention element 15 support 15 consists of a corrugated sheet 101. Corrugated sheet 101 is adapted to make contact with the side of sheet member 6 remote from the skin. If necessary, a cover sheet (not shown in Figure 10) covering the side of the corrugated sheet 101 far from the skin can be used., or rails (not shown in Figure 10) along the corrugated sheet side edges 101, to provide additional stiffness and to avoid any tendency for the sheet 101 to fold or fold along the corrugated pleats when applied force next to blade 101 far to the skin. Optionally, the corrugated sheet 101 may have a plurality of openings therein, thereby making it possible for the agent to move through the corrugated sheet 101. The size and number of openings (not shown in Figure 10) is not Critical as long as the integrity and structural rigidity of the corrugated sheet 101 is not compromised. This would make it possible to place additional deposit material in the recesses 104 adjacent to the side of the sheet 101 remote from the skin. As in the other modalities, a deposit material can be loaded in the holes 103 formed between the corrugations and the underlying sheet element 6 (not shown in Figure 10). Figure 11 depicts an alternate embodiment of a corrugated sheet 101 in which the corrugation folds are not all parallel with one another. Similar to the device of Figure 10, the device of Figure 1 1 may also be provided, if necessary, with a cover sheet on the side of the corrugated sheet 101 remote from the skin, or alternatively with an annular rail that surround the corrugated sheet 101, in order to increase the structural rigidity of the corrugated sheet 101. Furthermore, as in the device of Figure 10, the device of Figure 1 1 may be provided with a plurality of openings (not shown in FIG. Figure 1 1) in the corrugated sheet 101 in order to allow agent delivery therethrough. Such openings make it possible to use gaps 104 to contain agent deposit material. A common feature of the support elements 15 illustrated in Figure 1-2, 4-7, 9-1 1 and 13 is that the support member 15 contains gaps (eg, recesses 7, 97 and 103) in which you can load deposit material. On the other hand, certain embodiments of the sheet member 6 such as those shown in Figure 5 may have their own recesses 51 for containing the deposit material. In cases like this and also in cases where the foil element is applied to the skin as a pretreatment step prior to the placement of a reservoir containing / taking agent sample in the pretreated skin site, the element of support 15 need not be integrally a part of or otherwise be fixedly attached to sheet member 6. Figure 12 illustrates a support element 115 which is the head of a hand-held device 112 used to press the element. of lamina 6 on the skin. The head 115 normally consists of a metal plate having sufficient thickness (for example, 0.5 cm or more) to impart sufficient rigidity thereto. The support element 115 is connected to the device 1 12 by means of screws 1 13. The surface 1 11 is pressed against the sheet element 6 in order to force the microprotrusions 4 to pierce the skin. The surface 11 may have either a convex curvature (as shown in FIG. 12 and as discussed above in relation to FIG. 8) or may simply be a flat surface. Optionally, the device 112 can be spirally loaded in order to cause the support member 15 to be impacted with the side of the sheet member 6 remote from the skin with a predetermined force. Although the support member 15 of the present invention has been described primarily in relation to the initial application and piercing of the body tissue (e.g., skin) by the foil element 6 and microprotrusion 4, those skilled in the art will appreciate that the element Rigid support 15 is also useful for reapplication (ie, subsequent application) of the sheet member 6 and subsequent perforation by means of the microprotrusions 4, either on the same body surface site as the first application or on a new site. body surface.

Subsequent skin piercing by the microprotrusions 4 at the original body surface site (i.e., the body surface site through which the microprotrusions 4 were initially punctured) is useful for keeping the cut micro-slices open by means of the microprotrusions 4 so that the flow of transdermal agent can continue without difficulty. Transdermal drug delivery / sampling devices, such as those described in Figures 13-18, are normally adapted to adhere to the skin during transdermal delivery or sampling. After the microprotrusions 4 initially create micro-cuts / micro-grooves through the stratum corneum, the skin immediately starts a healing process. Eventually, the microgrooves will close as the healing process continues. In this way, finger pressure reapplication is desired to reapply the foil member 6 against the skin in order to keep the microgrooves open and the flow of transdermal agent without difficulty. This can be easily achieved with the support structure of the present invention. When the transdermal delivery / sampling device is adhered to the skin, the patient or technician may simply reapply finger or hand pressure periodically to the side of the device far away from the skin in order to cause the microprotrusions 4 to pierce the stratum corneum. . The microprotrusions or micropads 4 are generally formed from a single piece of material and are sharp and long enough to penetrate at least the stratum corneum of the skin. In a embodiment, the microprotrusions 4 and the sheet member 6 are essentially impermeable or impervious to the passage of an agent. The width of each microprotrusion can be any width scale. The width of the microprotrusion at the intersection of the microprotrusion and the body surface after the microprotrusion deployment has been inserted is normally at least about 25 μm. The required length of the pallets is subject to the variation of the body surface that is penetrated and corresponds at least to the natural thickness of the stratum corneum, since one of the main characteristics of the invention is that the microprotrusions penetrate at least through the stratum. horny and the epidermis. Typically, the microprotrusions will have a length and configuration which reaches a penetration depth of about 25 μm to about 400 μm, with the penetration depth for most applications being between about 50 μm to about 200 μm. The microprotrusions 4 may have inclined projecting edges 64 (i.e., angular) (Figure 3) to also reduce the insertion force required to press the microprotrusions into the skin tissue. The protruding edges of each microprotrusion 4 may all be of the same angle or may be at different angles suitable for penetration into the skin. Alternatively, the protruding edge of each microprotrusion may be curved having, for example, a convex or concave shape or be divided into any number of angular segments, for example the first segment being relatively steep with respect to the vertical and the second segment being angled more gradually with respect to the vertical. The sheet member 6 can be produced with a photolithography process followed by a chemical etching process followed by a microperforation operation as described in WO 97/48440, descriptions of which are incorporated herein by reference. The embodiment of the sheet element 6 illustrated in FIG. 5 requires an additional step of forming the flat sheet element 6 into the desired shape of the hollow definition (i.e., spiral, serpentine, concentric circles, etc.). This can be achieved using well-known bending, rolling, folding and / or metal foil molding techniques. Generally the microprotrusions 4 are at an angle of approximately 90 ° to the surface 48 (Figure 3) of the sheet member 6 after being punched, but they can be arranged at any angle forward or backward of the perpendicular position which will facilitate the penetration of the stratum corneum. The sheet member 6 and microprotrusions 4 may be made of materials having sufficient strength and manufacture to produce microprotrusions, such as glasses, ceramics, rigid polymers, reinforced polymers (eg, reinforced carbon fibers), metals and metal alloys. Examples of metals and metal alloys include but are not limited to stainless steel, iron, steel, tin, zinc, bronze, gold, platinum, aluminum, germanium, zirconium, titanium and titanium alloys. Each The foil elements and microprotrusions can have a thin layer of bath gold, platinum, iridium, titanium or rhodium. Examples of glasses include silicas and devitrified glasses such as "PHOTOCERAM" available from Corning in Corning, NY. Examples of polymers include but are not limited to polystyrene, polymethylmethacrylate, polypropylene, polyethylene, "BAKELiTE", cellulose acetate, ethylcellulose, styrene / acrylonitrile copolymers, styrene / butadiene copolymers, acrylonitrile / butadiene / styrene (ABS) copolymers, polyvinyl chloride and acrylic acid polymers including polyacrylates and polymethacrylates. The number of microprotrusions 4 and openings 8 of any of the embodiments of the sheet element 6 is variable with respect to the desired flow rate, agent that is taken from sample or supplied, device of supply or sampling used (ie, electrotransport, passive, osmotic, handled under pressure, etc.), and other factors that will be evident to the person skilled in the art. In general, the larger the number of microprotrusions per unit area (ie density of micropacks), the less concentrated the agent flow (microgrooves) in the skin because there are a greater number of access routes to the skin. through the skin. Consequently, a smaller number of microprotrusions per unit area leads to the transport of the agent through the skin becoming more concentrated in fewer access routes. Higher concentrations of agents in a pathway to the skin can lead to higher incidences and / or severity of skin reactions (eg, irritation). Therefore, larger micropalette densities reduce the incidence and / or severity of skin reactions. It may be provided with an optional connecting means (not shown) on the skin-contacting side 48 of the sheet element 6 having the configuration shown in Figures 1-3 as shown in WO 98/28037, descriptions of which are incorporated herein by reference. The connection means, if used, acts as a conduit for the agent and acts as a bridge between the collecting or agent-containing deposit, and the skin thus allowing an agent to be transported without difficulty through it. One type of transdermal delivery / sampling device, which can be used with the present invention is based on the application of an electric current through the body surface or "electrotransport". It will be appreciated by those working in the field that the present invention can be used in conjunction with a wide variety of electrotransport systems, since the invention is not limited in any way in this respect. As examples of electrotransport systems, reference may be had to U.S. Patent Nos. 5,147,296 to Theeuwes et al., 5,080,646 to Theeuwes et al., 5,169,382 to Theeuwes et al., 5,423,739 to Phipps et al., 5,385,543 to Haak et al. al., 5,310,404 for Gyory et al. and 5,169,383 to Gyory et al., of which any described electrotransport system can be used with the present invention.

Figures 13-17 illustrate a representative electrotransport delivery / sampling device 10 that can be used in conjunction with a support member 15 and a skin penetration device 2 according to the present invention. The device 10 consists of an upper housing 16, a circuit board assembly 18, a lower housing 20, donor electrode 22, against electrode 24, donor reservoir 27, against reservoir 28 and adhesive compatible to the skin 30. The upper housing 16 it has lateral wings 31 which help to support the device 10 on the skin of a patient. The printed circuit board assembly 18 consists of an integrated circuit 19 attached to separate components 40 and battery 32. The circuit board assembly 18 is attached to the housing 16 by posts 33 (only one shown in Figure 17 being shown). pass through the openings 13a and 13b, the ends of the posts being heated / fused in order to heat fix the circuit board assembly 18 to the housing 16. The lower housing 20 is attached to the upper housing 16 by means of adhesive layer 30, the upper surface 34 of the adhesive layer 30 is adhered to both the lower housing 20 and the upper housing 16 including the base surfaces of the wings 31. On the underside of the circuit board assembly 18 is (partially) shown button cell battery 32. Other types of batteries may also be used to operate the device 10 depending on the need. The device 10 generally consists of battery 32, electronic circuit systems 19, 40, electrodes 22, 24, against reservoir 28, element of support 15, reservoir donor housing 27 and skin penetration device 2, all integrated in a separate unit. The electrodes 22, 24 and reservoirs 27, 28 are retained by the lower housing 20. The outlets (not shown in FIG. 13) of the circuit board assembly 18 make electrical contact with the electrodes 24 and 22 through the openings 23. , 23 'in the depressions 25, 25' formed in the lower housing 20, by means of electrically conductive adhesive bands 42, 42 '. In turn, the electrodes 22 and 24 are in direct mechanical and electrical contact with the upper portions 44 ', 44 of the reservoirs 27 and 28. The base end 46 of the counter reservoir 28 makes contact with the patient's skin through the opening 29 in the adhesive layer 30. The base side 46 'of donor reservoir 27 makes contact with the skin of the patient through the plurality of openings 8 in the skin penetration device 2 as best shown in Figure 1. The donor deposit agent 27 is usually in the form of a solution, preferably an aqueous solution, which is contained in a solid matrix material such as a sponge, a hydrophilic polymer matrix (e.g., a hydrogel) that allows free mobility of the agent therethrough. The reservoir matrix material fills the openings 8 so that in the agent reservoir it is in contact with the body surface as can be seen in Figure 1. As discussed above, a connecting means can be placed as a layer in the sheet side 6 close to the skin, with the micropads 4 passing therethrough. The optional connection means provides a flow path of more consistent agent between the donor deposit 27 and the skin. Normally, the agent is initially present both in the reservoir and in the connection means due to diffusion or because the reservoir and the connection means are the same material. The device 10 adheres to the patient's body surface (for example, skin) by means of a peripheral adhesive layer 30 (which has upper adhesive end 34 and adhesive end that makes contact with the body 36) and optionally, fastening elements in the device 2 of any of the modalities discussed in FIG. the present. In addition, optionally, the connecting means 65 can be tacky or adhesive to help maintain interface contact with the skin. The adhesive end 36 covers the entire low end of the device 10 except where the device 2 and the counter-electrode reservoir 28 are located. The adhesive end 36 has adhesive properties which ensure that the device 10 remains in its proper place in the body during the normal activity of the user and allows even reasonable removal after a predetermined period of use (eg 24 hours). The upper adhesive end 34 adheres to the lower housing 20 and retains the electrodes and reservoirs of agent within the housing depression 25, 25 'as well as retains the device 2 in the lower housing 20 and the lower housing 20 in the upper housing 16. In an embodiment of the agent delivery / sampling device there is a release liner (not shown) in the device 10. to maintain the integrity of the adhesive layer 30 when the device is not in use. In use, the release liner is detached from the device before the device is applied to the skin. The device 10 further has a push-button switch 12, which when pressed turns on the device 10 which is evident to the user by means of the LED 14 which is turned on. The agent is delivered through the skin of the patient (for example, in the arm) by electrotransport over a predetermined delivery interval. In other embodiments of the present invention, passive transdermal sampling or delivery devices are used with the support member 15 predisposed on the upper surface of the element 6. It will be appreciated by those working in the field that the present invention can be used together with a wide variety of passive transdermal systems, since the invention is not limited in this respect. For examples of passive systems, reference may be had but is not limited to U.S. Patent Nos. 4,379,454 to Campbell, et al., 4,588,580 to Gale et al., 4,832,953 to Campbell et al., 4,698,062 to Gale et al., 4,867,982. for Campbell et al. and 5,268,209 to Hunt et al., of which any of the described systems can be used with the present invention. An example of a passive transdermal delivery / sampling device is illustrated in Figure 18. The support member 15 having the edges of the sheet member 6 embedded in the outer annular wall 53 thereof is housed in a foam pad or in the form of a foam pad. band 57 which can be applied to the body surface. The edges of the sheet element 6 do not need to be embedded in the outer annular wall, since the sheet element 6 can be attached to the support element 15 as described in the above embodiments. Through the annular wall 53 and transverse element 5 a rigid cover 59 extends. The cover 59 is rigid enough not to deform when force is applied to it and to transmit more uniformly the applied force and displacement of microprotrusions 4. through the length and width of the sheet element 6. Preferably, although not required, the passive supply / sampling device has a peripheral adhesive on the surface of the foam pad 57 that contacts the body and a gel of adhesive interface (not shown) on the side of the element 2 that makes contact with the body. It will be appreciated by those working in the field that the present invention can also be used in conjunction with a wide variety of pressure and osmotic systems, since the invention is not limited to a particular device in this aspect. For examples of pressurized and osmotic devices, reference may be had in U.S. Patent Nos. 4,340,480 to Eckenhoff, 4,655,766 to Theeuwes et al., 4,753,651 to Eckenhoff, 5,279,544 to Gross et al., 4,655,766 to Theeuwes, 5,242,406 to Gross et al. to the. and 4,753,651 to Eckenhoff, any of which may be used with the present invention.

This invention has utility in relation to the delivery of agents within any of the broad class of drugs normally delivered through body surfaces and membranes including the skin. In general, this includes drugs in all the main therapeutic areas. This invention is further useful in the transdermal delivery of proteins, peptides and fragments thereof, whether natural, chemically synthesized or recombinantly produced. The invention may also be used in conjunction with the delivery of vaccines, nucleotide drugs, including oligonucleotide drugs, polynucleotide drugs and genes. These substances typically have a molecular weight of at least about 300 daltons, and typically have a molecular weight of at least about 300 to 40,000 daltons. As mentioned, the device 2 of the present invention can also be used with sampling devices including, but not limited to, reverse electrotransport (i.e., reverse iontophoresis and / or reverse electroosmosis in the case of sampling non-charged materials such as as glucose), osmosis and passive diffusion. For example, reference may be had to the patents of US Pat. Nos. 4,756,314 to Eckenhoff et al., 5,438,984 to Schoendorfer, 5,279,543 to Glikfeld et al. and 5,362,307 for Guy et al. The person skilled in the art will appreciate that the invention can be modalized in other specific forms without departing from the invention or the essential character thereof. The modalities currently described are therefore considered in all aspects as illustrative and not restrictive The scope of the invention is indicated by the appended claims more than in the foregoing description.

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - A device (2) for use in introducing or withdrawing an agent through a body surface, consisting of an element (6) having a plurality of microprotrusions (4) extending from a portion close to the body surface (48) of element (6) and a structural support (15) which contacts and extends through at least a portion of the element (6), the support (15) having greater rigidity than the element (6) , the device being characterized by microprotrusions (4) having a length sufficient to pierce the body surface to a depth of less than 500 μm, the structural support (15) having a plurality of recesses (7) therein, and an agent receiving tank or containing agent (27) within the gaps.

2. The device according to claim 1, further characterized in that the support (15) has greater rigidity at a force applied perpendicular to the body surface than the element (6).

3. The device according to claim 1, further characterized in that the support (15) is sufficiently rigid to deviate less than 300 μm under pressure of the device (2) manually applied with finger or hand against the skin.

4. - The device according to claim 3, further characterized in that the support (15) deviates less than 50 μm under said pressure.

5. The device according to claim 1, further characterized in that the support (15) is sufficiently non-compressible to compress less than 250 μm under pressure of the device (2) manually applied with finger or hand against the skin.

6. The device according to claim 5, further characterized in that the support (15) compresses less than 50 μm under said pressure.

7. The device according to claim 1, further characterized in that the element (6) consists of a sheet that when in use is oriented approximately parallel to the body surface, the sheet having a plurality of openings (8) in the same and the plurality of microprotrusions (4) that extend from a surface (48) of the sheet close to the body, said microprotrusions (4) being adapted to pierce the body surface.