Abstract:
A dermal, transdermal, mucosal or transmucosal delivery device includes a backing layer overlying an ingredient containing reservoir, and having a microprotrusion array attached thereto, a cover for the reservoir having at least one opening therethrough, an adhesive layer and a liner layer. Upon removal of the liner layer, the device may be placed over the desired area of the skin or mucosa and adhesively applied thereto allowing the ingredients to flow from the reservoir through the at least one opening to the skin or mucosa.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 60/555,841, filed on Mar. 24, 2004, the entire contents of which are hereby incorporated by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     The concept of minimally invasive transdermal drug delivery systems has been developed over time to overcome, or at least provide an alternative to, the drawbacks of conventional metal needle drug delivery. These minimally invasive transdermal mucosal drug delivery systems have been designed to allow drugs to pass through the stratum corneum layer of the skin and the epithelial cells of the mucosa thereby enabling drugs to bypass this skin and mucosa barrier and deliver drugs into the microvascularization of the dermis and mucosa or their lower tissues and potentially into systemic circulation. 
     The present invention relates to such transdermal drug delivery devices. Such devices typically comprise a patch containing a drug to be delivered. The patch typically includes an adhesive layer for adherence to a patient&#39;s skin. The drug may be present as a liquid in a reservoir, or in a gel, or may be incorporated into the adhesive layer of the patch. The patch is applied to a person&#39;s skin and the drug passes through the skin into the patient&#39;s system as well as the dermal, mucosal and transmucosal. 
     In some drug delivery systems, one removes the stratum corneum layer of the skin in preparation of topical administration of a drug. Removal of the stratum corneum layer is typically done by scrapping the skin with a mechanical device or by repeatedly applying a tape strip to the surface of the skin and then removing the tape to remove the stratum corneum layer of the skin. Both of these methods of removing the stratum corneum layer of the skin are cumbersome and uncontrolled methods utilized in preparation of topical administration of a drug. 
     Transdermal delivery devices have also been developed which include hollow microneedles which are forced through the stratum corneum. U.S. Pat. No. 6,611,707 B1 to Prausnitz et al. discloses a microneedle drug delivery device having one or more drug reservoirs positioned over a housing which includes an array of hollow microneedles, with a seal located therebetween. An adhesive layer is applied in-between the microneedles at their base, or to an attachment collar or tabs adjacent the microneedles, to facilitate adherence of the device to the skin. The delivery of drug from a reservoir is initiated by removing or breaking the seal and applying a force, such as by pressing the top of the reservoir, to cause the reservoir contents to flow out through the microneedles. The microneedle device includes a feedback means so that the user can (1) determine whether delivery has been initiated, and/or (2) confirm that the reservoir has been emptied. Representative feedback means include a sound, a color change indicator, or a change in the shape of a deformable reservoir. U.S. Pat. No. 6,656,147 to Gertsek is similar to Prausnitz U.S. Pat. No. 6,611,707, but has a housing which forms a collar extending away from the microprotrusion array. A pressure sensitive adhesive is applied to the underside of the collar so that the device is adhered to the skin. 
     U.S. Pat. No. 6,821,281 to Sherman et al. discloses a transdermal delivery device in which a reservoir is positioned above an array of microprotrusions which are not hollow, but which may include grooves. The microprotrusions are used to scrap skin cells from the skin when the device is moved in at least one direction. Medication forced out of the reservoir and flows down between the array of microprotrusions and into and through the patient&#39;s skin. 
     All of the above microneedle or microprotrusion array devices are relatively bulky and/or rigid devices employing some type of housing for the microneedle or microprotrusion array, and for the ingredient reservoir. The housing is typically made of a plastic material. U.S. Pat. No. 6,656,147 to Gertsek suggests a housing or bladder made of a flexible plastic or rubber like material. 
     As used herein, “microprotrusion” will be used as a generic term, encompassing microneedles as well as other types of small abrading protrusions. The “micro” portion of this term is usually understood to mean something so small that it can only be seen with a microscope. However, in this art, the micro portion of the term is understood to mean relatively small protrusions which often are typically at least sufficiently large to be seen with the naked eye. As used herein, “transdermal” will be used as a generic term encompassing dermal, mucosa and transmucosal as well. 
     SUMMARY OF THE INVENTION 
     In one aspect of the present invention, a microneedle or microprotrusion array is incorporated into a film type of ingredient delivery device. A backing layer of film overlying an ingredient reservoir includes a microprotrusion array attached thereto. A release liner film overlies the backing layer and the microprotrusion array. 
     These and other objects, advantages and features of the invention will be more fully understood and appreciated by reference to the written specification and appended drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a top plan view of the device of the preferred embodiment; 
         FIG. 2  is an exploded cross-sectional view of the principle subassemblies of the device of the preferred embodiment; 
         FIG. 3  is an exploded cross-sectional view of the principle subassemblies of the device of a second preferred embodiment; 
         FIG. 4  is an exploded cross-sectional view of the principle subassemblies of the device of a third preferred embodiment; 
         FIG. 5  is an exploded cross-sectional view of the principle subassemblies of the device of a fourth preferred embodiment; 
         FIG. 6  is a fragmentary, cross-sectional view of a microprotrusion member and recoil device; 
         FIG. 7  is an exploded cross-sectional view of the principle subassemblies of the device including a recoil device according to another aspect of the present invention; 
         FIG. 8  is an exploded cross-sectional view of the principle subassemblies of the device including a bumper guard according to another aspect of the present invention; and 
         FIG. 9  is an exploded cross-sectional view of the principle subassemblies of the device including a reservoir having a plurality of discreet chambers according to another aspect of the present invention. 
     
    
    
     It will be appreciated that the thicknesses and shapes for the various layers have been exaggerated in the drawings to facilitate understanding of the device. The drawings are not “to scale.” 
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     Basic Reservoir System 
     In the preferred embodiment, device  1  comprises a backing layer (sometimes referred to as a base or backing member)  10  having a cavity or reservoir  16  overlying an ingredient reservoir  18  ( FIGS. 1 ,  2 ,  3  and  4 ). A retaining ring or cover  14  having an opening  15  therein is sealed via a first ring-like seal  17  to backing member  10  around the periphery of reservoir  18 . Seal  17  is made of a material that is not subject to degradation, permeation or solubilization by ingredients to be contained in reservoir  18 . Seal  17  may be omitted according to other aspects of the invention. If seal  17  is not utilized, cover  14  is heat sealed or otherwise directly to backing. Adhesive layer  11  is adhered to backing member  10  and serves to adhere the device to a patient&#39;s skin or mucosa. Adhesive layer  11  may cover a portion of cover  14 , but includes an opening  11   a  such that adhesive layer  11  does not cover opening  15 . Adhesive layer  11  preferably leaves a ring-like edge portion of the surface of cover  14  exposed in the area surrounding opening  15 , the area being referred to herein as cover sealing surface  14   a . A microprotrusion member or layer  19  is disposed between the adhesive layer  11  and a liner  12 . The term microprotrusion as used herein is used generically to describe any type of protruding implement which is capable of penetrating a patient&#39;s skin. Thus, the microprotrusions might be solid needles, hollow needles, solid protrusions or other such configurations, hollow protrusions or other such configurations, grooved protrusions or any other configuration capable of penetrating the patient&#39;s skin. 
     Turning to  FIG. 1  which is a plan view of the device of the present invention, there is an opening  15  in cover  14  for release of the medication to the patient&#39;s skin from the reservoir  18  that may contain a thin absorbable ingredient containing woven or non-woven layer, which, in turn, is contained within the cover  14  that is sealed to backing layer  10 . A kiss cut line  12   a  is present in release liner  12  to aid in removing the disposable release liner  12 . While device  1  may be any shape,  FIG. 1  shows the preferred shape of the present invention. 
     Port Fitting Design 
     Device  1  may optionally include a fitting  5  that is connected to a tube  6 . Fitting  5  may be a Luer Lock fitting having a male fitting  8  that is releasably, yet sealingly connected to a female fitting  9 . A pump  7  may be utilized to pressurize reservoir  18  to promote transdermal delivery of the ingredients in reservoir  18 . Pump  7  may comprise a syringe, an I.V. bag that is elevated above reservoir  18 , or a mechanical pump that is manually powered. Alternately pump  7  may comprise a powered pump that is operably connected to a controller (not shown) to provide pressure according to a predetermined program or schedule. Also an injectable sealing layer (not shown) may also be used in place of the Luer Lock fitting. A hollow needle (not show) that is attached to tube  6  is used to pierce the resealable membrane to thereby provide a fluid connection between pump  7  and reservoir  18 . 
     The microprotrusion layer  19  includes a base  19   a  and a plurality of protrusions  19   b  projecting from base  19   a . Microprotrusion layer  19  also includes at least one opening  19   c  therethrough that corresponds with the opening  11   a  in adhesive layer  11  such that the reservoir ingredients may flow into and through these openings  11   a  and  19   c  when the device  1  is in use. Liner  12  covers at least opening  15  and sealing surface  14   a  of cover  14 , and is sealed to sealing surface by a ring-like second seal  21 . Second seal  21  is made of a material that is not subject to degradation by any of the ingredients in the reservoir. Preferably, liner  12  comprises the release liner for the device  1 , and therefore covers not only opening  15  and sealing surface  14 , but also releasably covers the at least one opening  19   c  in microprotrusion layer  19  and opening  11   a  adhesive layer  11 . As described in more detail below, when device  1  is used, release liner  12  is removed, thereby exposing opening  15 . Device  1  is then applied and adhered to the patient&#39;s skin or mucosa via adhesive layer  11 . During the application process, the microprotrusion layer  19  is depressed into a patient&#39;s skin or mucosa to a desired depth with reservoir  16  and cover opening  15  positioned over the area to which ingredients are to be delivered. 
     Reservoir Shell Covering 
     The preferred embodiment device may also include a shell  2  ( FIG. 2 ) covering the exterior of reservoir overlying portion  16 . The shell  2  of the device should be impermeable or impervious to the liquid being delivered to the treatment site, in order to prevent loss by evaporation or wetting. The shell  2  may also protect the active ingredient and/or liquid against radiant energy sources such as ultraviolet and visible light. The shell  2  can be either dimensionally stable or dimensionally non-stable, preferably dimensionally non-stable. A dimensionally non-stable shell is not capable of withstanding a compressive force of one psi or less, i.e. will at least partially crush or collapse. Suitable materials for the shell  2  can include but are not limited to ceramics, metals such as titanium, aluminum or steel, plastics such as polyolefins, barex, styrene, polyesters, polyacrylics, vinylpolymers, polyamides, polyfluorocarbons, polyimides, polylactams, polyaramides, polycarbonates, polysulfones, polyethylene, polypropylene, nylon, polyvinyl chloride, polyvinylidiene chloride or combinations or composites thereof. It will be appreciated that the shell could replace the reservoir overlying portion  16  of the film of material comprising backing layer  10 . In that case, the reader should consider the shell to be a part of backing layer  10  for purposes of this discussion. The shell would then be the portion of backing layer  10  defining overlying reservoir portion  16  for containing the ingredients to be delivered. The reservoir overlying portion  16  can be either dimensionally stable or dimensionally non-stable, as discussed above. The first heat seal  17  around reservoir overlying portion  16  should also be resistant to permeation, disintegration or degradation e.g., dissolving by the ingredients and actives contained herein. 
     The size or diameter of opening  15  may vary, as a function of the speed with which one wants to deliver active ingredients, or the total amount of active ingredient one wants to deliver from reservoir  16 . Depending on intended use, the diameter of opening  15  may range from 0.05 to 5.0 inches. The larger openings may require the use of hydrogel in the reservoir  18 , so the ingredient solution does not immediately run out of reservoir area  16  when liner  12  is removed. In the preferred embodiment as shown in  FIG. 2 , the diameter of opening  15  is approximately 0.125 inches. Also, cover  14  may have a plurality of openings  15 . The geometry of opening  15  may be in the form of many shapes, i.e., round, rectangular, elliptical, square, etc. 
     Reservoir Layer 
     Ingredients may be contained within reservoir  18  in any of a variety of ways. For example, ingredient reservoir  18  can simply be in liquid or gel matrix form within overlying cavity or reservoir  16 . The ingredients may be contained in a pad of hydrogel material, which basically comprises a gel matrix containing ingredients to be delivered through opening  15 . Alternatively, ingredients may be contained in a woven or non-woven absorbable material reservoir pad  18  located beneath overlying reservoir  16 , made of, for example, 5.0 mil STRATEX® 90% polypropylene/10% non-woven rayon. Other suitable materials for the absorbable woven or non-woven material include any non-dimensionally stable materials, such as woven polyester cloth, bonded nylon fibers, cotton gauze, fiberglass, polyester fibers and cotton fibers. This material may partially or completely contain the ingredient or ingredients to be delivered to the user&#39;s skin or mucosa. Also, the size and shape of opening  15  may be varied depending upon the requirements of a particular application. Also, a plurality of openings  15  may be utilized. If the device  1  is to be used on a skin surface that is generally vertical for substantial periods of time, opening  15  may be positioned off center, and an arrow or other indicia on backing  10  may be provided so a user can apply the device in an upright orientation. In this way, the opening  15  can be positioned at the bottom of the cavity  18  to ensure that the ingredients flow from reservoir  18  and through opening  15 . 
     Ingredients Contained in Reservoir 
     The term ingredient or ingredients as used herein refers to all ingredients contained within ingredient reservoir  18 , and not only to those of the ingredients which are to be delivered to or through the user&#39;s skin or mucosa. The latter may be referred to as “active” ingredients in the broadest sense. However, the term “active” ingredient is not intended to limit the ingredients to be delivered to drugs, since other types of ingredients may be delivered for purposes other than to serve as a drug. 
     Optionally, a rate controlling membrane layer  13  may be disposed between any of the layers of device  1  ( FIG. 4 ). Rate controlling layer  13  is preferably disposed either between backing layer  10  and cover  14  or between cover  14  and adhesive layer  11 . In  FIG. 4 , rate controlling membrane  13  is located between base layer  10  and cover  14 . The rate controlling membrane may be a film of dense, microporous or pourous material. 
     Alternatively, cover  14  could be replaced entirely with a rate controlling membrane  13 , as shown in  FIG. 5 , having no opening, such as opening  15  in cover  14 . The rate controlling layer may include microporous openings that control the rate of passage of the reservoir containing ingredients from the reservoir  18  to the skin or mucosa. When rate controlling membrane  13  is utilized in place of cover  14 , the exposed inner surface portion  32   a  of outer protective layer  32  is sealed to sealing surface  13   a  of rate controlling membrane  13  by a ring-like second seal  21  which is made of a material that does not degrade become permeable or solubilized when exposed to any of the ingredients contained in reservoir  18 . 
     Backing Layer 
     Backing layer or base member  10  is made of a relatively hard polymer material, or a relatively soft polymer, such as a polyethylene terephthalate (P.E.T.) or polyvinylchloride (P.V.C.) material which is substantially impermeable to ingredients contained in reservoir  18 . One example of a suitable material is 3.0 mil, 3M® 9722 polyethylene film. Base member  10  is thermoformed to form reservoir  16 . Backing layer or base member  10  may be from about ½ mil to about 5 mils thick, preferably from about 1 mil to about 4 mils thick and most preferably about 3 mils thick. Retaining ring or cover  14  is also made of a material which is substantially impermeable to ingredients contained in reservoir  18 , for example, 4.0 mil ROLLPRINT® polyethylene film that forms a reservoir  16 . Preferably, the thickness of cover  14  may be from about 1 mil to about 10 mils thick, preferably from about 2 mils to about 8 mils thick and most preferably from about 3 mils to 6 mils thick. 
     Skin or Mucosa Adhesive Layer 
     Adhesive layer  11  is preferably a composite of three different layers ( FIGS. 2 ,  3  and  4 ). Adhesive layer  11  is typically a composite of the following layers: first or upper adhesive layer  20 , made of, for example, a 1.0 mil, NATIONAL STARCH 80-1197™ acrylic adhesive; barrier layer  22 , made of, for example, a layer of 0.5 mil, PET film; and second or lower adhesive layer  24 , made of, for example, 3.0 mil, NATIONAL STARCH 80-1197™ acrylic adhesive that comes into contact with the patient&#39;s skin. Adhesive layer  11  preferably has a thickness of from about 1 mil to about 10 mils, more preferably from about 2 mils to about 8 mils and most preferably from about 4 mils to about 6 mils. First or upper adhesive layer  20  and second or lower adhesive layer  24  each preferably have a thickness of from about ½ mil to about 5 mils, whereas barrier layer  22  preferably has a thickness of from about ½ mil to about 7 mils. The second or lower adhesive layer thickness may vary depending on the size of the transdermal device, the length of desired use, and the aggressiveness of the adhesive. 
     Other suitable materials for attaching the device  1  to the skin or mucosa may include waterproof tape or other materials that have an adhesive underside. A pressure sensitive adhesive or a combination of pressure sensitive adhesives are preferred. The adhesive may be resistant to permeation and/or dissolution by the ingredients in reservoir  18 , but this is not essential in view of the first seals  17  and second seals  21  discussed above. Other suitable adhesives may include but are not limited to the following: A) Solvent-based acrylic adhesives such as: Monsanto GMS 737, trademark of Monsanto Corporation, St. Louis, Mo.; National Starch Durotak 72-9720 and 80-1197, trademark of National Starch &amp; Chemical Corp., Bridgewater, N.J.; Ashland&#39;s AROSET 11 13-AD-40 and 1085-A-45, trademark of Ashland Oil Co., Ashland, Ky.; B) Solvent-based rubber adhesives such as: National Starch 36-6172; C. Acrylic emulsion adhesives such as: Monsanto GME 2397 Rohm &amp; Haas N580, trademark of Rohm &amp; Haas Co., Philadelphia, Pa.; Unocal 76 RES 9646, trademark of Unocal Corp., Los Angeles, Calif.; and Ashland&#39;s AROSET 2022-W-50; and C) Adhesive Transfer Tapes such as: 3M F-9465 PC, trademark of 2M Co., St. Paul, Minn. Avery-Denison MED 1116, trademark of Avery Dennison Corp., Pasadena, Calif.; ARCare 7530, trademark of Adhesive Research Inc., Glen Rock, Pa.; and RX230U, trademark of Coating Science Inc., Bloomfield, Conn. 
     The upper and lower adhesive layers  20  and  24  are both adhered to the intermediate barrier layer  22 . Adhesive layer  20 , in turn, is adhered to backing member  10 , and also partially to cover  14 , but does not extend beyond and over the sealing surface  14   a  of cover  14 . Adhesive layer  11  may be any shape, however, ring-shaped is preferable. 
     Microprotrusion Layer 
     A microprotrusion layer  19  is disposed between the adhesive layer  11  and liner  12 . Microprotrusion layer  19  includes a base layer  19   a  adjacent microprotrusions  19   b . The microprotrusion layer  19  includes at least one opening  19   c  therein that corresponds with the opening in adhesive layer  11  such that the reservoir-containing ingredients may flow through these openings when the device  1  is in use. The microprotrusion layer side adjacent liner  12  contains microprotrusions  19   b  that project from the microprotrusion layer  19 . As noted above, microprotrusions  19   b  may contain one or more channels or bores extending along an internal longitudinal axis of the microprotrusion. However, microprotrusions  19   b  may also be boreless (i.e., without internal channels). Alternatively, device  1  may include a microprotrusion layer  19  that has a combination of both boreless microprotrusions and bore-containing microprotrusions. The ingredient(s) in reservoir  18  may flow through these bores or channels in the microprotrusions, or may flow around and between solid microprotrusions when device  1  is in use. The microprotrusion layer  19  may also be any shape, including, but not limited to any geometric shape or, preferably, a ring-shape having an opening  19   c  in the center thereof. The microprotrusions themselves may be any shape. The base layer  19   a  is preferably formed of a flexible material but also can be of rigid material. The device of the present invention may be applied to areas of a patient&#39;s skin or mucosa that require the base layer  19   a  be flexible. The base layer  19   a  of microprotrusion layer  19  preferably is from about 1 mil to about 10 mils thick, more preferably from about 2 mils to about 8 mils thick and most preferably from about 4 mils to 6 mils thick. The microprotrusions  19   b  of microprotrusion layer  19  preferably project from base layer  19   a  a length of from about 20 to about 500 microns, more preferably from about 50 to about 400 microns and most preferably from about 100 to about 250 microns. However, the microprotrusions may be longer (e.g., 500-1000 microns or more) depending on the particular application. 
     Channeled Surface Flow Layer 
     The microprotrusion base layer  19   a  includes a surface  19   f  ( FIG. 6 ) adjacent at least a portion of the adhesive layer  11 , which optionally includes corrugations or channels  19   e  to direct the flow of ingredient(s) from reservoir  18 . Alternatively, if the microprotrusion layer side  19   f  that is adjacent the adhesive layer  11  is substantially smooth (i.e., non-corrugated/non-channeled) the adhesive layer side adjacent the substantially smooth microprotrusion layer side  19   f  may include a pattern coated adhesive to create corrugations or channels to direct the flow of ingredient(s) between the substantially smooth microprotrusion layer side and the adhesive layer  11 . When the above-noted corrugations or channels are present, either in microprotrusion base layer  19   a  or in the pattern coated adhesive, active ingredient(s) flow from reservoir  18  through the openings in cover  14 , and adhesive layer  11  and at least a portion of the ingredient(s) are channeled to flow laterally between adhesive layer  11  and microprotrusion base layer  19   a . The ingredient(s) then flow down through openings in the microprotrusions  19   b , or through openings in base layer  19   a , and then down around and between microprotrusions  19   a , and then into and through the stratum corneum layer of the skin. 
     Microprotrusion Composition 
     The microprotrusion layer  19  may be comprised of any materials, including, but not limited to, thermoforming polymer materials that are synthetically and/or naturally derived. For example, suitable biocompatible, biodegradable polymers include poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, polyanhydrides, polyorthoesters, polyetheresters, polycaprolactones, polyesteramides, poly(butyric acid), poly(valeric acid), polyurethanes and copolymers and blends thereof. Representative non-biodegradable polymers include polyacrylates, polymers of ethylene-vinyl acetates and other acyl substituted cellulose acetates, non-degradable polyurethanes, polysytrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, blends and copolymers thereof. Other potential materials include metals including pharmaceutical grade stainless steel, gold, titanium, nickel, iron, tin, chromium, copper palladium, platinum and alloys of these and/or other metals. Additionally, glass, ceramics, epoxides or any combination or derivation of any of the above may be utilized, however, the preferred material is a polyamide such as nylon. 
     Release Liner Layer 
     Release liner  12  also preferably is comprised of a plurality of layers of material as follows: release coating layer  26  made of, for example, LOPAREX® (REXAM®) 92A release coating; barrier layer  28  made of, for example, 3.0 mil, PET film; adhesive layer  30 , made of, for example, 1.0 mil NATIONAL STARCH 80-1197™ acrylic adhesive; and outer protective layer  32 , which is a co-laminated film of polyamide and polyolefins layer, made of, for example, TOLAS™ 4050. These layers that comprise release liner  12  may be modified in thickness to accommodate the length of the microprotrusions and to provide adequate protection of the microprotrusions during storage and transportation. For example, if the microprotrusions are longer, then the thickness of the layers that comprise release liner  12  will be thicker. Conversely, if the microprotrusions are shorter in length, the layers that comprise release liner  12  will be thinner. 
     A release coating layer  26  is bonded to barrier layer  28 . Adhesive layer  30  is bonded to the other side of barrier layer  28 , and to outer protective layer  32 . This entire assembly of layers functions as a unitary release liner. 
     Release coating layer  26 , barrier layer  28  and adhesive layer  30  preferably have openings  26   a ,  28   a  and  30   a , respectively, which are coextensive with the outer perimeter of microprotrusion layer  19  or, when present, the outer perimeter of one or more matrix active rings. In other words, layers  26 ,  28  and  30  of release liner  12  may partially overlay, or not overlay at all, cover  14  leaving sealing surface  14   a  and opening  15  exposed. Outer protective layer  32 , on the other hand, has no such opening and entirely covers sealing surface  14   a  and opening  15  of cover  14 . Thus it is preferably the exposed inner surface portion  32   a  of outer protective layer  32  which is sealed to sealing surface  14   a  of cover  14  by the previously referred to second seal  21  which is not subject to degradation, permeation or solubilization by any ingredient to be contained in reservoir  18 . Outer protective layer  32  may be shaped such that it extends upwardly into openings  26   a ,  28   a  and  30   a.    
     While those skilled in the art can select various adhesives for the first seal  17  and second seal  21  which would not be degradable by the particular ingredients to be contained in reservoir  18 , the first seal  17  and second seal  21  are preferably heat seals. Thus, cover  14  is preferably heat sealed to backing layer  10  in the area thereof surrounding reservoir  18 , and outer layer  32  of release liner  12  is preferably heat sealed in area  32 A to sealing surface  14 A. The materials and sealing conditions used to seal area  32 A to sealing surface  14 A are preferably such that this second seal  21  is “releasable” when force is applied to remove release liner  12  from adhesive composite  11 . In contrast, the first seal  17  between cover  14  and backing layer  10  should be “permanent” to the extent that cover  14  is not peeled away from backing layer  10  when a force is applied to remove release liner  12  from the assembly. 
     Delivery of Active Ingredients 
     Preferred embodiment device  1  delivers active ingredients at high concentrations over short periods of time (i.e. ranging from about 0.1 hour to about 24 hours per wear). Some active ingredients at lower concentrations may be delivered for more than about 24 hours. The preferred embodiment device  1  is useful for delivering active ingredients in liquid solution without adding or incorporating an adhesive film (i.e. with no layer between the skin and the liquid containing the active ingredient) into the preferred embodiment device  1 . Preferred embodiment device  1  may be used to treat the following conditions or to deliver the following active ingredients, the conditions and active ingredients including, but not limited to: warts (i.e. salicylic acid, and/or other keratolytic agents); acne (i.e. salicylic acid, benzoyl peroxide, antibiotics, and/or other keratolytic agents); pain (i.e. local anesthetics, non-steroidal anti-inflammatory drugs); moisturizers (i.e. urea, water); finger and toenail beds (i.e. urea, water, anti-fungal agents); skin buffering (i.e. buffering agents); vaccines (i.e. small pox, measles, flu, anthrax, polio, etc.); poorly soluble drugs; larger molecular weight molecules (i.e. about 500 to about 1500 molecular weight molecules such as heparin, LHRH); larger macromolecules (i.e., DNA, antibodies, growth factors, Factor VIII) vaccines; wound care (i.e. water, debriding agent(s), enzymes); sampling and diagnostic agents (i.e. glucose, lactic acid, potassium, allergens, etc.); iontophoresis, electroporation, sonophoresis, radio frequency, thermal enhancement (reservoir) (i.e. electrode (anode, cathode)); microneedles (reservoir) (i.e. alone or in combination with iontophoresis, electroporation, sonophoresis, radio frequency, thermal enhancement). The preferred embodiment device  1  may also be combined with other components, deliver other active ingredients, and/or deliver molecule(s) for diagnostic purposes to the skin. 
     Description of Layers 
     The following is a description of the array of layers in device  1 , from the backing layer  10  to the release liner  12  (top to bottom on  FIG. 2 ) by layer number and description:
           10 . Backing layer, i.e. 3.0 mil, 3M® 9722 polyethylene film;     18 . Reservoir ingredients, i.e. 5.0 mil STRATEX® 90% polypropylene/10% non-woven rayon;     14 . Cover or retaining ring, i.e. 4.0 mil ROLLPOINT® polyethylene film;     11 . Adhesive layer
             20 . First adhesive coating, i.e. 1.0 mil National Starch 80-1197 acrylic adhesive     22 . Barrier layer, i.e. 0.5 mil PET film; and     24 . Second adhesive coating, i.e. 3.0 mil National Starch 80-1197 acrylic adhesive;         19 . Microprotrusion layer, i.e., a polyamide such as nylon;     12 . Release liner;
             26 . Release coating layer, i.e. LOPAREX® (REXAM®) 92A release coating;     28 . Barrier layer, i.e. 3.0 mil PET film;     30 . Adhesive coating, i.e. 1.0 mil NATIONAL STARCH 80-1197™; and     32 . Outer protective layer, i.e. TOLAS™ 4050;           

     Any commercially known method of manufacturing the preferred embodiment device  1  may be employed. However, one preferred method of producing device  1  includes the following steps: 1) pre-cut the materials used in the backing  10  and the reservoir overlying portion  16  (i.e., pre-cut cover  14  and any woven and/or non-woven ingredients); 2) peel away the strip layers from first adhesive layer  20  and second adhesive layer  24  and adhere the skin contact adhesive layer  11  to at least a portion of microprotrusion layer  19  and to at least a portion of the release liner  12 ; 3) place cover  14  in position on completed step 2 assembly, heat seal cover  14  to the outer protective layer  32  and set aside; 4) form reservoir overlying portion  16  in the backing material; 5) place ingredients  18  in the formed reservoir, insert any active ingredient(s), place completed step 3 assembly in position over reservoir  16  and heat seal backing  10  to cover  14 ; 6) die cut finished shape; 7) inspect for defects and contamination; and 8) place the finished device  1  in a pouch and seal the pouch. 
     In use, the release liner  12  is removed from the microprotrusion transdermal delivery device  1  thereby breaking second seal  21  between the release liner  12  and sealing surface  14 A of cover  14 , exposing the microprotrusion layer side containing the microprotrusions and/or microneedles and exposing at least a portion of adhesive layer  11 . The microprotrusion transdermal delivery device  1  is then applied to a subject&#39;s skin or mucosa. During application, the microprotrusions and/or microneedles pierce the stratum corneum layer of the skin or epithelial cells of the mucosa creating perforations in the skin or mucosa and are depressed to a desired depth. The ingredients contained within reservoir  16  flow through the one or more openings in cover  14  and contact the skin or mucosa. At least a portion of the adhesive layer  11  contacts the skin or mucosa and forms an adhesive seal creating the outer boundary of a second reservoir. Upon contacting the skin or mucosa, the ingredients from the reservoir seep through the perforations created in the skin or mucosa by the microprotrusions and/or microneedles. Alternatively, ingredients from reservoir  18  may pass through opening  15  in cover  14  and, while a portion of ingredients may directly seep into the skin through the perforations as described above, a separate portion of the ingredients may be channeled, via the channels in the microprotrusion layer side adjacent adhesive layer  11 , through the optional bores within the microprotrusion and/or microneedles and be delivered through the stratum corneum layer of the skin. Alternatively, if the microprotrusion layer side adjacent the adhesive layer is substantially smooth, the channels may be created by a pattern coat adhesive. During the application and ingredient delivery process, the second reservoir contains the ingredients. 
     Force Gauge Indicator 
     Another embodiment of the microprotrusion transdermal delivery device of the present invention includes device  50  ( FIG. 3 ). Device  50  is identical to device  1  as described above, but further includes force gauge  34 . Force gauge  34  may be structurally incorporated into backing layer  10  or shell  2  or may be a separate attachment wherein backing layer  10  is adapted to receive force gauge  34 . Force gauge  34  includes an indicator such as an audio, visual or otherwise sensory indicator. 
     The application of microprotrusion transdermal delivery device  50  is substantially similar to the application process described above, however, pressure is applied to force gauge  34  to depress the microneedles and/or microprotrusions to the desired depth in a subject&#39;s skin. Upon applying an adequate amount of pressure to depress the microprotrusion and/or microneedles in the stratum corneum, the sensory indicator is activated (i.e., changes color, changes shape, makes a noise, etc.), which informs the person applying the device that the microprotrusions and/or microneedles are properly depressed in the patient&#39;s skin. 
     Force gauge  34  may be comprised of any material, including, but not limited to all of the microprotrusion materials previously disclosed, plastics, rubbers or any combination or derivation of any of the above. Force gauge  34  may be any shape as long as the shape is capable of being, or of being connected to, a sensory indicator. The illustrated force gauge  34  is the form of a dimple or dome that collapses upon application of a known, predetermined force. The force gauge  34  may generate an audible click sound as it collapses. The magnitude of the force being applied by a user also decreases abruptly as it collapses. The drop in force and/or click provide feedback to the user, thereby indicating that the proper amount of force has been used. 
     Secondary Active Matrix 
     Referring to  FIG. 4  in yet another embodiment, the microprotrusion transdermal delivery device  100  includes substantially the same components as device  1  described in the preferred embodiment (see  FIG. 2 ), but further includes one or more matrix active ring(s)  36 . The matrix active ring(s)  36  are disposed between adhesive layer  11  and release liner  12 . The matrix active ring(s)  36  may contain any active and/or non-active ingredients, including, but not limited to, immediate-acting active ingredients, controlled, sustained, or otherwise prolonged active ingredients, any non-active ingredients, and/or ingredients that are incompatible with the ingredients contained within reservoir  18  of the device  1 . The matrix active ring(s)  36  may be comprised of any material, including, but not limited to a gel matrix which incorporates the ingredient to be dispensed, or an absorbent material which absorbs active ingredients and releases them. It can also comprise an adhesive matrix which incorporates ingredients to be dispensed into the matrix. The overall thickness of the matrix active ring(s)  36  are relatively thin. 
     Optionally, microprotrusion layer  19  may also be included in this embodiment. When microprotrusion layer  19  is utilized in this embodiment, ingredient(s)  18  flow from reservoir  16  through the opening  15  in cover  14 , and adhesive layer  11  and at least a portion of the ingredient(s) from reservoir  18  are channeled to flow laterally between adhesive layer  11  and microprotrusion layer  19 . The ingredient(s) then flow down through the openings in the microneedles into and through the stratum corneum layer of the skin. When both matrix active ring(s)  36  and microprotrusion layer  19  are utilized in the device of this embodiment, matrix active ring(s)  36  are adjacent adhesive layer  11  and distal from the at least one opening in microprotrusion layer  19 . 
     Microprotrusion Recoil Layer 
     With reference to  FIG. 6 , the transdermal delivery device may include a recoil device such as a thin layer of compressible/resilient foam  60 . In use, a user applies a force to the microprotrusion member  19  to push the microneedles  19   b  into the skin. As the microneedles  19   b  enter the skin, the foam layer  60  is compressed such that surface  61  shifts as indicated by the line “A”. Upon release of a force by a user, the foam  60  generates a force tending to pull the microneedles  196  out of the skin, thereby providing a recoil device. 
     With further reference to  FIG. 7 , a ring  65  of resilient material may also be utilized to provide a recoil device. As illustrated in  FIG. 7 , the resilient ring  65  may have a shape and location that is substantially the same as active ring  36 . The resilient ring  65  may be adhered to barrier layer  22  via adhesive  24 . Alternately, resilient ring  65  could extend around the outside of an active ring  36  in a concentric manner (not shown). 
     The microprotrusion layer  19  shown in  FIG. 6  includes a plurality of openings  19   d  therethrough to provide for flow of ingredients from reservoir  18  through microprotrusion layer  19 . As discussed above, openings through hollow microneedles could also be utilized. 
     Microprotrusion Protector Spacers 
     As illustrated in  FIG. 8 , a bumper guard such as a ring  70  may be adhered to the liner  12 . Ring  70  is made of a material that is substantially incompressible, such as a suitable polymer material, and prevents damage to microneedles  19   b  in the event outer protective layer  32  is bumped or the like during shipping storage and the like. In use, the ring  70  is removed with liner  12  immediately prior to application of device  1 . It will be readily appreciated that a bumper guard could have a variety of configurations. For example, the bumper guard could have the shape of a shallow cup or cap, including a sheet of relatively rigid material (not shown) formed integrally with ring  70  and extending over microneedles  19   b  to further protect microneedles  196 . 
     Additional Separate Ingredient Compartments 
     With further reference to  FIG. 9 , reservoir  18  could include multiple separate compartments  18   a ,  18   b  that hold two or more different ingredients. It will be appreciated that the reservoir compartments  18   a  and  18   b  may be completely sealed off by cover  14  and backing layer  10 . The multiple compartments may be utilized for different ingredients that are not compatible with one another or the like. 
     Having described specific preferred embodiments of the invention with reference to the accompanying drawings, it will be appreciated that the present invention is not limited to those precise embodiments and that various changes and modifications can be effected herein by one of ordinary skill in the art without departing from the scope or spirit of the invention as defined by the appended claims.