Patent Document

CROSS-REFERENCE TO RELATED PATENT APPLICATION 
       [0001]    This patent application claims the benefit of U.S. Provisional Patent Application No. 61/663,915, filed Jun. 25, 2012. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    The present invention relates generally to the field of drug delivery devices. The present invention relates specifically to wearable active drug delivery devices which facilitate drug delivery using one or more drug cartridges having microneedles as the point of drug delivery. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0003]    This application will become more fully understood from the following detailed description, taken in conjunction with the accompanying figures, wherein like reference numerals refer to like elements in which: 
           [0004]      FIG. 1  is a bottom view of the device prior to actuation; 
           [0005]      FIG. 2  includes a cross-sectional view of a drug delivery cartridge prior to actuation; 
           [0006]      FIG. 3  includes a cross-sectional view of a drug delivery cartridge following actuation and during drug delivery; and 
           [0007]      FIG. 4  includes a cross-sectional view of a drug delivery cartridge after needle retraction. 
       
    
    
     DETAILED DESCRIPTION 
       [0008]    Before turning to the figures, which illustrate the exemplary embodiments in detail, it should be understood that the present application is not limited to the details or methodology set forth in the description or illustrated in the figures. It should also be understood that the terminology is for the purpose of description only and should not be regarded as limiting. 
         [0009]    A multi-drug delivery device stores individual drugs, pharmaceuticals, hormones, vaccines, or nutrients in separate containers for storage and administration. In a typical embodiment, the drugs are therapeutic or prophylactic vaccines. The vaccines may be, for example, the individual monovalent vaccines of the DENVax vaccine. In another example, the drugs are a combination of monovalent and polyvalent vaccines for the seasonal influenza, pneumonia, chicken pox and shingles delivered from individual fluid containers. The device is employed to deliver the contents to discrete but nearby areas of the intradermal layers of skin. 
         [0010]    The delivery of vaccines to the intradermal layers may elicit a more robust immune response compared to a standard needle and syringe delivery to the muscle or subcutaneous layer. For example, simultaneous but independent delivery of the dengue monovalent vaccines, i.e., multi-monovalent delivery, to the dermal layer provides all four monovalent vaccine viruses equal opportunity to replicate thus avoiding the interference observed when delivered in a single tetravalent formulation. Several vaccines including polio and influenza, rabies, yellow fever have been demonstrated to have improved efficacy when delivered intradermally compared to intramuscularly. The multi-monovalent vaccines are injected into the dermal layer of the skin, mimicking the natural route of dengue infection that occurs, for example, from the bite of an infected mosquito. 
         [0011]    The vaccine may encompass but is not limited to a live or killed virus, a subunit or conjugate, a viral protein, a DNA plasmid encoding for viral antigens, an anti-sense RNA, a liposome containing viral peptides, a polysaccharide, or any combination of these provided as a liquid formulation. The vaccine may be intended for use in humans or in veterinary applications whether for domestic, dairy or livestock. 
         [0012]    For vaccination purposes, skin is a highly accessible organ and represents an effective immune barrier, mainly attributed to the presence of Langerhans cells residing in the epidermis and dendritic cells in the dermis. Skin immunization elicits a broad range of immune responses, including humoral, cellular, and mucosal responses. 
         [0013]    No single device exists that allows for the simultaneous delivery of multiple vaccines to the intradermal layers of the skin. Multiple vaccine delivery intramuscularly is currently achieved by sequential delivery, resulting in multiple injections for individual recipients. Such delivery of separate vaccines to neighboring but non-overlapping skin sites could be performed using sequential administrations by needle and syringe. This approach is extremely inefficient and requires additional time for the healthcare worker as well as the patient. 
         [0014]    Referring to  FIG. 1 , a multiple drug delivery device  2  is shown. Delivery device  2  provides concomitant delivery of multiple vaccines from discrete containers through separate needles and to distinct but proximal sites. Delivery device  2  is shown as a housing  4  having a base  6  and four separate drug cartridges  12 . Base  6  of delivery device  2  may be provided with an adhesive to secure delivery device  2  to the skin of a patient, thereby tensioning the skin of the patient during needle insertion and drug or vaccine injection. Drug cartridges  12  are inserted and held within housing  4  of delivery device  2 . Housing  4  further contains a main spring, trigger, and retraction actuator as discussed in further detail below. In one embodiment, base  6  of delivery device  2  has a footprint of 5 cm by 7 cm. 
         [0015]    In other embodiments, the delivery device may be configured with one, two, three, or five or more drug cartridges. In some embodiments, delivery device  2  may be configured to hold four cartridges, but an operator can insert fewer than the maximum number of cartridges and actuate the device. Each drug cartridge  12  stores a drug or vaccine and delivers it, via a dedicated fluid path, to a discrete location in the skin or subcutaneous tissue. Thus, delivery device  2  allows the simultaneous but independent delivery of different vaccines. In some embodiments, each vaccine is a monovalent vaccine so that simultaneous delivery multi-monovalent delivery. In other embodiments, one or more cartridges  12  may contain a combination vaccine while other cartridges  12  contain monovalent vaccines. In a typical embodiment, drug cartridges  12  are spaced at a distance of less than 1 cm from adjacent drug cartridges. In other embodiments, a larger spacing between drug cartridges  12  may be provided. 
         [0016]    Referring to  FIG. 2 , a cross-sectional view of a drug cartridge  12  prior to actuation is shown. Drug container  12  is a generally cylindrical cartridge having a cartridge housing  12  defining a central bore  14 . Drug cartridges  12  are inserted into the base of the delivery housing prior to patient administration. Drug cartridge  12  may be provided with retaining barbs  16  to lock the drug cartridge  12  into housing  4  and prevent removal after insertion. Drug containers  12  usable with delivery device  2  are preferably cartridges that can be filled and stored outside of delivery device  2  and inserted into the device as needed. In other embodiments, drug cartridges  12  may be secured in delivery device  2  by an adhesive, ultrasonic welding, a retaining ring, etc., and may be installed as part of an integrated manufacturing process and prior to use. 
         [0017]    Each cartridge is made up of a primary drug container  20 , which includes components that contain and protect the dosage form. Primary drug container  20  moves inside central bore  14  of cartridge housing  12  during needle insertion and retraction. Primary drug container  20  is formed generally as cylinder having top cap  22 , cylinder wall  24 , plunger interference latches  26 , and bottom wall  28 . Components of primary drug container  20 , for example, top cap  22 , bottom wall  28 , and microneedle array  38 , may be ultrasonically welded to cylinder wall  24 . Needle arrays are nested inside the cartridge housing for safety and are protected by a label that is to be removed just prior to actuation. Cartridge housing  12  is provided with one or more recesses  30  sized to receive plunger interference latches  26 . A plunger  32  is fitted within cylinder wall  24 , defining a fluid chamber  34 . A plunger spring  36  is interposed between top cap  22  and plunger  32 . Prior to actuation, plunger spring  36  is in a compressed state between top cap  22  and plunger  32 , and plunger  32  is held in place by plunger interference latches  26  molded or formed into cylinder wall  24 . 
         [0018]    Primary drug container  20  is further provided with a microneedle array  38 . Microneedle array  38  is an array of one or more hollow microneedles as described in U.S. patent application Ser. No. 13/288,266, which is hereby incorporated by reference in its entirety. Microneedle array  38  may be, for example, an array of polymeric microneedles less than 2 mm in length, and having a hollow lumen and multiple ports located near each tip for fluid delivery. The polymeric material may be a liquid crystal polymer. The microneedles thereby direct vaccine to the immune-rich intradermal layers of the skin leading to improved efficacy. In other embodiments, microneedles may be shorter, e.g. 1 mm in length. In still other embodiments, the microneedles may be longer, e.g. 3 mm, 4 mm, or more, thereby allowing for subcutaneous delivery of the contents of fluid chamber  34  to a patient. Microneedle array  38  is in fluid communication with fluid chamber  34  through opening  40  in bottom wall  28 . Prior to actuation, microneedle array  38  is nested inside cartridge housing  12 . A protective label  8  seals the microneedle array  38  of primary drug container  20  from contact with external objects. 
         [0019]    In another embodiment, cartridge  38  may be provided with one or more metal needles in place of polymeric microneedle array  38 . In such an embodiment, the metal needles may be at least 3-4 mm in length, thereby allowing for subcutaneous delivery of the contents of fluid chamber  34  to a patient. In a preferred embodiment using metal needles, each container  12  is provided with a single metal needle. In other embodiments, one or more metal needles may be shorter, e.g. 2 mm, 1 mm, or less, thereby allowing for intradermal delivery of the contents of fluid chamber  34  to a patient. 
         [0020]    Geometry of the primary drug container  20 , position of plunger latches  26  and dimensions of the plunger  32  may be varied to develop cartridges of different volumes (e.g. 100 μl, 250 μl, and 500 μl). In a preferred embodiment, drug cartridges  12  are designed to be filled through the center of top cap  22  with a septum over-molded into plunger  32  to prevent tampering. The geometry and size of drug cartridges  12  may be selected for compatibility with existing aseptic liquid fill technology. For example, according to ISO 13926-1 the standard dimensions for cartridges and pen systems include outside diameters of 8.65 mm, 10.85 mm, and 10.95 mm. 
         [0021]    Primary drug container  20  and the components thereof are formed from suitably inert materials, for example polypropylene, medical grade liquid crystal polymer, stainless steel, glass, etc. The primary drug container, plunger and microneedle array materials a preferably selected based on USP recommendations for primary drug containers in a parenteral device and on materials currently cleared for long-term storage of injectable fluids. In some embodiments, primary drug container  20  may be provided with a glass liner. Vapor barriers may be included if the selected materials exhibit higher than acceptable vapor transmission rates at intended storage conditions. In one embodiment, delivery device  2  may be provided with an aluminum vapor barrier. 
         [0022]    Still referring to  FIG. 2 , one or more main springs  42  are provided. A single main spring  42  may be provided for multiple drug cartridges  12 , or independent springs may be provided for one or more drug cartridges  12 . As shown in  FIG. 2  main spring  42  is a flat cantilever spring element. In a preferred embodiment, main spring  42  is formed from stamped steel. In other embodiments, main spring  42  may be a coil spring, a torsion spring, or another mechanical spring. In still other embodiments, main spring  42  may be a gas spring, or pressure may be applied to top cap  22  by gas discharge or by another pressure source. In a preferred embodiment, main spring  42  is optimized to ensure positive needle penetration into skin. The force required to fully penetrate the skin generally depends on the number and geometry of needles in microneedle arrays  38 , and the distance of needle travel from pre-actuated to actuated/penetrated state. In one embodiment, a force of about  26  pounds of force may be used to insert needles of microneedle array  38  into the skin of a patient. In preferred embodiments, main spring  42  is actuated by use of a trigger mechanism, thereby actuating each drug cartridge  12  simultaneously. In other embodiments, a trigger may actuate multiple drug cartridges  12  sequentially rather than simultaneously. In an especially preferred embodiment, a trigger actuation force of less than  4  pound-foot is required to trigger delivery device  2 . 
         [0023]    In preferred embodiments, microneedle arrays  38  retract fully within device housing  4  after use, thereby preventing injury and contamination from sharps. In the embodiment shown, a retraction spring  44  is provided between cartridge housing  12  and primary drug container  20 . As shown, retraction spring  44  is a helical spring oriented coaxially with center bore  14 . Prior to actuation, retraction spring  44  is in a generally uncompressed state. Where a retraction spring is provided, main spring  42  additionally must overcome the force of the retraction spring  44 . The opening in the base of each cartridge  12 , dimension of microneedle arrays  38 , and distance between needles and base  6  of housing  4  when delivery device  2  is placed in a retracted state may be designed to minimize or eliminate any human exposure to the needles of microneedle array  38 . 
         [0024]    Referring to  FIG. 3 , upon actuation main spring  42  applies a downward force to top cap  22  of primary drug container  20 , thereby driving primary drug container  20  downwards relative to cartridge housing  12  to a mechanical stop  46 . The downward motion of primary drug container  20  thereby injects the microneedles of microneedle array  38  into the intradermal layer of a patient. Additionally, downward motion of primary drug container  20  compresses refraction spring  44 . 
         [0025]    As primary drug container  20  moves downward, plunger interference latches  26  move into alignment with recesses  30  of cartridge housing  12 . When the primary drug container  20  is moved inside cartridge housing  12  to the mechanical stop  46 , interference latches  26  are forced out of the way into recesses  30  of cartridge housing  12  by the spring force, thereby allowing plunger  32  to travel to the bottom of its stroke within cylinder wall  24 . In another embodiment, plunger interference latches  26  may be formed or provided with a spring bias such that the latches  26  rotate into recesses  30 , thereby releasing plunger  32  within cylinder wall  24 . 
         [0026]    Upon release of plunger  32  by plunger interference latches  26 , plunger spring  36  moves plunger  32  downwards toward bottom wall  28 . As shown, plunger spring  36  is a helical spring oriented coaxially with center bore  14  and retraction spring  44 . As plunger  32  moves towards bottom wall  28 , plunger  32  forces the contents of fluid chamber  34  through opening  40  and the microneedles of microneedles array  38 , and thereby injects the contents of fluid chamber  34  into the skin of a patient. During injection, main spring  42  maintains a downward force on top cap  22  of primary drug container  20 . Plunger interference latches  26  move back to their original state on the top side of the plunger once the plunger has completed its stroke. 
         [0027]    Referring to  FIG. 4 , upon completion of injection, main spring  42  is removed from contact with top cap  22 . In one embodiment, main spring  42  is rotated off of top cap  22  of each drug cartridge  12 , thereby releasing primary drug container  20  within center bore  14  of cartridge housing  12 . Upon release of the primary drug container  20 , retraction spring  44  forces primary drug container  20  upwards, thereby withdrawing the microneedle array  38  from the skin of the patient and retracting the microneedles into cartridge housing  12 . The force of retraction spring is generally selected to overcome any plunger interference latches  26  that may remain or protrude into recesses  30  in cartridge housing  12 . 
         [0028]    Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only. The construction and arrangements, shown in the various exemplary embodiments, are illustrative only. Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.) without materially departing from the novel teachings and advantages of the subject matter described herein. Some elements shown as integrally formed may be constructed of multiple parts or elements, the position of elements may be reversed or otherwise varied, and the nature or number of discrete elements or positions may be altered or varied. The order or sequence of any process, logical algorithm, or method steps may be varied or re-sequenced according to alternative embodiments. Other substitutions, modifications, changes and omissions may also be made in the design, operating conditions and arrangement of the various exemplary embodiments without departing from the scope of the present invention.

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