KR20000016696A - Device for enhancing transdermal agent delivery or sampling - Google Patents

Abstract

PURPOSE: Disclosed is a percutaneous agent delivery or sampling device for piercing and anchoring to the skin for increasing transdermal flux of an agent and for improving the attachment of the device to the skin. CONSTITUTION: The percutaneous agent delivery or sampling device (10, 88, 98, 104) comprising a sheet (6) having a plurality of micro blades (4) for piercing and anchoring to the skin for increasing transdermal flux of an agent and for improving the attachment of the device (10, 88, 98, 104) to the skin. The device comprises a sheet (6) having at least one opening (8) there through and a plurality of blades (4) extending downward therefrom, and an anchoring means for anchoring the device (2) to the body surface

Description

Apparatus for Enhancing Transdermal Formulation or Sampling

As more and more, medically useful peptides and proteins become available in large quantities and in tablet form, there is a growing interest in percutaneous or transdermal administration of peptides and proteins into the human body. have. However, transdermal administration of peptides and proteins still faces serious problems. In many cases, because the polypeptide is attached to the skin, the flux or dosage of the polypeptide through the skin is not sufficient to achieve the desired therapeutic effect. In addition, peptides and proteins are easily lost during and after skin penetration, even before reaching the target cell. Likewise, the passive flux of small water soluble molecules, such as salts, is limited.

One method of enhancing transdermal administration of a formulation relies on the application of electric current or electrotransport to the human epidermis. In general, "electrotransportation" means the transfer of useful agents, such as drugs or drug precursors, through the human epidermis, such as skin, mucous membranes, nails and the like. The application of the potential causes the transfer of the agent to be induced or facilitated, and the application of the potential induces an electrical current which in turn causes or facilitates the administration of the agent. Electrical delivery of the formulation through the human epidermis can be accomplished in a variety of ways. One widely used method of ion transport, iontophoresis, involves the electrophoretic transfer of charged ions. Another form of electrotransportation, electrooosmosis, involves the movement of the agent and the solvent through the membrane under the influence of an electric field. In addition, another form of electroporation, electroporation, involves the transfer of a formulation through a pore formed by applying a high voltage electric pulse to the membrane. In many cases, one or more of these processes may occur simultaneously to some degree. In general, electrotransfer administration enhances formulation administration, particularly high molecular weight (eg, polypeptide) dosages, compared to transdermal administration without manual or electrical assistance. However, during transdermal administration, increased transdermal dose and reduced polypeptide loss are highly desirable.

One method of increasing the transdermal dose of an agent involves pretreatment of the skin with a skin penetration enhancer or, alternatively, administering a useful formulation with a skin penetration enhancer. At this time, the term "penetration enhancer" is widely used to describe a substance that, when applied to the human epidermis to which the formulation is administered, enhances its electrical transport flux. The mechanism may be to reduce the electrical resistance of the human epidermis to the transport of the formulation, to increase the permeability of the human epidermis, to create a hydrophilic pathway through the human epidermis, and / or to reduce the loss of the formulation during electrical delivery (eg, loss by skin enzymes). ) May be included.

Many attempts have been made to increase transdermal flux by mechanically puncturing the skin prior to transdermal drug administration. See, for example, US Pat. No. 5,279,544 to Gross et al., US Pat. No. 5,250,023 to Lee et al. And US Pat. No. 3,964,482 to Gerstel et al. Gustel describes other forms of use, but in general, such devices use tubular or cylindrical structures to penetrate the outer layers of the skin. Each of these devices causes manufacturing difficulties, limited mechanical attachment of the structure to the skin, and / or undesirable skin pain.

As described above, various chemical and mechanical means have been studied to increase transdermal flux. However, there is still a need to provide a device suitable for increasing transdermal flux and to improve the skin adhesion of the device, which can be manufactured inexpensively and in large quantities reproducibly (ie, without significant change from device to device).

The present invention relates to transdermal agent delivery and sampling. In particular, the present invention relates to transdermal administration of agents such as peptides and proteins, as well as to transdermal sampling of agents such as glucose, human electrolytes, and abuse substances not limited to alcohol and illegal drugs. The present invention uses skin-piercing microblades and anchoring members to assist in securing the dosing or sampling device to the skin to increase the transdermal flux of the formulation during transdermal administration or sampling.

1 is an exploded perspective view of one embodiment of an electrical delivery agent dosage system having a blade array device in accordance with one embodiment of the present invention.

2 is an enlarged perspective view of a skin adjacent surface of the blade array device according to an embodiment of the present invention.

3 is a partial plan view of a blade array pattern according to an embodiment of the present invention for forming a blade having a fixing member.

4 is a partial plan view of another embodiment of the blade array pattern of FIG.

5 is an enlarged view of a blade portion of the blade array pattern of FIG.

Figure 6 is an enlarged view of the blade tip according to an embodiment of the present invention.

Figure 7 is an enlarged view of the blade tip according to another embodiment of the present invention.

8 illustrates a method of making a blade of the present invention from the blade array pattern of FIG.

9 is an enlarged cross-sectional view of an inclined blade according to an embodiment of the present invention.

10, 11 and 12 show yet another embodiment of a blade having a fixing member of the present invention.

13 is a right front view of another embodiment of a blade having a fastening member.

14 is an end view of the blade of FIG.

15 and 16 show another embodiment of a blade and a fastening member.

17 is a right front view of a blade with a securing member in accordance with one embodiment of the present invention.

18 is a sectional view taken along line 18-18 of FIG.

19 is a right front view of another embodiment of a blade having a fastening member.

20 is a partially enlarged plan view of another embodiment of a blade array pattern.

21 is a partially enlarged plan view of another embodiment of a blade array pattern.

FIG. 22 is a bottom view of the electrical delivery formulation administration system of FIG. 1.

FIG. 23 is a right front view of the electrical delivery formulation administration system of FIG. 1.

FIG. 24 is a rear view of the electrical delivery formulation administration system of FIG. 1.

FIG. 25 is a cross-sectional view taken along lines 25-25 of the assembled electric delivery agent dosage system of FIG. 23.

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

Figure 27 is a schematic cross-sectional view of another embodiment of a manual formulation administration system according to one embodiment of the present invention.

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

29 is a schematic cross-sectional view of another embodiment of a blade of the present invention.

Mode for carrying out the invention

Referring now to the drawings in detail, one embodiment of the device 2 of the present invention for use in an electrophoretic dosing device 10 is shown in FIG. 1. The device 2 is used for transdermal administration or sampling of the formulation. The terms "substance", "agent" and drug "are interchangeable herein and refer to birds, pets, sport or farm animals, humans and primates. It includes a wide range of physiologically or pharmacologically active substances which induce local or systemic effects or effects in a mammal, or which are administered to experimental animals such as mice, rats, guinea pigs, etc. The terms include substances that can be sampled through the skin, such as glucose, electrolytes, alcohols, illegal drugs, etc. The main barrier properties of the skin, such as resistance to drug penetration, are in the stratum corneum.In general, the inside of the epidermis The part consists of three layers, usually called granular layer, maldermal layer, and embryonic layer. Substantial resistance to penetration through the underlying granular, maldermal, and embryonic layers for drug absorption and circulation into the body is reduced The device of the present invention forms micro slits in the stratum corneum and transdermal administration or sampling of the formulation. It is used to form an osmotic area in the skin to enhance the skin.

The apparatus 2 comprises a plurality of microblades 4 (ie blade arrays) extending downward from one surface of the sheet or plate 6 (position where the apparatus 2 is inverted to represent the microblades). See FIG. 2). Microblade 4 penetrates the stratum corneum of the epithelium when pressure is applied to the device, thereby increasing the administration or sampling of the substance through the human epidermis. Here, the term "human epidermis" generally refers to the skin, mucous membranes, and nails of animals or humans, and the skin of plants.

In addition, the device 2 of the present invention improves the skin adhesion of the device so that the osmotic area and the continuous path can be maintained even while the human epidermis is moving. In the embodiment shown in FIG. 2, protrusions in the form of barbs 50 on one or more blades 4 help to secure the device 2 and any corresponding device or structure used with the device to the skin. . Barb 50 can be formed on any number of blades, from one blade to all blades. Hereinafter, another embodiment will be described that helps to secure the device to the skin.

In general, the microblade 4 is formed of one material and is sharp and long enough to penetrate the stratum corneum of the skin. In one embodiment, the microblades 4 and the sheet 6 are opaque or necessarily impermeable to the formulation route. The sheet 6 is formed to have an opening 8 between the microblades 4 to increase the movement of the formulation. When a therapeutic agent (e.g., a drug) is administered, the drug is released from the reservoir storing the drug (not shown in Figure 2) through the microslit formed by the microblade 4 penetrating the stratum corneum, The drug is transported down the outer surface of the microblade and through the stratum corneum to achieve local or systemic treatment. When sampling the formulation (eg, human analyte), the analyte is transported from the human body through the microslit in the stratum corneum cut by the microblade 4. In one embodiment, the opening 8 corresponds to the portion of the sheet 6 occupied by each microblade 4 before the blade is displaced to the suspended position below. The number of microblades 4 per opening can be any number, but preferably between 1 and about 30 blades per opening. In addition, the number of openings per device and the number of blades per device are independent. This device may have only one opening and one microblade. The formulation can be administered at a controlled release from the reservoir via the formulation release controlling material (not shown) covering the opening 8.

As shown in FIG. 2, the microblade 4 has a thickness that is much smaller than the blade width near its base, ie near the point where the blade is attached to the plate 6. The geometry of this blade provides the smallest blade penetration area in the largest drug osmotic area, thereby reducing tissue damage. The drug osmotic area is the skin area in contact with the blade provided for drug penetration in the skin. The microblade is formed in such a way as to have the largest surface area possible with the smallest cross-sectional area in order to ensure the largest possible osmotic area. For the same cross section, thin microblades are superior to round protrusions for this purpose, because thin blades than round protrusions cause more osmotic area and less tissue damage. This is a decisive advantage over conventional round members such as needles and tubes. In addition, thinner blades require less insertion force than round protrusions. The width of each blade can be any of the widths in any range. The width may vary from blade to blade of the array pattern. As such, the width may vary depending on the length of the blade, which will be described in detail below.

After the blade is inserted, the blade width at the intersection of the blade and the human epidermis is preferably within the range of about 25 μm to about 500 μm, more preferably about 50 μm to about 400 μm, even more preferably about 100 It is the range of micrometers-300 micrometers.

In addition, in one embodiment, the slanted (ie angled) leading edge 64 is micro to further reduce the insertion force needed to press the microblade into the skin tissue. It is provided on the blade 4 (FIG. 5). The angle of the leading edge is indicated by α. The inclined leading edges cause cuts in the skin tissue equal to the full width of the blade 4 but reduce the amount of metal in the skin tissue. That is, a flat leading edge (ie, α is 90 °) results in a blade with a greater amount of blade material in the skin tissue than is produced by a blade with a slanted leading edge. The leading edges of each blade may all be the same or different angles as shown in FIG. 5. The angle α of each leading edge can be any angle between about 10 ° and 90 °, preferably between 10 ° and 60 °, more preferably between 10 ° and 40 °. In addition, the leading edge can be divided into two parts at different angles. For example, the first segment may have an angle α of between about 10 degrees and 40 degrees, and then transition to a second segment having an angle between 20 degrees and 60 degrees. In addition, the leading edge of each blade may be in the form of an arch (ie curved) having, for example, a convex or concave shape. In one embodiment, the leading edge is a curved tip over the entire width of the blade.

Hereinafter, the photoetching process for forming the microblade 4 will be described in detail.

This process allows the microblade 4 to be reproducibly formed in a very small (ie tens of microns) size. This process also allows the microblade 4 to be formed in a form that helps to secure the device 2 to the skin. In one embodiment, any form of barb 50 (FIGS. 2, 3, and 5) is applied to the microblade so that after application of pressure, the device 2 and any corresponding device attached thereto remain attached to the skin. 4) is provided. The degree of adhesion, and the number and size of barbs, is such that the dosing or sampling device is maintained while the wearer is in normal motion, but not causing pain upon removal. As the microblades are pressed into the skin tissue, the leading edge 64 of each microblade is pushed through the skin tissue. After the microblade stops in the skin, the elasticity causes the skin to return to its original state at least partially around the edge of the microblade, and in this way, the surface 66 on each microblade with the barb 50 becomes skin The tissue is bound to secure the device in the skin. If the blade is to remain in the skin for a long time (eg, 24 hours), the skin tissue will begin to heal in the area behind the barb surface 66, thus improving the fixability of the device. Although only one barb per blade is shown in the figures, each blade may have a plurality of barbs to which each blade extends. In one embodiment, the microblade has a wider cross section in the skin distal end region of the blade than in the proximal end region, thereby allowing more fixation of the distal skin to the skin. For example, the blade may have an "arrowhead" form. In addition, the barbs 50 shown in the figure are coplanar with the blades, but use some form of punch and die to form curves in the blades and barbs, or separate bending processes, for example. By this, the barb may be located outside the plane. In general, the tips of the blades in a curved shape outwardly of the blade surface provides better fixability. Inserting such a blade causes the barb to bend in a curved direction, but withdrawing the blade causes the barb to return to its previous position. The curved cross section of the final blade may be angled, semi-circular, C-shaped, or banana-shaped, but not limited to, to make the opening cross section larger in the skin.

The plurality of blades 4 penetrating the stratum corneum are in a predetermined arrangement, for example a set of blades arranged in any desired number of rows spaced apart, or one surface of the device 2 in a state spaced apart from one another ( 48). The device 2 of the embodiment shown in FIGS. 1 and 2 is produced by the pattern shown in FIG. 3. Each blade has a width and thickness that allows penetration of the stratum corneum without bending. In the embodiment of FIG. 3, there are six blades 4 in each opening 8 of the sheet 6. Each opening 8 in this embodiment is 1 mm long and 300 μm wide. Thus, the width of each blade is between about 137.5 μm and about 175 μm and the blade length is about 250 μm. Since one of the main features of the present invention is that the blade penetrates the stratum corneum and enters the epithelium, the required length of the blade is susceptible to changes in the human epidermis to be penetrated, which corresponds to the natural thickness of the stratum corneum. Typically, the length of the blade is from about 25 μm to about 400 μm, and in most devices the length is between about 50 μm and about 200 μm.

Patterns for all blade array devices of the present invention are produced by a photo etching process. Thin metal sheets or plates 6, such as stainless steel or titanium, are etched in a pattern comprising a blade-like structure using a photolithographic method. Generally, a thin laminated dry or wet resist is applied to the sheet at a thickness of about 7 μm to about 100 μm, preferably about 25 μm to about 50 μm thick. The resist is developed after exposure using a mask having a desired pattern. This is done in much the same way as manufacturing printed circuit boards. Thereafter, the sheet is etched using an acidic solution. After the pattern is etched in the sheet, the sheet is placed on a die 52 (shown schematically in FIG. 8) having a plurality of openings 56 corresponding to the openings 8 in the sheet. First, a punch 54 having a plurality of protrusions 58 corresponding to the openings in the sheet is placed on the sheet and the die. Initially, the blade 4 is coplanar with the rest of the seat 6. Then, the projection 58 on the punch 54 is pressed into the openings 56 to bend the blade 4 to be at an angle (eg, substantially right angle) below the sheet surface. When the device 2 is attached to the skin, adjacent openings 8 for material transport are provided in the blade 4 due to the final structure. Although rectangular openings 8 are shown in the figure, the present invention includes the use of any type of opening, including but not limited to square, triangle, circle and oval.

In order to relieve curls generated during punching and / or in some embodiments the sheet 6 becomes very stiff after punching, in order to provide flexibility in the dense blade array, some areas of the sheet 6 are subjected to extra etching. May have opened openings 80 (FIG. 4). The openings may be in any of a variety of forms (eg, rectangular, round, oval, triangular, etc.). In addition, the openings make the sheet more easily curved to match the curvature of the human epidermis to which the sheet is to be attached, thereby improving the fixability of the device. The present invention takes full advantage of the openings in the sheet, but has a sufficient number of horizontal and vertical continuous portions in the sheet so that the sheet does not become too flexible (ie, flimsy). If the openings are too long only in either direction, the sheet is likely to bend (wrink). It is also possible to treat the device with thermal or plastic deformation after punching so that the radius of curvature of the sheet is equal to or slightly smaller than the curvature of the human body to which it is attached to improve fixability. The concave surface may be formed to match the convex portion of the human body.

In order to obtain maximum pattern resolution for a constant sheet thickness, and to make a knife-like edge that cannot be achieved with conventional stamping and punching processes, the blades 4 are double-sided (48, 49) It is patterned with resist on it and then etched from both sides simultaneously (FIG. 7). In addition, the blade 4 may be patterned and then etched only from one side (ie face 49) (FIG. 6). When a blade is etched from only one side, it forms a single angle 60 at the blade tip to maximize the sharpness of the blade-like edge of the blade (eg For example, the etching process may be controlled so that the plate 6 is etched by a selective depth). In this embodiment, the lithographic process forms a blade portion thinner than the rest except for the thickness of the blade and sheet. In addition, this lithography process can also form very small members for the fixed and penetrating side of the present invention.

In another embodiment of the double sided etching process, the blade array pattern of any of the embodiments of the present invention is etched and placed on the upper surface 49 of the sheet 6. The second pattern, corresponding to the area bounded by each opening 8 (eg rectangular), is etched such that each blade in the blade array pattern is thinner than its surrounding sheet 6. Located on surface 48. Thus, the sheet 6 forms a strong base, and each blade is plastically made to make the blade 54 more straight and more substantially perpendicular to the sheet while the punch 54 deforms the blade 4 downward. Is deformed.

In one embodiment of the etching process, a dry resist (eg, “Dynachem FL” available from Dynachem, Tustin, Calif.) On one or both sides of the sheet is 12.5 μm. It is applied in a thickness and then exposed by standard methods. Next, a spray etcher suitable for spraying a mixture of ferric chloride and hydrochloric acid, for example, "Dynamil VRP 10 available from Western Tech. Assoc., Located in Anaheim, California. / NM "is used on the resist and sheet at 52 ° C. (125 ° F.) for 2 minutes. Standard caustic strippers are used for resist removal.

In another embodiment of the etching process, a wet resist (eg, “Shipley 111S” available from Shipley Corporation, Marlborough, MA) on one or both sides of the sheet is about 20 ° C. ( 70)) at a thickness of 7.5 μm and then exposed by standard methods. A suitable etchant (eg, ferric chloride) is then sprayed onto the resist and sheet at 49 ° C. (120 ° F.). Standard corrosive strippers are used for resist removal.

In general, after the blade 4 is punched, it forms an angle of about 90 ° to the surface 6 of the sheet 6, but is moved forward and backward from the vertical position, which can facilitate penetration of the stratum corneum and adhesion to the stratum corneum. It can be arranged at any angle. In one embodiment (FIG. 9), the blades are arranged at an angle between about 1 ° and about 89 °, so that the device slides easily along and into the skin, preferably between 10 ° and about 60 °, more preferably. Preferably at an angle between 20 ° and about 45 °. Beveled blades have two major advantages. First, unlike pressing vertically on the skin of the blade, it slides horizontally into the skin, so that the penetration of the blade is not subject to skin elasticity resistance. Second, since any movement of the skin is not easy to move the blade, the inclined blade serves to secure the device within the skin. In addition, other fastening members, such as barbs, openings, etc., may be used with the inclined blades to further improve the fastness of the device.

In one embodiment (FIG. 29), the surface 48 of the sheet 6 and the surface 82 of each blade 4 are coated with an adhesive to secure the device. One method of realizing this embodiment involves spraying the adhesive onto the device 2 along the direction indicated by the arrow 84. In this embodiment, the formulation passes freely through the opening 8 and along the surface 86 of each blade not blocked by the adhesive. It is also possible to apply the adhesive only on the sheet surface 48 and not on the blade surface 82. For example, this can be done by applying the adhesive on the surface 48 by spraying the adhesive in a direction parallel to the blade 82 axis after the blade 82 is punched. In addition, although this last form is the least preferred adhesive fixing means, it is also possible to apply the adhesive only on the blade surface 82 and not on the sheet 6 surface 48 to secure the device.

Sheets and blades can be made from materials having strength and manufacturability sufficient to produce blades such as glass, ceramics, hard polymers, metals and alloy metals. Examples of metals and alloy metals are titanium alloys consisting of stainless steel, iron, steel, tin, zinc, copper, platinum, aluminum, germanium, nickel, zirconium, titanium and nickel, molybdenum and chromium, nickel, gold, Rhodium, iridium, titanium, platinum, and the like, but is not limited thereto. Examples of glass include opaque glass such as “Photoceram” available from Corning, Inc., Corning, NY. Examples of hard polymers are polystyrene, polymethylmethacrylate, polypropylene, polyethylene, "Bakelite", cellulose, acetate, styrene / acrylonitrile copolymer, styrenebutadiene copolymer, acrylonitrile / butadiene / styrene (ABS) air Acrylic acid polymers including copolymers, polyacrylates and polymethacrylates and polyvinyl chloride.

A very dense pattern can be created in the unit cell, and as shown in FIG. 3, the unit cell has a width A and a length. In one embodiment (not shown), the pattern has the following characteristics: unit cell area of 0.63 mm x 3.8 mm; The line length of the cut in the unit cell is approximately 15 mm; And the open skin length per square centimeter is 625 mm.

The microblades of the present invention create long, thin, fine cuts (i.e. slits) on the skin surface because the blades have a small thickness (relative to width and length), thereby minimizing the cross-sectional area of the blade with respect to the blade portion in the skin. Due to the geometry of the microblade 4, the blade volume in the skin is minimal and the blade surface area in the skin is maximum. Advantages of the present invention are as follows: (1) the thin blade geometry creates a maximum drug osmotic area for a certain cross section of the blade; (2) minimal tissue damage occurs because the amount and volume of blade material in the skin is minimal; (3) Inclined leading edges (or equivalent pointed shapes) further minimize volumetric load or tissue damage while maintaining a wide osmotic area; (4) For a constant volume load, the greater the surface area, the greater the friction holding force of the skin; (5) Since fewer blades are needed for certain desired osmotic areas, this includes, but is not limited to, greater force on each tip to facilitate skin penetration.

In other embodiments (FIGS. 10-16), other fastening members are used in the present invention. In the embodiment shown in FIGS. 10-14, some or all of the blades 4 are etched, and as shown in FIGS. 10 and 14, the prongs 68 protrude outwards from each side of the blade. Lightly punched. After punching the prongs, the blades may be punched again to be in a substantially vertical orientation. Hinge 72 (FIG. 13) can be used to control the holding force of the barb for securing. Since the force required to bend or punch the prong is set by the shape or size of the hinge regardless of the size of the blade, the holding force can be adjusted by the hinge regardless of the size of the blade. In other words, the force can be controlled by the degree of attachment of the prongs to the plate, and the greater the degree of attachment, the greater the force.

If desired, prongs may protrude from one or both sides of the blade. Each prong can be of any of a variety of shapes, such as triangles and squares. In another embodiment, curved slits 70 (FIGS. 15 and 16) are made by etching and punching the slits of some or all of the blades. The prongs and curved protrusions serve to secure the device in the skin similar to the manner described above.

In another embodiment, other fastening members are used. In the embodiment of FIGS. 17-19, the blade 4 has an extra opening 74 extending through the blade to improve fixability. Edges forming holes or other linear openings are etched through the blades. Alternatively, or in addition, many small pit (ie, indentation) rather than holes may be etched at the surface of the blade. As described above, the elasticity of the skin tissue causes the skin to move to an opening or pit. In embodiments with openings, the skin tissue may be reconnected through the opening after healing, providing greater fixation.

In another embodiment (FIG. 20), the plurality of blades in the opening 8 is arranged at 90 ° relative to another plurality of blades in the opening 8 ′ to be fixed in two directions. In other words, the blades (not shown) associated with the opening 8 are located parallel to the edge 76 of the device 2, and the blades (not shown) associated with the opening 8 ′ are edges 78 of the device. Is located parallel to). The blades associated with each opening 8 can be positioned at any angle with respect to the blades associated with each opening 8 '. In addition, the blade in each opening may be in a direction along the vertical planes of the opening. Similarly, the blades in each opening may be formed in a serrated pattern as shown in FIG. This pattern allows the blades to be controllable and different from each other, defined by the angle of the punch used and the etch angle β of the pattern.

As will be apparent to those skilled in the art, the number of blades and openings in all embodiments of the present apparatus 2 can be determined by the desired flux, the formulation to be sampled or administered, the dosing or sampling device used (ie, electrophoretic, manual, osmotic, pressure driven, etc.). ), And other factors. In general, the greater the number of blades per unit area (ie blade density), the greater the number of formulation transport paths through the skin, resulting in more dispersion of the formulation flux through the skin. Thus, the fewer the blades per unit area, the fewer the paths, and the more concentrated the flux of the formulation through the skin. The present invention has a blade density of about 10 blades / cm ² or more and 1000 blades / cm ² or less, preferably about 600 blades / cm ² or more, more preferably about 800 blades / cm ² or more. Similarly, the number of openings per unit area through which the formulation passes is at least about 10 openings / cm ² and about 1000 openings / cm ² . In one embodiment, the present invention produces an osmotic region of about 0.005 to 0.05 cm ² / cm ^{2 in} the human epidermis, preferably an osmotic region of 0.01 cm ² / cm ^{2 in} the human epidermis.

One embodiment of the invention relies on energizing or "electrically carrying" the human epidermis. In general, electrotransportation refers to the transport of useful agents, such as drugs or drug precursors, through the human epidermis, such as skin, mucous membranes, nails and the like. The application of the potential results in or facilitates the transfer of the formulation, which in turn induces an electrical current to administer the formulation or facilitate the administration of the formulation, or to sample or enhance the sampling for "reverse" electrical delivery. Let's go. Electrical delivery of the formulation into the human body can be accomplished in a variety of ways. One widely used electroporation process, ion permeation therapy, involves the electrophoretic transfer of charged ions. Electropenetration, another form of the electrical transport process involved in the transdermal delivery of uncharged or neutrally charged molecules (eg, transdermal sampling of glucose), involves the movement of the agent and solvent through the membrane under the influence of an electric field. . Another form of electroporation electroporation involves the transfer of a formulation through an aperture formed by applying an electrical pulse, a high voltage pulse to a membrane. In many instances, one or more of these processes may occur to some degree simultaneously. Thus, the term "electric delivery" herein is the broadest possible interpretation involving the electrical induced or enhanced transfer of one or more charged or uncharged agents or mixtures thereof, regardless of the particular mechanism by which the agent is actually delivered. .

In this regard, the present invention is not limited in any way, so the present invention can be used with a wide variety of electric delivery drug administration systems. As examples of electric delivery drug administration systems, U.S. Patent No. 5,147,296 to Theeuwes et al., U.S. Patent No. 5,080,646 to Tuuwes et al., U.S. Patent No. 5,169,382 to Tuuwes et al. And U.S. See patent 5,169,383.

Generally, an electrical delivery device uses two or more electrodes in electrical contact with the skin, nails, mucous membranes, or other human epidermis. For transdermal formulation administration, one of the two electrodes is generally referred to as a "donor" or "active" electrode, and the other is the electrode through which the formulation is administered into the human body. For transdermal formulation sampling, one of the two electrodes is referred to as a "receptor" electrode and the other is the electrode to which the formulation (eg human electrolyte) aggregates when the formulation is extracted from the human body. Typically, the second electrode is referred to as a "counter" or "return" electrode and is used to connect electrical circuits in the human body. For example, if the agent to be administered is a cation, i.e. positively charged ions, the anode becomes the active or donor electrode, while the cathode is used to complete the circuit. Conversely, when the agent to be administered is anion, ie negatively charged ions, the cathode becomes the donor electrode. If the agent to be sampled is a cation, the cathode becomes the receptor electrode, while the anode is used to complete the circuit. If the agent to be sampled is an anion, the anode becomes the receptor electrode, while the cathode is used to complete the circuit. If the formulation to be sampled does not have any net charge (eg glucose), the positive or negative electrode, or both, can be used as the receptor electrode. When anionic and cationic agents are administered simultaneously, both the anode and the cathode may be donor electrodes. In general, an electrical delivery dosage system requires one or more formulation sources or reservoirs to be administered to the human body. Similarly, an electrical delivery sampling system requires one or more reservoirs to aggregate the formulation to be sampled. Examples of such reservoirs include, among other examples, pouches described in US Pat. No. 4,250,878 to Jacobsen et al., Osmotic sponges described in US Pat. No. 4,141,359 to cavity, Jacobson et al. Or pre-formed gel bodies described in US Pat. No. 4,383,529 to Pad and Webster et al. Such reservoirs are electrically connected to and positioned between the anode or cathode and the human epidermis, for example, to provide one or more drug sources that are fixed or replaceable when administering a formulation. In addition, the electrical delivery system includes an electrical power source, such as one or more batteries, and an electrical controller designed to adjust the timing, amplitude and / or frequency of the applied current, thereby adjusting the timing and speed of formulation administration / sampling. Adjust This power source component is electrically connected to two electrodes. Optional electrical delivery devices include counter reservoirs, adhesive coatings, insulating separation layers, and speed control membranes.

1 and 22-25 illustrate representative electrotransport dosing / sampling devices 10 that may be used with the present invention.

The device 10 includes an upper housing 16, a circuit board assembly 18, a lower housing 20, a positive electrode 22, a negative electrode 24, an anode reservoir 26, a cathode reservoir 28 and a skin. And a skin-compatible adhesive 30. The upper housing 16 has side wings 15 which help to secure the device 10 to the skin of the patient. The printed circuit board assembly 18 includes separate component members 40 and an integrated circuit connected to the battery 32. The circuit board assembly 18 is formed by posts (not shown in FIG. 1) passing through the openings 13a and 13b, that is, the heat of the posts to fix the circuit board assembly 18 to the housing 16. The end is attached to the housing 16 by receiving / recording heat. The lower housing 20 is attached to the upper housing 16 by an adhesive layer 30, wherein the upper surface 34 of the adhesive layer 30 comprises the upper housing 16 and the lower surface of the wing 15. All are bonded to the housing 20. The button cell battery 32 is shown (partially) at the bottom of the printed board assembly 18. In addition, other types of batteries may be used in the power device 10 as necessary.

In general, the device 10 consists of a battery 32, electrical circuits 19, 40, electrodes 22, 24, drug / receptor reservoir 26, counter reservoir 28, and device 2. All of which are integrated into a self-contained unit. The output of the circuit board assembly 18 (not shown in FIG. 1) is an opening 23 in the depressions 25, 25 ′ formed in the lower housing 20 by electrically conductive adhesive strips 42, 42 ′. 23 ', it is in electrical contact with the electrodes 24 and 22. The electrodes 22 and 24 are then in direct, mechanical and electrical contact with the top surfaces 44 'and 44 of the drug reservoirs 26 and 28. The bottom 46 of the drug reservoir 28 is in contact with the patient's skin through the opening 29 in the adhesive layer 30. The bottom 46 ′ of the drug reservoir 26 is in contact with the patient's skin through a plurality of openings in the device 2. The formulation of the reservoir 26 is preferably a tacky gel that fills the opening 8 so that the reservoir 26 is in direct contact with the skin as the blade penetrates the stratum corneum. Contact between the reservoir and the skin provides a route for the formulation to be delivered. If the reservoir 26 is not in direct contact with the skin, typically, initially, sweat accumulates within the restricted area and provides a route of agent transport between the reservoir 26 and the skin.

Optionally, the device 10 is characterized by allowing the patient to directly administer one dose of the drug or to sample the human electrolyte directly by electrical delivery. When the push button switch 12 is pressed, the electronic circuit on the circuit board assembly 18 transmits a predetermined DC current to the electrodes / stores 22, 26 and 24, 28 at predetermined length intervals. The push button switch 12 is conveniently located on the top surface of the device 10 and is easily driven through the clothing. It is desirable to press the push button switch 12 twice within a short time, for example 3 seconds, to drive the device, thereby minimizing the possibility of the device 10 being inadvertently driven. Using a suitable light signal such as an LED and / or an audible sound signal such as, for example, a "beeper", it is desirable to inform the user that the device has started visually and / or audibly. By electrical delivery at predetermined intervals, the formulation is administered / sampled through the patient's skin, eg, the patient's arm. The positive electrode 22 is preferably made of silver, and the negative electrode 24 is preferably made of silver chloride. The reservoirs 26 and 28 are preferably both composed of polymeric gel material. The electrodes 22, 24 and the reservoirs 26, 28 are carried by the lower housing 20.

When administering a therapeutic agent (ie a drug), a liquid drug solvent or suspension is included in at least one of the reservoirs 26 and 28. Drug concentrations ranging from about 1 × 10 ⁻⁴ M to 1.0 M or more may be used, but drug concentrations in the lower portion of the range are preferred.

The push button switch 12, the electronic circuit on the circuit board assembly 18 and the battery 32 are glued, “sealed” between the upper housing 16 and the lower housing 20. The upper housing 16 is preferably composed of rubber or other elastic material, for example injection molded ethylene vinyl acetate. The lower housing 20 is made of a plastic or elastic sheet material (eg, polyethylene) that can be easily cast to form depressions 25, 25 ′ and can be easily cut to form openings 23, 23 ′. It is preferred to be configured. The assembled device 10 is preferably water resistant (ie splash waterproof), most preferably waterproof. The system is formed in a low profile for easy registration with the human body, thereby freeing movement around and around the wearing point. The reservoirs 26 and 28 are located on the skin contacting surface of the device 10 and are sufficiently separated to prevent inadvertent electrical shorts during normal handling and use.

By means of an adhesive layer 30 (having an upper adhesive face 34 and a human body contact adhesive face 36) and a fixing member on the device 2 of any of the above-described embodiments, the device 10 is subjected to a patient. Is attached to the human epidermis (eg, skin). The adhesive surface 36 covers the entire lower surface of the device 10 except where the device 2 and the reservoir 28 are located. The adhesive surface 36 has an adhesive property that the device 10 remains in place on the human body while the user is moving normally, and can be properly removed after a predetermined (eg, 24 hour) attachment period. . The upper adhesive surface 34 is adhered to the lower housing 20 and not only keeps the electrodes and reservoir in the housing depressions 25, 25 ′, but also keeps the device 2 in the lower housing 20 and in the lower housing. Fix 20 to upper housing 16.

In one embodiment of the drug administration or sampling device, when the device is not used, there is a band cover (not shown) on the device 10 for device preservation. In use, the band cover is removed from the device before the device adheres to the skin.

In another embodiment of the present invention, a manual transdermal administration or sampling device is used with the device (2). Two examples of manual transdermal administration or sampling device are shown in FIGS. 26 and 27. In FIG. 26, a manual transdermal administration device 88 includes a reservoir 90 containing a formulation. The reservoir 90 is preferably in the form of a matrix containing the dispersed formulation. The reservoir 90 is positioned between the backing layer and the rate-controlling membrane, which is preferably opaque to the formulation. In FIG. 26, the reservoir 90 is formed of a material such as a rubber polymer having sufficient viscosity to maintain the shape of the reservoir. When a low viscosity material such as an aqueous gel is used for the reservoir 9, the backing layer 92 and the flow control film 94 are sealed together in their surroundings to prevent leakage. In the sampling configuration, the reservoir 90 does not initially contain the formulation. The microblade array device 2 is located below the membrane 94. Using the contact bonding layer 96 near the outer circumference of the device 2 and the fastening members of any of the embodiments described above, the device 88 is attached to the human epidermis. Optionally, the adhesive layer 96 may comprise a formulation. Generally, a removable release liner (not shown) is provided along the exposed surface of the adhesive layer 96 and removed prior to attaching the device 10 to the human epidermis.

In addition, as shown in FIG. 27, the transdermal treatment device 98 may be attached to the human epidermis using the fixing member and the flexible adhesive overlay 100 used in the device 2. Apparatus 98 consists of a formulation storage reservoir 90 (for administration configuration), which reservoir is preferably in the form of a matrix containing the dispersed formulation. In the sampling scheme, initially the reservoir 90 does not contain the formulation. An opaque backing layer 102 is provided adjacent one side of the reservoir 90. The adhesive overlay 100, together with the securing members of any of the embodiments described above with respect to the device 2, holds the device 98 on the human epidermis. The adhesive overlay 100 is fabricated with the remaining members of the device 98, or provided separately. For some formulations, an adhesive overlay 100 may be more desirable than the contact adhesive 96 shown in FIG. 26. This is true, for example, when the formulation reservoir contains a material that adversely affects the adhesion of the contact adhesive layer 96 (such as, for example, an oily surfactant penetration enhancer). The opaque backing layer 102 is preferably slightly larger than the reservoir 90, thereby preventing the agent in the reservoir 90 from adversely affecting each other with the adhesive of the overlay 100. Optionally, a flow control membrane (not shown in FIG. 27) similar to the membrane of the apparatus 88 (FIG. 26) may be provided on the skin / mucosa surface of the reservoir 90. Also, generally, a removable release liner (not shown) is provided to the device 98 and removed just prior to attaching the device 98 to the human epidermis.

The formulation of the manual transdermal device may be an aqueous or non-aqueous base. The formulation is designed to administer the drug in the required flux. Typically, aqueous formulations include water and a hydrophilic polymer that is about 1 to 2% by weight of a gelling agent, such as, for example, hydroxyethylcellulose or hydroxypropylcellulose. Typical non-aqueous gels consist of silicone fluid or mineral oil. Also, mineral oil based gels typically also contain 1 to 2 percent by weight of a gelling agent such as colloidal silicon dioxide.

The reservoir matrix must be compatible with the agent being administered, any excipient (eg flux enhancer, anti-irritant) and / or any carrier. When using a non-aqueous based system, the reservoir matrix is preferably composed of a hydrophobic polymer. Suitable polymer matrices are well known in the art of transdermal drug administration.

If a constant drug dosage is required, the drug is in a supersaturated concentration in the matrix or carrier, and the excess is a function of the desired length of the drug administration cycle of the system. However, without departing from the present invention, the drug may exist in an unsaturated state.

In addition to the drug, the matrix or carrier may also comprise components in dyes, pigments, inert fillers, penetration enhancers, excipients and other conventional pharmaceutical products or transdermal devices known in the art.

In general, the amount of drug contained in the reservoir and the size of the reservoir are not limited, and in the released form, the drug is equal to or greater than the amount of drug effective to induce physiological or pharmacological local or systemic effects.

In general, the preferred form in which the formulation is to be administered or sampled determines the type of administration or sampling system to be used and vice versa. That is, the choice of an "manual" system to administer or sample a formulation by diffusion or an electrical drive system to administer or sample a formulation by electrical delivery is largely determined by the type of formulation. For example, in the case of manual administration systems, it has generally been recognized that the formulations are preferably administered in inorganic or acid form, rather than in the form of water-soluble salts. On the other hand, in the case of an electrophoretic dosing device, it has been recognized that the drug is in an ionized state, and that the drug salt should be water soluble. In general, manual and electrical delivery transdermal drug administration routes through pristine skin, where manual administration is through the lipid regions of the skin (ie, hydrophobic regions), and electrical delivery administration is hydrophobic, such as those associated with pores and sweat glands. It is recognized that they are different from each other in that they are made through a path or a hole. In the case of penetrated skin, there is a substantial passive flux through the microslits produced by the microblades penetrating the stratum corneum. Generally, the drug for manual administration is in the form of a hydrophobic, eg inorganic, whereas the preferred form of the drug for electro-carrying administration is in the form of hydrophilic, eg, water-soluble salts. In the case of osmotic and pressure driven systems in which the drug is administered or sampled by a connective flow carried by the solvent, it is preferred that the drug has sufficient solubility in the carrier solvent. In this respect, since the present invention is not limited to a specific device, those skilled in the art will understand that the present invention can be used with a wide variety of osmotic administration or sampling systems. Osmotic devices usable with the present invention are described, for example, in US Pat. No. 4,340,480 to Echenhoff, US Pat. No. 4,655,766 to Tyuwes et al., US Pat. No. 4,753,651 to Ekenhof.

The present invention has the utility of connecting to drug administration of any one of a wide range of drugs commonly administered through the human epidermis and membranes, including the skin. In general, the present invention relates to anti-asthmatic agents such as analgesics, anesthetics, appetite suppressants, anti-arthritis agents, terbutalin, including anti-infective agents such as antibiotics and antiviral agents, fentanyl, sufentanil, buprenorphine, and analgesic mixtures. Agents, anticonvulsants, antidepressants, antidiabetics, antidiabetics, antihistamines, anti-inflammatory agents, migraine medications, motion sickness medications such as scopolamine and ondansetron, anti-emetic drugs, anti-tumor agents, parkinsonism medications, antipruritic agents, antipsychotics, Cardiovascular preparations including antipyretic drugs, anti-inflammatory drugs including gastrointestinal and urinary anticholinergic drugs, sympathetic stimulants, xanthine derivatives, calcium channel blockers such as nifedipine, beta blockers, beta agonists such as dobutamine and ritodrine, antiarrhythmic agents Antihypertensives such as atenolol, ACE inhibitors such as ranitinin, diuretics, common coronary, peripheral and Vasodilators, including central nervous system stimulants, cough and cold preparations, decongestants, diagnostic reagents, hormones such as parathyroid hormone, bisphosphoriates, hypnotics, immunosuppressants, muscle relaxants, parasympathetic nerve blockers, parasympathetic neurostimulants, prostaglandins, It includes drugs in all major therapeutic areas, including but not limited to psychostimulants, sedatives and mental stabilizers. In addition, the present invention reduces the sensitization arising as a result of the electrotransportation administration of proteins, peptides and their fragments, whether naturally occurring, chemically synthesized or produced by synthesis. Useful for preventing or preventing The invention may also be used for the administration of nucleotide drugs, including oligonucleotide drugs, polynucleotides and genetic factors.

The present invention has particular utility in the administration of peptides, polypeptides, proteins, nucleotide drugs and other such kinds through the human epidermis, such as the skin. In general, these materials have a molecular weight of at least about 300 daltons, and more generally have a molecular weight of at least about 300-40,000 daltons. Specific examples of peptides and proteins within this size range include LHRH analogues such as LHRH, goserelin, buserelin, gonadorelin, naparelin and leuprolide, GHRH, GHRF, insulin, insulin, calcitonan, Octreotite, endorphin, TRH, NT-36 (chemical name: N-[[(s) -4-oxo-2-azetidinyl] carbonyl] -L-histidyl-L-prolinamide), ripressin, pituitary hormone (e.g. For example, growth factors such as HGH, HMG, desmopressin acetate, etc.), follicular luteoid, αANF, growth factor releasing factor (GFRF), βMSH, GH, somatostatin, bradykinin, somatotro Pin, platelet-induced growth factor, asparaginase, bleomycin sulfate, chymopine, cholecystokinin, chorionic gonadopropine, corticotropin (ACTH), erythropoietin, eposterone (platelet aggregation inhibitor), glucagon, HCG , Hirlog, Auroronidase, interferon, interleukin, menotropin (uropolytropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analog, ANP , ANP clearance inhibitor, angiotensin ∥ antagonist, antidiuretic hormone agonist, bradykinyl antagonist, seredase, CSI's, calcitonin gene related peptide (CGRP), enkephalin, FAB fragment, Ige peptide inhibitor, IGF-1, nerve stimulating factor, colony stimulation Factors, parathyroid hormone and ..., parathyroid hormone antagonists, prostaglandin antagonists, pentizide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytic agents, TNF, vaccines, vasopressin antagonist-like substances, alpha- 1 antitrypsin (formulated) and TGF-beta, but are not limited thereto.

In addition, as described above, the apparatus 2 of the present invention includes, but is not limited to, reverse ion permeation therapy, osmosis, passive diffusion, phonophoresis, and suction (ie, negative pressure). Can be used with known sampling devices. The osmotic sampling device uses a variety of preparations (e.g., human analytes, legal and illegal drugs) including, but not limited to, illegal substances such as glucose, human electrolytes, alcohols, blood gases, and abuse drugs through the human epidermis. Can be used to sample. The osmotic sampling device 104 is attached to the human epidermis by the flexible adhesive overlay 100 and the fixing members of the device 2. The device 104 consists of a salt layer 106 positioned between the semipermeable or osmotic membrane 94 and the optional agent sensing member 108. The optional agent sensing member may be any of a variety of chemical reaction sensors and reaction indicators, such as color indicator test strips associated with glucose testing. In order for the reaction indicator to be easily visible, the adhesive overlay 100 may have a cut or transparent window within the reaction indicator region. In an alternative embodiment, the agent sensing member may be located between the device 2 and the salt layer.

The following examples are merely illustrative of the present invention, which examples and other equivalents thereof are apparent to those skilled in the art in light of the specification, drawings and appended claims, and are therefore to be understood as limiting the scope of the invention in any way. It should not be.

Experimental Example

The effect of this design on the leather resistance of hairless guinea pigs was evaluated. A two square centimeter blade array was attached to a five square centimeter ECG electrode. The blade array and electrodes were then attached to the animal's skin. Two minutes after attaching the electrode to the animal skin, the resistance was measured. A decrease in resistance was observed indicating that the blade penetrated into the skin.

The device was evaluated for the effect of decapeptide on the electrical transport flux of hairless guinea pigs. The following is a specification of the device: The device consists of a sheet with a plurality of rectangular openings with six blades, three blades on each of the long sides of a 860 μm × 250 μm rectangle, for each opening The open area was 0.22 mm ² . Each set of three blades started at the opposite end of the rectangle, the opposite set of blades. All blades were 200 μm in length. All six blades had sloped leading edges, and each end of the blade had a barb. Six blade groups were arranged in two slightly offset rows, each row being provided with ten groups. Each device was a 2 cm ² piece of stainless steel etched to a thickness of 25 μm and punched out with eight pairs of offset rows or six blades in 160 groups, with all 960 blades memorized. Was a 1 cm ² of space area per 40, there is a blade 240 per 1 cm ^2.

For research purposes, a compartmental electrical delivery system was used. It contains a negative electrode compartment containing Dulbelco's phosphate buffered saline imbibing gel, 2 mmol of decahatide, 10% cholestyramine chloride and 3% of buffered to pH 7.5. It consisted of the donor anode compartment containing hydroxyethyl cellulose. After loading the gel in the system, the release liner was removed from the bottom of the adhesive foam of the electrical delivery system. The microblade was pulled away from the gel and the device was carefully attached onto a 1.6 cm diameter hole containing donor gel. Thereafter, an electric delivery system was placed on the skin of a slightly anesthetized hairless guinea pig. Gently pressure was applied downwards to attach the system to the animal skin, while the engineer's thumb applied pressure to the underside of the system (thumb trap trapped the animal skin's roll, thereby Some pressure was applied upwards directly to the underside of the animal skin in contact with the microblade of the device). After 2 minutes, the current and resistance were observed and recorded. While the electrical transport continued (5 to 24 hours), the electrical transport system was packaged in Vetrap and the animals were sent to their cages. The decapeptide flux was measured by measuring the urine output of this peptide. During the first five hours of transport, only a slight device effect on the decapeptide flux was observed. Between 5 and 24 hours, perhaps due to the path disruption or the possibility of attachment of the peptide in the path, the electrical transport flux of a typical electric transport device was very drastically reduced (a decrease in flux between 5 and 24 hours was reproducible). By completely avoiding this decrease in flux using a blade array device, the decapeptide flux overall increased 10-fold over a 24-hour dosing period.

Although the present invention has been described in conjunction with certain preferred embodiments, it is to be understood that the foregoing detailed description as well as the examples are intended to illustrate, but not limit, the scope of the invention. Other aspects, advantages, and modifications within the scope of the invention will be apparent to those skilled in the art.

The present invention provides a reusable, mass production, low cost device suitable for increasing transdermal flux and improving skin adhesion without minimal skin pain or skin pain. The device of the present invention usually has a structure that adheres to the skin more effectively than the device of the prior art. The present invention includes a plurality of microblades for puncturing and fixing the skin. Typically, the blade has a length of about 0.4 mm or less and a much smaller width and thickness. Despite its small size, the blades can be made in highly reproducible size and shape so that the microslit formed by the blades that puncture the skin has a very reproducible size and depth. Since the blades have a small thickness (ie, small relative to the width and length of the blades), the blades cause less tissue damage for a certain cross section than skin penetrating microneedles having a circular cross section. The device of the present invention is capable of extracting (e.g., a route or substance (e.g. human electrolyte) through which the substance (e.g. drug) can enter through the stratum corneum of the human epidermis. Sampling) path.

In one aspect of the invention, the device comprises a sheet having a plurality of openings, a plurality of microblades extending downwardly and essential to the sheet and means for securing the device to the human epidermis. In many different aspects of the invention, the apparatus comprises a plurality of methods, namely a method having an extension, such as a prong or barb, extending from at least some blades, at least some blades A method having an opening extending perpendicular to the method; a method of necessarily covering the entire surface area of the skin contact surface with the adhesive of the device, except one side of the microblade; Orienting the blade at a 90 ° angle, or directing at least some of the plurality of microblades at an angle within the range of about 1 ° to about 89 ° to the remaining blades of the plurality, wherein the device is more compatible with the human epidermis Any method comprising providing a plurality of second openings in the sheet such that But it fixed to a human body skin, and the like. The device of the present invention may be used with drug administration, human analyte or drug sampling, or both. Dosage devices for use with the present invention include, but are not limited to, electric delivery devices, passive devices, osmotic devices, and pressure-driven devices. Sampling devices for use with the present invention include, but are not limited to, "reverse" electric carriers, passive devices, osmotic devices, and negative pressure drive devices described in US Pat. No. 5,279,543 to Glikfeld et al. It doesn't happen.

The present invention also provides a high yield, low cost method for producing the device of the present invention in a very reproducible manner.

Claims (30)

Apparatus (2) for penetrating the stratum corneum of the human epidermis and forming a route through which the agent can be introduced or extracted, A sheet 6 having one or more openings 8 and a plurality of blades 4 extending thereunder, wherein at least one of the plurality of blades is adapted for securing the device 2 to the human epidermis. Apparatus (2) characterized by having anchors (50, 68, 74, 82). Apparatus (2) for penetrating the stratum corneum of the human epidermis and forming a route through which the agent can be introduced or extracted, A plurality of blades (4) having a sheet (6) having a plurality of openings (8) through which one or more of the openings (8) are located along their periphery and extend downward from the sheet (6) And anchors (50, 68, 74, 82) for fixing the device (2) to the human epidermis. The method according to claim 1 or 2, The anchor, (i) protrusions 68 extending from one or more blades 4; (Ii) barb 50; (Iii) one or more openings 74 extending through the one or more blades 4; (Iii) an adhesive on the body contacting surface 48 of the sheet 6 and at least one surface 82 of at least one of the plurality of blades 4; (v) each blade 4 has an axis, the blade 4 is oriented such that the blade axis is substantially parallel and the axis forms an angle of about 1 ° to 89 ° with respect to the sheet 6, (Iii) each of the plurality of blades 4 necessarily defines one side, and the anchor includes a portion of the plurality of blades 4 oriented at an angle of about 90 ° with respect to the rest of the plurality of blades. and ; And (Iii) each of the plurality of blades 4 necessarily defines one surface, and the anchor is oriented in an angle within a range of about 1 ° to about 90 ° relative to the remainder of the plurality of blades (4) Device selected from the group consisting of. The method of claim 3, wherein The protrusion (68) is characterized in that it extends from a plane defined by one or more blades (4). The method of claim 4, wherein And the protrusion (68) is a prong (4). The method of claim 3, wherein Wherein the protrusion is integrated with at least one blade edge and is in a plane defined by the at least one blade. The method according to claim 1 or 2, A therapeutic agent dosage device 10, 88, 98, 104 connected to the penetrating device 2 and positioned to administer the therapeutic agent to the human epidermis through the opening 8, wherein the agent dosage device 10 , 88, 98, 104 is selected from the group consisting of an electric carrier (10), a passive diffuser (88, 98), an osmotic device (104) and a pressure drive device. The method of claim 7, wherein The agent is characterized in that the device comprises a polypeptide or protein. The method according to claim 1 or 2, And further comprising a sampling device (10, 88, 98, 104) connected to the penetrating device and positioned to sample material from the human epidermis through the opening (s) (8), wherein the sampling device comprises a reverse electric conveying device ( 10), a passive diffusion device (88, 98), an osmotic device (104) and a negative pressure drive device. The method of claim 9, And said sampled material is selected from the group consisting of human electrolyte, illegal drugs and glucose. The method of claim 1, A portion of the plurality of blades (4) is characterized in that it is located along the outer periphery of the opening (8) through the seat (6). The method according to claim 1 or 2, And a plurality of second openings (80) through the sheet (6), spaced between the plurality of openings (8). The method according to claim 1 or 2, Wherein the device has about 600 to about 1000 blades / cm ² . The method according to claim 1 or 2, Wherein the device has at least about 800 blades / cm ² . The method according to claim 1 or 2, Some of said plurality of blades (4) have a length sufficient to penetrate the stratum corneum of the human epidermis to a depth of at least about 25 μm. The method according to claim 1 or 2, The device as characterized in that each of the plurality of blades (4) is located perpendicular to the seat (6). The method according to claim 1 or 2, And each of said plurality of blades (4) is oriented at an angle in the range of about 1 ° to about 89 ° with respect to said sheet (6). The method according to claim 1 or 2, And each of the plurality of blades (4) is oriented at an angle in the range of about 10 ° to about 60 ° with respect to the sheet (6). The method according to claim 1 or 2, Some of said plurality of blades (4) have a thickness in the range from about 7 μm to about 100 μm. The method according to claim 1 or 2, Some of said plurality of blades (4) have a thickness in the range from about 25 μm to about 50 μm. The method according to claim 1 or 2, Said plurality of blades (4) are made of a material selected from the group consisting of metals, metal alloys, glass, ceramics and hard polymers. The method according to claim 1 or 2, The device (6) and the plurality of blades (4) are characterized in that they are opaque to the passage of the preparation. The method according to claim 1 or 2, Said plurality of blades (4) are thinner than said sheet (6). In the method of manufacturing the device (2) penetrating the stratum corneum of the human epidermis, Applying a photoresist layer to the first side 49 of the sheet 6; Exposing the photoresist layer through a mask pattern to form a plurality of blades (4); Etching the photoresist and the exposed portion of the sheet (6) to form the plurality of blades (4) and openings (8) in the sheet (6); Punching the plurality of blades (4) through the openings (8) such that the plurality of blades (4) extend below the sheet (6); And Coupling said device (2) through said stratum corneum with a dosing device (10, 88, 98, 104) or sampling device (10, 88, 98, 104). The method of claim 24, The photoresist is a resist selected from the group consisting of wet resist and dry resist. The method of claim 24, Wherein said etching step comprises spray etching. The method of claim 24, The punching step, Placing the sheet (6) on a die (52) having a plurality of openings (56) corresponding to the plurality of blades (4) and openings (8) of the sheet (6); And The sheet 6 using a punch 54 having a plurality of protrusions 58 corresponding to the plurality of openings 56 of the die 52 and the plurality of openings 8 of the sheet 6. Bending the plurality of blades (4) of the opening (56) so as to be perpendicular to the vertical direction. a. Attaching the device 2 on the human epidermis from which the formulation is to be extracted; b. Extracting said agent through said pathway and said opening (8); And c. Collecting the agent in a reservoir (26, 90, 106), wherein the device (2) comprises one or more openings (8), a plurality of blades (4) extending below and the openings (8); A transdermal formulation sampling method comprising a reservoir (26, 90, 106) involved in formulation delivery, thereby forming a formulation delivery path through the stratum corneum of the human epidermis. The method of claim 28, And said sampled formulation is selected from the group consisting of human analyte, electrolyte, blood gas, illegal drug, legal drug and glucose. The method of claim 28, Connecting a sampling device 10, 88, 98, 104 to an opposite side of the sheet 6 surface 48 with the blade 4 extending downward, wherein the sampling device 10, 88, 98, 104 further comprises a reverse electric conveyance sampling device (10), a manual sampling device (88, 98), an osmotic sampling device (104) and a sound pressure driven sampling device.