Abstract:
The apparatus comprises a mold assembly including at least one bore therethrough having a cavity therein defining the shape of the finished microneedle shape to be formed therein. The bore has an inlet opening and an exit opening. The apparatus also comprises means for locating the polymer to be formed at one end of the cavity and means for introducing fluid into the inlet opening of said bore and into the cavity. The apparatus also comprises exhaust means communicating with the exit opening of the bore, so that introducing the fluid through the polymer causes the polymer to assume the shape of the cavity and the fluid forms a hollow channel to define a needle-like structure in the polymer as the fluid is exhausted through the cavity and the bore.

Description:
This application is a U.S. National Phase of International Patent Application Ser. No. PCT/US2004/023806, filed Jul. 21, 2004 which claims priority to U.S. Patent Application Ser. No. 60/488,905 filed Jul. 21, 2003. 

   BRIEF DESCRIPTION OF THE INVENTION 
   Apparatus and methods are disclosed for manufacturing a microneedle array consisting of spaced-apart microneedles integral with and extending above a base sheet. A channel is formed extending from the tip of the microneedle through the base allowing fluids to pass completely through the microneedles in the array. 
   Prior art patents document the uses to which such microneedles are intended to be put and demonstrate known efforts to manufacture microneedles. In particular, U.S. Pat. Nos. 6,471,903, 6,451,240, 6,379,324, 6,312,612 and 6,256,533, all assigned to the Procter &amp; Gamble Company describe in great detail the characteristics and uses of such microneedle arrays. To date, the manufacturing processes detailed in these references have proven less than satisfactory on a commercial scale. 
   Preferably, the microneedle array is made from a polymer with flow characteristics that will take on the shape of the mold form and allow channels to be formed through the needles. Polymers such as urethanes, polysulfone, nylon, polycarbonates, acrylic and formulated radiation curable products may be used. The polymer may be applied in liquid form at a thickness of about 125 to 250 microns (0.005 to 0.010 inches thick) and may be heat cured, or room temperature cured, ultraviolet cured or cured by other radiation wavelengths. An alternative method is to apply the polymer as a film sheet then heat the polymer to a liquid state and cool back to a solid state once it has been formed with the gas channels. 
   One array of microneedles known to be of interest is formed with a height of about 160 microns (0.0064 inches), a base diameter of about 50 microns (0.002 inches), and spaced with adjacent microneedles being about 300 microns (0.012 inches) apart. Preferably the center channel is formed as a through hole, tapered or constant diameter depending on the application required. 
   In the present invention, a mold assembly is separable into upper and lower manifolds. The lower manifold has a gas inlet communicating with an internal cavity and has a top surface with one or more ports communicating with the internal cavity. A gasket material is placed on the top surface of the manifold having apertures generally in register with the top surface ports. A gas-permeable sheet or membrane is placed on top of the gasket and, in a first embodiment of the invention, a layer of polymer is applied to the membrane above the ports. 
   The upper manifold is sized, shaped and adapted to be fluid tight attachable to the lower manifold and has an upper internal bore communicating at one end with the upper ports and at the other end with an exhaust gas port. A micro-structure mold form is positioned above the polymer layer. The mold form has cavities in the shape of the microneedles formed precisely thereon, preferably as a series of generally frustoconical sections. Each cavity has a hole formed centrally such that a gas-tight path is formed from the lower manifold through the mold form and into the upper manifold. The microneedle mold form may be of metallic or polymeric construction depending on the temperature requirements to cure the polymer to be formed into microneedles. 
   In use, after the liquid polymer to be formed has been applied between the gas permeable membrane and the mold form, the upper manifold is attached to the lower manifold and gas under pressure is directed through the lower manifold inlet to pressurize the polymer and force it into the mold form. It has been found that if the gas pressure is maintained before the polymer in the mold form cures, the gas forces its way through the polymer and through the mold form holes, thereby forming channels which extend through the molded microneedles, from the base through the tip of each section, exiting through the top opening of the mold form. 
   Depending on the viscosity of the polymer to be formed, the gas pressure may range from less than 1 kilopascal per square centimeter (1 pound per square inch) to as much as 15-20 kilopascals per square centimeter (15-20 pounds per square inch). In some case it may be possible to use ambient air which has been filtered and dehumidified as the process gas. If UV or other radiation curable polymers are used it is anticipated that the use of inert gas may be of some advantage. 
   In another variation of the invention a thermoplastic film is substituted for the liquid polymer. The film is liquefied by heat, and then allowed to cool and solidify again after taking on the shape of the mold form and having channels formed through the microneedles. 
   Yet another variation of the invention substitutes a polymer powder for the liquid polymer. The powder is liquified by heat, then cooled and solidified after taking of the shape of the mold form and having channels formed through the microneedles. 
   Another embodiment uses a combination of gas pressure at the inlet of the manifold and vacuum pressure at the outlet side to draw gas through the polymer forming the channels. 
   When a UV-curable polymer is used, the upper manifold can be formed with transparent or translucent sections to allow such polymers to be exposed to ultraviolet light or other wavelengths while still in the mold form. After the polymer has set and has cured, the manifold halves are separated and the cured polymer sheet, with the molded microneedles, is removed. 
   In another embodiment of the present invention, a support sheet is formed from a rigid material such as sintered brass, porous Teflon or other porous materials allowing the gas to pass from the lower manifold to the gas permeable membrane while supporting the mold and polymer substrate. 
   In yet another embodiment, a second membrane is disposed in the upper manifold to absorb and collect excess polymer that may be extruded through the mold holes during the manufacturing process. 
   While the following describes a preferred embodiment or embodiments of the present invention, it is to be understood that this description is made by way of example only and is not intended to limit the scope of the present invention. It is expected that alterations and further modifications, as well as other and further applications of the principles of the present invention will occur to others skilled in the art to which the invention relates and, while differing from the foregoing, remain within the spirit and scope of the invention as herein described. For the purposes of the present disclosure, two structures that perform the same function within an environment described above may be equivalent structures. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     These and further objects of the present invention will become apparent upon consideration of the drawings in which: 
       FIG. 1  is a perspective view of an apparatus for the manufacture of microneedle arrays showing the upper and lower manifold attached one to the other; 
       FIG. 2  is a perspective view of the lower manifold separated from the upper manifold; 
       FIG. 3  is a perspective view of the lower manifold with the gasket in place; 
       FIG. 4  is a perspective view of the lower manifold showing a gas permeable membrane placed on the gasket and a layer of polymer placed on the membrane; 
       FIG. 5  is a perspective view of the mold form having the microneedle array pattern formed thereon seen next to the lower manifold; 
       FIG. 5A  is a magnified side view of the mold form; 
       FIG. 6  is a perspective view of the mold form positioned upon the lower manifold; 
       FIG. 7  is a perspective view of the upper and lower manifolds reassembled one to the other and with a gas supply line connected to the lower manifold; 
       FIG. 8  is a sectional schematic view of the lower manifold with the gasket, membrane, polymer and mold form in place; 
       FIG. 9  is a sectional schematic view showing the upper and lower manifolds assembled together and the polymer in the mold form after the process has been carried out and the polymer is curing; 
       FIG. 10  is a sectional schematic view of an alternative method showing the upper and lower manifolds assembled together and the polymer in the mold form after the process has been carried out and the polymer is curing; 
       FIG. 11  is a partial perspective view of a single microneedle; and 
       FIG. 12  is a top schematic view of a support pad formed with a regularly spaced array of through holes. 
       FIG. 13  is a schematic view of a cylindrical flexible mold form of multiple microneedle array patterns joined to form a continuous belt. 
       FIG. 14  is a schematic view of the apparatus using the cylindrical mold in  FIG. 12  to continuously fabricate product. 
   

   DETAILED DESCRIPTION OF THE INVENTION 
   Referring now to  FIG. 1 , the numeral  10  indicates generally a mold assembly having a lower manifold  12  and an upper manifold  14 . Attached fluid tightly to lower manifold  12  is a gas inlet coupling  16  and in like fashion, a gas outlet coupling  18  is attached fluid tightly to upper manifold  14 . 
   Referring now to  FIG. 2 , lower manifold  12  is seen separated from upper manifold  14 . Lower manifold  12  has a top surface  20  through which a pair of gas ports  22 ,  24  are drilled communicating with an inner, hollow inlet bore  26  shown schematically in  FIG. 8 . Bore  26  extends to communicate with a gas inlet  28  to which coupling  16  is attached. 
   Referring now to  FIG. 3 , a gasket material  30  is placed on top surface  20  of lower manifold  12 . In the embodiment shown in  FIG. 3 , pad  30  is formed from silicone rubber and has pad openings  32 ,  34  sized and positioned to align with ports  22  and  24 . 
   Referring to  FIG. 4 , a gas permeable membrane  36  is shown positioned on pad  30 . Membrane  36  can be formed from a variety of gas permeable materials such as fabrics, meshes, sintered metals and the like. In a preferred embodiment of the present invention polyester fabric is used. 
   As further seen in  FIG. 4 , a selected quantity of polymer  38  is deposited on membrane  36  prior to the reassembly of mold  10 . Polymer  38  can be selected from a number of known polymers such as urethane and can be supplied in forms as diverse as extruded films, powders, liquid solutions and UV ultraviolet curable solutions so long as these polymer variations retain flow characteristics which allow the polymer to fill the mold form to flow under pressure. Preferably these physical characteristics are present at room temperature and the selected polymer can thereafter be cured to retain its molded shape. Curing can be accomplished by elevated mold temperature, exposure to ultraviolet radiation, cooling of molten polymer or other commonly known process expedients. 
   Referring now to  FIG. 5  a mold form  42  is shown next to lower manifold  12 . Manifold  12  is shown as in  FIG. 3 , with support pad  30  and pad openings  32 ,  34  positioned thereon. In the embodiment herein described, mold form  42  has microneedle array patterns  44  formed therein, preferably over those portions of mold form  42  that register with openings  32 ,  24 . In other embodiments, array  44  is molded as a repeating pattern covering the entire surface of mold form  42 . Manufacture of the precision patterns required to successfully mold microneedles is represented in the prior art by U.S. Pat. Nos. 4,601,861, 4,478,769 and 4,486,363 all of which teach techniques for forming precision patterns in polymeric sheets. 
   Referring to  FIG. 5A , there is shown a magnified side view of mold form  42  showing microneedle cavities  44  with openings at the top  45  and bottom  46 . 
   Referring now to  FIG. 6 , mold form  42  is shown positioned on gasket or pad  30  with arrays  44  aligned with apertures  32 ,  34 . As described above, apertures  32 ,  24  are aligned with ports  22 ,  24  respectively. 
   Practice of the present invention may now be described by referring to  FIGS. 7 ,  8  and  9 . After polymer  38  is placed on membrane  36  and mold form  42  is positioned over membrane  36 , mold  10  is reassembled as shown in  FIG. 7  with upper manifold  14  reattached to lower manifold  12  and with gas supply line  40  attached to gas inlet coupling  16 . 
     FIG. 8  is a schematic cross sectional view of lower manifold  12  of mold  10 . Lower manifold  12  is shown with gasket pad  30  positioned upon top surface  20 , with ports  22  and  24  aligned with gasket openings  32  and  34 . Membrane  36  is positioned atop gasket pad  30  and polymer  38  has been deposited upon membrane  30  above aligned ports and openings  22 ,  32  and  24 ,  34  respectively. Mold form  42  with microneedle pattern arrays  44  is positioned above polymer  38 . 
   In a preferred embodiment, the microneedle pattern array  44  comprises a series of spaced-apart frustoconical cavities  46  which, in the present invention, correspond to the size and shape of the microneedles to be formed. 
   Referring now to  FIG. 9 , mold  10  is shown assembled and in schematic cross section. After mold  10  has been sealed, gas is introduced via gas line  40  to gas inlet  28 , passing through bore  26  and forced under pressure through ports  22 ,  24  and pad openings  34 , through membrane  36  into contact with polymer  38 . Polymer  38 , when introduced to mold  10  is in a flowable state and the gas forces polymer  38  into mold form  42 , filling the microneedle cavities in array  44  and forming a series of channels  50  by displacing the polymer and exiting through mold form holes  52  into upper manifold ports  52 ,  54  and an upper mold bore  56 , thereby, exiting mold  10  by gas outlet  48 , to which gas outlet coupling  18  is attached. The gas flow is maintained until polymer  38  is cured, making channels  50  permanent. 
   Referring now to  FIG. 10 , as an alternative method to the apparatus in  FIG. 9 , mold  10  is shown assembled and in schematic cross-section. After mold  10  has been sealed, gas is introduced via gas line  40  to gas inlet  28 , passing through bore  26  and forced under pressure through ports  22 ,  24  and pad openings  34 , through membrane  36 . Polymer  38 , when introduced to mold  10  is in a flowable state and occupies the cavities of the mold form  42 . In this case the mold form  42  is inverted, so the larger opening appears at the top of the tapered cavity section, as illustrated in the enlarged view of  FIG. 10 . In this case it may not be necessary to utilize the upper manifold  14 . The gas forces a series of channels  50  by displacing the polymer and exiting through holes  52  at the top of the polymer into upper manifold ports  52 ,  54  and an upper mold bore  56 , thereby exiting mold  10  by gas outlet  48 , to which gas outlet coupling I 8  is attached. The gas flow is maintained until polymer  38  is cured, making channels  50  permanent. Mold  10  is then separated and the cured polymer  38  having an array of microneedles formed thereon is removed therefrom. 
   While the channels  50  appear to be uniform in size from top to bottom, in actual practice, dependent upon the viscosity of the polymer and the gas pressure, the channel may change in diameter to complement the mold shape. 
     FIG. 11  is a single molded microneedle  58  from the array shown having side walls  60  and a central opening  62  which is the uppermost portion of channel  50 . The wall thickness of microneedle  52  can be varied by varying the rate of flow of the gas through polymer  38  as well as by varying the viscosity of the polymer  38 . 
   Referring to  FIG. 12 , numeral  64  includes a second preferred embodiment of a support pad formed as a rigid metallic strip having a series of holes  66  formed therethrough, the size and spacing of holes  66  is thought to make the process of forming microneedles  58  more efficient. 
   The gas used in the foregoing process may be filtered in dehumidified air at ambient temperature. Under some circumstances, using certain polymers, such as UV curable polymers it is thought that using an inert gas such as nitrogen will be more efficient. 
   Referring to  FIG. 13 , numeral  81  is a cylindrical mold form comprised of microneedle array patterns joined together to form a continuous belt. 
   Referring to  FIG. 14 , numeral  80  illustrates a form of apparatus which may be used to continuously fabricate microneedle products. The apparatus may comprise a variation of a double-belt press similar to that sold by Hymmen GmbH of Bielefeld, Germany, as models ISR and HPI, which are examples of continuous press, high-pressure processing machinery. By incorporating a generally cylindrical flexible mold  81  shown in  FIG. 13  with a porous backing  82 , polymer film  83  is introduced into the machine and melted to a fluid state by hot air plenum  84  beneath a lower porous belt  87 . After fluidizing the polymer  83 , the hot air from plenum  84  then forces air channels  50  through the polymer  83  which exits as a through channel  52  at the top side of the polymer. It further vents through the top porous mold backing  82 . The gas flow is maintained until polymer  83  is cured, making channels  50  permanent. 
   Cured polymer  85  having an array of microneedles formed thereon is then separated from mold  81  and wound into rolls  86  with an interlayer of foam (not shown) to protect the microneedles. In a later operation the product is then cut into discrete sections. 
   In the foregoing description, it will be readily appreciated by those skilled in the art that modifications may be made to the inventions without departing from the concepts disclosed herein. Such modifications are to be considered as included in the following claims.