Patent Publication Number: US-2007106207-A1

Title: High-speed vaccination device

Description:
This application claims the benefit of U.S. Provisional Application Ser. Nos. 60/733,190, filed Nov. 4, 2005, 60/734,012, filed Nov. 7, 2005 and 60/740,507, filed Nov. 30, 2005. 
    
    
     BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates to a hand-held device operable for the high-speed intradermal delivery of a biological such as a vaccine to a patient. The device contains a plurality of doses of a vaccine releasably disposed on microneedle clusters affixed to a tape and can be used for vaccinating a plurality of people before refilling the device.  
      2. Prior Art  
      The human skin is comprised of several layers. The uppermost is the epidermis, covered by the stratum corneum, which serves as an effective mechanical barrier between tissues of the body and the outside environment. Cells populating the epidermis include keratinocytes, melanocytes, and especially important to vaccine delivery, Langerhans cells. Beneath the epidermal layer is the highly vascularized dermal layer, which nourishes the epidermis. The dermal layer includes blood vessels, nerves, lymph vessels, dendritic cells, hair follicles, collagen, and sweat glands. Underlying the dermal layer is is the fatty subcutaneous layer, with fat cells, blood vessels, and connective tissue.  
      Injections that are given subcutaneously or intramuscularly necessarily involve contact between the needle and nerves within the dermal layer and cause pain. To overcome this problem, microneedles and/or arrays of microneedles, such as porous silicon microneedles, are currently under development to create a delivery device that can deliver compounds to the interface between the stratum corneum (i.e., the barrier that prevents most topically-applied substances from being absorbed) and the dermal layer and thereby avoid impacting a nerve with a needle and causing pain.  
      In order to effect vaccination, a biological such as an antigen must pass from outside the skin to inside the skin wherein it is presented to cells of the immune system. Not only is the stratum comeum relatively impermeable, the antigen (biological) must traverse considerable skin tissue before the antigen is presented to cells of the immune system. Transdermal patches are effective for delivering small molecules to the interface between the epidermis and the dermis but are relatively ineffective for delivering larger molecules. Electrophoresis or iontophoresis can also be employed to improve the permeability of the stratum corneum. It would be an improvement in the art of vaccination if the transport of a biological into the interface between the epidermis and dermis did not require penetration of the stratum corneum by the antigenic substance.  
      U.S. Pat. No. 5,318,514 to Hofmann discloses an applicator for the electroporation of drugs and genes into cells. The applicator includes a plurality of needle electrodes which can be penetrated into the skin of a patient. Material to be electroporated into the skin is retained in a fluid reservoir which wets an open cell foam elastomer carrier for the fluid. Because the material to be electroporated is retained in a fluid, in both the reservoir and the open cell foam elastomer, careful control of the amount of the material at the electrode surfaces is difficult. It is difficult to control how much fluid flows down from the reservoir and the open cell foam elastomer to the surfaces of the needle electrodes, and, thereby, it is difficult to control how much of the treatment molecules is actually present on the surfaces of the needle electrodes as the electroporation process is being carried out on the patient. Moreover, the device lacks a cassette housing a plurality of doses of treatment molecules and further lacks a plurality of independent, discrete microneedle clusters disposed on a transportable tape. Accordingly, the device is inoperable for rapidly administering a single dose of treatment molecules to a large number of patients.  
      Microneedles have been known for many years. For example, U.S. Pat. No. 3,964,482 discloses the construction of microneedles. Commercialization of microneedle technology has been advanced by the recent development of inexpensive production methods as well as the identification of suitable production materials which produce strong microneedles that will overcome tissue penetration problems and that will not break easily. Radiation-sensitive polymers may be employed to fabricate microneedles. Polymeric microneedles can be coated, using electrochemical or sputtering techniques, with an electrically conductive material such as, titanium, gold and/or aluminum. These coated, electrically conducting microneedles can be used to enhance the permeability of the epidermis and dermis to facilitate drug delivery by employing electrophoresis: that is, passing an electric current between microneedles when the microneedles are at least partially embedded within the stratum comeum.  
      King et al., in pending U.S. Patent Application Pub. No. 2004/0203124, discloses the use of a (conductively-coated) microneedle assembly for the delivery of DNA vaccines to target cells, the DNA thereafter to be incorporated within the genome of the target cells. The apparatus employs a pulsed electric field having a defined waveform to increase penetration of the vaccine. Although the microneedle assembly is disposable, the device and method is limited to the administration of a single inoculation of DNA. Notwithstanding this limitation, the disclosure teaches the practicality of using a microneedle assembly for the intradermal delivery of a vaccine.  
      Although the recent developments in microneedle fabrication technology have improved the utility of microneedles for intradermal delivery of molecules such as vaccines, there remains a need for a multi-dose microneedle-based vaccination device, and a method for using the device for the mass vaccination of an at-risk population. Preferably, the device can be used by relatively unskilled healthcare workers for the rapid and painless administration of a vaccine to a large number of people. The present invention provides a multi-dose microneedle-based vaccinating device and a method for using the device to deliver a vaccine to cells adjacent the interface between the epidermal and dermal layers of the skin of an animal. While the device is discussed in the context of delivering a vaccine to people, it is understood that the device may be used for administering a vaccine to other animals as well.  
     SUMMARY  
      The present invention is directed to a multi-dose vaccinating device and a method for using the device to administer a vaccine that substantially obviates one or more of the limitations of the related art. To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, the invention includes a hand-held applicator device that has a delivery opening and includes a multi-dose vaccine cassette removably housed within the applicator device. The cassette has a protective window that can be opened prior to use and houses a tape that has a plurality of discrete microneedle clusters disposed on an outer surface thereof, each cluster of microneedles having a single dose of vaccine coated thereon. The applicator device further includes a tape drive operable for positioning the tape such that a single cluster of microneedles underlies the protective (integrity) window in the cassette and the delivery opening in the applicator. When a trigger on the applicator is actuated, the delivery opening on the applicator is exposed and the cluster of microneedles affixed to the tape is advanced through the delivery opening on the applicator. When the applicator is pressed against a person&#39;s skin, the cluster of microneedles is driven into the epidermis of the person&#39;s skin. When the applicator is withdrawn from contact with the person&#39;s skin and the trigger released, a tape transport advances the tape such that a new cluster of microneedles is disposed to underlie the delivery opening in preparation for administering the vaccine to another person. An electrical pulse, or train of electrical pulses, may also be applied to the microneedles after they enter the skin. The force on the microneedle cluster pressed against the skin actuates an electrical pulse generator, causing an electrical pulse, or a pulse train to be applied to the microneedle cluster to assist penetration of the vaccine adhered to the microneedle cluster into the skin.  
      An essential feature of the present invention is the tape that supports and stores multiple doses of a vaccine. The tape has a length and a plurality of microneedle clusters affixed to a surface of the tape. The microneedle clusters are discretely disposed and equally spaced along the length of the tape. The microneedle clusters, which are preferably electrically conductive, have a therapeutic composition or a vaccine releasably attached to the microneedle clusters. The tape supporting the microneedle clusters and vaccine is wound on a delivery reel which is rotatably mounted within a cassette.  
      It is a further aspect of the invention to provide a method for making a tape having a plurality of microneedles clusters affixed to a surface thereof and a method for releasably coating the microneedle clusters with a vaccine.  
      The features of the invention believed to be novel are set forth with particularity in the appended claims. However the invention itself, both as to organization and method of operation, together with further objects and advantages thereof may be best understood by reference to the following description taken in conjunction with the accompanying drawings. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  is a side elevational view of a vccine applicator device in accordance with a preferred embodiment of the present invention.  
       FIG. 2  is a top plan view of a vaccine cassette adapted to be removably. housed within the cassette compartment of  FIG. 3 .  
       FIG. 3  is a top plan view of a cassette compartment within the applicator of  FIG. 1 , the cassette shown in phantom within the compartment. The cassette compartment is accessed through a door in the outer wall of the applicator. When the cassette is correctly positioned within the cassette compartment, the tape reels are engaged by tape transport mechanisms in the applicator.  
       FIG. 4  is a top plan view of a cassette compartment in accordance with a preferred embodiment of the invention, showing the position of the components contained therein prior to inoculation.  
       FIG. 5  is a top plan view of a cassette compartment in accordance with  FIG. 4 , showing the position of the components contained therein during inoculation of a patient with a vaccine.  
       FIG. 6  is a side view of a mechanical embodiment of an integrity door opening assembly.  
       FIG. 7  is a top plan view of a section of tape having a plurality of microneedle clusters affixed to an upper surface thereof.  
       FIG. 8  is an enlarged side view of a microneedle cluster.  
       FIG. 9  is a side view of a roller illustrating a recessed portion in the roller to prevent contact of the microneedle cluster on the tape with the surface of the roller.  
       FIG. 10  is a plan view of an exemplary embodiment of a tape strain relief mechanism which can be employed to prevent rupture of the tape when the applicator is actuated and the tape backing plate (and the portion of the tape supporting a microneedle cluster) is advanced through the delivery opening in the applicator.  
       FIG. 11  is a top view of a section of a protective tape bearing a plurality of discrete, equally-spaced apertures wherein the apertures are positioned to overlie microneedle clusters that project upwardly from the vaccination tape when the protective tape is brought into registered juxtaposition with the vaccination tape of  FIG. 12 .  
       FIG. 12  is a top view of the tape having microneedle clusters affixed to discrete segments of conductive film that is protected by the tape set forth in  FIG. 11 .  
       FIG. 13  is a schematic view of a first embodiment of an apparatus for making a tape having a plurality of discrete, electrically conductive, vaccine-coated microneedle clusters affixed thereto.  
       FIG. 14  is a schematic view of a second embodiment of an apparatus for making a tape having a plurality of discrete, electrically conductive, vaccine-coated microneedle clusters affixed thereto.  
       FIG. 15  illustrates, in top  15   a  and side  15   b  view, the general shape of a pocket in a vaccination tape wherein the pocket is recessed to accommodate a microneedle cluster (not shown) therein. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
      The invention described herein provides a device operable for the rapid and painless delivery of a vaccine to a large number of people by relatively unskilled personnel. The invention also provides a method for storing multiple doses of a vaccine on a plurality of discrete microneedle clusters affixed to a tape housed within a cassette. The vaccine is stored on the outer surface of the microneedles comprising the linearly-spaced microneedle arrays (clusters), and rolled on a reel of plastic tape. The reels are housed in cassettes which fit into a hand-held delivery device (applicator) which operates automatically to drive the microneedles comprising a particular cluster into the epidermis when the operator presses the applicator against the skin of a patient and actuates a trigger. The applicator, alternatively referred to herein as “delivery device”, includes a tape transport means and either an integral power supply, or means for connecting the applicator to an external power supply. The applicator further includes sequencing logic which controls the tape position for vaccine delivery and automatically prepares the applicator for the next injection cycle.  
      Turning now to  FIG. 1 , a representative embodiment of an applicator (delivery device) in accordance with the present invention is shown in side elevational view at numeral  10 . While the applicator  10  is intended to be hand-held, it will be obvious to the artisan that the size and shape of the applicator  10  may vary in order to accommodate the tape cassette and the particular choice of tape transport mechanism, power supply and mechanical actuators selected for the operation of the applicator  10 . The applicator  10  has an openable delivery port  11  through which an array (cluster) of microneedles  12 , supported by a microneedle backing plate  13 , project. The applicator  10  includes a cassette access door  14  which provides means for mounting a vaccine cassette  20  ( FIG. 2 ) in a cassette receptacle  30  ( FIG. 3 ) or, more preferably, the cassette compartment indicated at  40  in  FIG. 4 , recessed within the applicator  10 . The applicator  10  further includes a trigger assembly  15  and either an integral power supply  16  (shown in phantom) or a cable  17  operable for electrical connection of the applicator  10  to an external power supply (not shown). The applicator  10  preferably further includes a viewable readout  18  indicating the number of doses of vaccine remaining in the applicator.  
      A vaccine cassette  20  for use with the applicator  10  is shown in top plan view in  FIG. 2 . The cassette  20  has a supply reel  21  and a take-up reel  22  rotatable mounted therein in a manner well known in the art. A slidable front cover or openable protective window  23  provides protection of the tape  24  and the microneedle cluster(s)  12  affixed to the tape from the external environment prior to use. The tape  24  is wound on the supply and take-up reels in a manner similar to a VHS video cassette. The tape  24  has a plurality of discrete microneedle clusters  12  affixed to an outer surface thereof (only a single microneedle cluster  12  is shown in  FIG. 2  for clarity). The tape  24  is drawn off of supply reel  21 , travels over tape guides  25 , and, after use, is wound onto take-up reel  22 .  
      With reference to  FIG. 3 , a simple embodiment of the cassette compartment  30  within the applicator  10  is shown in top view with portions of the cassette  20  (shown in phantom) positioned within the compartment  30 . The compartment  30  has a retractable integrity cover  31  that is shown in an open position to expose delivery opening  32 . A portion of the tape  24  bearing a cluster of microneedles  12  is centrally disposed within the delivery opening  32  forward of the backing plate  13 . A solenoid  34 , illustrated in an activated position, thrusts backing plate  13  forwardly, advancing the microneedle cluster  12  through the delivery opening  32  in response to an actuating signal from switch  15 . As the cluster of microneedles  12 , laden with vaccine, advances through the opening  32 , the cluster of microneedles penetrate the skin of a patient (not shown), depositing the vaccine therein. While the embodiment of the cassette compartment indicated at numeral  30  teaches the general operation of the cassette compartment components, the embodiment  30  is not suitable for use in the applicator due to the potential for damage to the tape during operation of the applicator.  
      A more preferred embodiment of a cassette compartment is illustrated in top view at numeral  40  in a nonactivated position ( FIG. 4 ) and an activated position ( FIG. 5 ). With reference first to  FIG. 4 , a cassette compartment disposed within an applicator  10  in accordance with a preferred embodiment of the present invention is indicated at numeral  40 . Prior to activation (i.e., prior to the administration of a dose of vaccine) the vaccination assembly  41 , mounted within compartment  40  of the applicator  10  (not shown in  FIG. 4 ) between supply reel  21  and take-up reel  22 , is disposed behind the openable integrity door  31 . The vaccination assembly  41  has a wheel  42  rotatably mounted on the foremost end of a shaft  43  which is slidably mounted within tube  46 . The tube  46  is constrained to linear motion by guides AA. The tube  46  bears a rack gear which is engaged by pinion  44  driven by stepping motor  45 . A pin  48  affixed to shaft  43  rides in a vertical slot  47  in the wall of tube  46  to constrain the travel of the shaft. Tube  46  also includes contact arms  49  and  49 ′ which can engage contacts  50  and  50 ′ which serve as limit switches to signal the controller when the wheel  42  is extended through the delivery opening  32  ( FIG. 5 ) by closure of switch  50 , or fully retracted within the compartment (as shown in  FIG. 4 ) by closure of switch  50 ′. When the wheel  42  is extended, as shown in  FIG. 5 , contact  50  closes to contact  49 ′. When wheel  42  is retracted, contact  49  closes with contact  50 ′. A spring  49   b  bears between the lower end of tube  46  and the lower end of shaft  43 , urging the shaft upward. The lower end of tube  46  also bears an insulated contact  49   a  that is coaxial with, but insulated from, spring  49   b . When the trigger  15  on the applicator  10  is pulled, and vaccination wheel  42  is pressed against the patient&#39;s skin, spring  49   b  compresses, allowing contact  49   a  to close against the lower end of shaft  43  which signals the controller to initiate the application of an electrical pulse or pulse train to the microneedle cluster to effect the delivery of vaccine to the patient. When the trigger  15  is released, the stepping motor  45  is then operated to retract wheel  42  and tape transport means advances the tape to position the next microneedle cluster adjacent the delivery opening  32 .  
      An example of a mechanical door-opening means operable for opening the integrity door  31  to expose the delivery opening  32  as the shaft  43  and wheel  42  advances is illustrated in  FIG. 6 . The integrity (delivery) door  31  is in two parts:  31   a  and  31   b , each part being slidably mounted on the cassette compartment  40  to expose ( FIG. 5 ) or occlude ( FIG. 4 ) the delivery opening  32 . Parts  31   a  and  31   b  of the integrity (delivery) door  31  include projections which ride in slots (not visible in  FIG. 6 ) in the applicator  10  housing. Arms  61   a  and  61   b  are pivotally mounted to the shaft  43  at a medial end thereof and to parts  31   a  and  31   b  at a lateral end thereof. As the shaft advances toward the delivery opening, the parts  31   a  and  31   b  slide laterally to expose the delivery opening  32  enabling the wheel  42  to extend through the delivery opening. As the shaft retracts, the door parts  31   a  and  31   b  are urged together to occlude the delivery opening  32 . Of course, it will be obvious to the artisan that springs may be used to facilitate opening or closing of the integrity (delivery) door  31 . A solenoid or similar electromechanical device may be used as well for opening and closing parts  31   a  and  3 l b.    
      The tape that is employed to support, store and transport a plurality of microneedle clusters having vaccine on a surface thereof is a critical part of the present invention. Turning now to  FIG. 7 , a section of tape  24  bearing a plurality of evenly-spaced microneedle clusters  12  disposed on an upper surface thereof is shown in top view. An enlarged side view of a microneedle cluster  12  supported by a tape  24  is illustrated in  FIG. 8 . Each of the microneedle clusters  12  are deposited on a discrete layer or film of a conductive material  81  applied to the upper surface of the tape  24 . The individual microneedles comprising each microneedle cluster  12  are either electrically conductive or coated with an electrically conductive layer. A vaccine  82  ( FIG. 8 ) is applied to the microneedle cluster to overlie the conductive coating and microneedle cluster thereon. The lateral edges of the tape  24  include a plurality of evenly spaced perforations  71  adapted to engage a rotating motor-driven sprocket to facilitate tape transport in a manner well known in the art. Wipers  72  maintain contact with the metalized portions of the tape and provide a signal to indicate tape position and to conduct electroporation pulse(s) to the microneedle clusters.  
      It should be noted that since the tape  24  has a plurality of sharp microneedle clusters  12  projecting from a surface of the tape, care must be taken not to dull or break the microneedle clusters  12  during tape transport and storage. Accordingly, it is desirable to employ guide rollers  25  having a recessed portion, indicated at X in  FIG. 9 , to underlie the microneedle clusters  12  as the tape is transported over the guide roller. It should also be noted that when the applicator  10  is actuated, the microneedle cluster overlying the backing plate is advanced through the delivery opening in the applicator which results in the application of tension to the tape. If the tape guide rollers  25  are supported by a strain relief mechanism such as illustrated in  FIG. 10 , as the shaft  43  is advanced, guide roller support(s)  101  travel inwardly as they ride along the conical surface of a cam  102  attached to the shaft. The inward travel of the guide roller support(s)  101  during advancement of the shaft  43  is sufficient to maintain constant tension on the tape (not shown in  FIG. 10 ) during advancement of shaft  43  and roller or wheel  42  ( FIGS. 4 and 5 ).  
      Process for Making Tape Having a Plurality of Microneedle Clusters Disposed on a Surface Thereof.  
      Three approaches for the production fabrication of the storage reels  21  containing vaccine are presented. With reference now to  FIG. 13 , which is a schematic view of a first process for fabricating a tape in accordance with the present invention, tape supply reel  130  feeds tape  24  between embossing wheels  131  and  132  which contain mating male an female dies disposed along the outer circumference thereof. As the tape  24  passes therebetween, a pocket, or intaglio-type depression  133  is created in the tape  24 . If a thermoset tape is used, wheels  131  and  132  can be supplied with internal heaters and thermostats powered by slip rings (not shown) to heat the tape. The purpose of forming the pockets  133  in the tape, as shown in detail in  FIG. 15 , is to allow the tape, with the formed microneedle clusters recessed within the pocket  133 , to be wound on reels without turn-to-turn damage to the needles. This is effected by making the depth of the pocket, H in  FIG. 15 , greater than the height of the microneedles, which are typically ˜0.1 to 0.8 mm. in length. The dimensions of the microneedle clusters  12  in  FIG. 8  are greatly exaggerated in order to better illustrate the construction of the microneedle cluster  12 . Also, in  FIGS. 13 and 14 , the tape spacing between the processing steps (stations) is relaxed for clarity.  
      After passing between the pocket-forming dies  131  and  132 , the tape  24  passes to spray station  134 , which is a conductive film spray station. Stepping motors (not shown) advance the tape  24  to a position wherein the pocket  133  is disposed before the spray head  134   a . The spray station  134 , which deposits a film of electrically conductive material such as a hot or cold metal powder in the pocket  133  through a spray mask  134   e , includes a powdered metal inlet  134   b , a gas inlet  134   c  that forces a gas through a (normally closed) solenoid-actuated valve X. A power cable  134   d  which is connected to a programmable process sequencer (not shown), controls the spraying of metallic film into the pocket  133 . An insulated, shaped, electrically conductive backing plate  134   f  is disposed behind the tape  24  and connected to a voltage source (not shown) through the programmable process sequencer. The backing plate  134   f  can be pulsed to a high positive voltage in synchrony with a pulse to the gas solenoid X to effect a controlled spray time of the metallic film into the pocket  133  in the tape.  
      After the conductive film is deposited into the pocket  133  to form a metallized pocket, a tape transport means such as a stepping motor advances the tape  24  until the metallized pocket  133  is disposed in front of a needle forming station  135 . The registerable positioning of the pocket  133  at any particular station during the process is facilitated by including position-sensing wiper(s)  72  along the feed path of the tape to stop the tape transport mechanism when the pocket  133  in the tape  24  is correctly positioned. As the tape is advanced to the needle forming station  135 , wipers  72  detect a metallized segment on tape  24  and stop the further advance of the tape with the pocket  133  facing extruder head  135   c . Needle forming station  135  is an extruder comprising a piston  135   p  slidably disposed within a cylinder  135   a , an extrusion head  135   c , a  3 -way solenoid valve  135   d , and extrudable material charging means such as a pump operable for charging the portion of the cylinder  135   a  between the piston  135   p  and the extrusion head  135   c  with a photopolymeric paste through check valve  135   e . The entire needle forming station  135  is slidably mounted and constrained to move along an axis (indicated by the double-headed arrow) by guides  135   f .  
      A cam pin  135   g  mounted off-center on a motor shaft at  143  engages the horizontal slot (not numbered) in the body of the extruder adjacent motor shaft  143 . When the stepping motor (not shown) is pulsed to rotate the cam motor shaft  143  180 degrees, the extrusion head  135   c  is brought proximal to the metalized pocket. The extrusion head  135   c  contains a plurality of holes; the diameter of the holes being equal to the desired diameter of the microneedles, and when a pressure pulse of gas or fluid from gas source  135   h  is passed by solenoid valve  135   d  into the portion of the cylinder  135   a  rearward of the piston  135   p , the piston  135   p  is urged toward the extruder head  135   c  and the polymer is extruded onto the metalized pocket forming a cluster of cylindrical needles. At the end of the extrusion cycle, the motor shaft is again pulsed to turn the cam 180 degrees, moving the extruder head  135   c  away from the pocket and drawing the polymer away from the base of the cylindrical needle to form an essentially “sharpend” tip on the (cylindrical) microneedles as shown in  FIG. 8  (the microneedles being exaggerated to illustrate the concept).  
      With continued reference to  FIG. 13 , when the pocket  133  in the tape is in position for extrusion of the microneedle cluster, a 2-way solenoid valve  135   k  connects vacuum line  135   n  to vacuum chamber  135   q . The portion of the tape containing pocket  133  is drawn against an apertured backing plate  135   m  and held firmly in position for extrusion of the microneedle clusters. As stated above, cam shaft  143  rotates to position the extruder head adjacent the pocket  133 . When the extruder head  135   c  is fully advanced, 3-way solenoid valve  135   d  then opens to pressure source  135   h  allowing pressure to bear against piston  135   p , forcing the photopolymeric paste (stippled) in cylinder  135   a  through the cluster of openings in the extruder head  135   c  to form the needles. After the cluster of substantially cylindrical needles are extruded, cam shaft  143  again rotates, withdrawing the assembly  135  away from the pocket in a controlled fashion to draw out the (viscous) extruded photopolymer to form tips on the needles. After the sharp tips are formed on the needles, valve  135   d  opens to the atmosphere to relieve the extrusion pressure and, simultaneously, valve  135   k  opens to vent the vacuum chamber  135   q  to the atmosphere thereby releasing the tape from the apertured backing plate  135   m  so that the pocket containing the freshly extruded clusters can be transported to the needle hardening station  136 . High voltage pulses can be applied in synchrony with the extrusion of the needles to the backing plate  135   m  and/or the metallized pocket  133  to facilitate needle formation. Pulses necessary to effect tape transport, reciprocal movement of the extruder assembly comprising needle forming station  135 , valve control and high-voltage pulsing are preprogrammed in the sequencing microprocessor and control power supply. All tubing and connections to the extruder  135  must be sufficiently flexible to permit reciprocal motion of the extruder assembly comprising needle forming station  135 .  
      The tape is then moved such that the pocket bearing the cluster of microneedles is adjacent a needle hardening station  136 , which may be a UV source, or sources, which both sets the polymer and sterilizes the polymeric microneedles. The vaccination tape  24  is then moved to a second spray station  137 , which is similar or identical to spray station  134 , where the polymeric microneedles are metalized by application of an electrically conductive coating thereto by the same process as previously described for depositing a metallic film in the pocket  133 .  
      Following metallization of the microneedle clusters at the second spray station  137 , the tape is advanced such that the electrically conductive microneedle cluster that is affixed to the metallized film in the pocket is adjacent the vaccine spray coating station  138  where the vaccine is spray-coated onto the metalized cluster of microneedles. Vaccine spray head  138   a  connects to a gas source  138   b  through solenoid valve  138   c , and to container  138   d  holding vaccine  138   e . A spray baffle  138   f  is connected to spray head  138   a  and to a high voltage terminal  138   g . The vaccine spray head  138   a  is electrically isolated and can be pulsed to a high voltage in synchrony with pulsing the valve  138   c  open, effecting a pulsed spray onto the microneedle cluster which is grounded by the guides  139   a  and  139   b . This vaccine coating method embraces a wide range of options that include the choice of gas, gas pressure, pulse “on” time, and magnitude and width of the high voltage pulse sufficient to insure that the microneedle cluster can be coated with a minimum of vaccine. This can be of critical importance with a vaccine that is both expensive and in short supply. The finished tape is now guided to the take-up reel  21 , where it can be stored until needed for the vaccination unit previously described. The process for making a tape in accordance with  FIG. 13  assumes fabrication from a standard plastic tape, purchased with the desired width and thickness, and with properties appropriate to the pocket forming step—which may include thermoplastic characteristics.  
      A second process, also designed to protect the needle array from turn-to-turn mechanical damage during winding without requiring the microneedle cluster(s) to be contained within a pocket, is shown in  FIG. 14 . In this second process, a protective tape  110  (a portion of the protective tape is shown in top view in  FIG. 11 ) and a standard tape  24  of the desired width, thickness and having a metallic film deposited thereon is purchased from the supplier with a specification for the shape and spacing of sprocket holes, both to control movement and to insure registration of the metalized vaccination tape  24  with the protective tape  110 , shown in top view in  FIG. 11 . The protective tape  110  has sprocket holes  71  and cut-outs or apertures  111  dimensioned and spaced to matingly overlie the microneedle clusterl 2  on vaccination tape  24  ( FIGS. 7 and 12 ). Sprocket drive mechanisms (not shown) operable for transport and synchronization of the vaccination tape as it moves from station to station during the fabrication process, is a mature technology, refined especially for motion picture film.  
      With continued reference to  FIG. 14 , supply reel  130  supplies the metalized and sprocket punched vaccination tape  24  which is controllably moved through the fabrication process by sprocket wheel  140 , driven by a stepping motor (not shown). The vaccination tape  24  is advanced from the supply reel  130  to a stripping station  141  which removes bands of metal from the metalized tape to create isolated, electrically conductive metal frames which can then be detected by wipers  72  to control the stepping motor drive on sprocket  140 . The stripping station  141  is preferably a pulsed scanning laser, such as a C 02  laser, which can be controlled to vaporize targeted portions of the metalic film on the vaccination tape  24 .  
      The vaccination tape  24  is then moved to a microneedle forming station  135  which comprises an extruder as previously described which is slidably mounted and constrained by guides  135   f  to move back an forth in the direction of the double-headed arrow in response to a 180 degree rotation of a carn arrangement  135   g  and  143  as previously described. Alternatively, the extruder  135  may be replaced with an inkjet printer employing ink jet printing technology, and bearing a matrix of printing orifices having a diameter equal to the diameter of the desired microneedles. The inkjet printer can be connected by cable to a print driver and a computer card in the control and sequencing unit. Extruder  135  is charged with a photo-setting polymer, which may be set by UV, visible or IR radiation. As previously described, the cam arrangement  135   g  brings the extruder head proximal to the vaccination tape  24 , extrudes a cluster of cylinders, and, at the end of the extrusion cycle, the cam shaft  143  and cam pin  135   g  mounted thereon rotates 180 degrees and moves the extruder head assembly away from the vaccination tape  24 , drawing the (unset) cylinder tips to a fine point as shown in  FIG. 8 . A simultaneously pulsed electric field can be applied to aid polymer transfer. The vaccination tape is then moved to setting station  136  which comprises a radiation source which may emit either UV, visible or IR as required to set the polymer.  
      After the microneedles are formed and cured, the vaccination tape  24  is moved to the spray metalizing station  137  as previously described, in order to metalize the needle array. The vaccination tape  24  is finally advanced such that the microneedle cluster is adjacent vaccine applying station  138 . The vaccine is sprayed onto the metalized microneedle cluster as previously described. Following application of the vaccine to the microneedle cluster and drying, the vaccination tape  24  is guided to the sprocket wheel  140  where the protective tape  110  is unwound from protective tape supply reel  147  and brought into registration contact with the vaccination tape  24  and wound onto the storage reel  21 . The sprockets engage the sprocket holes  71  ( FIGS. 11 and 12 ) on both the vaccination tape  24  and the protective tape  110  to insure perfect registration of the cutouts  111  with the microneedle clusters  12  during winding of the laminate onto the storage reel  21  to protect microneedles from damage during winding and storage.  
      All of the electrical operations required for tape transport, as well as their synchronism with controlling the tape movement, are well known to those skilled in the art. The operation of the tape transport mechanism generally involves the generation of precise pulse trains to operate stepping motors, triggering high voltage pulses of controlled width and amplitude, pulsing the solenoid valves in the proper sequence, pulsing radiation sources and all other control functions. The control signals can be provided by a single programmable microprocessor. Power for the control module can be supplied by an internal battery, by an external direct current 12 volt supply or by a 120-230 volt, 50-60 Hz source of power.  
      Two approaches that are operable for the (essentially continuous) production and storage of a vaccination tape supporting a plurality of discrete microneedle clusters, each microneedle cluster bearing a dose of vaccine, have been disclosed. A third process for forming the vaccination tape consists of fabricating suitable large-scale microneedle arrays disposed on a substrate by means of a batch process such as extrusion, vacuum sputtering or deposition, photoetching or the like. The individual microneedle clusters and supporting substrate can be cut from the array and attached to the tape by adhesive means. Suitable spacing between microneedle clusters on the tape can be maintained by positioning means that are well known in the art.  
      In each of the processes, the vaccination tape  24  is rolled onto a reel and stored in a cassette for use. An instrument (applicator  10 ) for accepting these prepared cassettes and delivering the vaccine to patients rapidly and painlessly by unskilled personnel is also disclosed herein. The systems and technologies disclosed herein are believed to meet or exceed the future requirements of mass vaccination. It is recognized that vaccines have a shelf-life that may vary from vaccine to vaccine. In the event that a vaccine has a particularly short shelf-life, immediatley prior to use, a cassette having a vaccination tape therewithin, but lacking a vaccine coating on the microneedle clusters, can be inserted into a vaccine coating apparatus (not shown) such as the spray station  131 , and the vaccine coating applied to the microneedle clusters. The vaccination tape  24 , thus coated, is then rewound to prepare the cassette for insertion into an applicator. Further, it is contemplated that a plurality of microtubes or nanotubes may be deposited on the surface of a substrate to form a “hairy” surface, a portion of which is suitable for providing a microneedle cluster as described hereinabove. While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.