Abstract:
A multi-site injection system includes a plurality of medicament delivering needles/microprotrusions, a needle/microprotrusion support, a supply of medicament, and a mechanism for providing the medicament to the plurality of needles/microprotrusions in order to effect delivery into a stratum corneum of a user.

Description:
[0001]    The present invention is generally directed to the administration of a medicament and is more particularly directed to a multi-site injection system for dermal delivery of a medicament. 
         [0002]    Topical delivery of medicament is a very useful method for achieving both systemic and localized pharmacological effects. A problem in such transcutaneous drug delivery is providing sufficient drug penetration across the skin. 
         [0003]    As is well know, the skin consists of multiple layers, starting with a stratum corneum layer of about 20 microns for humans, a viable epidermal tissue layer of about 70 microns and a dermal layer of about 2 mm in thickness. 
         [0004]    As such, the stratum corneum represents a major barrier for chemical penetration through the skin being responsible for the majority of the skin barrier property. This is, of course, dependent upon the medicament water solubility and molecular weight. 
         [0005]    Delivering medicament through the skin may be attained by piercing the stratum corneum and delivering a drug to the skin in or below the stratum corneum Such devices for piercing the stratum corneum may include a plurality of micron-sized needles or blades having lengths sufficient to pierce the stratum corneum without passing completely through the epidermis. Once a medicament is passed through the stratum corneum, there typically is no major hindrance to penetration of the remaining epidermal layers or the dermis. 
         [0006]    Do to sometimes painful use of individual needle penetration of the stratum corneum, it is desirable to provide a plurality of micro needles or protrusions for simultaneous delivery of a medicament through a larger area of stratum corneum. 
         [0007]    Accordingly, the present invention provides for a multi-site injection system utilizing a plurality of microprotrusions or needless for piercing the stratum corneum of the skin to a depth sufficient for delivering a medicament through the skin of a patient. 
       SUMMARY OF THE INVENTION 
       [0008]    A multi-site injection system in accordance with the present invention generally includes a plurality of medicament delivering needles/microprotrusions along with a support therefore. A supply of medicament is provided and a means provided for supplying the medicament to the plurality of needles/microprotrusions in order to effect delivery into a stratum corneum of a user. 
         [0009]    One embodiment of the present invention generally includes a rotatable drum having an outer surface with the microprotrusions thereon. 
         [0010]    The microprotrusions may include passages, or lumens, there through for enabling transport of the medicament therethrough from an inner surface of the rotatable drum and into the stratum corneum of a user. Alternatively the microprotrusions may be solid and coated with the medicament. 
         [0011]    A fixed inner drum may be provided for supporting the rotatable drum and includes at least one radial opening therein for providing the medicament to the microprotusions. 
         [0012]    The supply of medicament is disposed within the inner drum and a housing is provided for supporting the rotatable drum and the inner drum. The housing includes an opening for exposing an arcuate portion of the rotatable drum in order to enable rotation of the rotatable drum by rolling the rotatable drum against a users skin. 
         [0013]    While not shown, a blatter may be provided for containing the medicament with the blatter being in fluid communication with the radial opening in a fixed inner drum for providing the medicament to the microprotrusion passages. 
         [0014]    An alternative embodiments of a multi-site injection system in accordance with the present invention generally includes a guide plate having a plurality of openings therethrough and needle plate having a plurality of needles projecting therethrough with each needle being aligned with a corresponding opening and a guide plate. 
         [0015]    The needle plate is movable from a first position with the needles position behind a top surface of the guide plate to a second position with the needles projecting from the top plate through the opening. A plunger base is provided for moving the needle plate from the first to the second position. 
         [0016]    The needles may be coated with a medicament or the needles may include lumens in communication with a medicament reservoir, or supply, disposed in the plunger base for delivery of the medicament into a stratum corneum of a users skin. 
         [0017]    The needles and openings may be arranged in order to applicate the medicament to a users skin in a definite pattern which, may be a symmetrical radial pattern, an asymmetrical radial pattern or a concentric pattern which may or may not be circular. A rectilinear pattern of needles may be utilized in accordance with the present invent ion and the medicament preferably comprises botulinum toxin. 
         [0018]    A further embodiment of a multi-site injection system in accordance with the present invention generally includes a needle plate and a plurality of hollow needles fixed to an outside of the needle plate, for transport of a medicament from an inside of the needle plate and into a stratum corneum of a user. 
         [0019]    A pressurizer is provided and disposed over an inside of the needle plate to form a cavity therebetween in communication with the hollow needles. 
         [0020]    In addition, an injection port is disposed in the pressurizer for introducing the medicament into the cavity. 
         [0021]    More particularly, in accordance with the present invention, the pressurizer is flexible for causing uniform transport of the medicament through the needles. 
         [0022]    Accordingly, the pressurizer provides a means for forcing the medicament from the cavity through needle lumens. 
         [0023]    A still further embodiment of a multi-site manifold injection system in accordance with the present invention generally includes a handle along with a syringe supported by the handle and including a plunger for dispensing a fluid medicament from the syringe. 
         [0024]    A manifold is attached to one end of the handle and in fluid communication with a syringe and a plurality of needles, protruding from the manifold, are provided for delivery of the fluid medicament from the manifold and into the stratum corneum of a user. 
         [0025]    In accordance with one embodiment of the present invention, the manifold may be disposed perpendicular to the handle and further comprise a plurality of concentric conduits interconnected with radial conduits. 
         [0026]    The concentric conduits may be circular and radially spaced apart from one another. 
         [0027]    In addition, a transparent sheet may be provided and interconnecting a concentric and radial conduits for enabling visual orientation of the manifold onto a patients&#39; skin by manipulation of a handle. 
         [0028]    Alternatively, the manifold may comprise a plurality of concentric conduits and a plurality of radial ribs supporting the plurality of concentric conduits. Preferably, the medicament utilized in combination with the syringe manifold and needle is botulinum toxin. 
         [0029]    Yet another embodiment of the present invention includes a multi-site blister injection system haying a carrier sheet including a plurality of medicament filled rupturable blister disposed or an inside surface thereof. 
         [0030]    A plurality of needles extending from the outside of the carrier stream may be provided with each needle being aligned with a corresponding blister and having a lumen for transport of the medicament into the stratum corneum of the user. 
         [0031]    Each of the needles is positioned for traversing the carrier sheet and rupturing the corresponding blister. 
         [0032]    A pressure plate is disposed an the carrier sheet inside surface for forcing a blister against the needles for causing rupture thereof and forcing a medicament through the needle lumens. 
         [0033]    The pressure plate may be fixed to the carrier sheet and a foam pad way be disposed on the carrier sheet outside. Preferably, the foam pad covers the needles extending the carrier sheet outside and is penetrable by the needles. 
         [0034]    The foam pad may be adhered to the pressure plate along a perimeter thereof for securing the carrier sheet between the foam pad and the pressure plate. Preferably, the medicament in accordance with the present invention comprises botulinum toxin. 
         [0035]    Still another embodiment of a multi-site injection system in accordance with the present invention generally includes a shell including a top and a bottom and a plurality of needles protruding from the shell bottom. Each of the needles include a lumen extending through the shell bottom. 
         [0036]    A membrane is provided and disposed between the shell top and the shell bottom and an inlet is provided for introducing a fluid between the shell top and the shell bottom. 
         [0037]    A diverter is also provided for selectively directing fluid between the membrane and the shell bottom and between the membrane and the shell top. 
         [0038]    The diverter may include a manually operated valve and the system may further include the supply of medicament, preferably botulinum toxin, for introduction between the membrane and the shell bottom. 
         [0039]    An inert fluid supply may also be provided for introduction between the membrane and the shell top. 
         [0040]    Also in accordance with the present invention, a method of multi-site injection comprises providing a shell between the top and a bottom with bottom having a plurality of needles protruding therefrom with each needle including a lumen therethrough and extending through the shell bottom. 
         [0041]    The method also includes providing a membrane between the shell top and the shell bottom. 
         [0042]    More particularly, in accordance with the present invention, the method includes introducing a medicament between the membrane and the shell bottom and introducing pressurized fluid between the membrane and the shell top for forcing the medicament through the needle lumens. 
         [0043]    The medicament in accordance with the present invention preferably comprises botulinum toxin. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0044]    The advantages and features of the present invention will be better understood by the following description when considered in conjunction with the accompanying drawings in which: 
           [0045]      FIG. 1  is a perspective view of a multi-site injection system in accordance with the present invention generally showing a housing, or shell, for supporting a rotatable drum along with a rotatable drum having an outer surface with microprotrusions therein, a port is also shown which provides an access for charging the system with a medicament to be injected, such as, for example botulinum toxin; 
           [0046]      FIG. 2  is a partial cross section of the system shown in  FIG. 1  more clearly illustrating a fixed inner drum for containing a medicament and at least one radial opening therein for providing medicament to a plurality of microprotrusions affixed to and rotatable with the rotatable drum, the rotatable drum is rotated by rolling the drum against a users skin, not shown, and the housing supporting the rotatable drum and the inner drum includes an opening for exposing an arcuate portion of the rotatable drum for enabling rotation thereof; 
           [0047]      FIG. 3  is a cross sectional view taken along line  3 - 3  of  FIG. 2  more clearly showing operation of the system; 
           [0048]      FIG. 4  is a perspective view of a multi-site injection system in accordance with the present invention generally showing a guide plate having a plurality of openings therethrough, a plunger base and a plurality of needles projecting from the guide plate; 
           [0049]      FIG. 5  is a partial cross section of one embodiment of the present invention showing a reservoir of medicament disposed in the plunger base with needle lumens in fluid communication therewith and disposed with needle points generally flush with a top surface of the guide plate; 
           [0050]      FIG. 6  is a cross sectional view similar to that shown in  FIG. 5  illustrating movement of the plunger base for protruding the needles from the top surface of the guide plate and into a stratum corneum of a users skin; 
           [0051]      FIG. 7  illustrates continued pressure on the plunger base for forcing medicament through the needle lumens and into the stratum corneum of the users skin; 
           [0052]      FIGS. 8 and 9  illustrate various needle patterns which may be suitable for various applications and areas of treatment on a users skin; 
           [0053]      FIG. 10  is a perspective view of a multi-site injection system in accordance with the present invention generally showing a needle plate with a plurality of needles projecting therefrom and fixed to an outside surface of the needle plate; 
           [0054]      FIG. 11  is a perspective view of the multi-site injection system shown in  FIG. 1  showing a reverse side with a pressurizer disposed over an inside of the needle plate along with an injection port and a pressurized reservoir of medicament interconnected to the port via a tube; 
           [0055]      FIG. 12  is a partial cross section of the injection system shown in  FIGS. 10 and 11  illustrating a cavity for and between the pressure plate and an inside surface of the needle plate illustrating medicament flow from the pressure reservoir through the tube into the cavity and through hollow needles for transport of the medicament into a stratum corneum of a user; 
           [0056]      FIG. 13  is a perspective view of the multi-site manifold injection system in accordance with the present invention generally showing a handle, a manifold attached to one end of the handle and a plurality of needles protruding from the manifold for delivery of fluid medicament from the manifold into a stratum corneum of a user, not shown; 
           [0057]      FIG. 14  is a cross sectional view of the system shown in  FIG. 13  more clearly shown a syringe supported by the handle and including a plunger for dispensing the fluid medicament from the syringe; 
           [0058]      FIG. 15  is a perspective view of a multi-site blister injection system in accordance with the present invention generally shoving a carrier sheet and a pressure plate disposed on an inside surface of the carrier sheet; 
           [0059]      FIG. 16  is an exploded perspective view of the system more clearly illustrating a carrier sheet with medicament filled blisters and a foam pad; 
           [0060]      FIG. 17  is a cross sectional view of the embodiments shown in  FIGS. 15 and 16  more clearly illustrating a plurality of needles extending from the carrier sheet, a plurality of rupturable blisters filled with a medicament, such as botulinum toxin, along with the pressure plate positioned for forcing the blisters against corresponding needles for causing rupture thereof and forcing medicament through needle lumens; 
           [0061]      FIG. 18  is a cross sectional view similar to that shown in  FIG. 17  in which the pressure plate has been forced against the blisters and medicament is forced into the stratum corneum of a users skin; 
           [0062]      FIG. 19  is a perspective view of a multi-site injection system in accordance with the present invention generally illustrating a shell having a top and a bottom with a plurality of needles protruding from the shell bottom. An inlet for introducing fluid between the shell top and bottom is shown along with a diverter; 
           [0063]      FIG. 20  is a cross sectional view of the system shown in  FIG. 19  more clearly illustrating the shell top, bottom and a membrane disposed between the shell top and the shell bottom along with a diverter valve for selectively directing fluid between the membrane and the shell bottom and between the membrane and the shell top,  FIG. 20  showing a filling cycle with medication being injected into a reservoir; 
           [0064]      FIG. 21  is a cross sectional view similar to  FIG. 20  showing the diverter selectively directing fluid between the membrane and top shell during an injection cycle in order to pressurize the reservoir of medicament thereby forcing the medicament through needle lumens; and 
           [0065]      FIG. 22  is an enlarged view of the needles illustrating a lumen therethrough for injection of the medicament into the stratum corneum of a users skin (not shown). 
       
    
    
     DETAILED DESCRIPTION 
       [0066]    With reference to  FIG. 1 , there is shown a multi-site injection system  10  which includes a rotatable drum  12  including an outer surface having a plurality of microprotrusions, or needles, affixed thereto. The microprotrusions may have lumens, or passages, therethrough. 
         [0067]    A housing  20  is provided for supporting the rotatable drum along with a fixed inner drum  24 , see  FIGS. 2 and 3 . An arcuate opening  28  in the housing  20  is provided for exposing the drum surface  14  which enables rotation of the drum  12  by rolling the drum  12  against a users skin  42 . 
         [0068]    Also shown in  FIG. 1  is an access  34  which is provided for introducing a medicament, such as botulinum toxin into the system via a syringe, not shown, or other suitable conveyance. 
         [0069]    As more clearly shown in  FIGS. 2 and 3 , an inner drum, fixed to the housing, or shell,  20 , is provided for containing a supply of medicament instilled through the access port  30  as hereinabove noted. 
         [0070]    This nonrotating inner drum, or reservoir,  36  includes a plurality of radial passages, or openings,  38  for providing the medicament  36  to the needles  18 . 
         [0071]    Preferably, a sponge-like material  40  is disposed on the rotatable drum  12  for both distributing medicament provided through the radial openings  18  and enabling application of the medicament via the needles  18  without excess medicament being deposited on the users skin  42 . 
         [0072]    In operation, rotation of the drum  12  on the users skin  42  causes rotation of the drum as indicated by the arrow  44  and medicament flows into the sponge and is applied to the users skin  42 . The needles penetrate the stratum corneum, or skin,  42  of the user, thus introducing the medicament thereinto. 
         [0073]    Alternatively, the protrusions, or needles may include lumens therethrough for direct transport of medicament  36  from the inner drum  34  upon rotation of the drum  12  against the users skin  42 . 
         [0074]    With reference to  FIG. 4 , there is shown an injection system  110  generally including a guide plate  112  having a plurality of openings therethrough along with a needle plate  120  including a plurality of needles  124  shown extending through the openings  116  and projecting from a top surface  128  of the guide plate  112 . Also shown is a plunger base  130  for moving the needle plate from a first position with the needles  124  positioned generally behind the top surface  128 , see  FIG. 5  to a second position with the needles  124  projecting from the top surface  128  as shown in  FIGS. 4, 5, and 6 . 
         [0075]    The needles  124  may be coated with a medicament, such as, for example, botulinum toxin. 
         [0076]    The guide plate  112 , needle plate  120 , needles  124 , and base  130  may be made form any suitable material and the needles preferably are about 128 gauge and 1 mm in length. Use of the multi-site injection system  110  for delivery of a medicament into the stratum corneum of a users skin is illustrated in  FIGS. 5-7 . 
         [0077]    As shown, the needle plate is configured in any suitable manner for being moveable from a first position shown in  FIG. 5  with the needles positioned behind, or flush with the top surface  128  of the needle plate  120  to a second position shown in  FIGS. 6 and 7  with the needles  124  projecting from the top surface  128  through the openings  116 . 
         [0078]    The plunger base  130  preferably includes and defines a reservoir  142  between the needle plate  120  and the base  130  for containing the medicament  134 . 
         [0079]    Incompressibility of the medicament  134  enables movement of the plunger base  130  to move the needle plate  120  from the first to the second position as indicated by the arrows  146 . 
         [0080]    Continued movement of the plunger base  130  forces medicament  134  through needle lumens  150  and collapse of the reservoir  142 . The guide plate  112 , needle plate  120 , and plunger based  130  may be integrally formed with a diaphragm arrangement, not shown, for enabling the relative motion hereinabove described. Other suitable configurations should be considered to be within the scope of the present invention. 
         [0081]    It should be appreciated that while the system  110  shown in  FIG. 4  illustrates, holds, or openings  116  and needles arranged in a generally symmetrical radial pattern, other patterns may be utilized for delivery of a medicament to body areas requiring different patterns of application.  FIGS. 8 and 9  illustrate systems  154 ,  156  showing an asymmetrical radial pattern and a rectilinear pattern respectively. 
         [0082]    With reference now to  FIGS. 10 and 11 , there is shown a multi-site injection system  208  in accordance with the present invention generally including a flexible needle plate  210  having a plurality of hollow needles  212  fixed to an outside surface  216  of the needle plate  210 . The needle plate  210  may be formed from any suitable material and the needles may be formed thereinto or affixed thereto in any conventional manner. 
         [0083]    As more clearly shown in  FIG. 11 , the system  208  may include a pressurizer  220 , which may be in the form of a flexible blatter or the like, for causing uniform pressure across an inside surface  224  of the needle plate  210 . 
         [0084]    As shown in  FIG. 12 , the pressurizer  220  establishes a cavity  226  between the pressurizer or  220  and the inside surface  224  of the needle plate  210 . 
         [0085]    As shown in  FIG. 12 , the inside surface  224  of the needle plate  210  may include a separate containment element  228  to facilitate construction of the system  208 . Thus, as illustrated the pressurizer  220  provides a means for forcing medicament, which is preferably botulinum toxin from the cavity  226  through needle lumens  232 . Spacing and orientation of the needles on the needle plate  210  is determined by the intended use of the needle plate  210  on specific user body parts, not shown. 
         [0086]    An injection port  234  is preferably interconnected to a pressure reservoir  236  through a tube  240 . Control of medicament flow from the pressure reservoir  236  through the tube and into the cavity  226  may be controlled in any conventional manner. 
         [0087]    Pressure medicament in the cavity  226  thus forces the medicament into a stratum corneum  242  of a user, not shown. 
         [0088]    Pressure provided by the flexible pressurizer as indicated by the arrows  244 ,  246  enable uniform flow of medicament as indicated by arrows  248 ,  250  through the needle lumens  232  as indicated by arrows  252 ,  254 . 
         [0089]    With reference to  FIGS. 13 and 14 , there is shown a multi-site injection system  310  including a handle  312 , a syringe  316 , which includes a plunger  318  for dispensing a fluid medicament from the syringe and into a manifold  322 , as illustrated by arrows  326  in  FIG. 14 . 
         [0090]    The handle  312 , syringe  316 , plunger  318 , and manifold  322  may be formed by any suitable materials. As shown in  FIGS. 13 and 14 , the manifold  322  may be disposed in a generally perpendicular relationship with the handle  312  and plunger  318  and a plurality of needles  330  protruding from the manifold  322  for delivery of fluid medicament from the manifold  322  into a stratum corneum of a user (not shown). 
         [0091]    The needles may be affixed to the manifold  322  in any conventional manner may be approximately 328 gauge with a length of approximately 1 mm and include needle lumens  334  in fluid communication with conduits  338  of the manifold  322 . The conduits may be concentric and in fluid communication with radial members  342 . 
         [0092]    In one embodiment of the present invention, the radial members may be hollow for providing fluid communication of medicament or alternatively in another embodiment of the present invention may be solid ribs for supporting the conduits  338 . 
         [0093]    A transparent sheet  346  may interconnect the conduits  338 ,  342  for enabling a constant pressure to be exerted over the entire area presented by the manifold  322  while enabling visual orientation of the manifold  322  onto a patient&#39;s skin (not shown) by manipulation of the handle  312 . 
         [0094]    In operation, finger pressure on the plunger  318  drives, or otherwise ratchets, a piston  350  disposed within the syringe for forcing medicament  354  downwardly through an exit port  356  and into the manifold conduits  338 , as hereinabove noted, forcing medicament through the needle lumens  334  as indicated by the arrows  360 . It should be appreciated that any suitable plunger, syringe, which may be fitted into the handle of the present invention is to be considered within the scope of the present invention. 
         [0095]    With reference to  FIGS. 15 and 16 , there is shown a multi-site injection system  410  in accordance with the present invention showing a carrier sheet  412  along with a foam pad  414 , see  FIG. 16 . A pressure plate  416  is disposed on a carrier sheet inside surface  420  and the foam pad  414  may include an adhesive for holding the carrier sheet  412  against the pressure plate  416 . 
         [0096]    With reference to  FIG. 17 and 18 , the carrier sheet  412  may be of conventional design and include blisters  424  filled with a medicament  426  as well as a plurality of protruding needles  430  extending from an outside surface  432  of the carrier sheet  412 . Each of the needles which may be, for example, 428 gauge and having 2 mm length and include lumens  436  or transport of medicament therethrough. 
         [0097]    Each of the needles  430  is aligned with a corresponding blister  424  and each needle including a point  438  for rupturing of corresponding blisters  424 . 
         [0098]    As shown, the pressure plate preferably includes a plurality of berms  440  for providing enhanced pressure against blisters as the pressure plate  416  is forced against the blisters  424 . 
         [0099]    The foam pad  414  preferably has a depth equal to or slightly greater than the length of the needles  430  in order to prevent inadvertent contact with the needles before use. 
         [0100]    In operation, as shown in  FIG. 18 , when the pressure plate  416  is forced downwardly as indicated by the arrows  444 , the needle points  438  are rupture the blisters  424  and continued pressure by the pressure plate  416  collapses the blisters  424  and forces medicament through the needle lumens  436  as indicated by the arrows  442 . 
         [0101]    This pressure also compresses the foam pad  414  as shown against a users shin  444  and into the stratum corneum  446 . It should be appreciated that the drawings are not to scale but rather enlarged to illustrate the operation of the multi-site injection system  410 . 
         [0102]    With reference to  FIGS. 19-22 , there is shown a multi-site injection system  510  in accordance with the present invention generally including a shell  512  having a top  516  and a bottom  518 . A plurality of needles  522  protrude from the shell bottom  518  with each needle  522  including a lumen  524  (see  FIG. 22 ) communicating with a reservoir  526  established by a membrane  528  disposed between the shell top  516  and the shell bottom  518 . 
         [0103]    It should be appreciated that the shell, membrane and needles may be made from any suitable material. Preferably, the needles have a gauge of about  528  and a length in the order of 2 mm. An inlet  530  including a tube  532  and passageway  534  provide a means for introducing a fluid between the shell top  516  and shell bottom  518 . 
         [0104]    A diverter  538  includes a manually operated valve  540  for selectively directing fluid between the membrane  528  and shell bottom  518  into the reservoir  526 . 
         [0105]    As shown by the arrow  544  during a filling cycle the inlet, or supply line, introduces a medicament, preferably botulinum toxin, into the reservoir by alignment with a dip tube  548  with the passageway  534  for filling of the reservoir  526 . 
         [0106]    Thereafter, the diverter  538  by way of the valve  540  aligns the passageway  534  for introducing a fluid, such as saline solution, between the membrane  528  and the top shell as illustrated by the arrows  552 ,  554 . This provides a pressure above the membrane  528  which forces the medicament from the reservoir  526  through the needle lumens  524  as illustrated by the arrows  558 . 
         [0107]    Although there has been hereinabove described various multi-site remotely pressurized injection systems in accordance with the present invention for the purpose of illustrating the manner in which the invention may be used to advantage, it should be appreciated that the invention is not limited thereto. That is, the present invention may suitably comprise, consist of, or consist essentially of the recited elements. Further, the invention illustratively disclosed herein suitably may be practiced in the absence of any element which is not specifically disclosed herein. Accordingly, any and all modifications, variations or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present invention as defined in the appended claims.