CA2257217C - Device for enhancing transdermal agent delivery or sampling - Google Patents

Device for enhancing transdermal agent delivery or sampling Download PDF

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Publication number
CA2257217C
CA2257217C CA002257217A CA2257217A CA2257217C CA 2257217 C CA2257217 C CA 2257217C CA 002257217 A CA002257217 A CA 002257217A CA 2257217 A CA2257217 A CA 2257217A CA 2257217 C CA2257217 C CA 2257217C
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Prior art keywords
blades
sheet
agent
openings
blade
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Expired - Fee Related
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CA002257217A
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French (fr)
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CA2257217A1 (en
Inventor
Michel J.N. Cormier
Armand P. Neukermans
Barry Block
Avtar S. Nat
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Alza Corp
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Alza Corp
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150015Source of blood
    • A61B5/150022Source of blood for capillary blood or interstitial fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150053Details for enhanced collection of blood or interstitial fluid at the sample site, e.g. by applying compression, heat, vibration, ultrasound, suction or vacuum to tissue; for reduction of pain or discomfort; Skin piercing elements, e.g. blades, needles, lancets or canulas, with adjustable piercing speed
    • A61B5/150061Means for enhancing collection
    • A61B5/150099Means for enhancing collection by negative pressure, other than vacuum extraction into a syringe by pulling on the piston rod or into pre-evacuated tubes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150206Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150274Manufacture or production processes or steps for blood sampling devices
    • A61B5/150282Manufacture or production processes or steps for blood sampling devices for piercing elements, e.g. blade, lancet, canula, needle
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150007Details
    • A61B5/150374Details of piercing elements or protective means for preventing accidental injuries by such piercing elements
    • A61B5/150381Design of piercing elements
    • A61B5/150412Pointed piercing elements, e.g. needles, lancets for piercing the skin
    • A61B5/150427Specific tip design, e.g. for improved penetration characteristics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150969Low-profile devices which resemble patches or plasters, e.g. also allowing collection of blood samples for testing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/150977Arrays of piercing elements for simultaneous piercing
    • A61B5/150984Microneedles or microblades
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15103Piercing procedure
    • A61B5/15105Purely manual piercing, i.e. the user pierces the skin without the assistance of any driving means or driving devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101Details
    • A61B5/15103Piercing procedure
    • A61B5/15107Piercing being assisted by a triggering mechanism
    • A61B5/15113Manually triggered, i.e. the triggering requires a deliberate action by the user such as pressing a drive button
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/15Devices for taking samples of blood
    • A61B5/151Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15142Devices intended for single use, i.e. disposable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/20Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/20Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A61N1/303Constructional details
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045Devices for taking samples of body liquids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/20Surgical instruments, devices or methods, e.g. tourniquets for vaccinating or cleaning the skin previous to the vaccination
    • A61B17/205Vaccinating by means of needles or other puncturing devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023Drug applicators using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0038Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a channel at the side surface
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046Solid microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053Methods for producing microneedles

Abstract

A percutaneous agent delivery or sampling device (10) comprising a shee t (6) having at least one opening (8) therethrough and a plurality of microblades (4) for piercing the skin for increasing transdermal flux of an agent. The microblades (4) having a relatively sharp angled leading edge (11, 11') whic h transitions to a relatively gradually angled blade edge (13, 13').

Description

z DELIVERY OR SAMPLING
s The present invention relates to transdermal agent delivery and sampling.
More particularly, this invention relates to the transdermal delivery of agents, s such as peptides and proteins, as well as the transdermal sampling of agents, such as s glucose, body electrolytes and substances of abuse, such as but not limited to alcohol 1o and illicit drugs. The present invention uses skin-piercing microblades to enhance the 11 transdermal flux of the agents during transdermal delivery or sampling.
1z 1s BACKGROUND ART

Interest in the percutaneous or transdermal delivery of peptides and proteins to 1s the human body continues to grow with the increasing number of medically useful 17 peptides and proteins becoming available in large quantities and pure form.
The 1s transdermal delivery of peptides and proteins still faces significant problems. In many 1s instances, the rate of delivery or flux of polypeptides through the skin is insufficient to zo produce a desired therapeutic effect due to the binding of the pofypeptides to the skin.
z1 In addition, polypeptides and proteins are easily degraded during and after zz penetration into the skin, prior to reaching target cells. Likewise, the passive flux of zs water soluble small molecules such as salts is limited.
z4 One method of increasing the transdermal delivery of agents relies on the application of an electric current across the body surface or on "electrotransport".
is "Electrotransport" refers generally to the passage of a beneficial agent, e.g., a drug or z7 drug precursor, through a body surface such as skin, mucous membranes, nails, and zs the like. The transport of the agent is induced or enhanced by the application of an zs electrical potential, which results in the application of electric current, which delivers or so enhances delivery of the agent. The electrotransport of agents through a body kl:\. W )\=I:I'\-III f:v.C:ill:\ ~i:> l . (.-;iti : :i:n;r _ ._.. ,~. ~.._ . _~.,~~ ..__.. c:1 I I I.W - -.I;~ ts:, _':s;l:i.1-lty:rr r CA 02257217 1998-12-02 "" ' 24r~6 CIP 1 surface may be attained in various manners. One widely used eaectrotransport 2 process, iontophoresis, involves the elec,~tncally induct transport of charged ions. Electroosmosis, another type of eiectrotransport process, involves the a movement of a solvent with the agent through a membrane under the influence s of an electric field. Electroporation, stiff another type of electrotranspcrt, involves the passage of an agent through pores formed by applying a high voltage electrical pulse to a membrane. (n many instances, mare than one or a these processes may be occurring simultaneously to different exten;s, ElECi:rotranspcrt daiivery generally inrrea.ses agent delivery, par~~icUiarty large vo molecular weight spLcies (e.g., polypeptides) delivey rates, relative to passive or nen-electrically assisted twansderr~al delivery. However, ;u~-~her increases in ~z transderma! delivery rates and reductions in polypeGtide degradatio~ during tr ansdes-mal delivery are highly desirablE.
One method c;f increasing the agent transdermal deliverer rate invol~:es ,s pre-treating the skin with, or alternatively co-delivering with the beneficial agent, 'a a skin permeation enhances. The term "permeation enhances" is broadly used herein to describe a substance which, when applied to a body surf2ce through ~a ~v~;ich the agent is delivered, enhances its transder ma; t3ux. The mechanism may involve an increase in the permeability of the body surface, a reduction in :o the degradation of the agent (e.g., degradation by skin enzymes dGring _. L~ansport, c~r in the case of eiectrotrensport delivervlsamplng, a reduction of the z2___ electrical resistance pf the body surface to the passa5e of the agent za therethrough or, the creation df hydrophilic pathways through the body surface.
z~ There have been many attsmpts to enhan_re transdermal flux by z5 mechanically puncturing the skin prior to transdermai drug delivery. See ';~r zs example U.S. patent Nos. 5,279,544 issued to Gross et al., 5,250,02 issued to z~ Lee et al., and 3,964,482 is::,ued to Gerstel et al and WO 96/17648 published ze June 13, 1998. These devices utilize tt~rbular or cylindrical structures generally, zs aitrough Gerste! and V'JO 96117648 do disclose the use of other shapes, to 3o pierce the outer layer of the skin. Each of these devices provide manufacturing IZC\. 1~.)\:f:f':\-\ll f:.\Cill;\ (c; : p_ f.-:lti , :s:~l:;
~_l.. I I I,l',I- r~l:l t~;) ;::i;J:i~l4l~.~:l,~ ti _ ~ ~ - ~ ~- ~ CA 02257217 1998-12-02 ' -' ' z~6~ ciF ~
2a challsr~ges, resistance to easy aenetraticn of the skin, and;cr undesiranle irritation of the skin.

As has been discussed, a variety of chemicals and mechanical means have z been explored to enhance transdermal flux. However, there is still a need to provide a s device suitable for increasing transdermal flux which device penetrates the skin with a very little insertion force, is low-cost and which can be manufactured reproducibly (i.e., without significant variation from device to device) in high volume production.
s DESCRIPTION OF THE INVENTION
a s The present invention provides a reproducible, high volume production, ~o low-cost device capable of penetrating the skin easily and suitable for increasing o transdermal flux. The invention comprises a plurality of microblades for piercing the ~z skin having a leading edge with a relatively sharp angled first segment which 13 transitions to a relatively gradually angled second segment. The particular microblade ~a geometry allows better penetration of the skin with less "push down" (i.e., penetration ~s and insertion) force required of the user. The first segment forms a relatively small s angle with respect to an axis extending along the length of the microblade to provide a very pointed section on the blade that pierces the skin readily. The leading edge then ~a transitions to a second segment which forms a larger angle relative to the axis than s the first segment. The second segment provides strength to the overall blade to zo prevent bending due to the wider blade along that portion compared to the portion z, along the first segment. The second segment, because of its larger width, also forms zz longer slits in the skin thereby increasing the size of the transdermal pathways through zs which agents can be delivered or withdrawn. Together, the sharper blade tip and the za relatively stronger blade base, improve the overall penetration characteristics of the zs microblade and thereby reduce the push down force needed to achieve the desired zs penetration quality.
z~ The blades typically have a length of less than about 0.5 mm and a width and za thickness which is even smaller. In spite of their small size, the microblades can be zs 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 blades), 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 drug) can be introduced (i.e., delivery) or through which a substance (e. g., a body electrolyte) can be withdrawn (i.e., sampling).
In one aspect of the invention, the device comprises a sheet having a plurality of openings therethrough, a plurality of microblades integral therewith and extending downward therefrom, at least a portion of the microblades having a leading edge with a first angled segment and contiguous with the first angled segment a second angled segment, the first angled segment being located distally on the microblade and having a first angle relative to an axis along the length of the microblade, the second angled segment having an angle greater relative to the axis than the first angle.
The device of the present invention can be used in connection with drug delivery, body analyte or drug sampling, or both. Delivery devices for use with the present invention include, but are not limited to, electrotransport devices, passive devices, osmotic devices and pressure-driven devices. Sampling devices for use with the present invention include, but are not limited to, "reverse" electrotransport devices such as disclosed in Glikfeld et al., U.S. Patent No. 5,279,543 and Guy et al., . ,. , ,..,~,".. ,.,~~.".,.~,..,.,~ "..

' 4a U.S. Patent No. 5,362,307, passive diffusion devices such as disclosed in Schoendorfer, U.S. Patent No. 5,438,984, osmotic devices such as disclosed in Eckenhoff et al., U.S. Patent No. 4,756,314, and negative pressure driven devices.
According to a broad aspect of the invention, there is provided a device for piercing the stratum corneum of a body surface to form pathways through which an agent can be introduced or withdrawn, comprising: a sheet having at least one opening therethrough and a plurality of blades extending downward therefrom, at least one of the plurality of blades having an anchor for anchoring the device to the body surface; wherein the anchor is selected from the group consisting of: (i) a projection extending out from a plane defined by the at least one blade; (ii) a barb; (iii) at least one opening extending through the at least one blade;
(iv) an adhesive on a body contacting surface of the sheet;
(v) each of the blades having an axis, the blades being oriented so that the blade axes are substantially parallel and the axes form an angle of 1° to 89° relative to the sheet; (vi) each one of the plurality of blades defines essentially a plane and wherein the anchor comprises a portion of the plurality of blades being oriented at an angle of 90° with respect to a remaining portion of the plurality of blades; and (vii) each one of the plurality of blades defines essentially a plane and wherein the anchor comprises a portion of the plurality of blades being oriented at an angle within a range of 1° to 89° with respect to a remaining portion of the plurality of blades.
According to another broad aspect of the invention, there is provided a device for piercing the i I ..iinYii ~ i ~i II ~n~~~..IbHWm.... iL Yii i 4b stratum corneum of a body surface to form pathways through which an agent can be introduced or withdrawn, comprising: a sheet having a plurality of openings therethrough, at least one of said openings having a plurality of blades located along a periphery thereof and extending downward from the sheet, and an anchor for anchoring the device to the body surface; wherein the anchor is selected from the group consisting of: (i) a projection extending out from a plane defined by at least one blade; (ii) a barb on a blade;
(iii) at least one opening extending through at least one blade; (iv) an adhesive on a body contacting surface of the sheet; (v) a portion of the plurality of blades being oriented at an angle of 90° with respect to a remaining portion of the plurality of blades; and (vi) each one of the plurality of blades defines essentially a plane and wherein the anchor comprises a portion of the plurality of blades being oriented at an angle within a range of 1° to 89° with respect to a remaining portion of the plurality of blades.
According to a further broad aspect of the invention, there is provided a method for producing a device for piercing the stratum corneum of a body surface, the method comprising: applying a layer of photo-resist to a first side of a sheet; exposing the layer of photo-resist through a mask pattern for producing a plurality of blades;
etching exposed portions of the photo-resist and the sheet to produce the plurality of blades and openings through the sheet; punching the plurality of blades through the openings such that the plurality of blades extend downward from the sheet; and incorporating the device for piercing the stratum corneum into a delivery device or sampling device.

I I."inl~P ,~ II ~n ~.,4mn»., I6 I

4c According to a still further broad aspect of the invention, there is provided a method of transdermally sampling an agent, comprising: a. placing a device on a body surface through which the agent is to be withdrawn, the device including a sheet having at least one opening therethrough and a plurality of blades extending downward therefrom whereby agent transmitting pathways are formed through the stratum corneum at the body surface, and a reservoir in agent-transmitting relation with the opening;
b. withdrawing the agent through the pathways and said opening; and c. collecting the agent in the reservoir.
BRIEF DESCRIPTION OF THE DRATnIINGS
Figure 1 is an enlarged perspective view of the skin proximal side of the microblade array device in accordance with one embodiment of the present invention;
1 Figure 2 is an enlarged view of a portion of the microblades of the blade array z pattern;
a Figure 3 is an enlarged view of a microblade in accordance with one 4 embodiment of the present invention;
s Figures 4-7 are enlarged views of other embodiments of the microblade in s accordance with the present invention;
Figure 8 is a perspective exploded view of one embodiment of an a electrotransport agent delivery system with a microblade array device according to the s present invention; and 1o Figure 9 is a bottom plan view of the electrotransport agent delivery system of 11 figure 8.

1s ~IIIODES FOR CARRYING OUT THE INVENTION' 15 Turning now to the drawings in detail, one embodiment of the skin-piercing 1s member 2 of the present invention is generally shown in Figure 1. Member 2 is used 1~ in conjunction with percutaneous administration or sampling of an agent.
The terms 1a "substance", "agent" and "drug" are used interchangeably herein and broadly include 1s physiologically or pharmacologically active substances for producing a localized or 2o systemic effect or effects in mammals including humans and primates, avians, 21 valuable domestic household, sport or farm animals, or for administering to laboratory ii animals such as mice, rats, guinea pigs, and the like. These terms also include 2s substances such as glucose, body electrolytes, alcohol, licit substances, 24 pharmaceuticals, illicit drugs, etc. that can be sampled through the skin.
The major zs barrier properties of the skin, such as resistance to drug penetration, reside with the . is outermost layer (i.e., stratum corneum). The inner division of the epidermis generally ~ comprises three layers commonly identified as stratum granulosum, stratum malpighii, $ and stratum germinativum. Once a drug penetrates below the stratum corneum, there Zs is substantially less resistance to permeation through the stratum granulosum, stratum malpighii, and stratum germinativum. The device of the present invention is used to form microslits in the stratum corneum and produce a percolation area in the skin for s improved transdermal delivery or sampling of an agent.
a Member 2 comprises a plurality of microblades 4 (i.e., a blade array) extending s downward from one surface of a sheet or plate 6 (see Figure 1 in which a portion of s member 2 is in an inverted position to show the microblades). The microblades 4 are sized and shaped to penetrate the stratum corneum of the epidermis when pressure is s applied to the device. The microblades form microslits in a body surface to increase s the administration of or sampling of a substance through the body surface.
The term "body surface" as used herein refers generally to the skin of an animal or human.
» The microblades 4 are generally formed from a single piece of sheet material ~z 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 essentialiy impermeable or are impermeable to the passage of an agent. The sheet 6 is formed with an opening 8 between the microblades 4 for enhancing the movement of an agent therethrough.
In ~s the case of therapeutic agent (e.g., drug) delivery, the drug is released from a drug-containing reservoir (not shown in Figure 2) through the opening 8 and passes ~a through microslits formed by the microblades 4 cutting through the stratum corneum, migrates down the outer surfaces of the microblades and through the stratum corneum 2o to achieve local or systemic therapy. In the case of agent (e.g., body analyte) 21 sampling, the analyte migrates from the body through the microsfits in the stratum 22 corneum which are cut by the microblades 4.
23 In one embodiment, the opening 8 corresponds to the portion of the sheet 6 Za occupied by each of the microblades prior to the blades being transpositioned into the 25 downward depending position. The number of microblades 4 per opening 8 can be is any number, preferably however between 1 and about 30 blades per opening.
z7 Furthermore, the number of openings per device and the number of blades per device zs are independent. The device may have only one opening and one microblade.
The 2s agent can be administered at a controlled rate of release from the reservoir through an 'rtC.\. \lJ.\~la'won_C.W .W ~..v m,> . I ~_ ,~..;,<, . .s.~r;r ;l ._u. ... .~.. . _u. u. ..-.... ~-~-I II L'...y~ YwI;J t5a1 _v5:l:l-I'11n:):J/
CA 02257217 1998-12-02 ' w~ w agent release rate controlling material (not shown) covering the openings 8.
z As is best shown in Figure 1, the micro blades 4 have a thickness which s is much smaller than the width of the blades near their base, i.e., near the point a where the blades are attached to the sheet 6. This blade geometry provides s maximum drug percolation area with a minimum blade penetration area, and s hence less tissue damage. The drug percoiatian area is the skin area in contact with the blades which provides for drug penetration in the skin. The a microbiades are shaped with the largest possible surface area with a minimal s cross-sectional area so as to givE the largest possible oercclation area, Thin ,a rn i4rcblades are better than round protrusions for this purpcse because for the ., same cross-section, a thin blade produces more percolation area and less ,a tissue darrjage than a protrusien having a circular cross-section (i.e., a v cylindrically shaped protrusionj. T his is a crucial advantage ovEr the prior art ,a ~ ound elerryents such as needles and tubes. Thin microblades also require less ~s insertion force than round protrusions. The width of each blade can be any of a ~s range of widths. The widths can be different from blade to blade in the array ,r pattern: Likewise, the width can be variable along the length of the blade, as ~a will be described in r-,ore d4tail Geiow. the width of t~;e blad8 at tl~e .a intersection of the blade and the body surface after the blade array has been zo inserted is preferably in the range of about 90 ~m to about 500 um, more z~ preferably about 25 ~m to about 4rJ0 elm, more preferably 25 um tc about .:OrJ
z~ um.
The microblades 4 are provided with slanted (i.e., angled) leading edges za fi4 having multiple segments to reduce the insertion force required to press the a blades into the skin tissue. Because the blade insertion force is reduced, it is za also possible to use a thinner and more flexible sheet 6, ~rrhich is advantageous z7 in devices adapted to be worn on the skin for extended (e.g longer than 30 2a minutes) periods of time. In Figures 1-5 and 7, the leading edges 84 have fiwo zs segments each having a different leading angle. The first segmant 11 is the distal most segment. Contiguous with the first segment 11 is second segment f~C\. \(>~-:.I:l:;\.~Il_f-:WIII'.'. sr='.. ..,;_L:- t:-;Jtt : :s.n:r . ell I I
L,W"_ +.f~J ti:l ~;i;J:J~~~ts-:4f CA 02257217 1998-12-02 w'w 7a ~ 3. The angle of the first segment relative to axis or reference line 15 is z designated as a. The angle of the second segment is hC'\. \f»,:l-:I'.A-\11L\C'lll:\ W '~ l r- o-:JtS . .: I( : ~:.f I l f,~\I-. -,I-;~ tt:f _:~:J;yl+.(s:-,:Nl I
. _.. . _. , _ .. _ : ~. .,; .,__..
CA 02257217 1998-12-02 ~ -"' " w 24fi8 C J P 1 designated Vii, The multiple segmented slanted leading edne produces a cu;
z through the skin tissue that is equal to the full widt"t of the blade 4 while reducing the amount of metal that is in the skin tissue. in other words, a fiat a leading edge (i.e., a is 90°) produces a blade with a larger amount of blade material in the skin tissue than is produced by a blade having a slanted leading s edge. The angle a of each segment 11 can be any angle between about 1 ° to 25°; preferably about 15°. The fast segment 11 then transitions to the second s segment 13 Having an angle ~i between about 26' to 8G°, preferably between 9 about 30' to 45°, more preferably 35°.
m The microblade 4 of ;he ernbodimer~ts shown in ; figures 4., 5 and 7 have sharp distal tips 19 for easy penerration of the skin. The embodiments or ~z microbiade 4 shown in Figures 1-3 and 5 have a fattened distal most tip 17 VIhIC~' !u easier to ma~~ufacture a.ld has ~re~tirr reSiStatti a t0 ~Endlng up'Jr' ',a insertion in the skin than the more pointed tip 19.
The embodiments of Figures 1-d and 6 have a single slanted loading ~s edge ~4 on the microbfade 4, whereas the embodime7ts of Figures 5 and 7 m have taro slanted leading edJes 64 beginning approximately an the center line to 1;, and extending out~,~ardfy therefrom on either side of tire center line, As ~e shown in Figure 7, the slanted leading edges need not be symmetrical about - z~ the center line. First segment 11' is not equal to segment 7 1 and second z1 segment l 3' is not equal to segment 13.
The rnultinle ~e merttPd Ica r n pr!r,n ~~ Gr ~~", ~f rh p p '' ~ ~,~~ ~.. , f ", W a OrHwViill 2V~ ;J
z3 previously described can have any number of segments. For example, the z~ embodiment of Figure 6 has a third segment 21. The angle of the third is segment 21 is designated y, The 'second segment 13 transnions to the third z6 segment 21 having an angle y relative to reference line .5 greater than the m angled. Preferably, angle Y is between about 35° to 80p, more preferably about ae ~S5°. As can be appreciated from Figure 6, a plurality of contiguous angled za segments wherein each of the subsequent angled segments progressing zo proximally along the microblade from the first segment has an angle relative to KC1 . 1(\:I:I'.1-vll I;'~.Cl)f'_~, o:~ i i t:-sftt : :t: p : ~~lr I I i i:.~n-. +-i:~ ~i;~ ~',3;~:ul~lf;;~: rr I
-. , .. ... _ . . '.-.- w--~ CA 02257217 1998-12-02 "'' " ' 8a 1 the reference hne ' 5 greater than the angle of the preceding angled segment z creates a leading edge which appears arcuate {i.e., curved) in shape. In one kL\. \(J'--=.I;!~1J.\Il-I'.C:III.'. o:'.. ...._~ ' f;-:)ti : :i: ~ I l-(;I !l I~.C1!- +-i;l Li;l :.::i:);J~I-ll:.->:Ili:i v- ' -' ~~ CA 02257217 1998-12-02 ~~-. .- . ..

embodiment, the leading edge appears curved across the entire width of the a blade.
s The microblades 4 are formed using a photo-etching process. The photo-etching process aliows the microblades 4 to be reproducibly formed on a s very small (i.e., tens cf microns) scale. This process also allows the microblades 4 to be formed in shapes which require lower force for penetrating the skin. Some of the microblades 4 are provided with barbs 50 (Figures 1 and 2) in some fashion so that the member 2 and any corresponding device s attached thereto stays attached to the skin after being applied with pressure.
~o T he decree of attachment and the number and size of the barbs 50 is such as ~~ to retain ttie delivery or sampling device during the normal acfivity of tfie ~2 wearer, but rlct cac.~se pain upon removal. As the microblades are pr essed into n the skin tissue or use, the leading edge 64 of each microbiade t. cuts ;iorough :~ and pushes aside the skin tissue. After the tt7icroblades have come to rust in 's the skin, the skin due to its elastic nature at least partially comes back together ~s around the edges of the microblades 4, in this way the sLrface fib on each ,~ microblade having a barb 50 engages skin tissue and anchors trw device in the '8 5nii~. If the miceobiade is left in the skin for an exte(~d2d period of tim4 ;e.g., 24 :~ hours), the skin tissue begins to heal together in the area behind the surface 68 as of the barb 50 thus improving the anchoring of the device._ only one barb per z, Made a shown in the figures but it is within the sx;pe of the prese;lt invention ti;at each b!adw can slave a pJtura!ity of r_:arbs p,.~~onr,;ling thpr'fr~vi'~. The z3 plurality of rnicroblades 4 for puncturing the stratum comei~;m are present on 2a one face surface 49 of the member 2 in any predetermined arrangement, for is example, as a cluster of blades spaced in rows having any desired number, or in any spaced apart relation of one blade to each other. Each ,blade has a width and thickness that facilitates penetration of the stratum corneum without 2e bending. In the Qmbodiment of Figure 1, there are six blades 4 along the as perimeter of each apening 8 in sheet 6. Preferably, the width of each blade is so between about 135 p,m to about 300 ~m and the length is about 600 Vim. The h~~. 1i)\ t.l'-~-,~ti I:._Wilt.:\.~~.~ ,_ ~.. , f'-~~m . .~. ~ I .,. i ~ i i m-- r.iyS;J ~;S;J;u1-~Sn.u:~.N~.4.
CA 02257217 1998-12-02 ~" " " '' pass clP ~
9a required length of the blGdss is 5u>t7iect to variation of the body surface being 2 penetrated and correspflnds to the natural thickness of the stratum corneum, i'or one of the principle features of t~Ce invention is IW \. W '. t.!':v-~It L~.~Lftl.. n:s n ~- .-;us .,. , , v.~.n . , t.u,n-, -,.~
.. _.~.s;ni im:~.n , _. . u. n . . . . . _. m. .._-.. _ , _ _ ' I , CA 02257217 1998-12-02 ~ '' that the blades arE to penetrate the stratum corneum into the epidermis.
z Usually, the blades will be about 25 ~m to about 700 um in lengttn with the length for most applications being between about 50 ~.m to abcut 640 urn. 8y way of example, the microblade 4 or Figure 3 is.254 pm wide and 508 wm in s length wherein dimension C is 127 u.m and dimension D is 89 u.m. The s microblade 4 of Figure 4 is 254 ~cm wide and 610 um in length ;nlherein dimension :~ is 127 ;.rm and dimension D is 178 pm. The sharp distal segment a of the microblade is supported by the remainder of the blade as it widens at an angle ;3 and provides a relatively urge base width which pr ovides the rnuuired Iu s;:ucturai integrifir to prevent blade deflection upon inser~on and penetration in t7 the skin.
,z The pattern fcr any of the blade array devices of the present invention is praauced with a photo-etching p~o~ss. Far example. refere~ce may be hud to ,4 WO 97148440 published December 24, .99' of which any of the disclosed ,s methods can be used to produce the member 2 of the present invention. A
thin ~E sheet or plate 6 of metal such as stainless steel or titanium is etched photo-lithographicalfy with patterns conta;ning blade-iiice structures. In general, ,a a thin laminate dry resist or wet resist is applies on a sheet about 7 um to about 1 C~u am thici<, preferably about 25 um to about 50 ~m thick. The resist is <o contact exposed using a mask having the desired pattern and is subseguently developed. ; hese ~peraticns are conducted in much the same way that they .Z? arc ?err ih~ mom yr.+yr.-»Y of +rt ' ~i H. .~ n. L,p..a ' at... s L _ ~
w ~.. '..~.~ . m ~ pnnm(a ~.~rvi~m ucaru. W G aW ,_.Gl IJ U7Cn eI~IICV
Za using acidic solutions. After the pattern has been etched through the sheet, the a4 sheet is placed on a die having a plurality of openings corresponding to the z5 openings 8 in the sheet. A punch having a plurality of protrusions 2a corresponding to the.openings in the sheet and die is initially located ab4ve the 27 sheet and die. At the initial stage, the blades 4 are in the same plane as the ze rest of the sheet 6. The protrusions on the punch are then pressed into the z~ openings, thus bending the blades 4 downward to be at an angle (e.g., 3o substantially perpendicular) to the plane of the sheet. The finished structure kC\.1(i'~.:;.,I'\-\II f.,lill'.v ~~: I ; - (,-!3t4 . :i i_ . Ci.p ~..I p.t.l1-+1;t ci;: '.=;S;i:)l i((:_,:~ilt4 . -. . _. . . . . . _ .. _.,.. CA 02257217 1998-12-02 ,. . . . . _ 2466 C;IP 1 1ga ~rovldes blades 4 wEtn an adJacent opening 8 for the passage of a substance z therethrough when the member KCy . ',v,v,:l-:I' y-vliJt.\Cflf:'. yrp . t.' - ''-'.at . :~ i~ : ~u ~ ~..;- t ;..'', +.1J t3L-1 =:3~-i:l-l.li;~;: rl t - ' ~ -' CA 02257217 1998-12-02 '' -~ ~ .
' 2466 C I P 1 1 2 is spplied to the skin. Rectarguiar openings 8 are shown in the figures but z the invention encompasses the use of any shape openings including, but not (invited to, square, triangular, circular and elliptical. The blades d can be patterned with resist on both sides of the sheet 6 and s~;bsequently etched simultaneously from both sides to achieve maximum pattern resolution for a s given sheet thickness and to produce a knife-like edge that can not be achieved v~'ith conventional stamping and punching processes. Aatematively, the blades 4 can be patterned and etched from one side aryiy.
s !n another embodiment or the two-sided etching process, the blade array w pauern of any of the embod;-nents of the present invention is e;oh2d into the ~~ top surface o. sheet C, A second pattern equivalent to the area bounded by fa each of the openings $ (e.g., rectangular) is etched into the bottom su.rtace 48 ~~ ~i~G", t~'a: iraCh Gf t~i~ ~Iad~S I!1 tl'l~ L?lad~ c"!r.'3y j3a'i'~'er:7 IS
ihir:nrr ih~utl tf',2 .. surroundinsheet ~. As a result, the sheet 6 forms a strong base and as the ~s punch deforms. the blades 4 downward, each of the Blades plastically deforms ,s so as to pr:,dc~ce ,blades that :urn straighter and more truly perpendic~.~lar to the s,h eel.
In o;.e e;r~bodiment o~ the etci,ing process, a dry resist;e,g., '~~ynachem ~a Fb" available from Cynachem located in Tustin, CA) is applied 1~,5 um thick to zo ore or both sides of the sheet and exposed in a stan6ard manner. Then a :' s;:ftable spray etcher (e g., "Dynamic VRF 1 OiNNt" available from L'~'estern za s ech. Assoc. ioaated i,n Anaheim,, r'Al is used t,, r~ra,r a rrti~rtr~ro ref fnrrin f ~. '.1t Vr v. 4, , iy 23 chloride and hydrochloric acid onto the resi,t and sheet at 52 'C (125 'f=) far ~a two minutes. A standard caustic stripper is used for the resist removal.
z~ In anc~her embodiment of the etching process, a wet resist (e.g., as "Shipley 111 S" available from Shipley Corporation, located in Mprfborough, MA) , m is applied 7.5 um thick at about 20 °C (70 °F) to one or both sides of the sr~eet z5 and exposed in a standard manner. Then a suitable etchant (e.g., ferric chloride) is sprayed onto the resist and sheet at 49 'C (12Q °F}, A
standard caustic stripper is used for the resist removal.

F;C~. \m'.:L.1'\-v11 I.W:flp..'. W, f l- E:-~~t; :t. , l.: : L I l I I.~'.1- +.1;J ;;:~ ~:i:l:f~i l fu,i: rr Ill ' ' ~ - J- ' "-' ~ ~ ~ CA 02257217 1998-12-02 w~ w ~ - --2466 C I P 1 ' I Generally, the blades a are at an angle of about 80° to the surface 48 of z the sheet 6 after being 'unGhed, but they can be disposed at any angle forward 3 an backv~ar d fn gm the perpenaicular position that wlU fac;litate penetration of a and attachment to the strafi.~m cvrneum. in one embodiment, the blades are all aligned at an angle between about 1 ° and about 89°, preferably about 1 p° to about o0°, core preferably about 20° to 45° to facilitate t~'~e device being slid along and into the skin. The angled blades have two principal advanaages.
a First, penetration of the blades is not as strongly opposed ny the elasticity cif the s skin because the blades are slid generally horizontalh~ into the skin as opposed ,c tc rressir;g uwTi;;aliy c;n the Skin, Second, the a~ngad blades act to anc;ar the ~~ cievi:;e in the skin as ally motion of the skin is Isss likely to dislodge the blades.
in additiGn, other anchoring elements su;.h as barbs, openingc, e'tc. can be ';~s>~'. ~~r~it~l th~~ angled bicdes to further enhance anchoring of the device.
m The sheet and blades can be made from materials that have suifcient 13 strength and manl~facturability to produce blades, such as, glasses, ceramics, 5e rigid pclymers, metals and metal allays. Examples of metals arid metal alloys '' nc!;~Ide but are not limited to stainless steel, iron, steel, tin, zinc, copper, °s platinum, al;Jminum. germanium, nic>rei, zirconium, titanium and ;itanium alloys rs consisting of nickel, molybdenum and chromium, metals plated with nickel, zo gold, rhodium, iridium, titanium, platinum, and the like. An example of glasses ~~ include a devitrifred glass such as "FHOTOCERAM" available ;'nom (:orning in r nirtr. !11~~ rv rr,r,l~r. hi nr.l, . '"..,;. .~.. L.. c .., a I:~:a_ .1 a.
_ « ~"jrm, ~, .r . wc~mr~c.s vyryriicW imrW ua uW arG itUL IIIIII:GU lV
pVI~IJ~IICnC, _ :3 polymethylmethacryiate, Polypropylene, polyethylene, "BAKEL?Tc", ceilulase ?a acet2te, athyl cellulose, styrenelacryloniirtie copolymers, s;yrenelbutadiene ~s copolymers, acrylonitrilelbutadienelstyrene (ABS) copoiycrlec-s, po(y~~inyi as chloride and acrr~rlic . acid polymers including poiyacrylates and ~ polymethacrylates.
z~ The microblades of the present invention mako an elvngaterd, thin s microcut (i.e.., a slit) in the skin surface because the blades have a small c thicimess (relative to their width and length) resulting in a minimal blade kv1 ,~r~~:~_p;\ 11( ~.,llil.v m:o 1 ~_ o;--:l:f . :i. I:~ : _ . _. . _. .. . _ . . .. ~-. ..~. L~.. i ~ i ,.~ ~,o- -1.~ r,:~ ::,i:~:ni ic~:,: ii I:~
' CA 02257217 1998-12-02 "w --' 24ES CAP ~
12a cross-sectional area for the Y

WO 97!48442 13 PCT/US97/10596 portions of the blade in the skin. The geometry of the microblades 4 results in minimal z blade volume in the skin with maximal blade surface area in the skin. The advantages a of the present invention include, but are not limited to: (1) the very sharp first segments a on the leading edges make skin penetration easier; (2) the thin blade geometry s produces the maximum drug percolation area for a given cross-section of the blade;
s (3) minimal tissue damage occurs because the amount of blade material in the skin and hence the volume loading is minimized; (4) slanted leading edges {or equivalent s pointed shapes) further minimize the amount of volume loading or tissue damage s while preserving a large percolation area; (5) for a given volume loading, the larger the ~o surface area, the larger the frictional retaining force in the skin; and {6) for a given 11 desired percolation area, there are fewer blades necessary and therefore the force on ~z each tip is higher making skin penetration easier.
13 The number of blades and openings of any of the embodiments of the device 2 ~a is variable with respect to the desired flux rate, agent being sampled or delivered, ~s delivery or sampling device used (i.e., electrotransport, passive, osmotic, s pressure-driven, etc.), and other factors as will be evident to one of ordinary skill in the ~ art. in general, the larger the number of blades per unit area (i.e., the blade density), is the more distributed is the flux of the agent through the skin because there are a s greater number of agent-conveying pathways through the skin. Consequently, the zo smaller the number of blades per unit area, the more concentrated is the flux of the z~ agent through the skin because there are fewer pathways. The present invention has zz a blade density of at least about 10 blades/cmz and less than about 1000 blades/cmz, zs preferably at least about 600 blades/cmz, more preferably at least about za blades/cmz. In similar fashion, the number of openings per unit area through which zs the agent passes is at least about 10 openings/cmz and less than about 1000 is openings/cmz. In one embodiment, the present invention produces a percolation area z7 of about 0.005 to .05 cmz/cmz of body surface, preferably about 0.01 cmzlcmz of body za surtace.

One embodiment of the present invention relies on the application of an electric current across the body surface or "electrotransport". Electrotransport refers generally s to the passage of a beneficial agent, e.g., a drug or drug precursor, through a body a surface such as skin, mucous membranes, nails, and the like. The transport of the s agent is induced or enhanced by the application of an electrical potential, which results s in the application of electric current, which delivers or enhances delivery of the agent or, for "reverse" electrotransport, samples or enhances sampling of the agent.
The a electrotransport of the agents into or out of the human body may be attained in various s manners. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process involved in the transdermal transport of uncharged or neutrally charged molecules (e.g., transdermal sampling of glucose), involves the ~s movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, still another type of electrotransport, involves the passage of an agent through pores formed by applying an electrical pulse, a high is voltage pulse, to a membrane. In many instances, more than one of these processes » may be occurring simultaneously to different extents. Accordingly, the term ~s "electrotransport" is given herein its broadest possible interpretation, to include the ,s electrically induced or enhanced transport of at least one charged or uncharged agent, 20 or mixtures thereof, regardless of the specific mechanisms) by which the agent is actually being transported.
ii It will be appreciated by those working in the field that the present invention can zs be used in conjunction with a wide variety of electrotransport systems, as the invention Za is not limited in any way in this regard. For examples of electrotransport drug delivery zs systems, reference may be had to U.S. Patent Nos. 5,147,296 to Theeuwes et al., is 5,080,646 to Theeuwes et al., 5,169,382 to Theeuwes et al., and 5,169,383 to Gyory 27 et al. For examples of "reverse" electrotransport devices, references may be had to za U.S. Patent Nos. 5,279,543 to Glikfeld et al. and 5,362,307 to Guy et al.

Eiectrotransport devices generally use at least two electrodes which are in z electrical contact with some portion of the skin, nails, mucous membranes, or other s body surface. In the case of transdermal agent delivery, one of the two electrodes is a commonly referred to as the "donor" or "active" electrode, and is the one from which s the agent is delivered into the body. In the case of transdermal agent sampling, one of s the two electrodes is referred to as the "receptor" electrode, and is the one into which the agent (e.g., body analyte) is collected after being withdrawn from the body. The 8 second electrode is typically termed the "counter" or "return" electrode, and serves to s close the electrical circuit through the body. For example, when the agent to be ~o delivered is a cation, i.e., a positively charged ion, the anode becomes the active or ~ donor electrode, while the cathode serves to complete the circuit.
Alternatively, if an ~z agent is an anion, i.e., a negatively charged ion, the cathode is the donor electrode.
~s When the agent to be sampled is a cation, the cathode becomes the receptor ~a electrode while the anode serves to complete the circuit. When the agent to be ~s sampled is an anion, the anode becomes the receptor electrode while the cathode s serves to complete the circuit. When the agent to be sampled has no net charge (e.g., glucose), then either the anode or the cathode, or both electrodes, can serve as the ~s receptor electrode. Both the anode and cathode may be donor electrodes if both s anionic and cationic agents are delivered simultaneously. Electrotransport delivery zo systems generally require at least one reservoir or source of the agent to be delivered z, to the body. Electrotransport sampling systems likewise require at least one reservoir zz in which to collect the agent being sampled. Examples of such reservoirs include a zs pouch or cavity as described in U.S. Patent No. 4,250,878 to Jacobsen, a porous za sponge or pad as described in U.S. Patent No. 4,141,359 to Jacobsen et al., and a zs pre-formed gel body as described in U.S. Patent No. 4,383,529 to Webster, among zs others. Such reservoirs are electrically connected to, and positioned between, the z7 anode or the cathode and the body surface, e.g. to provide a fixed or renewable zs source of one or more drugs in the case of agent delivery. In addition, electrotransport is delivery systems also typically have an electrical power source, e.g., one or more batteries, and an electrical controller designed to regulate the timing, amplitude and/or z frequency of the applied electric current, and hence regulate the timing and rate of s agent delivery/sampling. This power source component is electrically connected to a the two electrodes. Optional electrotransport device components include a counter s reservoir, adhesive coatings, insulating separation layers, and rate-controlling s membranes.
Figures 8 and 9 illustrate a representative electrotransport delivery/sampling s device 10 that may be used in conjunction with the present invention. Device s comprises an upper housing 18, a circuit board assembly 18, a lower housing 20, ~o anode electrode 22, cathode electrode 24, anode reservoir 26, cathode reservoir 28 and skin-compatible adhesive 30. Upper housing 16 has lateral wings 9 which assist ~z in holding device 10 on a patient's skin. Printed circuit board assembly 18 comprises an integrated circuit 19 coupled to discrete components 40 and battery 32.
Circuit ,a board assembly 18 is attached to housing 16 by posts (not shown in Figure 8) passing through openings 13a and 13b, the ends of the posts being heated/melted in order to ~s heat stake the circuit board assembly 18 to the housing 16. Lower housing 20 is ~7 attached to the upper housing 16 by means of adhesive layer 30, the upper surface 34 ~a of adhesive IayFr 30 being adhered to both lower housing 20 and upper housing 16 including the bottom surtaces of wings 9. Shown (partially) on the underside of circuit zo board assembly 18 is a button cell battery 32. Other types of batteries may also be z~ employed to power device 10 depending on the need.
22 The device 10 is generally comprised of battery 32, electronic circuitry 19,40, zs electrodes 22,24, drug/receptor reservoir 26, counter reservoir 28, and member 2, all za of which are integrated into a self-contained unit. The outputs (not shown in Figure 8) zs of the circuit board assembly 18 make electrical contact with the electrodes 24 and 22 zs through openings 23,23' in the depressions 25,25' formed in lower housing 20 by z~ means of electrically conductive adhesive strips 42,42'. Electrodes 22 and 24, in turn, za are in direct mechanical and electrical contact with the top sides 44',44 of drug zs reservoirs 26 and 28. The bottom side 46 of drug reservoir 28 contacts the patient's skin through the opening 29 in adhesive layer 30 (Figure 9). The bottom side 46' of z drug reservoir 26 contacts the patient's skin through the plurality of openings 8 in the s member 2. The formulation of reservoir 26 is preferably a viscous gel that fills the a openings 8 such that the reservoir 26 is in direct contact with the skin when the blades s have penetrated the stratum corneum. The contact between the reservoir and skin s provides a path for the agent to be transported along. If the reservoir 26 is not in direct contact with the skin initially typically sweat accumulates in the confined area and s provides an agent-transmitting pathway between reservoir 26 and the skin.
s Device 10 optionally has a feature which allows the patient to self-administer a ~o dose of drug , or self sample a body electrolyte, by electrotransport. Upon depression ~~ of push button switch 12, the electronic circuitry on circuit board assembly 18 delivers ~z a predetermined DC current to the electrode/reservoirs 22,26 and 24,28 for a delivery is interval of predetermined length. The push button switch 12 is conveniently located on ~a the top side of device 10 and is easily actuated through clothing. A double press of ~s the push button switch 12 within a short time period, e.g., three seconds, is preferably ~s used to activate the device, thereby minimizing the likelihood of inadvertent actuation » of the device 10. Preferably, the device transmits to the user a visual and/or audible la confirmation of the onset of operation by means of LED 14 becoming lit and/or an ~s audible sound signal from, e.g., a "beeper". Agent is delivered/sampled through the 2o patient's skin, e.g., on the arm, by electrotransport over the predetermined delivery z~ interval. Anodic electrode 22 is preferably comprised of silver and cathodic electrode ii 24 is preferably comprised of silver chloride. Both reservoirs 26 and 28 are nreferablv 23 comprised of polymeric gel materials. Electrodes 22,24 and reservoirs 26,28 are Za retained by lower housing 20.
is In the case of therapeutic agent (i.e., drug) delivery, a liquid drug solution or zs suspension is contained in at least one of the reservoirs 26 and 28. Drug 7 concentrations in the range of approximately 1 x 10'~ M to 1.0 M or more can be used, 2a with drug concentrations in the lower portion of the range being preferred.

WO 97/48442 1$ PCT/US97/10596 - .
The push button switch 12, the electronic circuitry on circuit board assembly z and the battery 32 are adhesively "sealed" between upper housing 16 and lower housing 20. Upper housing 16 is preferably composed of rubber or other elastomeric a material, e.g., injection moldable ethylene vinyl acetate. Lower housing 20 is s preferably composed of a plastic or elastomeric sheet material (e.g., polyethylene) s which can be easily molded to form depressions 25,25' and cut to form openings 23,23'. The assembled device 10 is preferably water resistant (i.e., splash proof) and a is most preferably waterproof. The system has a low profile that easily conforms to the s body, thereby allowing freedom of movement at, and around, the wearing site.
The ~o reservoirs 26 and 28 are located on the skin-contacting side of the device 10 and are » sufficiently separated to prevent accidental electrical shorting during normal handling ~z and use.
~s The device 10 adheres to the patient's body surface (e.g., skin) by means of an is adhesive layer 30 (which has upper adhesive side 34 and body contacting adhesive ~s side 36}. The adhesive side 36 covers the entire underneath side of the device 10 except where the member 2 and reservoir 28 are located. The adhesive side 36 has adhesive properties which assures that the device 10 remains in place on the body ~s during normal user activity, and yet permits reasonable removal after the ~s predetermined (e.g., 24-hour) wear period. Upper adhesive side 34 adheres to lower zo housing 20 and retains the electrodes and reservoirs within housing depression 25,25' z~ as well as retains member 2 to lower housing 20 and lower housing 20 to upper zz housing 16.
zs In one embodiment of the drug delivery or sampling device there is a release za liner (not shown) on the device 10 for maintaining the integrity of the device when it is zs not in use. In use, the release liner is stripped from the device before the device is zs applied to the skin.
z7 In other embodiments of the present invention, passive transdermal delivery or za sampling devices are used with member 2. In one embodiment the passive zs transdermal delivery device comprises-a reservoir containing agent. The reservoir is WO 97/48442 ~ 9 PCT/US97/10596 -~ preferably in the form of a matrix containing the agent dispersed therein.
The reservoir z is sandwiched between a backing layer, which is preferably impermeable to the agent, s and a rate-controlling membrane. The reservoir is formed of a material, such as a a rubbery polymer, that is sufficiently viscous to maintain its shape. If a lower viscosity s material is used for the reservoir, such as an aqueous gel, the backing layer and s rate-controlling membrane would be sealed together about their periphery to prevent leakage. In a sampling configuration, the reservoir would initially not contain the a agent. Located below the membrane is the microblade array member 2. The device s adheres to a body surface by means of a contact adhesive layer around the periphery ~o of the member 2. The adhesive layer may optionally contain agent. A
strippable ~ ~ release liner (not shown) is normally provided along the exposed surface of the ~z adhesive layer and is removed prior to application of the device to the body surface.
~s Alternatively, a transdermal therapeutic device in accordance with another ~a embodiment of the present invention can be attached to a body surface by means of a ~s flexible adhesive overlay. In this embodiment, the device is comprised of an s agent-containing reservoir (for a delivery configuration) which is preferably in the form ~ of a matrix containing the agent dispersed therein. In a sampling configuration, the ~a reservoir would initially not contain the agent. An impermeable backing layer is ~s provided adjacent one surface of the reservoir. The adhesive overlay maintains the zo device on the body surface. The adhesive overlay can be fabricated together with, or z~ provided separately from, the remaining elements of the device. With certain zz formulations, the adhesive overlay may be preferable to the contact adhesive zs described previously. This is true, for example, where the agent reservoir contains a za material (such as, for example, an oily surfactant permeation enhancer) which zs adversely affects the adhesive properties of the contact adhesive layer.
The - zs impermeable backing layer is preferably slightly larger than the reservoir, and in this z7 manner prevents the agents in the reservoir from adversely interacting with the za adhesive in the overlay. Optionally, a rate-controlling membrane (not shown) can be zs provided on the skin/mucosa side of -the reservoir. A strippable release liner (not WO 97/48442 2~ PCT/US97/10596 -shown) is also normally provided with the device and is removed just prior to z application of the device to the body surface.
s The formulation for the passive transdermal devices may be aqueous or non-a aqueous based. The formulation is designed to deliver the drug at the necessary fluxes. Aqueous formulations typically comprise water and about 1 to 2 weight percent s of a hydrophilic polymer as a gelling agent, such as hydroxyethylcellulose or hydroxypropylcellulose. Typical non-aqueous gels are comprised of silicone fluid or a mineral oil. Mineral oil-based gels also typically contain 1 to 2 weight percent of a s gelling agent such as colloidal silicon dioxide.
~o The reservoir matrix should be compatible with the delivered agent, any ~ 1 excipients (e.g., flux enhancers, irritation preventing agents) andlor any carrier ~z therefore. When using an aqueous-based system, the reservoir matrix is preferably a 3 hydrophilic polymer, e.g., a hydrogel. When using a non-aqueous-based system, the a reservoir matrix is preferably composed of a hydrophobic polymer. Suitable polymeric 5 matrices are well known in the transdermal drug delivery art.
s The preferred form in which an agent is delivered or sampled generally m determines the type of delivery or sampling system to be used, and vice versa. That ~s is, the selection of a "passive" system which delivers or samples the agent by diffusion s or an electrically powered system which delivers or samples the agent by zo electrotransport will be mostly determined by the form of the agent. For example, with z~ passive delivery systems, it has generally been recognized that the agent is preferably zz delivered in either its free base or acid form, rather than in the form of a water soluble 23 salt. On the other hand, with electrotransport delivery devices, it has been recognized za that the drugs should preferably be ionized and the drug salt should be soluble in zs water. For the case of pierced skin, there is substantial passive flux through the zs microslits created by the microblades piercing the stratum corneum. For osmotic and z7 pressure driven systems which deliver or sample drugs by connective flow carried by a is solvent, the drug preferably has sufficient solubility in the carrier solvent. It will be zs appreciated by those working in the field that the present invention can be used in conjunction with a wide variety of osmotic delivery or sampling systems, as the z invention is not limited to a particular device in this regard. Osmotic devices are s disclosed for example in U.S. Patent Nos. 4,340,480 to Eckenhoff, 4,655,766 to a Theeuwes et al., and 4,753,651 to Eckenhoff.
s This invention has utility in connection with the delivery of drugs within any of s the broad class of drugs normally delivered through body surfaces and membranes, including skin. In general, this includes drugs in all of the major therapeutic areas.
a The present invention has particular utility in the delivery of peptides, s polypeptides, proteins, nucleotidic drugs, and other such species through body to surfaces such as skin. These substances typically have a molecular weight of at least ~ 1 about 300 daltors, and more typically have a molecular weight of at least about 300 to ~z 40,000 daltons. Specific examples of peptides and proteins in this size range include, s without limitation, LHRH, LHRH analogs such as goserelin, buserelin, gonadorelin, la napharelin and leuprolide, GHRH, GHRF, insulin, insultropin, calcitonin, octreotide, s endorphin, TRH, NT-36 (chemical name:
~s N-[[(s)-4-oxo-2-azetidinylJcarbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary ~ hormones (e.g., HGH, HMG, desmopressin acetate, etc.), follicle luteoids, aANF, 8 growth factors such as growth factor releasing factor (GFRF), bMSH, GH, s somatostatin, bradykinin, somatotropin, platelet-derived growth factor, asparaginase, zo bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin z~ (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, HCG, zz hirulog, hyaluronidase, interferon, interleukins, menotropins (urofollitropin (FSH) and 23 LH), oxytocin, streptokinase, tissue plasrninogen activator, urokinase, vasopressin, za desmopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II
zs antagonists, antidiuretic hormone agonists, bradykinin antagonists, ceredase, CSI's, is calcitonin gene related peptide (CGRP), enkephalins, FAB fragments, IgE
peptide z~ suppressors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid zs hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, zs pentigetide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, vaccines, vasopressin antagonists analogs, alpha-1 antitrypsin (recombinant), 2 and TGF-beta.
s As mentioned above, the member 2 of the present invention can also be used a with known sampling devices including, but not limited to, reverse iontophoresis, s osmosis, passive diffusion, phonophoresis, and suction (i.e., negative pressure).
s Osmotic sampling devices can be used to sample any of a variety of agents through a body surface including, but not limited to glucose, body electrolytes, alcohol, blood s gases, licit drugs and illicit substances such as drugs of abuse. In another embodiment, an osmotic sampling device is attached to a body surface by means of a ,o flexible adhesive overlay. The osmotic sampling device is comprised of a salt layer " located between a semi-permeable or osmotic membrane and an optional agent ,2 sensing element. The optional agent sensing element can be any of a variety of ,s chemically reactive sensors and indicators, for example the color indicating test strips ,a associated with glucose testing. The adhesive overlay can have a cut-out or ,s transparent window in the area of the indicators so that the indicators can be readily ,s viewed. In an alternate embodiment, the agent sensing element can be located ,7 between the osmotic sampling device and the salt layer.
,e While the invention has been described in conjunction with the preferred ,s specific embodiments thereof, it is to be understood that the foregoing description is Zo intended to illustrate and not limit the scope of the invention. Other aspects, 2, advantages and modifications within the scope of the invention will be apparent to ii those skilled in the art to which the invention pertains.

Claims (50)

CLAIMS:
1. A device for piercing the stratum corneum of a body surface to form pathways through which an agent can be introduced or withdrawn, comprising:
a sheet having at least one opening therethrough and a plurality of blades extending downward therefrom, at least one of the plurality of blades having an anchor for anchoring the device to the body surface;
wherein the anchor is selected from the group consisting of:
(i) a projection extending out from a plane defined by the at least one blade;
(ii) a barb;
(iii) at least one opening extending through the at least one blade;
(iv) an adhesive on a body contacting surface of the sheet;
(v) each of the blades having an axis, the blades being oriented so that the blade axes are substantially parallel and the axes form an angle of 1° to 89° relative to the sheet;
(vi) each one of the plurality of blades defines essentially a plane and wherein the anchor comprises a portion of the plurality of blades being oriented at an angle of 90° with respect to a remaining portion of the plurality of blades; and (vii) each one of the plurality of blades defines essentially a plane and wherein the anchor comprises a portion of the plurality of blades being oriented at an angle within a range of 1° to 89° with respect to a remaining portion of the plurality of blades.
2. The device of claim 1, wherein the projection is a prong.
3. The device of claim 1, wherein the projection is integral with an edge of the at least one blade and in a plane defined by the at least one blade.
4. The device of claim 1, further comprising a therapeutic agent delivery device connected to the piercing device and positioned to deliver a therapeutic agent through the opening to the body surface, the agent delivery device being selected from the group consisting of an electrotransport device, a passive diffusion device, an osmotic device, and a pressure driven device.
5. The device of claim 4, wherein the agent comprises a polypeptide or protein.
6. The device of claim 1, further comprising a sampling device connected to the piercing device and positioned to sample a substance from the body surface through the opening, the sampling device being selected from the group consisting of a reverse electrotransport device, a passive diffusion device, an osmotic device, and a negative pressure driven device.
7. The device of claim 6, wherein the sampled substance is selected from the group consisting of body electrolytes, illicit drugs and glucose.
8. The device of claim 1, wherein a portion of the plurality of blades are located along a periphery of an opening through the sheet.
9. The device of claim 1, wherein a portion of the plurality of blades are located along a periphery of a plurality of openings through the sheet.
10. The device of claim 9, further comprising a plurality of second openings through the sheet being spaced between the plurality of openings.
11. The device of claim 1, wherein the device has 600 to 1,000 blades/cm2.
12. The device of claim 1, wherein the device has at least 800 blades/cm2.
13. The device of claim 1, wherein at least a portion of the plurality of blades have a length sufficient to pierce the stratum corneum of the body surface to a depth of at least 25 µm.
14. The device of claim 1, wherein each of the plurality of blades is oriented approximately perpendicular to the sheet.
15. The device of claim 1, wherein each of the plurality of blades is oriented at an angle in the range of 1° to 89° to the sheet.
16. The device of claim 1, wherein each of the plurality of blades is oriented at an angle in the range of 10° to 60° to the sheet.
17. The device of claim 1, wherein at least a portion of the plurality of blades have a thickness in the range of 7 µm to 100 µm.
18. The device of claim 1, wherein at least a portion of the plurality of blades have a thickness in the range of 25 µm to 50 µm.
19. The device of claim 1, wherein the plurality of blades is composed of a material selected from the group consisting of metals, metal alloys, glasses, ceramics and rigid polymers.
20. The device of claim 1, wherein the sheet and the plurality of blades are substantially impermeable to the passage of the agent.
21. The device of claim 1, wherein the plurality of blades are thinner than the sheet.
22. A device for piercing the stratum corneum of a body surface to form pathways through which an agent can be introduced or withdrawn, comprising:
a sheet having a plurality of openings therethrough, at least one of said openings having a plurality of blades located along a periphery thereof and extending downward from the sheet, and an anchor for anchoring the device to the body surface;
wherein the anchor is selected from the group consisting of:
(i) a projection extending out from a plane defined by at least one blade;
(ii) a barb on a blade;
(iii) at least one opening extending through at least one blade;
(iv) an adhesive on a body contacting surface of the sheet;
(v) a portion of the plurality of blades being oriented at an angle of 90° with respect to a remaining portion of the plurality of blades; and (vi) each one of the plurality of blades defines essentially a plane and wherein the anchor comprises a portion of the plurality of blades being oriented at an angle within a range of 1° to 89° with respect to a remaining portion of the plurality of blades.
23. The device of claim 22, wherein the projection is a prong.
24. The device of claim 22, wherein the projection is integral with an edge of the at least one blade and in a plane defined by the at least one blade.
25. The device of claim 22, wherein the anchor comprises a plurality of openings extending through at least one blade.
26. The device of claim 22, further comprising a therapeutic agent delivery device connected to the piercing device and positioned to deliver a therapeutic agent through the opening to the body surface, the agent delivery device being selected from the group consisting of an electrotransport device, a passive diffusion device, an osmotic device, and a pressure driven device.
27. The device of claim 26, wherein the agent comprises a polypeptide or protein.
28. The device of claim 22, further comprising a sampling device connected to the piercing device and positioned to sample a substance from the body surface through the openings, the sampling device selected from the group consisting of a reverse electrotransport device, a passive device, an osmotic device, and a negative pressure driven device.
29. The device of claim 28, wherein the sampled substance is selected from the group consisting of body electrolytes, illicit drugs and glucose.
30. The device of claim 22, further comprising a plurality of second openings through the sheet being spaced between the plurality of openings.
31. The device of claim 22, wherein the device has 600 to 1,000 blades/cm2.
32. The device of claim 22, wherein the device has at least 800 blades/cm2.
33. The device of claim 22, wherein at least a portion of the plurality of blades have a length sufficient to pierce the stratum corneum of the body surface to a depth of at least 25 µm.
34. The device of claim 22, wherein each of the plurality of blades is oriented approximately perpendicular to the sheet.
35. The device of claim 22, wherein each of the plurality of blades is oriented at an angle in the range of 1° to 89° to the sheet.
36. The device of claim 22, wherein each of the plurality of blades is oriented at an angle in the range of 10° to 60° to the sheet.
37. The device of claim 22, wherein the plurality of blades have a thickness in the range of 7 µm to 100 µm.
38. The device of claim 22, wherein the plurality of blades have a thickness in the range of 25 µm to 50 µm.
39. The device of claim 22, wherein each of the plurality of blades are composed of a material selected from the group consisting of metals, metal alloys, glasses, ceramics and rigid polymers.
40. The device of claim 22, wherein the sheet and the plurality of blades are substantially impermeable to the passage of the agent.
41. The device of claim 22, wherein the plurality of blades are thinner than the sheet.
42. A method for producing a device for piercing the stratum corneum of a body surface, the method comprising:
applying a layer of photo-resist to a first side of a sheet;
exposing the layer of photo-resist through a mask pattern for producing a plurality of blades;
etching exposed portions of the photo-resist and the sheet to produce the plurality of blades and openings through the sheet;
punching the plurality of blades through the openings such that the plurality of blades extend downward from the sheet; and incorporating the device for piercing the stratum corneum into a delivery device or sampling device.
43. The method of claim 42, wherein the photo-resist is a resist selected from the group consisting of wet resist and dry resist.
44. The method of claim 42, wherein the etching step comprises spray etching.
45. The method of claim 42, wherein the punching step comprises:
placing the sheet on a die having a plurality of openings corresponding to the plurality of blades and openings of the sheet; and bending the plurality of blades through the openings to be substantially perpendicular to the sheet with a punch having a plurality of protrusions corresponding to the plurality of openings in the die and the plurality of openings of the sheet.
46. A method of transdermally sampling an agent, comprising:
a. placing a device on a body surface through which the agent is to be withdrawn, the device including a sheet having at least one opening therethrough and a plurality of blades extending downward therefrom whereby agent transmitting pathways are formed through the stratum corneum at the body surface, and a reservoir in agent-transmitting relation with the opening;
b. withdrawing the agent through the pathways and said opening; and c. collecting the agent in the reservoir.
47. The method of claim 46, wherein the sampled agent is selected from the group consisting of body analytes, electrolytes, blood gases, illicit drugs, licit drugs and glucose.
48. The method of claim 46, further comprising:
connecting a sampling device to a side opposite of a side of the sheet having the blades extending downward therefrom, the sampling device being selected from the group consisting of a reverse electrotransport sampling device, a passive sampling device, an osmotic sampling device, and a negative pressure driven sampling device.
49. The device of claim 1, wherein the anchor is the adhesive on the body contacting surface of the sheet, the adhesive further being on at least one surface of at least one of the plurality of blades.
50. The device of claim 22, wherein the anchor is the adhesive on the body contacting surface of the sheet, the adhesive further being on at least one surface of at least one of the plurality of blades.
CA002257217A 1996-06-18 1997-06-18 Device for enhancing transdermal agent delivery or sampling Expired - Fee Related CA2257217C (en)

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