MXPA00005725A - Device for enhancing transdermal agent flux - Google Patents

Abstract

A device (2) comprising a sheet member (6) having a plurality of microprotrusions (4) extending from a bottom edge (5) for penetrating the skin of a patient. The sheet member (6) when in use being oriented in an approximately perpendicular relation to the patient's skin.

Description

DEVICE TO INCREASE THE TRANSPERMIC FLOW OF AGENTS TECHNICAL FIELD The present invention relates to transdermal delivery and sampling of agents. More particularly, this invention relates to the transdermal delivery of agents, such as peptides and proteins, through the skin, as well as to the transdermal sampling of body agents, such as glucose, other body analytes and substances of abuse, such as alcohol and illicit drugs.

BACKGROUND OF THE ART Interest in percutaneous or transdermal delivery of peptides and proteins to the human body continues to grow with the increasing number of medically useful peptides and proteins that become available in large amounts and in pure form. The transdermal delivery of peptides and proteins still faces significant problems. In many cases, the delivery regimen or flow of polypeptides through the skin is insufficient to produce a desired therapeutic effect due to its large / high molecular weight size and the resulting inability to pass through natural pathways (pores, hair follicles). , etc.) through the skin. In addition, the polypeptides and proteins are easily degradable during penetration of the skin, before reaching the target cells. Similarly, the passive flow of water-soluble small molecules such as salts is limited.

A method to increase the transdermal delivery of agents depends on the application of an electric current through the body surface or the "electrotransport". "Electrotransport" refers generally to the passage of a beneficial agent, v. g. , a drug or drug precursor, through a surface of the body such as skin, mucous membranes, nails, and the like. The transport of the agent is induced or increased by the application of an electric potential, which results in the application of an electric current, which delivers or increases the delivery of the agent. The electrotransport of agents through a body surface can be achieved in several ways. A widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electrosmosis, another type of electrotransport process, 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 pores formed by the application of a high voltage electrical pulse to a membrane. In many cases, more than one of these processes may be occurring simultaneously in different degrees. Accordingly, the term "electrotransport" is hereby given its broadest possible interpretation, to include the induced or electrically enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of (the) specific mechanism (s) by which the agent (s) is actually being transported. Delivery by electrotransport generally increases the transdermal flow of agents, particularly large molecular weight species (eg, polypeptides), relative to passive or non-electrically assisted transdermal delivery. However, further increases in transdermal delivery regimens and reductions in polypeptide degradation during transdermal delivery are highly desirable. A method for increasing the transdermal delivery regimen of agents involves pre-treating the skin with, or co-delivering with the beneficial agent, a skin penetration promoter. The term "penetration promoter" 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 electrical resistance of the body surface to the passage of the agent for that, an increase in the permselectivity and / or permeability of the body surface, the creation of hydrophilic trajectories through the body surface, and / or a reduction in the degradation of the agent (eg, degradation by enzymes of the skin) during the ßlectrotransport . There have been many attempts to mechanically disrupt the skin in order to increase the transdermal flow, such as US Patents, 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., 5,611, 806 issued to Jang, and 3,964,482 issued to Gerstel et al., U.S. Patent No. Re. 25637 issued to Kravitz et al., And published PCT Applications WO 96/37755.; WO 97/48440; and WO 97/4844. These devices typically use tubular or cylindrical structures generally, even though the U.S. Patent of Gerstel and the last two PCT publications describe the use of other shapes to pierce the outer layer of the skin. The piercing elements described in these references extend generally perpendicular to a thin flat member, such as a metal cushion or sheet, which is placed on the surface of the skin. The flexible nature of the flat member and the tubular shape of the piercing elements result in a variety of drawbacks, such as manufacturing difficulties, flexing of the flat member when pressure is applied to the upper part of the device, poor or uneven penetration of the skin by microblades or microtubes resulting in little transdermal flow of agent and, for electrotransport, increased irritation due to the concentration of drug flow through few trajectories. The perforating elements in the Patent of E. U. No. 5,61 1, 806 of Jang are points extending from the circumferential surface of separate discs mounted on an axle. The discs are rolled over the surface of the skin as a pre-treatment before transdermally delivering a drug. A further drawback of the devices described in WO 97/48440 and WO 97/4844 have to do with the degree of difficulty of its manufacture. First, the thin flexible metal sheets / plates must be subjected to a gravure process to form openings in the sheet / plate through which the agent that is being delivered or transdermally sampled can pass. Photogravure is also used to form the microblades. However, a second drilling step is required to bend the microspheres at an angle approximately perpendicular to the plane of the sheet. Due to the tiny size of the openings (approximately 0.4 x 0.5 mm) and due to the large number of openings (approximately 50 to 300 openings / cm2), the precise alignment of the micro-perforations with the micro-openings is problematic and time-consuming.

DESCRIPTION OF THE INVENTION The present invention provides a suitable device for increasing the transdermal flow of agents. The device has microprotrusions that consistently and reliably penetrate a body surface (eg, skin) to increase delivery or sampling of agents. The device of the present invention can be manufactured in high volumes and at low cost. The device of the present invention can penetrate the corneal layer of the skin with a plurality of microprotrusions to form trajectories through which a substance such as a drug can be introduced (ie, delivered) or can be extracted (i.e. sample) a substance such as an analyte of the body. A main advantage of the present invention is that the device ensures uniform penetration (i.e., that generates the same size and depth of trajectories) by means of the microprotrusions across the width of the device. In addition, the present invention reproducibly provides uniformity in penetration from patient to patient.

In one aspect, the invention comprises a rigid structure comprising a thin sheet which in use is oriented with its width perpendicular to the patient's body surface. The sheet has a plurality of microprotrusions in the same plane as the sheet and extends outwardly from a proximal edge of the sheet body to pierce the body surface. The thin sheet transmits the force applied to a distal edge of the sheet body to the microprotrusions with substantially less dissipation of the application force in the thin sheet than in the prior art devices. The rigid structure formed by the thin sheet provides the assured transmission of a load applied externally to the microprotrusions without wasting energy in the deviation of any portion of the device for easier penetration of the skin., complete and reproducible. The improved penetration of the skin by the microprotrusions due to the rigid structure formed by the thin sheet is particularly beneficial to produce increased flow of agents. The transmitted charge provides almost complete penetration through all the microprotrusions to produce a substantial number of micro-tracts in the corneal layer for continuous and reproducible transdermal agent flow. Optionally, although preferably, the rigid structure forms a vacuum to contain an agent reservoir. The vacuum can be filled with a reservoir material to contain the agent to be delivered or sampled. The sheet with the plurality of microprotrusions can be made more easily and less expensively than the prior art designs consisting of a thin sheet having perforated sheets perpendicular thereto since the present invention does not require a separate perforation operation. In one aspect of the invention, the device utilizes a plurality of separate sheet members which are held together in an approximately parallel configuration, each of the sheet members having a plurality of microprotrusions extending downwardly from their proximal edges of the laminate. body. In another aspect of the invention, the device utilizes a sheet member bent into a serpentine configuration and having a plurality of microprotrusions extending downwardly from a proximal body edge of the sheet member. In another aspect of the invention, the device utilizes a plurality of cylindrical sheet members forming concentric circles having a plurality of microprotrusions extending downward from their proximal body edges, respectively. In still another aspect of the invention, the device utilizes a sheet member wound in a loose spiral and having a plurality of microprotrusions extending downward from the proximal body edge of the sheet member. Optionally, although preferably, the device has a rigid support member that contacts the distal body edge (s) of the sheet member (s) opposite the proximal body edge. 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-driven devices. Sampling devices for use with the present invention include, but are not limited to, inverse electrotransport devices, passive devices, negative pressure driven devices, and osmotic devices.

BRIEF DESCRIPTION OF THE DRAWINGS In the figures, similar reference numerals refer to similar elements in the different drawings. Figure 1 is a perspective view of a first embodiment of a skin penetrating sheet member and a rigid support therefor; Figure 2 is a front elevational view of a portion of the sheet member of Figure 1 before being rolled; Figure 3 is a perspective view of a second embodiment of a skin penetrating sheet member; Figure 4 is a perspective view of a third embodiment of the skin penetrating sheet member; Figure 5 is a cross-sectional view of the rigid support and skin penetrating sheet member of Figure 1 taken along the line 5-5 with an agent-containing material within the voids between successive coils of the sheet member; Figure 6 is a front elevation view of a portion of a fourth embodiment of a sheet member before forming the sheet member in a pattern; Figure 7 is a bottom perspective view of the sheet member of Figure 6 before being formed into a pattern; Figure 8 is an alternative embodiment for microprotrusions in the sheet member; Figure 9 is an exploded perspective view of an embodiment of an electrotransport delivery / sampling system of agents according to an embodiment of the present invention; Figure 10 is a bottom plan view of the electrotransport delivery / sampling system of agents of Figure 9; Figure 11 is a view in right lateral elevation of the electrotransport delivery / sampling system of agents of Figure 9; Figure 12 is a rear elevation view of the electrotransport delivery / sampling system of agents of Figure 9; Figure 13 is a cross-sectional view taken along line 13-13 of the assembled electrotransport delivery / sampling system of agents of Figure 1 1; Figure 14 is a diagrammatic cross-sectional view of a passive agent delivery / sampling system according to an embodiment of the present invention; and Figure 15 is an exploded view of another embodiment of the skin penetrating sheet member.

MODES FOR CARRYING OUT THE INVENTION Turning now to the drawings in detail, the skin penetration and reservoir device 2 of the present invention is shown generally in Figure 1 for use in the percutaneous administration or sampling of an agent. The terms "substance", "agent" and "drug" are used interchangeably herein and broadly include physiologically or pharmaceutically active substances to produce a localized or systemic effect or effects in mammals including humans and primates, animals for sports or of farm, related to birds, valuable domestic, or to administer to laboratory animals such as mice, rats, guinea pigs, and the like. These terms also include substances such as glucose, other body analytes found in tissue, interstitial fluid and / or blood, substances such as alcohol, illicit substances, illicit drugs, etc. , what can be sampled through the skin. The main barrier properties of the skin, such as resistance to electrotransport of water soluble drug agents, reside in the outer layer (ie, corneal layer). The inner portions of the epidermis generally comprise three layers commonly identified as stratum granulosum, stratum malpighii, and stratum germinativum. There is much less resistance to transport or to the absorption of an agent through the stratum granulosum, stratum matpighii, and stratum germinativum compared to the resistance to the transport of agents through the stratum comeum.

Thus, the microprotrusions 4 penetrate at least through the stratum corneum so that the agent is conducted with little or no resistance through the skin. The device 2 comprises a plurality of microprotrusions 4 extending outward from the edge 5 (also referred to as the proximal body edge) of a sheet member or tape 6, thin (Figure 2). The sheet member 6 is generally compliant and flexible due to its relatively thin thickness, for example, from about 5 μm to about 100 μm, preferably from about 25 μm to about 50 μm. The rolled (Figure 1), folded (Figures 4 and 7), curved (Figure 3), stacked (Figure 15), as well as other forms to form the sheet member 6 from its generally flatter condition throughout of its entire length, it forms a rigid structure having a plurality of voids 27, 127 for holding a reservoir that contains the agent to be delivered or that is adapted to receive the agent to be sampled. Those skilled in the art will appreciate that spacers may be placed within the voids 27, optionally secured together with fasteners such as screws or fastening pins, to maintain constant separation between adjacent turns (Figure 1) or folds (Figure 4) of the member. 6 of sheet. In order to prevent deformation or bending side by side of the sheet member 6 as the array of microprotrusions is applied to the body surface, the support member 15 is preferably placed across the edge 7 (also referred to as the top edge) of the distal the skin of the sheet member 6 (Figures 1 and 5). The optional support member 15 may be of a variety of configurations, for example, but not limited to the embodiments shown in Figures 1 and 5. The support member 15 transmits the force that is applied to the upper part of the support member. through the distal edge 7 of the skin of the sheet member 6 so that each of the microprotrusions 4 receives substantially the same amount of force to penetrate the skin. The force applied to the edge 7, and directed towards the skin, causes the microprotrusions 4 to pierce at least through the stratum corneum. The various embodiments of the device 2 are illustrated in the figures although other configurations than those specifically illustrated are within the scope of the invention. In each of these embodiments, the device 2 is constituted of the sheet member 6, or a plurality of sheet members 6, 106 (see Figures 3 and 15) having their width oriented generally perpendicular to a body surface (eg, skin). ), whereby vertical walls are formed, to efficiently transmit (i.e., without bending or flexing the sheet member 6) a force applied through the distal edge 7 of the skin of the sheet member 6 to the microprotrusions 4. The Width (i.e., the distance from the distal edge of the skin to the proximal edge to the skin) of the sheet member 6 is optionally, but preferably, sufficient to create a plurality of voids 27 for the agent reservoir. The number and volume of voids 27 depends on a variety of factors, for example, the relative structural integrity or flexibility of the sheet member 6, the distance through device 2, the size of the skin contact area of the agent reservoir. , and the volume of deposit required for the therapy (in the case of delivery of drugs from the deposit). A particularly preferred configuration for the device is illustrated in Figure 15 and comprises a plurality of individual sheet members 106 stacked together to form the device 2 '. Each of the sheet members 106 has a pair of holes 102, 103 through which screws 105 are inserted. Spacers 100 (eg, tubes) are placed between each adjacent pair of sheet members 106 to form voids 127 between those . The separate sheet members 106 are held together as a unit by securing nuts 104 at the ends of the screws 105, or using other known fasteners. As in the device of Figure 1, voids 127 can be filled with a reservoir matrix material (eg, a gel) adapted to contain the beneficial agent to be delivered or to receive the analyte from the body to be sampled. Those skilled in the art will appreciate that spacers having other non-tube-like configurations (see g., square or rectangular blocks) may also be used to provide voids 127 between adjacent sheet members 106 provided that the separators do not form a complete barrier between the agent reservoir 8 (ie, the agent reservoir contained in the voids 127) and the skin. In addition, more than two sets of screws 105, or other fastener pins, can be used to secure the spacer members 106 together and the spacer 105. The microprotrusions 4 can be microblades or any of a 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 (distal side of the body) of the support member 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 conduction of agent from the system to the body, or vice versa. In some configurations, spaces 9 (see Figure 2) are formed between each of the microprotrusions 4 to create a lower density of sheets and / or provide "stops" that prevent the device from penetrating the body surface beyond the length of the microprotrusions 4. The agent can be administered or sampled at a controlled rate of release from or collection in the voids 127 that clog the reservoir containing the agent or that receives the agent through a material that controls the agent regimen such as a flow control membrane (not shown) placed between the voids 27, 127 and the body surface. The microprotrusions or microspheres 4 are generally formed from a single piece of material (as shown in Figure 2) and are sufficiently acute and long to penetrate at least the stratum corneum of the skin. In one 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 4 can be any of a range of widths. The width of the microprotrusion 4 at the intersection of the microprotrusion and the body surface after the arrangement of microprotrusions has been inserted as typically at least about 25 μm. The required length of the sheets is subject to variation of the body surface that is penetrated and corresponds to at least the natural thickness of the stratum corneum, for one of the main aspects of the invention is that the microprotrusions will penetrate at least through the stratum corneum and the epidermis. Usually, the microprotrusions 4 will have a length and configuration reaching 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 (i.e., angled) leading edges to additionally reduce the insertion force required to press the microprotrusions into the skin tissue. The leading edges of each microprotrusion 4 may all be at the same angle or may be at different angles suitable for penetrating the skin. Alternatively, the leading edge of each microprotrusion 4 may be curved having, for example, a convex or concave shape or be divided into any number of angled segments such as the first segment that is relatively steep with respect to the vertical and the second segment which is angled more gradually with respect to the vertical. The sheet member 6 of the present invention may optionally include microprotrusion anchoring means to improve the attachment of the device to the skin so that a continuous conductive path of agent is maintained across the body surface even during the movement of the patient and / or body surface of the patient. Some or all of the microprotrusions 4 may have a tip that aids in the anchoring of the sheet member 6 and any corresponding device or structure used in combination therewith for the skin. The microblade anchoring tips are described in more detail in WO 97/48440, and U.S. Patent Nos. 5,312,456 and 5,569,272 to Reed et al., of which any of the configurations described with the present invention may be used. The tips are but an example of means of anchoring microprotrusions. In addition to the anchoring means in the sheets, other means may be used to keep the device in contact with the skin, such as, but not limited to, adhesive agent-containing deposits in the voids 27, 127, peripheral adhesive, tape, a strip or an elastic band. The microprotrusion configurations of Figures 6, 7 and 8 facilitate penetration of the body surface, but also help to anchor the device to the body surface. The sheet member 6 in Figure 6 has angled or inclined microprotrusions 4. In sections 72 and 76 of the sheet member 6, the microprotrusions 4 are inclined to the right along the length of the sheet member 6. In section 74, the microprotrusions are tilted to the left along the length of the sheet member 6. As a result, when the sheet member 6 is bent by the lines 78 in the serpentine pattern shown in Figure 7, all the microprotrusions 4 are inclined in the same direction. With this configuration, the sheet member 6 and elements attached thereto can be slid down the body surface in the direction of the inclined microprotrusions while the device is pressed down to facilitate better penetration against the viscoelastic nature of the body surface. This configuration also helps to anchor the device to the body surface because the upper edges 80 of each of the microprotrusions act in a manner similar to the tips previously described. Similarly, the sheet member 6 in Figure 8 has wide curved microprotrusions. The microprotrusions 4 sweep to the left along the length of the sheet member 6. As a result, when the sheet member ß is formed in a curved configuration, such as for example those of either Figure 1 or 3, the sheet member 6 and elements attached thereto can be rotated in the clockwise direction the direction of the microprotrusions that sweep while the device is pressed down to facilitate better penetration against the viscoelastic nature of the Body surface. This configuration also helps to anchor the device to the body surface because the upper edges 80 in each of the microprotrusions act in a manner similar to the tips previously described. The pattern for the microprotrusion arrangement members 6 can be produced with a photolithographic process followed by a chemical etching process. A member 6 of thin sheet metal such as stainless steel or titanium is patterned by photolithography with patterns containing sheetlike structures. In general, a thin dry or moisture resistant laminate is applied to the sheet member 6 typically having a thickness of about 7 μm to about 100 μm, preferably about 25 μm to about 50 μm. The resist is exposed to contact using a mask that has a desired pattern and is subsequently developed. These operations are conducted by much in the same way as they are for the manufacture of a printed circuit board. The sheet member 6 is then etched using acidic solutions. After the pattern has been etched, the sheet member 6 is rolled or folded into the desired configuration (i.e. spiral, serpentine, concentric circles, etc.) having voids 27 to contain the reservoir containing the agent. The finished structure provides microprotrusion 4 on the edge 5 proximal to the skin of the sheet member 6. Adjacent turns of member 6 (see Figures 1 and 5) form adjacent vertical walls between which there are voids 27 containing a reservoir 8 (eg, a gel reservoir; see Figure 5) to contain an agent (eg, a drug) in the same or for the passage of an agent therethrough when the sheet member 6 is applied to the body surface. In one embodiment of the etching process, a dry resist (eg, "DYNACHEM FL" (available from Dynachem located in Tustin, CA)) is applied with 12.5 μm thickness to one or both sides of the sheet member d and is exposed to a standard way After using a suitable spray recorder (eg, "DYNAMIL VRP 10 / NM" available from Western Tech. Assoc. Located in Anaheim, CA) a mixture of ferric chloride, water and hydrochloric acid is sprayed onto the resistant sheet member 6 about 52 ° C for two minutes. A caustic remover is used for the removal of the resist. In another embodiment of the etching process, a wet resist (eg, "SHIPLEY 1 1 1S" available from Shipley Corporation, located in Martborough, MA) is applied with 7.5 μm thickness at approximately 21 ° C to one or both sides of the member 6 of laminate and is exposed in a standard manner. Then a suitable etchant (v. G, ferric chloride) is sprayed on the resistive and sheet member at about 49 ° C. A caustic stripping agent is used for the removal of the resist. The member 6 of sheet and microprotrusions 4 are made from materials having sufficient strength and manufacturing ability to produce microprotrusions, such as glasses, ceramics, rigid polymers, reinforced polymers (eg, reinforced carbon fiber), metals and alloys of metals. Examples of metals and metal alloys include, but are not limited to, stainless steel, iron, steel, tin, zinc, copper, gold, platinum, aluminum, germanium, zirconium, titanium, and titanium alloys. Each of the foil member and microprotrusions may have a thin layer of gold, platinum, iridium, titanium, or rhodium bath. 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, ethyl cellulose, styrene / acrylonitrile copolymers, styrene / butadiene copolymers, acrylonitrile / butadiene / styrene copolymers ( ABS), polyvinyl chloride and acrylic acid polymers, including polyacrylates and polymethacrylates. The number of microprotrusions 4 and reservoirs 8 of any of the embodiments of the sheet member 6 is variable with respect to the desired flow rate, the agent being sampled or delivered, the used delivery or sampling device (i.e., electrotransport, passive, osmotic, pressure driven, etc.), and other factors as will be apparent to someone of ordinary skill in the art. In general, the larger the number of microprotrusions per unit area (i.e., the density of the microspheres), the less concentrated the agent flow in the skin because there are a large number of trajectories through the skin. Consequently, with delivery or sampling by electrotransport, a smaller number of microprotrusions per unit area, leads to the transport of the agent through the skin becomes more concentrated in a few trajectories. Higher concentrations of agents in a skin path can lead to greater incidences and / or severity of skin reactions (eg, irritation). Therefore, higher densities of microspheres are generally preferred to reduce the incidence and / or severity of skin reactions. The present invention can also be used to sample a body analyte (eg, glucose) transdermally. The analyte to be sampled is extracted through the openings cut in the stratum corneum by the microprotrusions 4 and collected in the sample reservoir 8 (Figure 5). Known analyte sensor elements (eg, glucose) can be placed directly in the reservoir 8. Alternatively, the reservoir 8 can be removed from the device and processed appropriately in order to determine the amount of analyte collected. Such devices are useful for monitoring the glucose concentration in the patient's blood (ie, through appropriate software which correlates the amount of glucose extracted with the blood glucose concentration) and can also be used to adjust a regimen. of treatment which typically includes the administration of insulin to the patient and / or the appropriate modification of diet and / or exercise. One embodiment of the present invention depends on the application of electrical current through the body surface or "ßlectrotransport". 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 regard. For examples of electrotransport systems, reference may be made to the Patents of EUt 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. collaborators, 5,310,404 to Gyory et al., and 5,169,383 to Gyory et al., of which any of the electrotransport systems described can be used with the present invention. The device 2 and support member 15 when used in an electrotransport system are preferably electrically isolated from an electrode or other electrically conductive members in order to avoid short circuiting of the container that contains an agent or that receives the agent contained in the voids 27, 127. This can be done using electrically insulating materials or coatings for the sheet member 6, 106 and / or support member 15. Figures 9-13 illustrate a representative electrotransport delivery / sampling device 10 that can be used in conjunction with the present invention. The device 10 comprises an upper housing 16, a circuit board assembly 18 a lower housing 20, a donor electrode 22, a counter electrode 24, a donor tank in empty spaces 27, a storage tank 28 and an adhesive 30 compatible with the skin. The upper housing 16 has lateral wings 31 which help to hold the device 10 in a patient's skin. The printed circuit board assembly 18 comprises an integrated circuit 19 coupled to discrete components 40 and battery 32. The circuit board assembly 18 is glued to the housing 16 by posts (not shown in the figures) extending from the bottom surface (proximal to the skin) of the housing 16 and passing through the openings 13a and 13b, the ends of the poles being heated / fused for the purpose of heat staking the circuit board assembly 18 to the housing 16. The lower housing 20 is attached to the upper housing 16 by means of the adhesive layer 30, the upper surface 34 of the adhesive layer 30 adhering to both lower housing 20 and upper housing 16 including the bottom surfaces of the wings 31. Shown (partially) on the side below the circuit board assembly 18 is a cell battery 32 button type. Other types of batteries can also be used to power the device 10 depending on the needs. The device 10 is generally made up of battery 32, electronic circuits 19, 40, electrodes 22, 24, against reservoir 28, and device 2 with lamellar member 6 and reservoir 8 donor therein, all of which are integrated into a gutocontent unit . The electrodes 22, 24, donor reservoir 8 and reservoir 28 are retained by the lower housing 20. The outlets (not shown in Figure 18) 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 dots 42, 42 '. The electrodes 22 and 24, in turn, are in direct mechanical and electrical contact with the upper sides 44 ', 44 of the donor reservoir 8 and the counter reservoir 28. The side 46 of the reservoir bottom 28 makes contact with the patient's skin through the opening 29 in the adhesive layer 30. The side 46 'of the bottom of the donor reservoir 8 makes contact with the skin of the patient through the opening 29'. The agent (eg, drug) in the donor tank 8 is typically in the form of a solution, most preferably an aqueous solution, said solution being contained in a solid matrix material such as a sponge, a hydrophilic polymer matrix (eg. , a hydrogel) that allows the free mobility of the agent through it. The reservoir matrix material fills the voids 127 between adjacent sheet members 106 (as shown more clearly in Figure 15) so that the agent reservoir 8 is in contact with the body surface. The device 10 adheres to the patient's body surface (eg, skin) by means of a peripheral adhesive layer 30 (having upper adhesive side 34 and adhesive side 36 that makes contact with the body) and, optionally, anchoring elements in device 2 of any of the modalities discussed in FIG. I presented. The adhesive side 36 covers the underside of the device 10 entirely except where the device 2 and the counter electrode deposits are placed. Adhesive side 36 has adhesive properties which ensure that device 10 remains in position in the body during normal user activity, and still allows for reasonable removal after the predetermined period of use (eg, 24 hours). The upper adhesive side 34 adheres to the lower housing 20 and retains the electrodes and agent reservoirs within the depression 25, 25 'of the housing as well as retains the device 2 in the lower housing 20 and lower housing 20 to the upper housing 16. In an embodiment of the agent delivery / sampling device there is a release layer (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 layer is released from the device before the device is applied to the skin. The device 10 also has a button switch 12 for pressing, which when pressed activates the device 10 which becomes apparent to the user by means of the LED 14 that is turned on. Agent is delivered through the patient's skin (eg, on the arm) by electrotransport in the predetermined delivery interval. In other embodiments of the present invention, passive transdermal delivery or sampling devices are used with the device 2. It will be appreciated by those working in the field that the present invention can be used in conjunction with a wide variety of passive transdermal systems, since that the invention is not limited in this respect. For examples of passive systems, reference may be made to, but not limited to, U.S. Patent Nos. 4,379,454 to Campbell et al., 4,588,580 to Gate et al., 4,832,953 to Campbell et al., 4,698,062 to Gate et al., 4,867,982 to Campbell et al., And 5,268,209 to Hunt et al., Of 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 14. The optional support member 15 having the edge distal to the body of the lamella member 6 embedded therein is housed in an outer housing 53 and a cushion or foam band 57 that can be applied to the surface of the body. The edges of the sheet member 6 need not be embedded in the support member 15. The support member 15 is sufficiently rigid not to deform when force is applied thereto and to more evenly transmit the force applied to the upper edge of the sheet member 6 across the width and length of the device 2. Preferably, although not required , the passive delivery / sampling device has a peripheral adhesive on the surface of the foam cushion 57 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-driven and osmotic agent delivery or agent delivery systems, since the invention is not limited to a device in particular in this respect. For examples of osmotic and pressure-driven devices, reference may be made to the Patents of E. U., Nos. 4,340,480 to Eckenhoff, 4,655,766 for Thßeuwes et al., 4,753,651 for Eckenhoff, ,279,544 for Gross et al., 4,655,766 for Theeuwes et al., 5,242,406 for Gross et al., And 4,753,651 for Eckenhoff, any of which may be used with the present invention. This invention has utility in relation to 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. The invention is also useful in the transdermal delivery of proteins, peptides and fragments thereof, whether occurring naturally, chemically synthesized or produced in a recombinant manner. The invention can be used additionally in conjunction with the delivery of vaccines, nucleotide drugs, including drug oligonucleotides, polynucleotide drugs, and genes. These substances typically have a molecular weight of at least about 300 daltons, and more typically have a molecular weight of about 300 to 40,000 daltons. As mentioned, the device 2 of the present invention can also be used with sampling devices that include, but are not limited to, inverse electrotransport (i.e., reverse iontophoresis and / or reverse electroosmosis in the case of sampling of unloaded materials. such as glucose), osmosis, and passive diffusion. For example, reference may be made to the Patents of E. U., Nos. 4,756,314 for Eckenhoff et al., 5,438,984 for Schoendorfer, 5,279,543 for Glikfeid et al., And 5,362,307 for Guy et al. It will be appreciated by those of ordinary skill in the art that the invention can be incorporated into other specific forms without departing from the spirit or essential character thereof. The embodiments described herein are therefore considered in all respects to be illustrative and not restrictive. The scope of the invention is indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalents thereof are intended to be encompassed herein.

Claims (18)

1. CLAIMS 1. A device for use in the introduction or removal of an agent through a body surface, the device having a side which in use is adapted to make contact with the body surface, the device comprising a sheet member that has a plurality of microprotrusions for piercing the body surface, the plurality of microprotrusions being in a plane defined by the sheet member and extending from one edge of the sheet member, the sheet member which is oriented in a perpendicular relationship approximately to side that makes contact with the body surface of the device with the edge having the microprotrusions that are proximal to the side that makes contact with the body surface of the device 2, the device 2 being characterized by: the sheet member having a configuration that defines a vacuum, and a deposit that contains agent or agent receives in a vacuum, the reservoir that is in transmitting agent communication with the side that contacts the body surface of the device and means for maintaining the foil member on the body surface, the means for keeping selected from anchoring tips in the microprotrusions, angled microprotrusions , curved microprotrusions, an adhesive, a tape, a strip and / or a bandage. The device of claim 1, wherein a plurality of said sheet members are held together. 3. The device of claim 2, wherein said sheet members are held together in a separate and approximately parallel orientation. The device of claim 1, wherein the foil member has a spiral configuration and the vacuum is defined by adjacent coils. The device of claim 1, wherein the sheet member has a serpentine configuration and the vacuum is defined by adjacent folds. 6. The device of claim 1, wherein the sheet member comprises a plurality of concentric circular sheets and the vacuum is defined by adjacent concentric circular sheets. The device of claim 1, wherein the reservoir is a reservoir containing agent. The device of claim 7, wherein the agent is a therapeutic agent. 9. The device of claim 8, wherein the agent is a therapeutic drug. 10. The device of claim 7, further comprising a therapeutic agent delivery device. The device of claim 10, wherein the delivery device comprises a transdermal drug delivery device. 12. The device of claim 1, wherein the reservoir is an agent reception reservoir. The device of claim 12, wherein the agent is an analyte of the body. 14. The device of claim 13, wherein the analyte of the body is glucose. 15. The device of claim 12, further comprising an agent sampling device. 16. The device of claim 15, wherein the sampling device samples glucose and measures or estimates the concentration of gtucose in the body. The device of claim 1, further comprising a rigid structural support extending through at least a portion of the configuration of the sheet member. 18. The device of claim 17, wherein the rigid structural support makes contact with a second edge of the sheet member said second edge is opposite the edge having the microprotrusions.