Patent Publication Number: US-2021170153-A1

Title: Transdermal drug delivery device

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
     This application claims the benefit of U.S. patent application Ser. No. 16/224,249, filed on Dec. 18, 2018, the entire contents of which are incorporated herein by reference. U.S. patent application Ser. No. 16/224,249 is a continuation of U.S. patent application Ser. No. 14/762,844, now U.S. Pat. No. 10,183,156, filed on July 23, 2015, the entire contents of which are incorporated herein by reference. U.S. patent application Ser. No. 14/762,844 is the U.S. national stage application of International Application No. PCT/M2014/059345, filed on Feb. 28, 2014, the entire contents of which are incorporated herein by reference. International Application No. PCT/IB2014/059345 claims priority to U.S. Provisional Patent Application No. 61/770,639, filed on Feb. 28, 2013, the entire contents of which are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present subject matter relates generally to devices for delivering drug formulations to a patient through the skin utilizing a microneedle assembly. 
     BACKGROUND OF THE INVENTION 
     Numerous devices have previously been developed for the transdermal delivery of drugs and other medicinal compounds utilizing microneedle assemblies. Microneedles have the advantage of causing less pain to the patient as compared to larger conventional needles. In addition, conventional subcutaneous (often intra-muscular) delivery of drugs via a needle acts to deliver large amounts of a drug at one time, thereby often creating a spike in the bioavailability of the drug. For drugs with certain metabolic profiles this is not a significant problem. However, many drugs benefit from having a steady state concentration in the patient&#39;s blood stream, a well-known example of such a drug is insulin. Transdermal drug delivery devices are technically capable of slowly administering drugs at a constant rate over an extended period of time. Thus, transdermal drug delivery devices offer several advantages relative to conventional subcutaneous drug delivery methods. 
     However, existing transdermal drug delivery devices often fail to consistently deliver all of the drug beneath the stratum corneum layer of the skin so that it can be absorbed into the body. In this regard, due to the small size of the needles, often times all or a portion of the drug is delivered only onto the top of the skin or into the stratum corneum layer where the drug cannot be absorbed into the body of the patient. This can happen for various reasons. For example, the needle depth may slightly retract from the desired insertion depth such as due to the inconsistent application of force on the needles or the natural elasticity of the skin acts to push the needles outwardly after insertion. Further complicating transdermal delivery with such small needles is that the skin may form such a complete juncture with the needle that the drug flows upwardly along the needle towards the point of insertion and away from the cellular layers capable of absorbing the drug into the body. 
     Accordingly, there remains a need for a transdermal drug delivery device having an improved ability to consistently and effectively deliver a drug formulation through a patient&#39;s skin. 
     BRIEF DESCRIPTION OF THE INVENTION 
     Aspects and advantages of the invention will be set forth in part in the following description, or may be obvious from the description, or may be learned through practice of the invention. 
     In one aspect, the present subject matter is directed to a transdermal drug delivery device. The device may comprise a housing including an upper housing portion and a lower housing portion. The lower housing portion may define a bottom surface including skin attachment means for releasably attaching the lower housing portion to skin of a user. The upper housing portion may at least partially surround a central region of the device. The device may also include a microneedle assembly and a reservoir disposed within the central region. The reservoir may be in fluid communication with the microneedle assembly. Additionally, the device may include a pushing element disposed above the microneedle assembly within the central region. The pushing element may be configured to provide a continuous bilateral force having a downward component transmitted through the microneedle assembly and an upward component transmitted through the skin attachment means. 
     In another aspect, the present subject matter is directed to a transdermal drug delivery device. The device may include an upper housing attached to a lower housing defining a cavity. The lower housing may define a bottom surface including skin attachment means for releasably attaching the lower housing to skin of a user. The lower housing may also define an opening and may surround a microneedle assembly. The device may be configured such that the lower housing is dissociated from the microneedle assembly. In addition, the device may include a reservoir disposed within the cavity that is in fluid communication with the microneedle assembly. Moreover, the device may include a pushing element disposed within the cavity between the microneedle assembly and the upper housing. The pushing element may be configured so as to be dissociated from the lower housing and may provide (i) a continuous force having a downward component, dissociated from the upper and lower housings, transmitted via the microneedle assembly towards the skin of a user, (ii) a continuous force having an upward component, dissociated from the microneedle assembly, transmitted to the lower housing. 
     In a further aspect, the present subject matter is directed to a method for transdermally delivering a drug formulation. The method may generally include positioning a transdermal drug delivery device adjacent to skin, attaching a housing of the device to the skin via a skin attachment means, applying, with a pushing element, a continuous bilateral force having a downward component transmitted through a microneedle assembly of the device and an upward component transmitted through the skin attachment means delivering the drug formulation from through the microneedle assembly and into or through the skin. 
     These and other features, aspects and advantages of the present invention will become better understood with reference to the following description and appended claims. The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       A full and enabling disclosure of the present invention directed to one of ordinary skill in the art, is set forth in the specification, which makes reference to the appended figures, in which: 
         FIG. 1  illustrates an assembled, perspective view of one embodiment of a transdermal drug delivery device in accordance with aspects of the present subject matter; 
         FIG. 2  illustrates a cross-sectional view of the device shown in  FIG. 1  taken about line  2 - 2 , particularly illustrating various components of the device in an un-actuated position; 
         FIG. 3  illustrates another cross-sectional view of the device shown in  FIG. 1  taken about line  2 - 2 , particularly illustrating various components of the device in an actuated position; 
         FIG. 4  illustrates an exploded, perspective view of the device shown in  FIGS. 1-3 ; 
         FIG. 5  illustrates an assembled, perspective view of another embodiment of a transdermal drug delivery device in accordance with aspects of the present subject matter; 
         FIG. 6  illustrates a cross-sectional view of the device shown in  FIG. 5  taken about line  6 - 6 , particularly illustrating various components of the device in an un-actuated position; 
         FIG. 7  illustrates another cross-sectional view of the device shown in  FIG. 6 , particularly illustrating various components of the device in an actuated position; 
         FIG. 8  illustrates an exploded, perspective view of the device shown in  FIGS. 5-7 ; 
         FIG. 9  illustrates a cross-sectional view of a bilateral pushing element of the device shown in  FIGS. 5-8 , particularly illustrating the bilateral pushing element in an un-actuated or un-expanded position; 
         FIG. 10  illustrates another cross-sectional view of the bilateral pushing element of the device shown in  FIGS. 5-8 , particularly illustrating the bilateral pushing element in an actuated or expanded position; and 
         FIG. 11  illustrates a close-up, partial view of one embodiment of a microneedle assembly configuration suitable for use with the disclosed transdermal drug delivery devices. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Reference now will be made in detail to embodiments of the invention, one or more examples of which are illustrated in the drawings. Each example is provided by way of explanation of the invention, not limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be used with another embodiment to yield a still further embodiment. Thus, it is intended that the present invention covers such modifications and variations as come within the scope of the appended claims and their equivalents. 
     In general, the present subject matter is directed to a transdermal drug delivery device configured to deliver a drug formulation into and/or through a user&#39;s skin. The device may generally include a housing configured to encase or surround various components of the device, with at least a portion of the housing being configured to be attached to the user&#39;s skin. The device may also include a reservoir in fluid communication with a microneedle assembly. The reservoir may generally be configured to retain a drug formulation for subsequent delivery through the user&#39;s skin via the microneedle assembly. In addition, the device may include a pushing element configured to apply a continuous bilateral force through the device. Specifically, in several embodiments, the pushing element may be configured to apply a continuous downward force through the microneedle assembly to push the microneedles of the assembly into the user&#39;s skin. Simultaneously, the pushing element may be configured to apply a continuous upward force against the housing that is transmitted through the housing to the user&#39;s skin (via a suitable skin attachment means disposed between the housing and the skin), thereby providing a tensioning force that tightens the user&#39;s skin around the microneedle assembly to enhance insertion and maintenance of the microneedles into/within the skin. 
     Referring now to the drawings,  FIGS. 1-4  illustrate several views of one embodiment of a transdermal drug delivery device  10  in accordance with aspects of the present subject matter. As shown, the device  10  may include an outer housing  12  configured to at least partially surround and/or encase the various components of the device  10 . In general, the housing  12  may include an upper housing portion  14  and a lower housing portion  16  formed integrally with and/or extending from the upper housing portion  14 . The upper housing portion  14  may generally be configured to define an open volume for housing the various device components. For example, as shown  FIGS. 2 and 3 , when the device  10  is placed onto the user&#39;s skin  18 , an open volume may be defined between the user&#39;s skin  18  and the upper housing portion  14  within which the device components may be contained. It should be appreciated that the upper housing portion  14  may generally be configured to define any suitable shape. For instance, as shown in the illustrated embodiment, the upper housing portion  14  defines a semi-circular or dome shape. However, in other embodiments, the upper housing portion  14  may have any other suitable shape that defines an open volume for housing the various components of the device  10 . 
     The lower housing portion  16  of the housing  12  may generally be configured to be positioned adjacent to the user&#39;s skin when the device  10  is in use. For example, as shown in the illustrated embodiment, the lower housing portion  16  may be configured as a flange or projection extending outwardly from the bottom periphery of the upper housing portion  14  such that a bottom surface  20  of the lower housing portion  16  may extend directly adjacent to the user&#39;s skin  18 . Additionally, in several embodiments, the lower housing portion  16  may be configured to be attached to the user&#39;s skin  18  using any suitable skin attachment means. For example, in one embodiment, an adhesive layer  22  may be applied to the bottom surface  20  of the lower housing portion  16 . As such, when the device  10  is placed onto the user&#39;s skin  18 , the housing  12  may be attached to the skin  18  via the adhesive layer  22 . However, in other embodiments, any other suitable skin attachment means known in the art may be utilized to attach the housing  12  to the user&#39;s skin  18 . 
     Additionally, as particularly shown in  FIGS. 2 and 3 , different zones or regions of the device  10  may be defined by and/or within the housing  12 . For example, the device  10  may include a central region  30  defined around its center line  31 . The device  10  may also include an outer region  32  generally defined around the device periphery at the location at which the device  10  is attached to the user&#39;s skin  18 . For example, as shown in  FIGS. 2 and 3 , the outer region  32  may be defined at the interface between the bottom surface  20  of the lower housing portion  16  and the adhesive layer  22  securing the housing  12  to the user&#39;s skin  18 . Moreover, the device  10  may include an intermediate region  34  extending between and separating the central and outer regions  30 ,  32 . 
     In several embodiments, the device  10  may include one or more components at least partially disposed within the central region  30 . For example, as shown in the illustrated embodiment, the device  10  includes a microneedle assembly  36 , a reservoir  38  and a bilateral pushing element  40  vertically aligned within the central region  30 , with the footprint of such components generally defining the outer perimeter of the central region  30 . As will be described below, the pushing element  40  may be configured to apply a downward force through the central region  30  in order to press the microneedle assembly  36  into the user&#39;s skin  18 . In addition, the pushing element  40  may also be configured to apply an upward force through the central region  30  that is transmitted through the housing  12  to the outer region  32  of the device  10 , thereby providing an upward force against the user&#39;s skin  18  via the adhesive layer  22 . 
     In general, the microneedle assembly  36  of the device  10  may have any suitable configuration known in the art for delivering a fluidic drug formulation into and/or through the user&#39;s skin  18 , such as by being configured to include a plurality of microneedles extending outwardly from a suitable substrate or support. For example, a partial, cross-sectional view of one embodiment of a suitable microneedle assembly configuration is illustrated in  FIG. 11 . As shown, the microneedle assembly  36  may include a support  42  defining a top surface  44  and a bottom surface  46  and a plurality of microneedles  48  extending outwardly from the bottom surface  46 . The support  42  may generally be constructed from a rigid, semi-rigid or flexible sheet of material, such as a metal material, a ceramic material, a plastic material and/or any other suitable material. In addition, the support  42  may define one or more apertures between its top and bottom surfaces  44 ,  46  to permit the drug formulation to flow therebetween. For example, as shown in  FIG. 11 , a single aperture  50  may be defined in the support  42  at the location of each microneedle  48  to permit the drug formulation to be delivered from the top surface  44  to such microneedle  48 . However, in other embodiments, the support  42  may define any other suitable number of apertures  50  positioned at and/or spaced apart from the location of each microneedle  48   
     Additionally, as shown in  FIG. 11 , each microneedle  48  of the microneedle assembly  36  may generally be configured to define a piercing or needle-like shape (e.g., a conical or pyramidal shape or a cylindrical shape transitioning to a conical or pyramidal shape) extending between a base  52  positioned adjacent to and/or extending from the bottom surface  46  of the support  42  and a tip  54  disposed opposite the base  52 . As is generally understood, the tip  54  may correspond to the point of each microneedle  48  that is disposed furthest away from the support  42  and may define the smallest dimension of each microneedle  48 . Additionally, each microneedle  48  may generally define any suitable length  51  between its base  52  and its tip  54  that is sufficient to allow the microneedles  48  to penetrate the stratum corneum and pass into the epidermis. In several embodiments, it may be desirable to limit the length  51  of the microneedles  48  such that they do not penetrate through the inner surface of the epidermis and into the dermis; such embodiments advantageously help minimize pain for the patient receiving the drug formulation. For example, in one embodiment, each microneedle  48  may define a length  51  of less than about 1000 micrometers (um), such as less than about 800 um, or less than about 750 um or less than about 500 um and any other subranges therebetween. In a particular embodiment, the length  51  may range from about 25 um to about 1000 um, such as from about 100 um to about 1000 um or from about 200 um to about 1000 um and any other subranges therebetween. 
     It should be appreciated that the length  51  of the microneedles  48  may vary depending on the location at which the disclosed device is being used on a user. For example, the length of the microneedles  48  for a device to be used on a user&#39;s leg may differ substantially from the length of the microneedles  48  for a device to be used on a user&#39;s arm. 
     Moreover, each microneedle  48  may generally define any suitable aspect ratio (i.e., the length  51  over a cross-sectional dimension  53  of each microneedle  48 ). However, in certain embodiments, the aspect ratio may be greater than 2, such as greater than 3 or greater than 4. It should be appreciated that, in instances in which the cross-sectional dimension  53  (e.g., width, diameter, etc.) varies over the length of each microneedle  26  (e.g., as shown in  FIG. 11 ), the aspect ratio may be determined based on the average cross-sectional dimension  53 . 
     Further, each microneedle  48  may define one or more channels  56  in fluid communication with the apertures  50  defined in the support  42 . In general, the channels  56  may be defined at any suitable location on and/or within each microneedle  48 . For example, as shown in  FIG. 11 , in one embodiment, the channels  56  may be defined along an exterior surface of each microneedle  48 . In another embodiment, the channels  56  may be defined through the interior of the microneedles  48  such that each microneedle  48  forms a hollow shaft. Regardless, the channels  56  may generally be configured to form a pathway that enables the drug formulation to flow from the top surface  44  of the support  42 , through the apertures  50  and into the channels  56 , at which point the drug formulation may be delivered into and/or through the user&#39;s skin  18 . 
     It should be appreciated that the channels  56  may be configured to define any suitable cross-sectional shape. For example, in one embodiment, each channel  56  may define a semi-circular or circular shape. In another embodiment, each channel  56  may define a non-circular shape, such as a “v” shape or any other suitable cross-sectional shape. 
     In several embodiments, the dimensions of the channels  56  defined by the microneedles  48  may be specifically selected to induce a capillary flow of the drug formulation. As is generally understood, capillary flow occurs when the adhesive forces of a fluid to the walls of a channel are greater than the cohesive forces between the liquid molecules. Specifically, the capillary pressure within a channel is inversely proportional to the cross-sectional dimension of the channel and directly proportional to the surface energy of the subject fluid, multiplied by the cosine of the contact angle of the fluid at the interface defined between the fluid and the channel. Thus, to facilitate capillary flow of the drug formulation through the microneedle assembly  36 , the cross-sectional dimension  58  ( FIG. 11 ) of the channel(s)  56  (e.g., the diameter, width, etc.) may be selectively controlled, with smaller dimensions generally resulting in higher capillary pressures. For example, in several embodiments, the cross-sectional dimension  58  may be selected so that the cross-sectional area of each channel  56  ranges from about 1,000 square microns (um.sup.2) to about 125,000 um.sup.2, such as from about 1,250 um.sup.2 to about 60,000 um.sup.2 or from about 6,000 um.sup.2 to about 20,000 um.sup.2 and any other subranges therebetween. 
     It should be appreciated that  FIG. 11  only illustrates a portion of a suitable microneedle assembly configuration and, thus, the microneedle assembly  36  used within the device  10  may generally include any number of microneedles  48  extending from its support  42 . For example, in one embodiment, the actual number of microneedles  48  included within the microneedle assembly  36  may range from about 10 microneedles per square centimeter (cm.sup.2) to about 1,500 microneedles per cm.sup.2, such as from about 50 microneedles per cm.sup.2, to about 1250 microneedles per cm.sup.2 or from about 100 microneedles per cm.sup.2 to about 500 microneedles per cm.sup.2 and any other subranges therebetween. 
     It should also be appreciated that the microneedles  48  may generally be arranged on the support  42  in a variety of different patterns, and such patterns may be designed for any particular use. For example, in one embodiment, the microneedles  48  may be spaced apart in a uniform manner, such as in a rectangular or square grid or in concentric circles. In such an embodiment, the spacing of the microneedles  48  may generally depend on numerous factors, including, but not limited to, the length and width of the microneedles  48 , as well as the amount and type of drug formulation that is intended to be delivered through the microneedles  48 . By way of non-limiting example, micro-needle arrays suitable for use with the present invention include those described in WO2012/020332 to Ross; WO2001/0270221 to Ross; and WO2011/070457 to Ross. 
     Referring back to  FIGS. 1-4 , as indicated above, the disclosed device  10  may also include a reservoir  38  in fluid communication with the microneedle assembly  36 . Specifically, as shown in  FIGS. 2 and 3 , the reservoir  38  may be positioned above the microneedle assembly  36  within the central region  30  of the device  10 . In several embodiments, the reservoir  38  may be configured to be attached to a portion of the microneedle assembly  36 . For example, as shown in  FIGS. 2 and 3 , an adhesive layer  60  may be disposed between a bottom surface  62  of the reservoir  38  and the top surface of the microneedle assembly  36  (i.e., the top surface  44  of the support  42 ) in order to secure the microneedle assembly  36  to the reservoir  38 . 
     In general, the reservoir  38  may have any suitable structure and/or may be formed from any suitable material that permits the reservoir  38  to initially retain the drug formulation prior to its subsequent delivery into the microneedle assembly  36 . Thus, it should be appreciated that, as used herein, the term “reservoir” may generally refer to any suitable designated area or chamber within the device  10  that is configured to retain a fluidic drug formulation. For example, as shown in the illustrated embodiment, the reservoir  38  may be configured as a rigid or semi-rigid member defining an open volume or cavity  64  for retaining the drug formulation. However, in other embodiments, the reservoir  38  may have any other suitable configuration. For example, in another embodiment, the reservoir  38  may be configured as a flexible bladder. In a further embodiment, the reservoir  38  may be configured as a solid container or matrix through which the drug formulation is capable of being directed, such as a permeable, semi-permeable or microporous solid matrix. In still a further embodiment, the reservoir  38  may comprise a flexible bladder contained within or shielded by a rigid member. 
     It should be appreciated that any suitable drug formulation(s) may be retained within reservoir  38  and subsequently delivered through the user&#39;s skin  18  via the microneedle assembly  36 . As used herein, the term “drug formulation” is used in its broadest sense and may include, but is not limited to, any drug (e.g., a drug in neat form) and/or any solution, emulsion, suspension and/or the like containing a drug(s). Similarly, the term “drug” is used in its broadest sense and includes any compound having or perceived to have a medicinal benefit, which may include both regulated and unregulated compounds. For example, suitable types of drugs may include, but are not limited to, biologics, small molecule agents, vaccines, proteinaceous compounds, anti-infection agents, hormones, compounds regulating cardiac action or blood flow, pain control agents and so forth. One of ordinary skill in the art should readily appreciate that various ingredients may be combined together in any suitable manner so as to produce a compound having or perceived to have a medicinal benefit. 
     It should also be appreciated that the drug formulation may be supplied to the reservoir  38  in a variety of different ways. For example, in several embodiments, the drug formulation may be supplied via an inlet channel  66  defined through a portion of the reservoir  38 . In such an embodiment, a suitable conduit, port or tube  68  (e.g., a micro-bore tube or any other suitable flexible tube) may be configured to be received within the inlet channel  66  and may be in fluid communication with a suitable drug source (e.g., a syringe containing the drug formulation) such that the drug formulation may be directed through the inlet channel  66  and into the reservoir  38 . In other embodiments, the drug formulation may be supplied to the reservoir  38  using any other suitable means/method. For example, the reservoir  38  may be configured to be pre-filled or pre-charged prior to being assembled into the device  10 . 
     Additionally, as particularly shown in  FIG. 4 , the device  10  may also include a rate control membrane  70  disposed between the reservoir  38  and the microneedle assembly  36 . In general, the rate control membrane  70  may be configured to slow down or otherwise control the flow rate of the drug formulation as it is released from the reservoir  38 . The particular materials, thickness, etc. of the rate control membrane  70  may, of course, vary based on multiple factors, such as the viscosity of the drug formulation, the desired delivery time, etc. 
     In several embodiments, the rate control membrane  70  may be fabricated from any suitable permeable, semi-permeable or microporous material(s). For example, in several embodiments, the material used to form the rate control membrane  70  may have an average pore size of from about 0.01 micron to about 1000 microns, such as from about 1 micron to about 500 microns or from about 20 microns to about 200 microns and any other subranges therebetween. Additionally, in a particular embodiment, the material used to form the rate control membrane 70 may have an average pore size ranging from about 0.01 micron to about 1 micron, such as from about 0.1 micron to about 0.9 micron or from about 0.25 micron to about 0.75 micron and any other subranges therebetween, Suitable membrane materials include, for instance, fibrous webs (e.g., woven or nonwoven), apertured films, foams, sponges, etc., which are formed from polymers such as polyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers. 
     Referring still to  FIGS. 1-4 , the device  10  may also include a plunger  72  positioned directly above of the reservoir  38 . In general, the plunger  72  may be configured to be moved relative to the housing  12  as the various components contained within the housing  12  are moved between un-actuated position ( FIG. 2 ), wherein the bottom of the microneedle assembly  36  is generally aligned with or recessed relative to the bottom surface  20  of the lower housing portion  16  and an actuated position ( FIG. 3 ), wherein the microneedle assembly  36  extends outward beyond the bottom surface  20  of the lower housing portion  16 , thereby allowing the microneedles  48  of the assembly  36  to penetrate the user&#39;s skin  18 . As shown in  FIGS. 2-4 , in one embodiment, the plunger  72  may generally include a cylindrical top portion  74  configured to be slidably received within a corresponding opening  76  defined in the housing  12  and a flattened bottom portion  78  configured to engage or otherwise be positioned directly adjacent to the reservoir  38 . In such an embodiment, when the plunger  72  is moved downward relative to the housing  12 , the bottom portion  78  of the plunger  72  may apply a force against the reservoir  38  that pushes the microneedle assembly  36  downward into the user&#39;s skin  18 . 
     Additionally, as indicated above, the disclosed device  10  may also include a bilateral pushing element  40  disposed within the central region  30  of the device  10 . In general, the pushing element  40  may be any suitable biasing mechanism and/or force application means that is configured to apply a continuous bilateral force (having both a downward component and an upward component) through the device  10  to the user&#39;s skin  18 . For example, as shown in the illustrated embodiment, the pushing element  40  comprises a spring compressed between the housing  12  and the plunger  72 . Thus, when the device  10  is moved to the actuated position during use ( FIG. 3 ), the spring may be configured to apply a continuous bilateral force against the housing  12  and the plunger  72  that is transmitted through the device  10  to the user&#39;s skin  18 . Specifically, the downward component of the force (indicated by arrows  84  in  FIG. 3 ) may be transmitted downward through the central region  30  of the device  10  (i.e., through the plunger  72  and the reservoir  38 ) to the microneedle assembly  36  such that the microneedles  48  of the assembly  36  are pressed into and maintained within the user&#39;s skin  18 . Similarly, the upward component of the force (indicated by arrows  86  in  FIG. 3 ) may be transmitted upward through the central region  30  of the device  10  to the housing  12 , thereby pushing housing  12  away from the user&#39;s skin  18 . However, since the housing  12  is attached to the user&#39;s skin  18  around its outer periphery (i.e., at the outer region  32  of the device  10 ), such upward force may generally be transmitted through the housing  12  and the adhesive layer  22  so as to provide an upward, tensioning force against the user&#39;s skin  18 . Thus, as the microneedles  48  are pushed downward into the user&#39;s skin  18 , the user&#39;s skin  18  may simultaneously be pulled upwards around the periphery of the device  10 , thereby tightening the skin  18  around the microneedle assembly  36  and enhancing the ease at which the microneedles  48  may be inserted into and maintained within the user&#39;s skin  18 . 
     In several embodiments, the device  10  may also include a locking mechanism configured to maintain the device components in the un-actuated position when the device  10  is not use. For example, as shown in  FIG. 1 , a lock pin  80  may be configured to extend through an opening  82  defined in the plunger  72  so as to engage opposing sides of the upper housing portion  14 , thereby maintaining the spring in a compressed or un-actuated state. However, when the lock pin  80  is removed, the spring may be decompressed so that the continuous bilateral force is transmitted through the device  10  to the user&#39;s skin  18 . In alternative embodiments, the locking mechanism may have any other suitable configuration and/or may be associated with any other suitable component of the device  10 . 
     It should be appreciated that, as an alternative to the spring/lock pin  80  arrangement, the plunger  72  may be moved between the un-actuated and actuated positions using any other suitable arrangement and/or configuration known in the art. 
     For example, in another embodiment, the top portion  74  of the plunger  72  extending outwardly beyond the top of the upper housing portion  14  may be used as a push-button to manually push the plunger  72  downward into the actuated position. In such an embodiment, the bottom of the spring  40  may, for example, be coupled to the plunger  72  so that the spring  40  biases the plunger  72  into the un-actuated position. 
     It should be noted that, since the reservoir  38  may be configured as a rigid or semi-rigid member in the illustrated embodiment, the force applied by the pushing element  40  is transmitted through the body of the reservoir  38  instead of being transmitted to the drug formulation itself. Accordingly, the microneedles  48  may be pressed into the user&#39;s skin  18  without increasing the pressure of the drug formulation or otherwise applying a significant downward force upon the drug formulation. Stated differently, the pushing element  40 , when actuated and applying a downward force on the microneedle assembly  36 , does not pressurize the fluidized drug passing out of the device and into the skin through the microneedle channels  56 . 
     Referring now to  FIGS. 5-10 , several views of another embodiment of a transdermal drug delivery device  110  are illustrated in accordance with aspects of the present subject matter. As shown, the device  110  may include an outer housing  112  configured to at least partially surround and/or encase the various components of the device  110 . In general, the housing  112  may include an upper housing portion  114  and a lower housing portion  116 . However, unlike the housing  12  described above with reference to  FIGS. 1-4 , the upper housing portion  114  and the lower housing portion  116  may comprise separate components configured to be separately attached to one another. For example, as shown in  FIGS. 6-8 , in one embodiment, a bottom peripheral surface  117  of the upper housing portion  114  may be configured to be secured to a top surface  118  of the lower housing portion  116  using an adhesive, thermal bonding/welding or any other suitable attachment means. 
     In general, the upper housing portion  114  may be configured as an outer shell defining an open volume for housing the various device components. For example, as shown  FIGS. 6 and 7 , when the housing  112  is assembled, an open volume may be defined between the upper housing portion  114  and the lower housing portion  116  within which the device components may be at least partially contained. It should be appreciated that the upper housing portion  114  may be configured to define any suitable shape. For instance, as shown in the illustrated embodiment, the upper housing portion  114  generally defines a semicircular or dome shape. However, in other embodiments, the upper housing portion  114  may have any other suitable shape that defines an open volume for housing the various components of the device  10 . The lower housing portion  116  of the housing  112  may generally be configured to be positioned adjacent to the user&#39;s skin  18  when the device  110  is in use. For example, as shown in the illustrated embodiment, the lower housing portion  116  may comprise a flat panel configured to extend both inwardly and outwardly from the bottom peripheral surface  117  of the upper housing portion  114  such that a bottom surface  120  of the lower housing portion  116  extends directly adjacent to the user&#39;s skin  18 . Additionally, as shown in  FIG. 8 , the lower housing portion  116  may define a central opening  121  through which the user&#39;s skin  18  may be accessed. For instance, as will be described below, a microneedle assembly  136  of the device  110  may be configured to extend through the opening  121  to allow such assembly to penetrate the user&#39;s skin  18 . 
     Moreover, in several embodiments, the lower housing portion  116  may be configured to be attached to the user&#39;s skin  18  using a suitable skin attachment means. For example, in one embodiment, an adhesive  122  may be applied to the bottom surface  120  of the lower housing portion  116 . As such, when the device  10  is placed onto the user&#39;s skin  18 , the housing  112  may be attached to the skin  18  via the adhesive layer  122 . However, in other embodiments, any other suitable skin attachment means known in the art may be utilized to attach the housing  112  to the user&#39;s skin  18 . 
     It should be appreciated that, in several embodiments, both the upper housing portion  114  and the lower housing portion  116  may be formed from a relatively flexible material, such as a flexible polymer material, to allow the housing  112  to generally conform the shape of the user&#39;s body and/or to facilitate proper adhesion to the skin  18 . In such embodiments, the device  110  may also include a rigid support member  124  extending between the upper and lower housing portions  114 ,  116  so as to provide structural support to the device  110 . For example, as shown in  FIG. 8 , the support member  124  may define a relatively flat platform  125 . The flat underside of the platform  125  may, in one aspect, provide a flat or substantially flat surface relative to the bilateral pushing element such that the bilateral pushing element can achieve a reliable and/or even engagement with this surface when actuated. In addition, the support member  124  may further include an outward projection  126  extending upward from the platform  125 . Additionally, as shown in  FIG. 8 , the upper housing portion  114  may be configured to define a support opening  128  configured to receive the projection  126 . Thus, when the projection  126  is received within the support opening  128 , at least a portion of the upper housing portion  114  may contact against and be supported by the platform  125 . Moreover, the top of the support member  124  may also provide a load-bearing surface through which a force may be applied by the user when attaching the device  110  to the user&#39;s skin  18 . 
     Similar to the embodiment described above with reference to  FIGS. 1-4 , the device  110  may include different zones or regions defined by and/or within the housing  112 . For example, as shown in  FIGS. 6 and 7 , the device  110  may include a central region  130  defined around its center line  131 . The device  110  may also include an outer region  132  generally defined at the location at which the device  110  is attached to the user&#39;s skin  18 . For example, as shown in  FIGS. 6 and 7 , the outer region  132  may be defined at the interface between the bottom surface  120  of the lower housing portion  116  and the adhesive layer  122 . Moreover, the device  110  may also include an intermediate region  134  extending between and separating the central and outer regions  130 ,  132 . 
     In several embodiments, the device  110  may include one or more components at least partially disposed within the central region  130 . For example, as shown in the illustrated embodiment, the device  110  may include a microneedle assembly  136 , a reservoir  138  and a bilateral pushing element  140  vertically aligned within the central region  130 , with the footprint of the microneedle assembly  136  and the pushing element  140  generally defining the outer perimeter of the central region  130 . As will be described below, the pushing element  140  may be configured to apply a downward force through the central region  130  in order to press the microneedle assembly  136  into the user&#39;s skin  18 . In addition, the pushing element  140  may also be configured to apply an upward force through the central region  130  that is transmitted through the housing  112  to the outer region  132  of the device  110 , thereby providing an upward force against the user&#39;s skin  18  via the adhesive layer  122 . 
     In general, the microneedle assembly  136  may be configured the same as or similar to the microneedle assembly  36  described above. For example, as shown in  FIG. 11 , in several embodiments, the microneedle assembly  136  may include a support  42  having a top surface  44  and a bottom surface  46  and defining a plurality of apertures  50  between the top and bottom surfaces  44 ,  46 . In addition, the microneedle assembly  136  may also include a plurality of microneedles  48  extending outwardly from the bottom surface  46 . As described above, each microneedle  48  may define a channel(s)  56  in fluid communication with the apertures  50 . As such, the drug formulation contained within the device  110  may be directed from the top surface  44  of the support  42  through the apertures  50  and into the microneedles  48  for subsequent delivery to the user&#39;s skin  18 . 
     Additionally, similar to the embodiment described above, the reservoir  138  of the device  110  may generally be configured as any suitable designated area or chamber within which the drug formulation may be initially retained prior to the subsequent delivery of the formulation to the microneedle assembly  136 . For example, as shown in the illustrated embodiment, the reservoir  138  may be configured as a flexible bladder. Specifically, as shown in  FIG. 8 , the reservoir  138  may include a flexible top layer  142  and a flexible bottom layer  144 , with the top and bottom layers  142 ,  144  being configured to be secured to one another around their edges  146 . In such an embodiment, to allow the drug formulation retained within the reservoir  138  to be delivered to the microneedle assembly  136 , the bottom layer  144  of the reservoir  138  may define an opening or window  148  that is in fluid communication with the microneedle assembly  136 . For example, as shown  FIG. 8 , the window  148  may be defined in the bottom layer  144  such that, when the reservoir  138  is positioned directly above microneedle assembly  136 , the drug formulation may be directed through the window  148  and along the top surface of the microneedle assembly  136  (i.e., the top surface  44  of the support  42 ). 
     It should be appreciated that the drug formulation may be supplied to the reservoir  138  in a variety of different ways. For example, in several embodiments, the drug formulation may be supplied via an inlet opening  150  defined in the top layer  142  (or the bottom layer  144 ) of the reservoir  138 . In such an embodiment, a suitable conduit, port and/or tube may be in fluid communication within both the inlet opening  150  and a suitable drug source (e.g., a syringe containing the drug formulation) such that the drug formulation may be directed through the inlet opening  150  and into the reservoir  138 . For example, as shown in  FIGS. 6-8 , a supply port  152  may include a bottom end  154  configured to be secured/sealed to the reservoir  138  around the inlet opening  150  such that the drug formulation may be delivered to the inlet opening  150  via a supply channel  156  defined through the bottom end  154 . Additionally, as shown in  FIG. 5 , a top end  158  of the supply port  152  may be configured to extend through a port opening  160  defined in the upper housing portion  114 . As such, the top end  158  may be accessed by the user or a healthcare professional to permit the drug formulation to be injected into the supply port  152 . Although not shown, the supply port  152  may also be configured to include a one-way valve to allow the drug formulation to flow through the port  152  in the direction of the reservoir  138  (i.e., from the top end  158  to the bottom end  154 ) and to prevent the flow of such drug formulation in the opposite direction (i.e., from the bottom end  154  to the top end  158 ). 
     In other embodiments, the drug formulation may be supplied to the reservoir  138  using any other suitable means/method. For example, in one embodiment, the reservoir  138  may be configured to be pre-filled or pre-charged prior to being assembled into the device  10 . 
     Additionally, the disclosed device  110  may also include a rate control membrane  170  to slow down or otherwise control the flow rate of the drug formulation as it is released into the microneedle assembly  136 . Specifically, as shown in  FIG. 8 , the rate control membrane  170  may be configured to be secured within the reservoir  138  around the perimeter of the reservoir window  148  such that the drug formulation passes through the rate control membrane  170  prior to exiting the reservoir  138  via the window  148 . However, in other embodiments, the rate control membrane  170  may be positioned between the bottom layer  144  of the reservoir  138  and the microneedle assembly  136  at the location of the window  148 . It should be appreciated that the rate control membrane  170  may generally be configured the same as or similar to the rate control membrane  70  described above, such as by being fabricated from any suitable permeable, semi-permeable or microporous material(s) that allows for the membrane  170  to control the flow rate of the drug formulation flowing between the reservoir  138  and the microneedle assembly  136 . 
     Referring still to  FIGS. 5-10 , as indicated above, the device  110  may also include a bilateral pushing element  140  disposed within the central region  130  of the device  110 . In general, the pushing element  140  may comprise any suitable biasing mechanism and/or force application means that is configured to apply a continuous bilateral force (having both a downward component and an upward component) through the device  110  and against the user&#39;s skin  18 . For example, as shown in the illustrated embodiment, the pushing element  140  comprises an expandable member positioned between the upper housing portion  114  and the reservoir  138 . The expandable member may generally be configured to be in an un-expanded state ( FIGS. 6 and 9 ), in which the member does not transmit any forces through the central region  130  of the device  100 , and an expanded or actuated state ( FIGS. 7 and 10 ), in which the member expands outwardly so as to apply a continuous bilateral force through the central region  130 . For example, as particularly shown in  FIGS. 9 and 10 , the expandable member may be configured to define a first height  172  when in the un-expanded state and a larger, second height  174  when in the actuated state. 
     Such expansion may generally provide a means for the expandable member to apply both a continuous downward force and a continuous upward force through the central region  130  of the device  110 . Specifically the downward component of the force (indicated by the arrows  184  in  FIG. 7 ) may be transmitted downward through the central region  130  (e.g., through the reservoir  138 ) to the microneedle assembly  136  such that the microneedles  48  of the assembly  136  extend through the central opening  121  ( FIG. 8 ) and are pressed into and maintained within the user&#39;s skin  18 . It will be appreciated that, in such an embodiment, fluid within the reservoir  138  will be pressurized as a result of the downward pressure component exerted by the bilateral pushing element  140 . Similarly, the upward component of the force (indicated by the arrows  186  in  FIG. 7 ) may be transmitted upward through the central region  130  (e.g., through the support member  124 ) to the housing  112 , thereby pushing the housing  112  away from the user&#39;s skin. However, since the housing  112  is attached to the user&#39;s skin  18  around its outer periphery (i.e., at the outer region  132  of the device  110 ), such upward force may generally be transmitted through the housing  112  to the adhesive layer  122  so as to provide an upward, tensioning force against the user&#39;s skin  18 . Thus, as the microneedles  48  are pushed downward into the user&#39;s skin  18 , the user&#39;s skin  18  may be pulled upwards around the device&#39;s periphery, thereby tightening the skin  18  around the microneedle assembly  36  and enhancing the ease at which the microneedles  48  may be inserted into and maintained within the user&#39;s skin  18 . 
     As particularly shown in  FIGS. 9 and 10 , in several embodiments, the expandable member may include an expandable material  176  (e.g., compressed foam) vacuum sealed within a suitable outer covering or jacket  178 . As such, the expandable member may be activated by releasing the vacuum and allowing air to flow into the jacket  178 . For example, as shown in the illustrated embodiment, a peel strip or removable tab  180  may be used to activate the expandable member by exposing a jacket opening  182  defined in the jacket  178 . Specifically, as shown in  FIG. 9 , the removable tab  180  may be initially positioned over the jacket opening  182  so as to seal the opening  182  and maintain the vacuum within the jacket  178 . However, as the removable tab  180  is pulled or peeled away from the opening (e.g., by pulling on an exposed end  188  of the tab  109 ), the seal may be broken and air may flow into the jacket  178 , thereby allowing the expandable material  176  contained therein to expand outwardly. In such an embodiment, a portion of the tab  180  may be configured to extend through a corresponding opening or slot  190  defined in the housing  112  to allow the tab  180  to be pulled or peeled away from the opening  182  by the user. It should be appreciated that the jacket  178  may be stretchable, elastic, over-sized and/or may have any other suitable configuration that allows for the expansion of the expandable material  176  contained therein. 
     In alternative embodiments, the vacuum contained within the jacket  178  may be released using any other suitable activation means. For example, in another embodiment, a push button or other component may be configured to be pressed such that a pin, needle or other penetrating mechanism penetrates the jacket  178 , thereby creating an aperture and releasing the vacuum. 
     Additionally, it should be noted that, since the reservoir  138  is configured as a flexible bladder, the reservoir  138  may be pressurized by the downward force applied by the pushing element  140 . As such, the pressure of the drug formulation contained within the reservoir  138  may be increased, thereby facilitating the flow of the formulation from the reservoir  138  to the microneedle assembly  136 . 
     As indicated above, in addition to having a central region  30 ,  130  and an outer region  32 ,  132 , the disclosed devices  10 ,  110  may also include intermediate region  34 ,  134  defined between and separating the central and outer regions  30 ,  130 ,  32 ,  132 . In several embodiments, the intermediate regions  34 ,  134  of the devices  10 ,  110  may correspond to areas along which the device(s)  10 ,  110  do not contact the user&#39;s skin  18 . For example, as shown in  FIGS. 2 and 3 , the intermediate region  34  of the device  10  may correspond to the open space defined underneath the housing  12  between the adhesive layer  22  and the footprint defined by the microneedle assembly  36 , the reservoir  38  and the pushing element  40 . Similarly, as shown in  FIGS. 6 and 7 , the intermediate region  134  of the device  110  may correspond to the open space defined underneath the housing  112  between the adhesive layer  122  and the footprint defined by the microneedle assembly  136  and the pushing element  140 . Thus, unlike the central and outer regions wherein forces are transmitted through the microneedle assemblies  36 ,  136  and adhesive layers  22 ,  122 , respectively, to the user&#39;s skin  18 , substantially no or no forces may be transmitted through the intermediate regions  34 ,  134  to the user&#39;s skin  18 . As such, in several embodiments, a width  192  of the intermediate regions  34 ,  134  may be selected such that the downward force applied to the skin  18  through central regions  30 ,  130  and the upward force applied to the skin  18  through the outer regions  32 ,  132  are sufficiently spaced apart from one another. For example, in one embodiment, the width of the intermediate regions  34 ,  134  may range from about 0.5 millimeters (mm) to about 15 mm, such as from about 1 mm to about 10 mm or from about 2 mm to about 5 mm and any other subranges therebetween. 
     The dissociation or functional separation of the lower housing  116  and the microneedle assembly  136  allows the two elements to move independently of one another as well as have transmitted to them substantially opposed components of force. Further, the superimposition of the microneedle assembly  136 , pushing element  140  and upper housing  114  allows for the simultaneous application of a continuous upward force to the lower housing  116  (e.g. via the upper housing  114 ) and a continuous downward force to the microneedle assembly  136 . However, it will be appreciated that to effectively allow the independent transmission of these generally opposing forces it will be appreciated that the pushing element  140  and lower housing  116  should also be dissociated or functionally separated from one another. 
     Additionally, it should be appreciated that, in several embodiments, the configuration of the disclosed pushing elements  40 ,  140  (e.g., the spring constant of the spring or the expansion constant of the expandable member) may be selected such that the constant force transmitted to the microneedle assemblies  36 ,  136  is sufficient to cause the microneedles  48  to penetrate the user&#39;s skin  18  and remain therein during delivery of the drug formulation. For example, in several embodiments, the pushing elements  40 ,  140  may be configured such that the upward and downward components of the force applied through the devices  10 ,  110  ranges from about 0.1 Newtons (N) to about 20 N, such as from about 0.15 N to about 10 N or from about 0.25 N to about 5 N and all other sub ranges therebetween. 
     It should also be appreciated that, in alternative embodiments of the present subject matter, the pushing element  40 ,  140  may comprise any other suitable element and/or member capable of providing a continuous bilateral force. For example, in one embodiment, the pushing element  40 ,  140  may comprise a mechanical actuator, such as a solenoid-activated cylinder or any other suitable actuator, positioned within the housing  12 ,  112 . In a further embodiment, the pushing element  40 ,  140  may comprise a threaded bolt or screw that is configured to be screwed into the housing  12 ,  112  so as to mechanically apply the continuous bilateral force through the device  10 ,  110 . Still further, a bladder or other element may be expanded with air pressure such as via a pump or other mechanism. 
     Moreover, it should be appreciated that the skin attachment means (e.g., adhesive layers  22 ,  122 ) may generally be configured to define any suitable width  194  so as to provide a sufficient surface area for transferring the upward component of the force to the user&#39;s skin  18 . For example, in several embodiments, the width  194  of the skin attachment means may range from about 5 millimeters (mm) to about 30 mm, such as from about 5 mm to about 25 mm or from about 10 mm to about 25 mm and any other subranges therebetween. 
     As indicated above, the present subject matter is also directed to a method for transdermally delivering a drug formulation. The method may generally include positioning a transdermal drug delivery device  10 ,  110  adjacent to skin  18  and applying, with a pushing element  40 ,  140 , a continuous bilateral force having a downward component transmitted through a microneedle assembly  36 ,  136  of the device  10 ,  110  and an upward component transmitted through skin attachment means  22 ,  122  of the device  10 ,  110 . 
     This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they include structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.