KR100500204B1 - Device and method for enhancing transdermal sampling - Google Patents

Abstract

Transdermal formulation sampling devices and methods are provided (10, 88, 98, 104). The apparatus comprises a collector 26, 90, 106 and a sheet 6 having a plurality of microblades which penetrate the skin to increase the transdermal flow of the preparation.

Description

      DEVICE AND METHOD FOR ENHANCING TRANSDERMAL SAMPLING}

The present invention relates to transdermal formulation sampling. More specifically, the present invention relates to transdermal sampling of agents such as glucose, electrolytes, and not limited to abuse substances such as alcohols and illegal drugs. The present invention utilizes a microblade that penetrates the skin to enhance the transdermal flux of the formulation during transdermal sampling.

There is a growing interest in transdermal sampling of formulations. Nevertheless, transdermal sampling of such formulations faces significant problems. In many cases, the flow of the agent through the skin is insufficient to quickly and accurately calculate the concentration of blood or substances in the human body.

One method of enhancing transdermal sampling of formulations relies on the application or “electrotransport” of current across the human epidermis. In general, "electrotransportation" refers to the transport of an agent through the human epidermis, such as skin, mucous membranes, nails and the like. The transport of this agent is induced or enhanced by the application of a potential, which generates a current to sample or to improve the sampling of the agent. Electrophoresis of the preparation through the human epidermis can be accomplished in a number of ways. One widely used electrotransportation method, iontophoresis, involves the movement of electroinduced charged ions. Another type of electrotransportation method, electroosmosis, involves the movement of the agent and the solvent through the membrane under the influence of an electric field. In addition, another type of electrotransportation method, electroporation, involves the transport of a formulation through pores formed by applying a high voltage electric pulse to the membrane. In many cases, one or more of these methods may occur simultaneously to different degrees. Increasing the transdermal sampling rate is required.

One method of improving formulation transdermal sampling rates involves pretreatment of the skin with a skin penetration enhancer. Here, the term "permeation enhancer" is widely used to describe substances which enhance the transdermal flow when the agent is applied to the human epidermis to be sampled. This mechanism may involve increasing the permeability of the human epidermis, or reducing the electrical resistance of the human epidermis to the movement of the agent through the human epidermis during electrotransport sampling, and / or forming a hydrophilic pathway through the human epidermis during electrotransport. It may be.

Many attempts have been made to mechanically puncture the skin prior to transdermal drug administration to improve transdermal flow. Examples include U.S. Patent 5,279,544 to Gross et al., U.S. Patent 5,250,023 to Lee et al. And U.S. Patent 3,964,482 to Gerstel et al. And WO 96/17648 published June 13, 1996. See. Although other forms of use are disclosed in Gerstel and WO 96/17648, in general, these devices use tubular or cylindrical structures to penetrate the outer layer of the skin for product delivery, but do not sample. Each of these devices causes manufacturing problems, limited mechanical adhesion of the structure to the skin, and / or undesirable skin pain.

As described above, in order to improve transdermal flow, various chemical and mechanical means have been studied. Nevertheless, there is still a need to provide a device that is suitable for increasing transdermal flow, which can be mass produced at low cost and reproducibly (ie without significant differences between devices).

1 is a schematic cross-sectional view of a sampling system according to an embodiment of the present invention.

2 is an enlarged perspective view of the skin base side of a microblade array device that may be used in the present invention.

3 is a schematic explanatory diagram of a method of manufacturing a microblade array used in the present invention.

4 is a schematic cross-sectional view of a manual formulation sampling system according to one embodiment of the invention.

5 is a schematic cross-sectional view of another embodiment of a manual formulation sampling system according to the present invention.

6 is an enlarged perspective view of one embodiment of a "reverse" electrocarrier formulation sampling system with a blade array in accordance with an embodiment of the present invention.

FIG. 7 is a bottom view of the “reverse” electrocarrier formulation sampling system of FIG. 6.

FIG. 8 is a right front view of the “reverse” electrocarrier formulation sampling system of FIG. 6.

FIG. 9 is a back side view of the “reverse” electrocarrier formulation sampling system of FIG. 6.

10 is a cross-sectional view taken along line 10-10 of the assembled “reverse” electrocarrier formulation sampling system of FIG. 8.

The present invention provides a reproducible, mass productive, low cost equipment suitable for increasing transdermal flow for formulation sampling and monitoring. The present invention includes a plurality of microblades that penetrate the skin. This microblade is typically less than about 0.5 mm long and has a smaller width and thickness. Despite this small size, the microblades can be formed in a very reproducible size and shape so that the microslit formed by the microblades that puncture the skin can also have a very reproducible size and shape. Because this microblade has a small thickness (ie, smaller than the width and length of the blade), this microblade has less tissue damage for a given cross section than skin penetrating microneedles having a circular cross section. The device of the present invention penetrates the stratum corneum of the human epidermis to form a route through which the formulation (eg, human electrolyte) can be taken out (ie, sampled or monitored).

According to one aspect of the invention, the apparatus comprises a sheet with a plurality of microblades integrally extending downwards and a collector on the top of the sheet for collecting the agent taken out through the path of the skin formed by the microblade. It is provided. The device of the present invention may be used with sampling of analyte or drug, or both. Collectors (ie, sampling devices) for use in the present invention include, but are not limited to, "reverse" electric transport devices disclosed in US Pat. No. 5,279,543 to Glikfeld et al. And US Pat. No. 5,362,307 to Guy et al., US Pat. Manual diffusion devices disclosed in, but not limited to, osmotic devices and negative pressure driving devices disclosed in U.S. Patent No. 4,756,314 to Eckenhoff et al.

Hereinafter, referring specifically to the drawings, an embodiment of the sampling apparatus of the present invention is shown in FIG. 1 shows an osmotic collector or sampling device 104 associated with a microblade array member 2 that penetrates the skin. This osmotic collector 104 is attached to the human epidermis by an opaque flexible adhesive overlay 100. The collector 104 consists of an absorbent pad 106 (infused with an osmotic active material, such as a high soluble salt), positioned between the semipermeable or osmotic membrane 94 and the optional agent detector 108. The semipermeable membrane 94 is permeable to the water and preparation to be collected and is opaque to the osmotic active material. Osmotic membranes are well known in the art as various natural and artificial semipermeable membranes. Suitable membranes can be illustrated in turn from US Pat. Nos. 3,845,770, 3,916,899, 4,077,407, and 4,014,334, all of which are incorporated herein by reference.

The pad 106 is passed through an osmotic agent that is not sufficiently fused so that the concentration of the solution formed as a result of the absorption of water through the semipermeable membrane 94 in the collection pad is maintained at the saturation level over the intended sampling period. It is preferable to disperse. In addition, the pad 106 may be collected, such as silica colloids, ion exchange resins, activated charcoal, or a substance that can be selectively attached to the formulation to be collected to prevent back diffusion of the formulation through the membrane 94. It may be included by dispersing the substance.

The optional agent detector may be a variety of chemical reaction sensors and reaction indicators, and may be, for example, color reaction indicator test strips related to glucose testing. The adhesive overlay 100 may have an incision or transparent window in the area of the indicator to facilitate viewing of the indicator. In an alternative embodiment, the agent detector may be located between the member 2 and the pad 106. Alternatively, the pad 106 and the osmosis membrane 94 can be integrated into one absorbent hydrogel layer that stores the absorbed fluid as well as the formulation. Preferably, the pad 106 is free of expansion or encapsulated in a semipermeable membrane or an osmotic membrane 94 to accommodate the fluid therein.

The member 2 is used in connection with the transdermal sampling of the formulation. Here, the term "sampling" is used broadly to include the withdrawal of an agent or monitoring the presence or amount of an agent. Here, the terms "material" and "formulation" are used interchangeably and broadly include substances that can be sampled through the skin, such as glucose, human electrolytes, alcohols, illegal drugs, legal drugs, pharmaceuticals, blood gases, and the like. do. The major barrier properties of the skin, such as resistance to formulation transport, depend on the outermost layer (ie, the stratum corneum). In general, the inner compartment of the shell consists of three layers, commonly referred to as granule layer, stratum malpighii and stratum germinativum. There is little or no resistance to the movement of the formulation through its granular, maldermal and embryonic layers. The device of the present invention is used to form microslits in the stratum corneum for in situ sampling of the formulation.

The member 2 has a plurality of microblades 4 (ie blade arrays) extending downward from one surface of the sheet 6 (in a position where a part of the member 2 is inverted to show the microblades. See FIG. 2). The microblade 4 is formed in a dimension and shape that penetrates the stratum corneum of the envelope when pressure is applied to the device but does not penetrate the skin in sufficient contact with the nerve endings of the patient. With this configuration, the microblade does not cause painful pain or bleeding. The microblade 4 forms a microslit on the human epidermis to increase the sampling of substances through the human epidermis. The term “human epidermis” as used herein generally refers to the skin of an animal or human. The arrangement of the member 2 in combination with the sampling system on the patient's human epidermis allows for in-situ sampling and monitoring without relying on taking blood or samples with syringes and needles or lances and test strips. . In one preferred embodiment, the device is designed to monitor glucose levels in diabetic patients. In the case of preparation (eg human electrolyte) sampling, the electrolyte travels from the human body through the microslit of the stratum corneum cut by the microblade 4. The sampled preparation may be taken directly from the skin, or the preparation may be contained in interstitial fluid and / or perspiration of the patient, and the perspiration of the patient may be taken for the purpose of sampling the preparation.

In one embodiment, the opening 8 corresponds to the portion of the sheet 6 occupied by each microblade before the blade is displaced to the suspended position. In the embodiment shown (FIGS. 2 and 3), the sheet 6 is formed with an opening 8 between the microblades 4. This opening 8 corresponds to a portion of the sheet 6 occupied by each microblade 4 before the microblade is bent to a position substantially perpendicular to the plane of the sheet 6. The number of openings 8 per device and the number of microblades 4 per device are independent of each other. The device may have only one large opening 8 with a plurality of microblades 4 arranged around it. As described below, the opening 8 may be covered with a formulation ejection member to enhance the movement of the formulation sampled into the formulation collection vessel past the electrode.

In general, the microblade 4 is formed of one material (not necessarily) and is at least sharp and long enough to penetrate the stratum corneum of the human epidermis. In one embodiment, this microblade 4 and sheet 6 are opaque or nearly opaque to the movement of the formulation. The width of each microblade can be any range of widths. Typically, the width of this microblade is in the range of about 25 μm to 500 μm. The length of the microblade is affected by changes in the human epidermis to be penetrated and corresponds to the normal thickness of the stratum corneum. It is usually about 20 μm to 400 μm in length. The microblade 4 may have an inclined (ie angled) tip 64 (see FIG. 2) to further reduce the insertion force required to press the microblade 4 into the human epidermis. The tips 64 of each microblade may all be at the same angle or at different angles as appropriate to penetrate the human epidermis. The tip may have several fragments with the end segment having a smaller angle with respect to the axis along the length of the microblade than the closer segment. Alternatively, the tip of each microblade may be arcuate (ie curved), for example with an uneven shape.

In addition, the member 2 may improve the adhesion of the device to the human epidermis, such that continuous formulation detection through the human epidermis is maintained during the movement of the human epidermis. In the embodiment shown in FIG. 2, protrusions in the form of barbs 50 on one or more microblades 4 secure the member 2 and any corresponding device or structure used in connection therewith to the human body. To assist. Barb 50 may be present on any number of microblades, from one microblade to all microblades. This barb 50 is optional and other means of supporting the member in contact with the human epidermis may be used. The present invention may be used in combination with various types of microblade configurations, see, for example, WO 97/48440 published December 24, 1997, any of which are disclosed herein. It can be used in the invention.

The pattern for any of the microblade array members 2 of the present invention can be produced by a photo etching process. For example, reference may be made to US Provisional Application No. 60 / 019,990, filed June 18, 1996, and any of the methods disclosed herein may be used to make the member (2) of the present invention. The thin metal sheet 6, such as stainless steel or titanium steel, is etched by photolithography in a pattern having a structure that penetrates the skin. Generally, a thin sheet dry resist or a wet resist is applied on top of the sheet 6 having a thickness of usually about 7 μm to about 100 μm, preferably about 25 μm to 50 μm. This resist is developed after contact and exposure using a mask having a desired pattern. These processes are carried out in the same manner as the manufacturing for printed circuit boards. Thereafter, the sheet 6 is etched using an acidic solution. After the pattern is etched over the sheet, the sheet 6 is disposed on the die 52 having a plurality of openings 56 corresponding to the sheet openings 8. Initially, a punch 54 having a plurality of protrusions 58 corresponding to the opening 8 of the sheet 6 and the opening 56 on the die 52, on the sheet 6 and the die 52. ) Is located. In this initial stage, the microblade 4 is coplanar with the rest of the sheet 6. Thereafter, the punch protrusions 58 are pressed into the openings 8 so that the microblades are bent to be almost perpendicular to the plane of the sheet 6. The final structure has a microblade 4 with an adjacent opening 8. In one embodiment, this opening 8 allows passage of the interstitial fluid through it when the member 2 is attached to the human epidermis. Although the rectangular opening 8 is shown in the figures, the invention is not so limited, but includes the use of any type of opening, including squares, triangles, circles and ellipses.

Generally, the microblade 4 is at an angle of about 90 ° to the surface of the sheet 6 (FIG. 2) after being drilled, but in a vertical position, which can facilitate passage of the human epidermis and attachment to the human epidermis May be arranged at any angle from the front to the back. In addition, other fastening members such as barbs, openings, and the like can be used for the inclined microblades to further improve the fastening of the device.

Optionally, member 2 may be attached to the human epidermis of the patient by a variety of means, including adhesive applied to the surface of the sheet 6 in contact with the human body or other fastening members on the members of any other embodiment discussed herein. have. In addition, a watch band or elastic bandage may be used to keep the device in contact with the skin. The adhesive should have sufficient viscosity to allow for easy removal after a period of wear (eg, 24 hours) while the member 2 remains in place on the human epidermis during normal user activity. Preferably, a suitable release liner is provided to maintain the integrity of the adhesive prior to use. In use, this separation liner is peeled off the adhesive before the device is attached to the skin.

As well shown in FIG. 2, the microblade 4 has a thickness smaller than the width of the blade near its base, ie near the point where the blade is attached to the seat 6. This geometry of the blades provides the largest drug percolation area with minimal blade penetration area. The formulation percolation area is a micro slit opening area smaller than the cross-sectional area of the blade, formed in the stratum corneum by the blade. The microblades are shaped with the largest possible surface area in the smallest cross-sectional area to provide the maximum possible percolation area. To this end, thin microblades are better than round protrusions because thin blades for the same cross section have less tissue damage and create more percolation area than round protrusions. This is a major advantage over conventional round members such as needles or tubes. Thinner microblades also require less insertion force than round protrusions. Each blade width may be any range of widths. The width may vary from blade to blade in the array pattern. Similarly, the width may vary depending on the length of the blade, as described in more detail below. After the blade array is inserted, the blade width at the intersection of the blade and the human epidermis is preferably about 25 μm to 500 μm, more preferably about 50 μm to about 400 μm, most preferably about 100 μm to 300 μm. Do.

The sheet 6 and the microblade 4 can be made of a material having strength and productivity sufficient to produce blades, such as glass, ceramics, rigid polymers, metals and metal alloys. Examples of metals and metal alloys are stainless steel, iron, steel, tin, zinc, copper, platinum, aluminum, germanium, nickel, zirconium, titanium alloys consisting of titanium and nickel, molybdenum and chromium, nickel, gold, rhodium And metals plated with titanium, platinum, and the like, but are not limited thereto. Examples of glass include opaque glass, such as "PHOTOCERAM" available from Corning, Inc., Corning, NY. Examples of polymers include polystyrene, polymethacrylate, polypropylene, polyethylene, "BAKELITE", cellulose acetate, ethyl cellulose, styrene / acrylonitrile copolymers, styrene / butadiene copolymers, acrylo Rigid polymers such as, but not limited to, nitrile / butadiene / styrene (ABS) copolymers, polyvinyl chloride, and acrylic acid polymers containing polyacrylates and polymethacrylates.

The number of microblades 4 and openings 8 of the embodiment of the optional member 2 can be determined by the desired flow rate, the agent to be sampled, the sampling device used (ie reverse electrophoresis, passive diffusion, osmotic pressure, suction, etc.), And other factors apparent to those skilled in the art. In general, the larger the number of blades per unit area (i.e. blade density), the more distribution of the formulation flows through the skin, since there are more formulation routes through the skin. Thus, the smaller the number of blades per unit area, the less the path, and the more concentrated the flow of the formulation through the skin. The present invention has a blade density of at least about 10 blades / cm ² and less than about 1000 blades / cm ² , preferably at least 600 blades / cm ² , more preferably at least 800 blades / cm ² . Similarly, the number of openings per unit area of the agent is passed, at from about 10 apertures / cm ^2, greater than about 1000 openings / cm ² under. In one embodiment, the present invention represents a percolation area of about 0.005 to 0.05 [cm ² / cm ^2] of the human skin, preferably, from about 0.01 [cm ² / cm ^2] of the human body skin.

In another embodiment of the present invention, the member 2 is used in a manual transdermal sampling device. Examples of two passive transdermal sampling devices are shown in FIGS. 4 and 5. The passive transdermal sampling device 88 in FIG. 4 preferably comprises a reservoir 90 sandwiched between a backing layer 92 and a wicking membrane 94 that are opaque to the formulation. In FIG. 4, the reservoir 90 is formed of a material having sufficient viscosity to maintain its shape, such as a rubber polymer. If a low viscosity material, such as an aqueous gel, is used for this reservoir 90, the backing layer 92 and the wick 94 will be sealed together around their rim to prevent leakage. The microblade array member 2 is located below the membrane 94. The device 88 is adhered to the human epidermis by a contact adhesive layer 96 around the rim of the member 2. Strip-shaped separation liners (not shown) are typically provided along the exposed surface of the adhesive layer 96 and removed prior to attaching the device 88 to the human epidermis.

Optionally, as shown in FIG. 5, the transdermal sampling device 98 may be attached to the human epidermis by a flexible adhesive overlay 100. Device 98 has an opaque backing layer 102 adjacent to one surface of reservoir 90. The adhesive overlay 100 supports the device 98 on the human epidermis. The adhesive overlay 100 may be made with the remaining members of the device 98, or may be provided separately. In some configurations, this adhesive overlay 100 may be preferred to the contact adhesive 96 shown in FIG. 4. This is the case, for example, when the formulation reservoir comprises a material that adversely affects the adhesion of the contact adhesive layer 96 (eg, such as an oily surfactant osmotic agent). The opaque backing layer 102 is slightly larger than the reservoir 90, thus preventing the agent collected in the reservoir 90 from mutually adversely affecting the adhesive in the overlay 100. A wick (not shown in FIG. 5) similar to the membrane 94 (shown in FIG. 4) of the device 88 is located on the skin / mucosa surface of the reservoir 90. In addition, strip-shaped separation liners (not shown) are typically provided in the device 98 and are removed just prior to attaching the device 98 to the human epidermis.

One embodiment of the present invention relies on the application or “electrical transport” of current across the human epidermis. In general, this electrotransportation refers to the passage of an agent through the human epidermis, such as skin, mucous membranes, nails and the like. Delivery of the agent is induced or enhanced by the application of a potential, which causes the application of an electric current, which results in sampling or enhancing the sampling of the agent for "reverse" electrotransport. Electrophoresis of the preparation from the skin can be accomplished in a number of ways. One widely used electrotransportation method, ion permeation, involves the electrophoretic transport of charged ions. Another type of electrotransportation method (e.g., transdermal sampling of glucose), which involves transdermal delivery of uncharged or neutrally charged molecules, allows the movement of agents and solvents through the membrane under the influence of an electric field. Entails. Another type of electrotransportation, electroporation, involves the passage of an agent through pores formed by applying electrical pulses, high voltage pulses to the skin. In many cases, one or more of these methods may be performed to different degrees at the same time. Thus, the term “electrotransport” herein, as broadly as possible, encompasses the electrically induced or enhanced delivery of one or more charged or uncharged agents, or mixtures thereof, regardless of the particular mechanism that actually delivers the agent. Should be interpreted.

The present invention can be used in combination with various electrical transport systems, and the present invention is not limited in this regard. As an example of an electrocarrying drug sampling system, reference may be made to US Pat. No. 5,279,543 to Glifeld et al. And US Pat. No. 5,362,307 to Guy et al.

In general, an electrical transport device uses two or more electrodes in electrical contact with skin, nails, mucous membranes, or other parts of the human epidermis. In the case of transdermal preparation sampling, one of the two electrodes is referred to as the "receiving" electrode, and is the electrode from which the preparation (eg, human body material) is collected after being taken out of the human body. Typically, the second electrode is referred to as a "counter" or "return" electrode and is provided close to the electrical circuit through the human body. For example, if the agent to be sampled is a cation, the cathode is the receiving electrode, but the anode is provided to complete the circuit. If the agent to be sampled is an anion, the anode becomes the receiving electrode, while the cathode is provided to complete the circuit. If the agent to be sampled does not have a net charge (eg glucose), either the anode or the cathode, or both electrodes are provided as the receiving electrode.

6-10 show representative reverse electrocarrier sampling devices 10 that can be used in conjunction with the present invention.

The device 10 includes an upper housing 16, a circuit board assembly 18, a lower housing 20, a first electrode 22, a second electrode 24, an electrically conductive gel reservoir 26, an electrically conductive gel. Reservoir 28 and skin-friendly adhesive 30. The upper housing 16 has side wings 15 to assist in securing the device 10 on the patient skin. The printed circuit board assembly 18 includes a separate component 40 and an integrated circuit 19 connected to the battery 32. The circuit board assembly 18 is attached to the housing 16 by a pillar (not shown in FIG. 1) passing through the openings 13a and 13b, the end of which being connected to the circuit board assembly 18 by the housing 16. Heat / melt to heat-fix). The lower housing 20 is attached to the upper housing 16 by an adhesive layer 30, and the upper surface 34 of the adhesive layer 30 comprises the bottom surface of the wing 15, so that the lower housing 20 And upper housing 34. Shown (partly) on the side of the circuit board assembly 18 is a button cell battery 32. In addition, other types of batteries may be used in the power supply 10 as needed.

Typically, device 10 includes a battery 32, electronics 19, 40, electrodes 22, 24, conductive gel reservoirs 26, 28, and device 2, all of which are Can be integrated into a standalone device. The output (not shown in FIG. 1) of the circuit board assembly 18 is through the openings 23, 23 ′ in the recesses 25, 25 ′ formed in the lower housing 20 through the electrically conductive adhesive strips 42, 42. Is in electrical contact with the electrodes 24 and 22. Next, the electrodes 22 and 24 are in direct mechanical and electrical contact with the top surfaces 44 ′, 44 of the conductive gel reservoirs 26 and 28. The bottom surface 46 of the conductive gel reservoir 28 contacts the patient skin through the plurality of openings 29 of the device 2. The bottom surface 46 ′ of the conductive gel reservoir 26 contacts the patient skin through the opening 8 of the adhesive layer 30. The gel in the reservoir 26 is preferably a viscous gel that fills the opening 8 so that the gel contacts the skin when the blades penetrate the stratum corneum. Contact between the gel and the skin provides a route to the formulation to be delivered. If the gel does not initially come in direct contact with the skin, sweat typically accumulates in a defined area, providing a route for delivery of the formulation from the skin.

Optionally, the device 10 has a form that allows a patient to perform a sampling or monitoring procedure by themselves. Upon the push of the push button switch 12, the electronic circuit on the circuit board assembly 18 applies a predetermined DC current to the electrodes / stores 22, 26 and 24, 28 for a predetermined length of sampling period. The push button switch 12 can be suitably positioned on the top surface of the device 10 and is easily manipulated through the clothing. Short presses, for example, two-stage presses of the push button switch 12 within three seconds, are used to activate the device for a sampling or monitoring procedure, thereby minimizing the possibility of unintended activation of the device 10. . Preferably, the device conveys an audible or audiovisual confirmation of the start of the sampling interval to the user by means of a glowing LED 14 and / or an audible acoustic signal, for example from a "beeper". The formulation is taken out, for example, through the skin of the patient's arm by electrotransmission over a predetermined sampling interval.

The push button switch 12, the electronics on the circuit board assembly 18 and the battery 32 are adhesively "sealed" between the upper housing 16 and the lower housing 20. The upper housing 16 preferably consists of rubber or other elastomeric material, for example injection moldable ethylene vinyl acetate. The lower housing 20 is made of plastic or elastomeric sheet material (eg, polyethylene), which can be easily shaped to form recesses 25, 25 ′ and cut to form openings 23, 23 ′. It is preferable to make. The assembled device 10 preferably has water resistance (ie, anti-fog), and most preferably waterproof. The system has a low profile that is easily adapted to the human body to allow free movement at and around the wearing point. The reservoirs 26 and 28 are located on the skin contacting side of the device 10 and are sufficiently isolated to prevent accidental electrical shorts during normal operation and use.

The device 10 is attached to the human epidermis (eg, volume) of the patient by an adhesive layer 30 (having an upper adhesive face 34 and a human contact adhesive face 36). The adhesive surface 36 covers the entire lower surface of the device 10 except for the portion where the device 2 and the reservoir 28 are located. The adhesive surface 36 has adhesive properties that allow the device 10 to remain in place on the human body during normal user activity and to allow for proper removal after a predetermined wearing period (eg, 24 hours). An upper adhesive surface 34 is attached to the lower housing 20 to hold the electrode and gel reservoir in the housing recesses 25, 25 ′ as well as to hold the device 2 to the lower housing 20, the lower housing 20. ) In the upper housing 16. In one embodiment of the sampling device, there is a separate liner (not shown) on the device 10 to maintain the integrity of the device when not in use. In use, this separation liner is peeled off the device prior to attaching the device to the skin.

In general, the preferred form in which the formulation is sampled determines the type of sampling system used. That is, the choice of an electromotor system that samples the formulation by electrophoresis or a "manual" system in which the formulation is sampled by diffusion will usually be determined by the type of formulation. In osmotic systems in which the agent is sampled by convection carried by the solvent, it is preferred that the formulation has sufficient solubility in the carrier solvent. In this case, the present invention is not limited to a specific device, and the present invention may be used in combination with various various osmotic sampling systems. For example, osmotic devices are disclosed in US Pat. No. 4,756,314 to Eckenhoff et al., US Pat. No. 4,655,766 to Theeuwes et al. And US Pat. No. 4,753,651 to Eckenhoff. As described above, the member 2 of the present invention can be used with, but not limited to, known sampling devices including reverse iontophoresis, osmotic pressure, passive diffusion, phonophoresis and suction (ie, negative pressure). Do not.

It will be apparent to those skilled in the art that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. Accordingly, the embodiments disclosed herein are to be considered in all respects as illustrative and not restrictive. The scope of the present invention is defined by the appended claims rather than the foregoing description, and is intended to cover all modifications falling within the scope and range of equivalents thereof.

Claims (8)

As a device (10, 88, 98, 104) penetrating the stratum corneum of the human epidermis, to form a passageway through which the agent can be taken out A sheet 6 having a plurality of microblades 4 extending downward; And On top of the sheet 6, there are collectors 26, 90, 106 for taking the agent out through the passage, The apparatus further comprises a formulation detecting unit for instructing a response to the formulation taken out through the formed passageway, the device that penetrates the stratum corneum of the human epidermis. The method of claim 1, The collector (26, 90, 106) is characterized in that it is positioned to sample the preparation from the human epidermis through the opening (8) of the sheet, the device penetrating the stratum corneum of the human epidermis. The method of claim 1, The collector is a reverse electrotransport (10), characterized in that the penetrating the stratum corneum of the human epidermis. The method of claim 1, And the collector is a passive diffusion device (88, 98). The method of claim 1, And the collector is an osmotic device (104). The method of claim 1, The collector, A semipermeable membrane 94 positioned across the opening 8 of the sheet 6; And And an absorbent pad (106) on said semipermeable membrane (94). The method of claim 6, The absorbent pad (106) is a device for penetrating the stratum corneum of the human epidermis, characterized in that it contains an osmotic active material. The method of claim 1, The agent detecting unit (108) is a glucose sensor, characterized in that penetrating the stratum corneum of the human epidermis.