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DEVICE AND METHOD FOR ENHANCING
TRANSDERMAL FLUX OF AGENTS BEING
CROSS REFERENCE TO RELATED
This is a continuation-in-part of U.S. patent application Ser. No. 08/877,155 filed Jun. 17, 1997, now abandoned which claims priority from a provisional U.S. patent application, Ser. No. 60/019,990 filed Jun. 18, 1996.
FIELD OF THE INVENTION
The present invention relates to transdermal agent sampling. More particularly, this invention relates to the transdermal sampling of agents, such as glucose, body electrolytes and substances of abuse, such as but not limited to alcohol and illicit drugs. The present invention uses skinpiercing microblades to enhance the transdermal flux of the agents during transdermal sampling.
BACKGROUND OF THE INVENTION
Obtaining a droplet of blood for the purpose of sampling a constituent (e.g., glucose) is commonly achieved by piercing the skin using a lancet or other blade-like element. Many such skin piercing devices are spring-driven so that the piercing is accomplished automatically by a pen or similar spring-loaded device. See for example, Suzuki et al. U.S. Pat. No. 5,368,047.
Many blood sampling devices also apply suction to the wound following piercing by the lancet. The suction assists in obtaining a blood sample of appropriate size for testing blood components such as glucose. See for example, Suzuki et al. U.S. Pat. No. 5,368,047; Swierczek U.S. Pat. No. 5,054,499; Ishibashi U.S. Pat. No. 5,320,607; Haber et al., U.S. Pat. No. 5,231,993; and Swierczek U.S. Pat. No. 5,201,324.
Apartial vacuum applied to the skin has also been used in order to create suction blisters wherein the upper epidermis layer of the skin is separated from the dermis layer of the skin. To separate the epidermis from the dermis, a partial vacuum of about 0.25 atm (200 mm Hg) is applied for a period of about 2 hours. Upon separation of the epidermis from the dermis, The epidermis layer is then pierced or removed thereby exposing the underlying dermis layer for subsequent enhanced transdermal delivery of therapeutic agents such as drugs. See for example, Svedman, U.S. Pat. No. 5,441,490.
Apartial vacuum has also been used in order to determine blood gas content by applying the partial vacuum to intact skin. The partial vacuum causes "suction effusion fluid" to appear on the skin surface and vaporization of blood gases therefrom. See for example, Kaneyoshi, U.S. Pat. No. 5,417, 206.
There have been many attempts to enhance transdermal flux by mechanically puncturing the skin prior to transdermal drug delivery. See for example U.S. Pat. Nos. 5,279,544 issued to Gross et al., U.S. Pat. No. 5,250,023 issued to Lee et al., and U.S. Pat. No. 3,964,482 issued to Gerstel et al. These devices utilize tubular or cylindrical structures generally, although Gerstel does disclose the use of other shapes, to pierce the outer layer of the skin. Each of these devices provide manufacturing challenges, limited mechanical attachment of the structure to the skin, and/or undesirable irritation of the skin.
In addition to sampling blood, attempts have been made to sample interstitial fluid and to correlate the analyte
content in the interstitial fluid with that in the blood. See for example, Joseph, U.S. Pat. No. 5,161,532; Erickson et al., U.S. Pat. No. 5,582,184; Brinda, U.S. Pat. No. 5,682,233; Erickson et al., U.S. Pat. No. 5,746,217 and Erickson et al.,
5 U.S. Pat. No. 5,820,570. One of the advantages of sampling interstitial fluid is that the wound created in the skin is not as deep as the wound needed for a blood sampling. Thus, interstitial fluid sampling is generally considered less invasive than blood sampling.
1° However, there is still a need for even less invasive sampling of interstitial fluid for the purpose of determining analyte concentrations in the blood, for example, blood glucose concentrations. Unfortunately, less invasive techniques tend to draw smaller and smaller fluid samples
15 making accurate analyte concentration analysis problematic.
DESCRIPTION OF THE INVENTION
The present invention provides a reproducible, high vol
20 ume production, low-cost device suitable for transdermal analyte sampling. The invention comprises a plurality of microblades for piercing the skin. The microblades typically have a length of less than about 0.4 mm and a width and thickness which is even smaller. In spite of their small size,
25 the microblades can be made with an extremely reproducible size and shape so that the microslits formed by the microblades puncturing the skin also have a very reproducible size and depth. Because the microblades have a small thickness (i.e., small relative to the width and length of the
30 microblade), the microblades produce less tissue damage for a given cross-section than a skin piercing microneedle having a circular cross-section. The device of the present invention pierces the stratum corneum of a body surface to form pathways through which a substance (e.g., a body
35 analyte such as glucose) can be withdrawn (i.e., sampled). The device of the present invention is used in connection with body analyte or drug sampling. The sampling device used with the present invention is a negative pressure driven device which applies a partial vacuum (also referred to
40 herein as "negative pressure") to the microslit skin. The negative pressure causes interstitial fluid to efflux from the micrcoslits. The interstitial fluid is collected and analyzed for content and/or concentration of a body analyte such as glucose.
45 In one aspect of the invention, the device comprises a sheet having a plurality of openings therethrough, and a plurality of microblades integral therewith and extending downward therefrom. The negative pressure driven device applies negative pressure (i.e., suction) to the microslits
50 through the openings in the sheet.
The device is optionally anchored to the body surface in any of a plurality of ways, including but not limited to, prongs or barbs on the microblades, and skin-contact adhesives.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of one embodiment of a negative pressure driven device with a microblade array shown in g0 section according to one embodiment of the present invention;
FIG. 2 is an enlarged perspective view of the skin proximal side of the microblade array device in accordance with one embodiment of the present invention; 65 FIG. 3 is a partial top plan view of a microblade array pattern in accordance with one embodiment of the present invention for forming microblades with anchoring elements;
FIG. 4 is partial top plan view of yet another embodiment of the microblade array pattern of FIG. 3;
FIG. 5 is an enlarged view of a portion of the microblades of the microblade array pattern of FIG. 3;
FIG. 6 is an enlarged view of a microblade tip in accordance with one embodiment of the present invention;
FIG. 7 is an enlarged view of a microblade tip in accordance with another embodiment of the present invention;
FIG. 8 is a diagrammatic representation of a method for producing microblades of the present invention from the microblade array pattern of FIG. 3;
FIG. 9 is an enlarged cross-sectional view of angled microblades in accordance with one embodiment of the present invention;
FIGS. 10, 11 and 12 are yet other embodiments of the microblades with anchoring elements of the present invention;
FIG. 13 is a right side elevational view of another embodiment of a microblade with an anchoring element;
FIG. 14 is an end view of the microblade of FIG. 13;
FIGS. 15 and 16 are another embodiment of the microblade and an anchoring element;
FIG. 17 is a right side elevation view of a microblade with anchoring elements in accordance with one embodiment of the present invention;
FIG. 18 is a cross-sectional view taken along line 18—18 of FIG. 17;
FIG. 19 is a right side elevational view of another embodiment of a microblade with an anchoring element;
FIG. 20 is an enlarged partial top plan view of still another embodiment of the microblade array pattern;
FIG. 21 is an enlarged partial top plan view of yet another embodiment of the microblade array pattern; and
FIG. 22 is a diagrammatic cross-sectional view of another embodiment of the microblades of the present invention.
MODES FOR CARRYING OUT THE
Turning now to the drawings in detail, one embodiment of the microblade array device 2 of the present invention is generally shown in FIG. 1 for use with negative pressure driven device 10. Device 10 and device 2, in combination, are used for the percutaneous sampling of an agent. Device 10 is a known negative pressure (i.e., suction) applying device such as that disclosed in Ishibashi, U.S. Pat. No. 5,320,607, the disclosures of which are incorporated herein by reference. Device 10 is mounted on the skin distal surface of device 2. The skin proximal side of device 2 is in contact with, and preferably anchored to, the surface of skin 20, with the microblades 4 extending at least through the stratum corneum layer of skin 20. By appropriately sealing the device 10 against the skin distal side of device 2, the negative pressure applied by device 10 causes suction to be applied through the openings 8 in sheet 6. In this manner, interstitial fluid is extracted out of the microslits cut in the skin 20 and drawn into device 10. The negative pressure driven sampling device 10 can optionally include an agent sensing element (not shown in the figures). The optional agent sensing element can be any of a variety of chemically reactive sensors and indicators, for example the color indicating test strips used with glucose testing. The device 10 can have a cut out or transparent widow in the area of the indicators so that the indicators can be readily viewed.
The terms "substance" and "agent" are used interchangeably herein and broadly include substances such as glucose,
electrolyte, alcohol, illicit drugs, etc. that can be sampled through the skin. The major barrier properties of the skin, such as resistance to substance efflux, reside with the stratum corneum. The inner division of the epidermis generally
5 comprises three layers commonly identified as stratum granulosum, stratum Malpighi, and stratum germinativum. There is substantially less resistance to permeation through the underlying stratum granulosum, stratum Malpighi, and stratum germinativum layers than the resistance to permeation through the stratum corneum. The device of the present invention is used to form microslits in the stratum corneum and produce a percolation area in the skin for improved transdermal sampling of an agent.
Device 2 comprises a plurality of microblades 4 (i.e., a
15 microblade array) extending downward from one surface of a sheet or plate 6 (see FIG. 2 in which device 2 is in an inverted position to show the microblades). The microblades 4 penetrate the stratum corneum to the epidermis when pressure is applied to the device to increase the sampling of
20 a substance through the skin. The term "body surface" as used herein refers to the skin of an animal, particularly a human.
Preferably, the device 2 of the present invention helps to keep the device attached to the skin so that the percolation
25 areas and a continuous pathway are preserved during movement of the body surface. In the embodiment shown in FIG. 2, projections in the form of barbs 50 on at least one of the microblades 4 assist in anchoring the device 2 and any corresponding negative pressure driven device or structure
30 used in combination therewith to the skin. Barbs 50 can be on any number of the microblades from one microblade to all microblades. Other embodiments which assist to anchor the device to the skin will be discussed below.
The microblades 4 are generally formed from a single
35 piece of material and are sufficiently sharp and long for puncturing the stratum corneum of the skin. In one embodiment, the microblades 4 and the sheet 6 are essentially impermeable or are impermeable to the passage of an agent. The sheet 6 is formed with an opening 8 between the
40 microblades 4 for enhancing the movement of an agent therethrough. In the case of agent (e.g., body analyte) sampling, the analyte (or interstitial fluid containing the analyte) migrates from the body through the microslits in the stratum corneum which are cut by the microblades 4. In one
45 embodiment, the opening 8 corresponds to the portion of the sheet 6 occupied by each of the microblades prior to the microblades being transpositioned into the downward depending position. The number of microblades 4 per opening 8 can be any number, preferably however between 1 and
50 about 30 microblades per opening. Furthermore, the number of openings per device and the number of microblades per device are independent. The device 2 has a microblade density of at least about 10 microblades/cm2 and less than about 1000 microblades/cm2, preferably at least about 50
55 microblades/cm2, more preferably at least about 100 microblades/cm2, and still more preferably at least about 150 microblades/cm2. In similar fashion, the number of openings per unit area through which the agent passes, is at least about 10 openings/cm2 and less than about 1000
60 openings/cm2, preferably about 100 to 500 openings/cm2. The present invention produces a percolation area of about 0.005 to 0.05 cm2/cm2 of body surface, preferably about 0.01 cm2/cm2 of body surface.
As is best shown in FIG. 2, the microblades 4 have a
65 thickness which is much smaller than the width of the microblades near their base, i.e., near the point where the microblades are attached to the plate 6. This microblade