KR20000016697A - Device for enhancing transdermal agent delivery or sampling - Google Patents

Abstract

PURPOSE: A percutaneous agent delivery or sampling device for piercing the skin for increasing transdermal flux of an agent is provided. CONSTITUTION: The percutaneous agent delivery or sampling device (10) comprising a sheet (6) having at least one opening (8) there through and a plurality of micro blades (4) for piercing the skin for increasing transdermal flux of an agent. The micro blades (4) having a relatively sharp angled leading edge (11, 11') which transitions to a relatively gradually angled blade edge (13, 13').

Description

Device for improving the administration or sampling of transdermal agents

As medically useful peptides and proteins become increasingly available in bulk and tablet form, there is a growing interest in transdermal administration of the peptides and proteins through the skin in vivo. However, transdermal administration of these peptides and proteins still faces serious problems. In many instances, since 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, polypeptides and proteins are easily lost during and after penetration into the skin before reaching the target cell. Likewise, the passive flux of water soluble micromolecules such as salts is limited.

One way to enhance transdermal administration of a formulation is to apply a current to the biological epidermis or rely on "electrotransport". In general, "electrotransport" means the transfer of a beneficial agent, such as a drug or drug precursor, through a bioepitheli of skin, mucous membranes, nails, and the like. The transport of this agent is induced or enhanced by the application of a potential difference that results in the application of a current resulting in the administration of the agent or enhancing its administration. Electrotransport of the agent through the biological epidermis can be accomplished in a variety of ways. Iontophoresis, one of the widely used electrotransport methods, involves the induction transport of electrically conductive ions. As another type of electrotransport process, electroosmosis involves the accompanying motion through the membrane with the solvent agent under the influence of an electric field. Electroporation, as another form of electrotransportation, involves the transfer of the material through pores formed by applying a high voltage electric pulse to the membrane. In many instances, one or more of these processes may occur simultaneously to different degrees. In general, electrotransport administration increases the administration of the agent, in particular the dosage of high molecular weight (eg, polypeptides), as compared to transdermal administration without manual or electrical assistance. However, it is highly desirable that the transdermal dosage flow during transdermal administration is further increased, and that the degradation of polypeptides is reduced.

One method of increasing the transdermal administration flow rate of a formulation involves pretreatment of the skin with a skin penetration enhancer or concomitant administration of a beneficial formulation. Here, the term "penetrant enhancer" is widely used to describe a substance that enhances the transdermal flux when the enhancer is applied to the biological epidermis to which the agent is administered. The mechanism may be to increase the permeability of the epidermis, to reduce the loss of the agent (e.g. by skin enzymes) during transport, or in the case of electrotransport administration / sampling, to the bioepidermal passage to the agent's pathway. May be accompanied by a decrease in the electrical resistance of or the generation of hydrophilic pathways through the epidermis.

Prior to transdermal drug administration, many attempts have been made to mechanically puncture the skin to enhance transdermal flux. 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. Although Girltel has disclosed other forms of use, these devices generally use tubular or cylindrical structures to penetrate the outer layers of the skin. These devices each provide problems in manufacturing, resistance to easy penetration into the skin, and / or undesirable skin pain.

As has been described, numerous chemical and mechanical means have been explored to enhance transdermal flux. However, it is possible to provide a device suitable for strengthening transdermal flux that can penetrate the skin with very low insertion force and can be made inexpensively and on a large scale and reproducible (ie without significant change in device and device). The need still remains.

The present invention relates to transdermal agent administration and sampling. More specifically, the present invention is not limited to alcohols and illegal drugs, and relates to transdermal sampling of agents such as peptides and proteins, as well as transdermal sampling of agents such as abusers, bioelectrolytes and glucose. The present invention uses skin-penetrating microblades to enhance the transdermal flux of the formulation during transdermal administration and sampling.

1 is an enlarged perspective view of a side facing the skin of a microblade array according to an embodiment of the invention.

2 is an enlarged view of a portion of the microblade of the blade array pattern.

3 is an enlarged view of a microblade according to an embodiment of the present invention.

4 to 7 are enlarged views of another embodiment of a microblade according to the present invention.

8 is an exploded perspective view of one embodiment of an electrotransport agent dispensing system having a microblade array device according to the present invention.

FIG. 9 is a bottom view of the electrotransport agent administration system of FIG. 8.

The present invention provides a reproducible and large scale inexpensive device that can easily penetrate the skin and is suitable for increasing transdermal flux. The present invention includes a plurality of microblades for penetrating the skin having a leading end portion in which the first fragment portion starts at a relatively sharp angle and the second fragment portion gradually changes at a relatively blunt angle. This special microblade geometry allows the user better penetration of the skin with a smaller "push down" (ie penetration and insertion) force. The first segment forms a relatively small angle with respect to the axis extending along the length of the microblade, providing a very sharp segment of the blade that easily penetrates the skin. The tip is then changed to a second piece that forms a larger angle than the first piece relative to the axis. This second piece provides strength to the entire blade, thereby preventing bending due to the width along which the blade along the portion along the piece is wider than the portion along the first piece. In addition, because of its wide width, the second fragment will form longer slits in the skin, increasing the size of the transdermal route through which the agent is administered or withdrawn. In addition, the sharper tips of the blades and the relatively stronger bases of the blades improve the overall penetration characteristics of the microblade, reducing the push down force required to achieve the desired penetration performance.

Typically, these blades have a length of less than 0.5 mm and are much smaller in width and thickness. Despite their small size, these microblades can be made in extremely reproducible sizes and shapes, so that the micro slits formed by the microblades penetrating the skin also have a very reproducible size and depth. Since these microblades have a thin thickness (i.e. thinner than the length and width of the blade), these microblades are less likely to cause tissue damage for a given cross section than skin penetrating microneedles having a circular cross section. . The device of the present invention is capable of penetrating the corneum and allowing the inflow (e.g. administration) of the substance (e.g. drug) or the extraction (e.g. sampling) of the substance (e.g. bioelectrolyte). Form a path.

According to one aspect of the invention, a device comprises a sheet having a plurality of openings, a plurality of microblades extending downwardly and integrated, a portion of which is adjacent to the first angled fragment and the first angled fragment. Having a second angled fragment, the first angled fragment being located at the distal end on the microblade and having a first angle with respect to the axis along the length of the microblade, the second angled fragment being greater with respect to the axis than the first angle. Has

The device of the present invention may be used in connection with drug administration, bioassay or drug sampling or both. Dosing devices used in the present invention include, but are not limited to, electrotransport devices, passive devices, osmotic devices, and pressure drive devices. Sampling devices used in the present invention include, but are not limited to, "reverse" electrotransport devices as described in US Pat. No. 5,279,543 to Glikfeld et al. And US Pat. No. 5,362,307 to Guy et al. , Passive diffusion devices, such as those described in Schöndorfer, US Pat. No. 5,438,984, osmotic devices, such as those described in US Pat. No. 4,756,314 to Eckenhoff, et al., And negative pressure drives.

EMBODIMENT OF THE INVENTION Hereinafter, with reference to drawings, one Embodiment of the skin permeable member 2 of this invention is shown in FIG. The member 2 is used in connection with sampling of the agent or dosing through the skin. Here, the terms "substance", "sanction" and "drug" are used interchangeably and produce a local or systemic effect on mammals, birds, useful livestock, varieties or farm animals, including humans and primates, It includes a wide range of physiologically or pharmacologically active substances for administering drugs to laboratory animals such as mice, rats, pig rats, and the like. In addition, these terms include substances such as glucose, bioelectrolytes, alcohols, banned substances, pharmaceuticals, banned drugs, and the like, which can be sampled through the skin. The main barrier properties of the skin, such as resistance to drug penetration, are present in the outermost layer (ie the stratum corneum). In general, the internal division of the epidermis has three layers, called granular, maldermal and embryonic layers. Once the drug penetrates beneath the stratum corneum, the resistance to penetration through the granular, maldermal and embryonic layers is substantially reduced. The device of the present invention is used to form microslits in the stratum corneum to create osmotic regions in the skin for sampling of the agent or for improving transdermal administration.

The member 2 has a plurality of microblades 4 (ie blade arrays) extending downward from one surface of the sheet or plate 6 (part of the member 2 so that the microblades can be observed) 1 in which is the inverted position. The microblade 4 is dimensioned and shaped to penetrate the stratum corneum of the skin when pressure is applied to the device. These microblades form micro slits in the biological epidermis to augment the sampling or administration of material through the biological epidermis. Here, the term "bioepider" generally refers to the skin of an animal or human.

In general, the microblade 4 is formed of a single sheet 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 either completely impermeable or impossible to penetrate the passage of the material. The sheet 6 is formed with an opening 8 between the microblades 4 in order to improve the movement of the material. In the case of administration of a therapeutic agent (eg, a drug), the drug is discharged from the drug reservoir (not shown in FIG. 2) through the opening 8 to remove the micro slit formed by the microblade 4 cutting the stratum corneum. Passing through, it is moved along the stratum corneum and below the outer surface of the microblade to realize local or systemic treatment. In the case of product (eg bioanalyte) sampling, the analyte is transported from the living body through the micro slits of the stratum corneum cut by the microblade 4.

In one embodiment, the opening 8 corresponds to the part of the sheet 6 that each microblade occupies before the blades are displaced to the suspended position. The number of microblades 4 per opening 8 can be any number, preferably with a range of 1 to 30 blades per opening. In addition, the number of openings per device and the number of blades per device are independent. The device may have only one opening and one microblade. The discharging material is controlled and discharged through the discharging flow rate control mechanism (not shown) covering the opening 8 from the reservoir.

As best shown in FIG. 1, the microblade 4 has a thickness much smaller than its base, i.e., the blade width on the side close to where the blade is attached to the seat 6. The geometry of such blades provides maximum chemical osmotic area with minimal blade penetration, thereby reducing tissue damage. This chemical osmotic area is the skin area which is in contact with the blade which penetrates the chemical into the skin. This microblade is shaped to have the largest available surface area with the smallest cross-sectional area to have the maximum available osmotic area. For the same cross section, thin microblades are superior to spherical protrusions for this purpose because thin blades provide a wider osmotic area than circular cross sections (ie cylindrical protrusions) and less tissue damage. This is a decisive advantage over the older devices of the prior art such as needles and tubes. Thinner microblades also require less insertion force than round projections. The width of each blade can be any width. The width can be different depending on the blades of the array pattern. Likewise, as described below, the width can be varied along the length of the blade. The blade width at the intersection of the biological epidermis and the blade after the blade array is inserted is preferably in the range of about 10 mm to about 500 mm, more preferably from about 25 mm to about 400 mm, more preferably about 25 mm to about 300 mm.

The microblade 4 is provided with an inclined (ie angular) tip 64 having multiple fragments to reduce the insertion force required to press the blade into the skin tissue. In addition, the blade insertion force is reduced, which makes it possible to use a thinner and more flexible sheet 6, which is advantageous in devices adapted to be worn on the skin for long periods of time (eg, 30 minutes or more). 1 to 5 and 7, the tip portion 64 has two fragment portions each having a different tip portion. The first fragment portion 11 is the last fragment portion. Adjacent to this first fragment portion 11 is a second fragment portion 13. The angle of the 1st fragment part with respect to the reference line 15 or an axis is represented by a. The angle of a 2nd fragment part is shown by b. The slanted tip of the multiple fragments creates a cut along the skin tissue equal to the overall width of the blade 4, while reducing the amount of metal in the skin tissue. That is, the flat tip (i.e., a is 90 °) yields a blade whose tip produces a greater amount of blade material in the skin tissue than the warp blade. The angle (a) of each fragment 11 may be any angle in the range of 1 ° to 25 °, preferably 15 °. Thereafter, the first fragment portion 11 is changed into a second fragment portion having an angle b of 26 to 80 degrees, preferably of 30 to 45 degrees, more preferably of 35 degrees.

The microblades 4 of the embodiments shown in FIGS. 4, 6 and 7 have sharp end tips 19 for easy penetration into the skin. The embodiments shown in FIGS. 1-3 and 5 have a flattened end tip 17 that is easy to manufacture and has greater resistance than the sharp tip 19 to the warping phenomenon upon insertion into the skin.

1 to 4 and 6 have a single inclined tip 64 on the microblade 4, while the embodiments of FIGS. 5 and 7 start almost from the centerline 15 and are from this centerline. It has two inclined tip portions 64 extending outwardly on either side. As shown in Fig. 7, this inclined tip need not be symmetrical with respect to the center line. The first fragment portion 11 ′ is not the same as the fragment portion 11, and the second fragment portion 13 ′ is not the same as the fragment portion 13.

In any of the embodiments described above, the multiple slanted tips 64 can have any number of fragments. For example, the embodiment of FIG. 6 has a third fragment portion 21. The angle of this 3rd fragment part is shown by g. The second fragment portion 13 is changed to a third fragment portion having an angle g which is greater than the angle b with respect to the reference line 15. Preferably, the angle g is in the range of about 35 ° to 80 °, more preferably about 45 °. As can be seen from FIG. 6, subsequent angled fragments running adjoining the microblade from the first fragment portion have a larger angle relative to the baseline 15 compared to the angle of the preceding angled fragment portion. A plurality of adjacent angled fragments having a front end creates an end portion that looks arcuate (that is, curved). In one embodiment, the tip appears to cross the entire width of the blade in a curved fashion.

The microblade 4 is formed using a photo etching process. This photoetching process allows the microblade 4 to be formed to be reproducible at a very small scale (ie tens of microns). This treatment is also formed into a shape such that the microblade 4 requires less force to penetrate the skin. Some microblades 4 are provided with some form of barb 50 (FIGS. 1 and 2) such that the member 2 and any corresponding device in contact with it remain after the pressure is applied to the skin. You will be exposed. The degree of contact and the number and size of the barbs 50 may be such as to retain the dosing or sampling device during normal activity of the wearer but not to cause pain upon removal. When the microblades are pressed into the skin tissue for use, the tip 64 of each microblade 4 penetrates the skin tissue. After the microblades have settled on the skin, the at least partial skin's inherent elasticity causes the skin to return together around the edges of the microblade 4 such that the surface 66 on each microblade with the barb 50 is It can be bitten by the skin tissue and fix the device to the skin. If the microblades are left to stay on the skin for an extended period of time (eg 24 hours), the skin tissue will heal together in the posterior region of the surface 66 of the barb 50, thereby improving the fixation of the device. Although only one barb per blade is shown in the figures, in the present invention each blade includes a plurality of barbs extending therefrom. The plurality of microblades 4 penetrating the stratum corneum may be formed of a member 2 by, for example, a group of blades spaced in a predetermined number of rows, or each blade is in a certain constant arrangement and in any spaced relationship. Present on surface 48. Each blade has a width and a thickness that the stratum corneum can penetrate without bending. In the embodiment of FIG. 1, six blades 4 are present along the rim of each opening 8 in the sheet 6. Preferably, the width of each blade is in the range of about 135 mm to about 300 mm, the length of which is about 600 mm. The essential feature of the present invention is that the blades penetrate the stratum corneum and pass through the stratum corneum, so that the required length of the blade is dependent on the change in the circumferential epidermis, and corresponds to the original thickness of the stratum corneum. Typically, the blades are about 25 mm to about 700 mm in length, and in most applications their length is between about 50 mm and 600 mm. For example, the microblade 4 of FIG. 3 is 254 mm wide and 508 mm long, dimension C is 127 mm and dimension D is 89 mm. The microblade 4 of FIG. 4 is 254 mm wide and 610 mm long, dimension C is 127 mm and dimension D is 178 mm. The sharp end fragments of the microblade are widened at an angle (b) to provide a relatively large base so that they are supported by the remainder of the blade to prevent deflection of the blade during penetration and insertion into the skin. Provide structural properties.

The pattern of any blade array device of the present invention is produced by a photoetching process. See, for example, U.S. Patent No. 60 / 019,990, filed June 18, 1996, and these disclosed methods can be used to calculate the member (2) of the present invention. The plate 6 or thin sheet of metal such as stainless steel or titanium is etched in a pattern having a blade-like structure by the photolithography method. Generally, a thin, dry or wet resist is applied on the sheet at a thickness of about 7 mm to about 100 mm, preferably from about 25 mm to about 50 mm thick. This resist is developed after the contact is exposed using a mask having a predetermined pattern. These operations are done in much the same way as in the manufacture of printed circuit boards. The sheet is then etched using the acidic solution. After this pattern is etched into the sheet, it is placed on a die having a plurality of protrusions corresponding to the opening 8 in the sheet. Initially, a punch having a plurality of protrusions corresponding to the die and the opening in the sheet is placed above the sheet and the die. In the initial stage, the blades 4 are coplanar with the remaining sheets 6. The punchy projections are then pressed into the openings so that the blades 4 bend down, with an angle (for example almost perpendicular) to the plane of the sheet. The final structure provides an adjacent opening for the passage of the material in the blade 4 when the member is applied to the skin. Although square openings 8 are shown in the figures, the present invention includes the use of any shape openings and is not limited to squares, triangles, circles and ovals. Since the blades 4 are patterned with resist on both sides of the sheet 6 and then etched from both sides simultaneously to achieve maximum pattern resolution for a given sheet thickness, conventional stamping and punching ( The punching process yields a blade-like edge that cannot be realized. Alternatively, the blade 4 can be patterned and etched from only one side.

In another embodiment of the two-side etching treatment, the blade array pattern of any embodiment of the present invention is etched on the top surface of the sheet 6. The second pattern, which is equivalent to the area (e.g. square) surrounded by each opening 8, is etched in the bottom surface 48 so that each blade of the blade array pattern is thinner than the surrounding sheet 6. As a result, the seat 6 forms a solid base, and when the punch deforms the blades 4 downward, each blade deforms plastically, yielding a blade that is more perpendicular and straighter to the seat. Done.

In one embodiment of the etching process, a dry resist (eg, “Dynachem FL” available from Dynachem, Tustin, CA) is applied to one or both sides of the sheet to a thickness of 12.5 mm. They are exposed in a general manner. Then, using a suitable spray etcher (e.g., "Dynamil VRP 10 / NM" available from the Western Technical Association of Anaheim, Calif.), This resist and sheet may be A mixture of ferric chloride and hydrochloric is sprayed at 52 ° (125 ° F.) for about 2 minutes. A common corrosion stripper is used for the extraction of this resist.

In another embodiment of the etching process, a wet resist (eg, “Shipley 111S” available from Shipley, Marlborough, Mass.) Is 7.5 mm at about 20 ° (70 ° F.) on one or both sides of the sheet. After being applied in thickness, it is exposed in the usual way. Then, an appropriate etchant (eg iron chloride) is sprayed at 49 ° (120 ° F.) on the resist and the sheet. A common corrosion stripper is used for the extraction of this resist.

In general, the blade 4 has an angle of about 90 ° to the surface 48 of the sheet 6 after being punched, but any front or rear from the vertical position to facilitate contact and penetration into the stratum corneum. Can be placed at an angle. In one embodiment, the blades are disposed at an angle between about 1 ° and about 89 °, preferably in the range of about 10 ° to about 60 °, and about 20 ° to allow the device to slide into the skin along the skin. The range of 45 degrees is more preferable. Angled blades have two main advantages. Firstly, the penetration of the blades generally slides horizontally into the skin due to the vertical pressing on the skin, so that these blades do not repel much against the elasticity of the skin. Second, these angled blades act to secure the device to the skin so that the blades are not ejected by any movement of the skin. In addition, other anchoring members, such as barbs, openings, etc., may be used with these angled blades to further improve the anchoring of the device.

Sheets and blades can be made from materials having strength and manufacturability sufficient to produce blades such as glass, ceramics, rigid polymers, metals and metal alloys. Examples of metals and metal alloys include stainless steel, iron, steel, tin, zinc, copper, platinum, aluminum, germanium, nickel, zirconium, titanium, titanium alloys composed of tin, molybdenum and chromium, tin, gold And metals plated with rhodium, iridium, titanium, platinum, and the like, but are not limited thereto. Examples of glass include devitrified glass, such as “PHOTOCERAM”, available from Corning, Corning, NY. Examples of polymers include, but are not limited to, polystyrene, polymethylmethacrylate, polypropylene, polyethylene, "BAKELITE", cellulose acetate, ethyl cellulose, styrene / acrylonitrile, copolymers, styrene / butadiene copolymers, Acrylic polymers including acrylonitrile / butadiene / styrene (ABS) copolymers, polyvinyl chloride and polyacrylates and polymethacrylates.

The microblades of the present invention, because of their small thickness (relative to their width and thickness), form long narrow microcuts (ie slits) within the skin surface, so that the cross-sectional area of the blades with respect to the blade portion in the skin Will be the minimum. Due to the geometry of these microblades 4, it has a maximum blade surface area on the skin and a minimum blade volume on the skin. Advantages of the present invention include, but are not limited to, (1) easy penetration of the skin due to the very sharp first segment on the tip, and (2) maximum chemical osmosis for a given cross section of the braid due to the geometry of the thin blades. Area is minimized by (3) the amount of blade material in the skin and thus minimizing the loading volume, and (4) the large osmotic area due to the inclined tip (or co-orientating shape) (5) For a given loading volume, the greater the surface area, the greater the frictional retention in the skin, and (6) for any given osmotic area. Since the number of blades required is smaller, the force acting on each tip becomes larger, making skin penetration easier. All.

The number of openings and blades in any of the embodiments of the device 2 can be determined by the person skilled in the art, as desired flux flow rate, sampling or administered formulation, dosage or sampling device used (ie, electrotrans). Port, manual, osmosis, pressure drive, etc.), and other factors. In general, the greater the number of blades per unit area (i.e. blade density), the greater the number of lumber conveyance routes through the skin, and thus the more flux of the lumber through the skin. As a result, the smaller the number of blades per unit area, the smaller the path, so that the flux of the lumber through the skin is more concentrated. The present invention has a blade density of at least about 10 blades / cm ² to about 1000 blades / cm ² , preferably a density of at least about 600 blades / cm ² , more preferably a density of about 800 blades / cm ² . Has Likewise, the number of openings per unit area through which the material passes is at least about 10 openings / cm ² to 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 on} the biological surface, preferably about 0.01 cm ² / cm ² of an osmotic region on the biological surface.

One embodiment of the present invention relies on the application or "electrotransport" of a current across a biological epidermis. In general, electrotransport refers to a pathway of beneficial agents, such as drugs or drug precursors, through the epidermis of the skin, mucous membranes, nails, and the like. The transport of this agent is induced or enhanced by the application of a current due to the application of a potential to administer the agent or enhance the dose or sample the agent or enhance the sampling for a "reverse" electrotransport. Electrotransport of the agent from or into the body epidermis can be accomplished in a variety of ways. Ion penetration, one of the widely used electrotransport processes, involves the electrically induced transport of conductive ions. Another type of electrotransport process, electroosmosis, involves transdermal transport of molecules that are unconducted or neutrally challenged (e.g., transdermal sampling of glucose), through the membrane of solvents and agents under the influence of an electric field. It entails companion exercise. Electroporation, another form of electrotransport, involves the passage of the material through pores formed by applying a high voltage electric pulse to the membrane. In many instances, one or more of these processes may occur simultaneously to different degrees. Thus, the term “electrotransport” herein encompasses the electrical causing or augmentation of the transport of one or more challenged or unconducted materials or mixtures thereof, regardless of which special mechanism the materials are transported by. It should be interpreted as broadly as possible.

Since the present invention is not limited in this respect, those skilled in the art will recognize that the present invention can be used in combination with various types of electrotransport systems. For examples of electrotransport drug administration systems, see US Pat. No. 5,147,296 to Theeuwes et al., US Pat. No. 5,080,646 to Theeuwes et al., US Pat. Can be. As an example of a "reverse" electrotransport device, see US Pat. No. 5,279,543 to Glikfeld et al. And US Pat. No. 5,362,307 to Guy et al.

In general, electrotransport devices use two or more electrodes in electrical contact with skin, nails, mucous membranes, or other parts of the epidermis. In the case of transdermal administration, one of these two electrodes is commonly referred to as a "donor" or "active" electrode, from which the canal is administered in vivo. In the case of transdermal product sampling, one of these two electrodes is called an "acceptor" electrode, where the product after being taken out of the living body is collected. In general, the second electrode is referred to as a "counter" or "return" electrode and acts close to the electronic circuit through the living body. For example, if the agent to be administered is a cation, i.e. a positively conductive ion, the anode serves as an active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if the material is not anion, that is, a negatively conductive ion, the cathode becomes a donor electrode. If the material to be sampled is cation, the anode becomes the receptor electrode while the cathode completes the circuit. If the material to be sampled is not purely charged (eg glucose), any one or both of the anode or cathode will serve as receptor electrodes. If the anode and cathode materials are administered simultaneously, both the anode and the cathode may be donor electrodes. In general, electrotransport administration systems require one or more reservoirs or sources of product to be administered in vivo. Similarly, electrotransport sampling systems require one or more reservoirs to aggregate the material being sampled. Examples of such reservoirs include, among others, pouches or cavities described in Jacobsen et al. US Pat. No. 4,250,878, porous sponges or pads described in Jacobsen et al. US Pat. No. 4,141,359, and Webster et al. Pre-formed gel bodies. Such reservoirs are electrically connected between and disposed between the anode or cathode and, for example, the epidermis, to provide a source of one or more limited or renewable medications upon administration of the formulation. In addition, the electrotransport system generally has an electrical power source, such as one or more batteries, and an electrical controller designed to control the timing, magnitude and / or frequency of the applied current to control the timing and flow rate of the sanctions / sampling. . This power supply component is electrically connected to two electrodes. Optional components of the electrotransport device include a counter reservoir, an adhesive coating, an insulation separator and a flow control membrane.

8 and 9 show representative electrotransport administration / sampling devices 10 that may be used in conjunction with the present invention. The apparatus 10 includes an upper hydration 16, a circuit board assembly 18, a lower housing 20, an anode electrode 22, a cathode electrode 24, an anode reservoir 26, a cathode reservoir. 28 and a skin compatible adhesive 30 are provided. The upper housing 16 has side wings 9 to assist in the attachment of the device 10 to the patient skin. The printed circuit board assembly 18 has an integrated circuit 19 and a battery 32 coupled to discrete components 40. The circuit board assembly 18 is attached to the housing 16 by posts (not shown in FIG. 8) passing through the openings 13a and 13b, the ends of which post heat the circuit board assembly 18 to form a housing ( 16) is heated / melted to fix it. The lower housing 20 is attached to the upper housing 16 by an adhesive layer 30, and the upper housing 34 of the adhesive layer 30 is the upper housing 16 and the lower housing as well as the bottom of the wing 9. 20 is adhered to all. A button cell battery 32 is shown (partially) at the bottom of the circuit board assembly 18. Other types of batteries may be used for the power supply 10 as needed.

In general, the device 10 consists of a battery 32, electronics 19 and 40, electrodes 22 and 24, a drug / receptor reservoir 26, a counter reservoir 28 and a member 2 They are all integrated into self-contained units. The output of the circuit board assembly 18 (not shown in FIG. 8) is an opening 23 and 23 ′ in the depressions 25 and 25 ′ formed in the lower housing 20 by conductive adhesive strips 42 and 42 ′. Electrical contact with the electrodes 24 and 22 is formed through. Thereafter, the electrodes 22 and 24 are in direct electrical and mechanical contact with the upper sides 44 and 44 'of the medication reservoirs 26 and 28. The bottom side 46 of the medication reservoir 28 comes into contact with the skin of the patient through the opening 29 of the adhesive layer 30 (FIG. 9). The bottom side 46 ′ of the medication reservoir 26 comes into contact with the patient's skin through a plurality of openings 8 in the member 2. The formulation of the reservoir 26 preferably has a viscous gel filling the opening so that the reservoir 26 is in direct contact with the skin when the blades penetrate the stratum corneum. Contact between the reservoir and the skin provides a pathway for the material to be transported. If the reservoir 26 is not initially in direct contact with the skin, moisture will typically accumulate in the area in which it is provided, providing a path between the reservoir 26 and the skin for transferring the material.

The device 10 optionally has features that allow, by electrotransport, a patient to self-administer a drug dose or self-sample a bioelectrolyte. Upon pushing the push button switch 12, the electronic circuit on the circuit board assembly 18 flows a predetermined DC current to the electrodes / reservaries 22 and 26, 24 and 28 for a predetermined administration period. The push button switch 12 is conveniently located on the top of the device 10 and is easily activated through clothing. It is desirable to push the push button switch 12 for a short period of time, for example three seconds, for activation of the device, which minimizes the possibility that the device may be inadvertently activated. Preferably, a visible and / or audible initiation notification from the device is transmitted to the user by means of a light emitting LED 14 and / or an audible audio signal, for example from a "beeper". The formulation is administered / sampled through the patient's skin, such as the arm, by electrotransport over a predetermined dosing period. Preferably, the anode electrode 22 is made of silver, and the cathode electrode 24 is made of silver chloride. The reservoirs 26 and 28 are held by the lower housing 20.

For therapeutic agent (ie, drug) administration, the liquid drug solution or suspension will be contained in at least one of the reservoirs 26 and 28. Drug concentrations in the range of about 1 × 10 ⁻⁴ M to 1.0 M or more are used, preferably the drug concentration in the lower portion of this range is used.

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. Preferably, the upper housing 16 is composed of rubber or other elastic material, for example ethylene vinyl acetate, which is moldable by injection. Preferably, the lower housing 20 consists of an elastic sheet material (for example polyethylene) or plastic that is easily molded to form depressions 25 and 25 'and cut to form openings 23 and 23'. do. Preferably, the assembled device 10 is water resistant (that is, splash resistant, anti-fog), and more preferably waterproof. The system has a low profile that is easily adapted to the living body, allowing for free movement around and around the worn area. The reservoirs 26 and 28 are arranged on the skin-contacting side of the device 10 and are sufficiently separated to prevent accidental electrical shorts during normal handling and use.

The device 10 is contacted with the biological epidermis (eg skin) of the patient by an adhesive layer 30 (having an upper adhesive side 34 and a biocontact adhesive side 36). The adhesive side 36 covers the entire lower side of the device 10 except where the member 2 and the reservoir 28 are located. The adhesive side 36 has an adhesive property that, during normal user activity, the device 10 remains in place in the living body, but can be simply taken out after a predetermined (eg, 24 hour) wearing period. The upper adhesive 34 is in contact with the lower housing 20, retains electrodes and reservoirs in the housing depressions 25 and 25 ′, as well as retaining the member 2 in the lower housing 20, and the upper housing. Hold the lower housing 20 in 16.

In one embodiment of the drug administration or sampling device, a release liner (not shown) is present on the device to preserve the integrity of the device when not in use. In use, this release liner is peeled off the device before it is applied to the skin.

In another embodiment of the invention, a manual transdermal administration or sampling device is used with the member (2). Preferably, the reservoir is in the form of a matrix containing the dispersed material therein. The reservoir is interposed between the support layer and the flow control membrane, which preferably do not penetrate the material. The reservoir is formed of a material that is sufficiently viscous to maintain its shape, such as a rubber polymer. If a low viscosity material such as an aqueous gel is used as the reservoir, the support layer and the flow control membrane are sealed together at their edges to prevent leakage. In the sampling configuration, the reservoir does not initially contain the material. The microblade array member 2 is located under the film. The device is bonded to the biological epidermis by a contact adhesive layer around the rim of the member 2. This adhesive layer may optionally contain a material. A detachable release liner (not shown) is normally provided along the exposed side of the adhesive layer and is withdrawn prior to applying the device to the biological epidermis.

Alternatively, the transdermal therapeutic device according to another embodiment of the present invention may be contacted with the biological epidermis by a flexible adhesive overlay. In this embodiment, the device is preferably composed of a matrix-type material retention reservoir (in the case of a dosing configuration) containing dispersed material therein. In the sampling configuration, the reservoir does not initially contain the material. An impermeable support layer is provided near one surface of the reservoir. The adhesive overlay may be manufactured or provided with or separately from the remaining elements of the device. Depending on the formulation, this adhesive overlay is more preferred over the contact adhesives described above. For example, this applies when the material reservoir contains a material that will adversely affect the adhesive properties of the contact adhesive layer. The impermeable support layer is preferably a little larger than the reservoir, which prevents the material in the reservoir from interacting with the adhesive in the overlay and adversely affecting it. Optionally, a flow control membrane (not shown) may be provided on the skin / mucosa of the reservoir. Also, the device is normally provided in a detachable release liner (not shown) so that the device is taken out just before being applied to the biological epidermis.

Formulations of passive transdermal devices may be aqueous or non-aqueous substrates. This formulation is designed to allow the drug to be administered at the desired flux. Generally, the aqueous formulation comprises about 1 to 2 percent by weight of hydrophilic polymer and water, which is a gelling agent, such as hydroxyethylcellulose or hydroxypropylcellulose. Typical non-aqueous gels consist of silicone fluid or mineral oil. Additionally, mineral oil based gels contain 1-2 weight percent of gelling agent, such as colloidal silicon dioxide.

The reservoir matrix must be compatible with the administered agent, any excipients (eg flux enhancers, anti-inflammatory agents) and / or carriers thereof. When using an aqueous based system, the reservoir matrix is preferably a hydrophilic polymer such as a hydrogel. When using a non-aqueous based system, the reservoir matrix preferably consists of a hydrophobic polymer. Suitable polymeric Patricks are well known in the art of transdermal drug administration.

In general, the dosage or sampling form of the preferred formulation will determine the type of dosage or sampling system used, and vice versa. That is, the choice of a "passive" system for administering or sampling a product by diffusion or an electrical drive system for administering or sampling a product by electrotransport is primarily determined by the type of the product. For example, in passive administration systems in general, it has been recognized that the agent is preferably administered as it is, or in any of its acidic forms, rather than in the form of salts that are soluble in water. On the other hand, in electrotransport administration devices, it has generally been recognized that a drug is ionized and the salt of the drug must be dissolved in water. In the case of penetrated skin, there is a practical passive flux through the microslit produced by the microblades penetrating the stratum corneum. In the case of osmotic and pressure driven systems in which the drug is administered or sampled by the connective flow administered by the solvent, it is preferred that the drug has sufficient solubility in the administration solvent. Those skilled in the art will appreciate that the present invention may be used in conjunction with a wide variety of osmotic administration or sampling systems, and is not limited to this particular device. This osmosis device is described, for example, in US Patent 4,340,480 to Eckenhoff, US Patent 4,655,766 to Theeuwes et al. And US Patent 4,753,651 to Eckenhoff.

The invention can be used in conjunction with the administration of a wide variety of drugs that are normally administered through the skin, as well as through the biological epidermis and membranes. In general, the present invention encompasses all drugs in the main therapeutic field.

The present invention is particularly used to administer peptides, polypeptides, porotes, nucleotide drugs, and other species of drugs through biological epidermis such as skin. In general, these materials have a molecular weight of at least 300 daltons, more preferably from 300 to 40,000 daltons. Specific examples of peptides and proteins in this size range include LHRH analogues such as LHRH, goserelin, buserelin, gonadorelin, naparelin and leuprolide, GHRH, GHRF, insulin, insultropin, calcito Egg, octreotite, endorphin, TRH, NT-36 (chemical name: N-[[(s) -4-oxo-2-azetidinyl] carbonyl] -L-histidyl-L-prolinamide), refreshin, pituitary hormone ( For example, growth factors such as HGH, HMG, desmopressin acetate, etc.), follicular luteoid, αANF, growth factor releasing factor (GFRF), βMSH, GH, somatostatin, bradykinin, soma Totropin, platelet-induced growth factor, asparaginase, bleomycin sulfate, chemopapine, cholecystokinin, chorionic gonadopropine, corticotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon , HCG, Hirulogue, Hyaluronidase, Interferon, Turukine, Menotropin (uropolytropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analog, ANP, ANP clearance inhibitor, angiotensin ∥antagonists, antidiuretic hormone agonists, bradykinyl antagonists, seredases, CSI's, calcitonin genetic peptides (CGRP), enkephalins, FAB fragments, Ige peptide inhibitors, IGF-1, nerve stimulating factors, colony stimulating factors, parathyroid hormones and. .., parathyroid hormone antagonist, prostaglandin antagonist, pentezide, protein C, protein S, renin inhibitor, thymosin alpha-1, thrombolytic agent, TNF, vaccine, vasopressin antagonist-like substance, alpha-1 antitrypsin (combination type) ) And TGF-beta.

As described above, the member 2 of the present invention includes ion permeation, osmosis, passive diffusion, phonophresis, suction (i.e. negative pressure) together with a known sampling device. Can be used. Osmotic sampling devices may be used to sample various types of agents through the bioepidermis, including, but not limited to, prohibited substances such as glucose, bioelectrolytes, alcohols, blood gases, illegal drugs, and abuse drugs. . In another embodiment, the osmotic sampling device is contacted with the biological epidermis by a flexible adhesive overlay. The osmotic sampling device consists of a layer of salt positioned between the semipermeable membrane or the osmotic membrane and the optional material sensing element. This optional material sensing element can be various kinds of chemical reaction sensors and indicators, such as color indicator test strips associated with glucose testing, for example. The adhesive overlay may have a transparent window or cut-out in the area of the indicator so that the indicator is easy to see. In another embodiment, the material sensing element can be located between the osmotic sampling device and the salt layer.

While the invention has been described in terms of specific preferred embodiments, the foregoing description is for the purpose of illustrating the invention and should not be understood as limiting the scope of the invention. Other aspects, advantages, and modifications within the scope of the invention are apparent to those skilled in the art.

Claims (16)

A device that penetrates the stratum corneum of the biological epidermis, forming a pathway through which the lumber can enter or withdraw, A sheet 6 having at least one penetrating opening 8 and a plurality of microblades 4 extending downwards, wherein some of the plurality of microblades 4 have a length of the microblade 4. Thus, the first angled fragments 11 and 11 ′ and the first angled fragments 11 and 11 ′ located at the distal end on the microblade 4 with a first angle a with respect to the axis 15. Adjacent to), characterized in that it has a second angled fragment (13 and 13 ') having an angle (b) greater than the first angle (a) with respect to the axis (15). The method of claim 1, The device characterized in that the first angle (a) is in the range of about 1 ° to 25 ° and the second angle (b) of the second angled fragments 13 and 13 'is in the range of about 26 ° to 80 °. (2). The method of claim 1, The device (2), characterized in that the first angle (a) is about 15 ° and the angle (b) of the second angled fragments (13 and 13 ') is about 30 °. The method of claim 1, The device (2), characterized in that the first angle (a) is about 15 ° and the angle (b) of the second angled fragments (13 and 13 ') is about 35 °. The method of claim 1, A third angled piece, adjacent to the second angled piece 13 and 13 'and having an angle g greater than the angle b of the second angled piece 13 and 13' with respect to the axis 15; An apparatus (2) characterized by further comprising a section (21). The method of claim 1, Each subsequent angled fragment further comprising a plurality of adjacent angled fragments 11, 11 ', 13, 13', and 21, proximate the microblade 4 from said second angled fragments 13 and 13 '. The device (2), characterized in that the part has an angle (g) greater than the preceding angled fragments (13 and 13 ') with respect to the axis (15). The method of claim 1, The device (2), characterized in that the first and second angled fragments (11 and 13) are part of the arcuate microblade tip. The method of claim 1, And further comprising a therapeutic agent administration device (10) arranged to administer the therapeutic agent to the biological epidermis through the opening (8) and connected to the penetrating device (2). The method of claim 1, And a sampling device (10) arranged to sample the material from the biological epidermis through the opening and connected to the penetrating device (2). A device that penetrates the stratum corneum of the biological epidermis, forming a pathway through which the lumber can enter or withdraw A sheet 6 having one or more through openings 8 and a plurality of microblades 4 extending downwards, wherein some of the plurality of microblades 4 are the length of the microblades 4. Thus, the first angled fragments 11 and 11 ′ and the first angled fragments 11 arranged at the ends on each side of the axis 15 and each having a first angle a with respect to the axis 15 And second angled fragments 13 and 13 'each having an angle b greater than the first angle a on each side of the axis 15, respectively adjacent to 11'). (2). The method of claim 10, The first angle a of each of the first fragment portions 11 and 11 'is in the range of about 1 ° to 25 °, and the second angle b of each of the second angled fragments 13 and 13' is approximately Apparatus (2) characterized by the range of 26 ° to 80 °. The method of claim 10, The device characterized in that the first angle a of each of the first fragments 11 and 11 'is about 15 ° and the angle g of each of the second fragments 13 and 13' is about 30 °. (2). The method of claim 10, The device (2), characterized in that the first angle (a) of each of the first fragment parts (11 and 11 ') is not the same angle. The method of claim 10, The device (2), characterized in that the second angle (b) of each of the second fragment parts (13 and 13 ') is not the same angle. The method of claim 9, And further comprising a therapeutic agent administration device (10) arranged to administer the therapeutic agent to the biological epidermis through the opening (8) and connected to the penetrating device (2). The method of claim 10, And a sampling device (10) arranged to sample the material from the biological epidermis through the opening and connected to the penetrating device (2).