Abstract:
A device comprising of a plurality of microprojections for piercing the outermost layer of skin is provided for increasing transdermal agent flux. The device includes penetration depth limiters for ensuring uniform depth of piercing by the microprojections, thereby preventing over penetration and undesirable bleeding and pain. The microprojections have a length (L1) which is substantially greater than the intended penetration depth (L2). The microprojection penetration depth limiters allow for more uniform penetration for optimum agent delivery or fluid sampling.

Description:
TECHNICAL FIELD  
         [0001]    The present invention relates to transdermal agent delivery and more particularly, to the transdermal delivery of drugs and vaccines and/or transdermal sampling of body analytes such as glucose. More particularly the invention relates to a device having a plurality of stratum corneum piercing microprojections which when applied to the skin, pierce to an predetermined uniform depth of penetration, thereby providing optimum results for agent delivery and/or sampling.  
         BACKGROUND ART  
         [0002]    Devices used for cutting skin, e.g. surgical scalpels and the like, have been known and used for sometime. See for example, MacKool U.S. Pat. No. 5,810,857. In addition, devices used for piercing the skin, e.g., using pointed knives that are pushed into the skin, are also known for applications such as surgically implanting hair plugs. See for example, Ashraf, U.S. Pat. No. 6,197,039. Devices of this type are intended to make relatively deep cuts. In the case of surgical knives, cuts have a depth measuring in centimeters and in the case of pointed knives used for implanting hair elements, depths are of at least 0.5 centimeters. Such devices are well outside the scope of the present invention. The present invention utilizes microprojection arrays designed to be minimally invasive, generally penetrating the skin to depths of less than 0.5 mm.  
           [0003]    Such micro-penetrating devices have been disclosed for example, in Daddona et al., U.S. Pat. No. 6,091,975, Cormier et al., U.S. Pat. Nos. 6,219,574 and 6,230,051 and in Godshall et al., U.S. Pat. No. 5,879,326. All of these devices disclose tiny microprojections extending from a base sheet or substrate and having lengths generally less than 0.5 mm. Godshall et al., (&#39;326) further discloses that the base plate acts as a stop for preventing the microprojections from penetrating the skin beyond a predetermined distance.  
           [0004]    More recently, it has been discovered that due to the elastic/rubbery nature of human skin, these types of microprojection arrays tend to have wide variability in depth of penetration from one microprojection to the next. Furthermore, because of the viscoelastic nature of skin, skin tends to dimple down in the areas of the skin surrounding the piercing microprojections with the result that the microprojection does not pierce to a depth that is equal to the microprojection length. The amount of skin dimpling can be lessened by stretching the skin at the time of microprojection piercing. See for example Trautman, et al., WO 01/41863. Unfortunately, even skin stretching does not completely compensate for the skin dimpling property and the resulting partial and variable penetration of the microprojections. While one potential solution is to use longer microprojections, because of the inherent variability in penetration depths of the devices and the piercing techniques used to date, longer microprojections have inevitably resulted in some portion of them penetrating the skin too deeply, with the attendant undesirable result of bleeding and in some cases, discomfort to the patient.  
         DISCLOSURE OF THE INVENTION  
         [0005]    The present invention provides a device and method for forming a plurality of microcuts in animal skin, the microcuts having a predetermined depth of penetration of less than 500 microns. The device includes a member having a plurality of skin-piercing microprojections extending therefrom. Each of the microprojections has a base, a tip, an edge, a face and a length that is measured from the base to the tip. The length of the microprojections are substantially longer than the predetermined depth of penetration. The device has a piercing depth limiter associated with at least a portion of the microprojections. The piercing depth limiter is positioned at a predetermined location between the tip and the base of the microprojection whereby the limiter greatly reduces the tendency of the microprojection to pierce the skin beyond the predetermined depth.  
           [0006]    According to one embodiment of the invention, at least a portion of the skin piercing microprojections, preferably at least about 10% of the microprojections, and most preferably substantially all of the skin-piercing microprojections, have a piercing depth limiter in the form of a skin surface abutting surface. The reference to the skin surface abutting surface refers to the fact that this surface is positioned directly on top of the skin after the microprojections have been applied to the skin. In one preferred embodiment, this surface comprises one or a plurality of shoulders adjacent to the microprojection tip which ensures that only the tip penetrates through the skin and not the remaining portions of the microprojection length.  
           [0007]    In a second embodiment, the microprojection device is comprised of a sheet, e.g., a metal sheet, having a plurality of openings therein with the microprojections extending from the sheet adjacent to the openings. In this embodiment, the limiter comprises a member having a plurality of stop protrusions which member is adapted to be positioned adjacent the skin distal side of the sheet with the microprojections and openings. In this embodiment, the sheet and the member are positioned adjacent one another so that the stop protrusions extend through at least a portion of, and preferably through substantially all of, the openings in the sheet.  
           [0008]    The invention will now be described in connection with certain preferred embodiments which are illustrated in the figures and disclosed hereinafter. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0009]    A better understanding of the present invention as well as other objects and advantages thereof will become apparent upon consideration of the following detailed description especially when taken with the accompanying drawings, wherein like numerals designate like parts throughout, and wherein:  
         [0010]    [0010]FIG. 1 is a top perspective view of a portion of a microprojection array as is known in the prior art;  
         [0011]    [0011]FIG. 2 is a side view of a single microprojection piercing through skin in accordance with one embodiment of the present invention;  
         [0012]    [0012]FIG. 3 is a perspective view of the microprojection shown in FIG. 2;  
         [0013]    [0013]FIG. 4 is a perspective view of a portion of a microprojection array having microprojections of the type shown in FIGS. 2 and 3;  
         [0014]    [0014]FIG. 5 is a perspective view of a single microprojection in accordance with one embodiment of the present invention;  
         [0015]    [0015]FIG. 6 is a perspective view of a microprojection array having microprojections of the type shown in FIG. 5;  
         [0016]    [0016]FIG. 7 is a perspective view of a single microprojection in accordance with another embodiment of the present invention;  
         [0017]    [0017]FIG. 8 is a perspective view of a microprojection array having microprojections of the type shown in FIG. 7;  
         [0018]    [0018]FIG. 9 is a perspective view of a single microprojection in accordance with another embodiment of the present invention;  
         [0019]    [0019]FIG. 10 is a side sectional exploded view of an unassembled alternative embodiment of a microprojection penetration stop mechanism in accordance with the present invention;  
         [0020]    [0020]FIG. 11 is a side sectional view of the device shown in FIG. 10 illustrating of the device in an assembled condition;  
         [0021]    [0021]FIG. 12 is a top view of a single microprojection in accordance with another embodiment of the invention; and  
         [0022]    [0022]FIG. 13 is a top view of a single microprojection in accordance with yet another embodiment of the invention. 
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0023]    The device of the present invention more consistently, uniformly, and reliably penetrates a body surface, e.g. the outermost stratum corneum layer of skin, to enhance agent delivery and/or body analyte sampling therethrough. The device of the present invention achieves greater uniformity in the depth of penetration from one microprojection to the next, and a decreased chance of microprojection piercing being so deep as to cause bleeding and/or discomfort. As used herein, the term “microprojections” refers to very tiny skin piercing elements, typically having a length of less than 500 μm, a width of less that 400 μm and a thickness of 5 to 100 μm which make correspondingly sized microcuts/microslits in the skin. Upon piercing through the outermost layer (i.e., the stratum corneum) of the skin, the microprojections form pathways through which an agent such as a drug can be introduced, i.e. transdermally delivered, and/or through which a body analyte such as glucose can be sampled by collection of body fluids, optionally stored within a reservoir associated with the microprojections. For agent delivery, the agent may be incorporated in a separate reservoir associated with one or more microprojections or the agent may be incorporated as a coating on the microprojections and/or other portions of the device. An important feature of the present invention is a microprojection device with the microprojections having lengths which are intentionally selected to be substantially longer than the desired depth of penetration. In addition, the device has a piercing depth limiter, which is on, is part of one or more microprojection or is closely associated one or more microprojections, which substantially reduces bleeding caused by the microprojections piercing too deeply into the skin. The limiter also allows for a more consistent amount of agent delivery or sampling due to a more uniform depth of microprojection penetration. Furthermore, the present invention reproducibly provides greater uniformity in microprojection penetration from patient to patient and from one microprojection to the next in a single microprojection array applied to a single patient.  
         [0024]    [0024]FIG. 1 illustrates a prior art microprojection array without the piercing depth limiter of the present invention. This can be contrasted with the device shown in FIG. 4 having a piercing depth limiter in accordance with one embodiment of the present invention.  
         [0025]    These microprojection arrays are typically formed from a sheet wherein the microprojections are formed by etching or punching the sheet and then the microprojections are folded or bent out of a plane of the sheet.  
         [0026]    Referring now to FIGS. 2 through 4, a plurality of microprojections  10  extend from a sheet  16 . The microprojection  10  are located around the periphery of openings  18 . The microprojections  10  have a penetrating portion  15 , a non-penetrating portion  13 , and two shoulder-like limiters  12 . The limiters  12  are located a predetermined length L2 from the end  14  of penetrating portion  15 . The overall length L1 of the microprojection  10  is substantially longer than the length L2 of the penetrating portion  15 . Although the invention is not limited to any particular values for the ratio of L2:L1, for microprojections having an L2 between about 50 microns and about 400 microns, the ratio of L2:L1 is typically less than about 0.5. This ratio will also be effected by the particular conditions of microprojection penetration, including the microprojection density (i.e., the number of microprojections per cm 2  of the array), the tautness of the skin and the piercing force applied to the array. What is important is to ensure that the length of the non-penetrating portion  13  (i.e., L3 which is equal to L1 minus L2) is sufficiently long to compensate for the dimpling property of skin and to allow the penetrating portion  15  to pierce completely into the skin  200  with the limiters  12  abutting against the surface of skin  200 . Thus, the distance L2 from the end  14  of the microprojection  10  to the limiter  12  is substantially equal to the depth of penetration into skin  200 .  
         [0027]    The leading edge of the projection may have a sharp arrowhead-like edge or a sloping angle point to cut or incise the skin  200 . Thus, the limiter  12  is designed to inhibit the microprojection  10  from penetrating any deeper than the predetermined length L2. When the array is impacted against the skin  200  using a spring loaded impacter of the type disclosed in Cormier et al., WO 02/30301A1, published Apr. 18, 2002, the disclosures of which are incorporated herein by reference, the microprojections  10  pierce the skin  200  to the point where the limiters  12  abut against the skin surface and retard further penetration into the skin  200 . The limiters  12  may be located on both sides of penetrating portion  15  as shown in FIGS.  2 - 4 .  
         [0028]    Alternatively, the limiter may be position between a pair of penetrating portions. One such embodiment is shown in FIGS. 5 and 6. A plurality of microprojections  50  are shown located around a plurality of openings  58  in sheet  56 . In this embodiment, limiter  52  is positioned between a pair of penetrating portions  55 . Though this and other embodiments of the invention disclosed herein provide for a single microprojection  50  extending from a single opening  58 , it is within the scope of the present invention that microprojection arrays may include one or more microprojections locate around the periphery of each opening.  
         [0029]    Another such embodiment is shown in FIGS. 7 and 8. A plurality of microprojections  70  are shown located around a plurality of openings  78  in sheet  76 . In this embodiment, limiter  72  is positioned between a pair of penetrating portions  75  that have a different shape than penetrating portions  55 . The effect of limiter  72  is to limit the penetration of microprojections  70  to the penetrating portions  75  while the non-penetrating portion  73  remains outside the skin.  
         [0030]    Yet another piercing depth limiter design is shown in FIG. 9. In this embodiment, the thickness of sheet  96  is intentionally selected to be substantially greater than the desired thickness of penetrating portion  95 . The penetrating portion  95  is then subjected to additional acid etching to form a limiter surface  92  between the penetrating portion  95  and the non-penetrating portion  93 .  
         [0031]    Referring now to FIGS. 10 and 11, there is shown an alternate embodiment of a microprojection piercing depth limiter in accordance with the present invention. In this embodiment, the limiter is a separate element from the microprojection array and hence can be used with microprojection arrays of the type illustrated in FIG. 1. In this embodiment, the limiter is shown as stop member  108  in the form of a layer having a plurality of stop protrusions  112  extending therefrom. The stop protrusions  112  are sized and spaced so as to extend through the openings in the sheet  116  of the microprojection array. FIG. 10 shows the sheet  116  and the stop member  108  prior to assembly whereas, FIG. 11 shows the two members after assembly and ready for use. If desired, small quantities of adhesive can be used in order to ensure that the sheet  116  and member  108  remain secured to one another. Member  108  can be composed of metals, ceramics, plastics and other suitable materials. Though stop protrusion  112  are not physically attached to or part of the microprojections, they function in the same manner as shown in the previous embodiments by controlling and limiting the dept of the penetration portion of the  
         [0032]    Additional embodiments of microprojection and limiter design are shown in FIGS. 12 and 13. FIG. 12 shows microprojection  120  located along the periphery of opening  128 . Microprojection  120  has a penetrating portion  125 , a limiter  122  and a non-penetrating portion  123 . This figure shows the microprojection after it has been formed out of the sheet and prior to being bent out of a plane of the sheet.  
         [0033]    [0033]FIG. 13 shows microprojection  130  located along the periphery of opening  138 . Microprojection  130  has three penetrating portions  135 , two limiters  132  and a non-penetrating portion  133 . This figure shows the microprojection after it has been formed out of the sheet and prior to being bent out of a plane of the sheet.  
         [0034]    In general, the limiters or “stops” are step like skin surface abutting surfaces that extend horizontally from either the narrow edge (e.g. see FIGS.  2 - 4 ) or the wider face of a microprojection (e.g. see FIG. 9). Each stop extends horizontally at the point of the predetermined length of the preferred penetration depth. At this point an extension perpendicular to the direction of penetration extends from the microprojection. These stops inhibit, and preferably substantially prevents, penetration of the microprojections deeper than the location of the stops. The stops can be configured in various ways in relation to the microprojection with which it is associated. For example, the stops can be on both sides of the penetrating portion, in between multiple penetrating portions, on only one side of the base of the penetrating portion, and/or perpendicular to the face of the penetrating portion. The width of each stop section should be wide enough to inhibit, and preferably substantially prevent, the penetrating portion from entering the material any further than the predetermined length. When the stop is formed by a horizontal extension from the narrow edge of the microprojection, the stop is of the same thickness as each microprojection and the sheet from which the microprojections were formed.  
         [0035]    By incorporating the limiter or stops on the microprojections, the undesired effects of the penetration being too deep and causing unwanted pain and bleeding are reduced, and preferably are substantially eliminated. Each stop lies approximately parallel to the surface or material being penetrated, therefore retarding further penetration. The number of stops can vary. It is not required that there be a stop adjacent to each microprojection within the array. Preferably at least about 10% of the microprojections have a stop or limiter closely adjacent thereto and most preferably substantially all of the microprojections have a stop or limiter closely adjacent thereto.  
         [0036]    In addition to penetration of the microprojection, the preferred application device provides bi-directional stretching of the skin. The skin is stretched from two directions as the applicator is pressed against the skins surface. Thus allowing a more uniform penetration e.g. generates the same size and depth pathways, by the microprojection. When piercing the skin with very tiny microprojections the degree of tension under which the skin is placed becomes more critical compared to skin piercing using substantially larger piercing elements. The applicator for the sheet of microprojections of the present invention may take on different shapes. The present invention can be used with any known application device and is not limited to any particular application device.  
         [0037]    Also within the present invention, there is no particular shape or form that is required for the microprojections. Within the preferred embodiment, each microprojection will include a sloped angle or arrowhead like pointed tip that allows incising the material (skin) more easily. The microprojection in its entirety can have one or multiple penetrating peaks or edges and one or more skin-abutting depth limiting surfaces variously configured.  
         [0038]    Other advantages of the present invention are further illustrated by the following examples.  
       EXAMPLE 1  
       [0039]    A study was performed to assess the uniformity of microprojection penetration through excised hairless guinea pig skin. Microprojection arrays of the type illustrated in FIG. 7 were applied to excised hairless guinea pig skin using a spring loaded impact device of the type illustrated in FIG. 1 of Cormier, et al., WO 02/30301A1. This device supplied an impact of about 0.05 Joules/cm 2 . The microprojection dimensions were as follows:  
         [0040]    L1=204 microns  
         [0041]    L2=75 microns  
         [0042]    Microprojection density: 348 microprojections per cm 2    
         [0043]    The patches were removed following impact application and the skin sites were stained with India ink. The sites were biopsied and sliced parallel to the surface of the skin using a cryotome to measure the depth of penetration of the ink.  
         [0044]    The penetration depth in his study did not exceed 60 microns and exhibited acceptable depth variability.  
       COMPARATIVE EXAMPLE 1  
       [0045]    A study similar to that described in Example 1 is performed with a microprojection array having microprojections of the shape illustrated in FIG. 1, i.e., without any piercing depth limiting feature. The microprojections had the following dimensions:  
         [0046]    L1=241 microns  
         [0047]    Microprojection density: 321 microprojections per cm 2    
         [0048]    The same impact conditions were used as in Example 1. After performing a biopsy and slicing the skin, the maximum penetration depth is found to be 140 microns with a greater variability in penetration depth than that seen in Example 1.  
       EXAMPLE 2  
       [0049]    A study similar to that described in Example 1 and Comparative Example 1 was performed with titanium sheet microprojection arrays having a circular shape and a skin contact area of 2 cm 2 . The skin contact area being the area enclosed by the periphery of the circular array. The arrays were fastened to adhesive overlays having an area of 5 cm 2 . The patches (i.e., array plus overlay) were applied to excised hairless guinea pig skin by an impact applicator having an impact energy of 0.053 joules/cm 2  and a hold down force of 0.44 Newtons. The skin sites were stained, biopsied and sliced as in Example 1. The results are shown in Table 1.  
                                   TABLE I                                   Micro-       Standard       Micro-           projection   Average   Deviation In       projection   L1   L2   Average   Penetration   Penetration       Design   (μm)   (μm)   Density (/cm 2 )   Depth (μm)   Depth (μm)                       206   116   348   64   20           197   N/A   348   58   22