Patent Publication Number: US-2009234301-A1

Title: Microneedle array and method for producing microneedle array

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This is a Continuation Application of PCT Application No. PCT/JP2007/072555, filed Nov. 21, 2007. PCT Application No. PCT/JP2007/072555 is based on and claims the benefit of priority from the Japanese Patent Application number 2006-315371, filed on Nov. 22, 2006; the entire contents of which are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a microneedle, a method for producing the microneedle, a microneedle array using the microneedle and a method for producing the microneedle array. 
     2. Description of the Related Art 
     Conventionally, for administration of a drug through the skin, the mucous membrane, or a like biological surface, usually, a liquid or gel drug is often applied. Although an application of a drug on a biological surface is a noninvasive method, the applied drug is easily removed by sweating, external contact, and the like. Further, when the administration is continued for a long period of time, a safety problem such as dermopathy may be caused. Further, when the subject drug has a large molecular weight, is water soluble, etc., such a drug is hardly absorbed into the body even if applied on a biological surface, and percutaneous administration thereof has thus been difficult. 
     In order to solve these problems, a microneedle array having a large number of 50 μm to 100 μm high microneedles provided on a substrate has been proposed (see, e.g., JP-T-2005-503194) (the term “JP-T” as used herein means a published Japanese translation of PCT patent Application 2005-503194). 
     Although the method of administering a drug directly into the body tissue using a microneedle array having a desired drug applied to the surface of microneedles is not a perfectly noninvasive method, this seldom stimulates the sense of pain and is less invasive to the patient because microneedles have a small diameter and only reach the dermis or the like which is a region at a relatively shallow depth in the body tissue. Further, the drug can be administered in the state that the microneedles run through the epidermis and the horny layer, and this accordingly gives the advantage that drugs heretofore difficult to percutaneously administrate can also be administered. 
     The above microneedles are excellent in the puncturing ability as they are formed on a silicon single crystal substrate, however, there is a problem in that when the microneedles break, the residues remain in the skin. 
     An example of producing a needle shape with a degradable polymer, such as polylactic acid, has also been proposed. In such a case, however, because of the high aspect ratio, air in the tip of a needle-forming portion of a mold remains to cause a problem in the shape reproducibility. 
     The present invention was accomplished in view of the above background. An object thereof is to provide a production method for molding a microneedle and a microneedle array which do not obtain blunt needle tips at the time of molding, do not undergo hydrolysis, thus maintaining a stable molecular weight, do not suffer from coloring, and have excellent shape stability; and also to provide products therefrom. 
     SUMMARY OF THE INVENTION 
     An aspect of the invention is a method for producing a microneedle, comprising feeding a resin fluid to a forming mold having a needle-forming portion with an opening diameter of 50 to 200 μm and a depth of 100 to 500 μm, for example a depth of 100 to 450 μm, charging the fed resin fluid into the needle-forming portion, and cooling and solidifying the charged resin fluid. The feeding, the charging, and the cooling and solidification are performed under reduced pressure or vacuum. Another aspect of the invention is a method for producing a microneedle, comprising feeding resin to a forming mold having a needle-forming portion with an opening diameter of 50 to 200 μm and a depth of 100 to 500 μm, for example a depth of 100 to 450 μm, fluidizing the fed resin to give a resin fluid, charging the resin fluid into the needle-forming portion, and cooling and solidifying the charged resin fluid, the feeding, the heating and melting, the charging, and the cooling and solidification being performed under reduced pressure or vacuum. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIGS. 1A and 1B  are sectional views each schematically showing a microneedle array according to a first embodiment of the invention; 
         FIGS. 2A and 2B  show a production method according to the same embodiment; 
         FIGS. 3A and 3B  are partial sectional views each schematically showing a modified example of the same embodiment; 
         FIGS. 4A and 4B  are sectional views each schematically showing a microneedle array according to a second embodiment of the invention; 
         FIGS. 5A and 5B  show a production method according to the same embodiment; 
         FIGS. 6A to 6C  are sectional views each schematically showing a microneedle array according to a third embodiment of the invention; 
         FIGS. 7A to 7G  show a production method according to the same embodiment; 
         FIG. 8  is a sectional view schematically showing a microneedle array according to a fourth embodiment of the invention; and 
         FIGS. 9A to 9F  show a production method according to the same embodiment. 
     
    
    
     
         
         
           
               1 ,  31 ,  51 ,  64 : Microneedle array 
               2 ,  32 ,  52 : Microneedle 
               3 ,  33 ,  53 : Substrate 
               4 ,  34 ,  54 : Microneedle 
               17 ,  63 ,  73 : Mold 
               19 : Polylactic acid (biocompatible material) 
               21   a : Communicating hole (let-out means) 
               22 ,  57 : Drug layer 
           
         
       
    
     DETAILED DESCRIPTION OF THE INVENTION 
     A microneedle array according to a first embodiment of the invention is explained with reference to  FIGS. 1A ,  1 B,  2 A,  2 B,  3 A and  3 B. 
     As shown in  FIG. 1A , a microneedle array  1  of this embodiment comprises a microneedle  2  and a substrate  3  which is provided beneath the microneedle  2  and supports the microneedle  2 . The microneedle  2  is made of PLA, a biocompatible material, and comprises a large number of conical-shaped needle portions  4  integrally formed on a sheet portion  5 . The substrate  3  is made of acryl (PMMA). The sheet portion  5  of the microneedle  2  is thermally fused to the surface of the substrate  3 , thereby forming the microneedle array  1 . The microneedle array  1  has microneedles formed at intervals of 200 to 1,200 microneedles/cm 2 . 
     The needle portions  4  and the sheet portion  5  are made of medical-grade polylactic acid (PLA), a biocompatible material. The needle portions  4  have a bottom diameter φ of 50 μm to 200 μm and a height h of 100 μm to 500 μm. In consideration of the balance between the degree of penetration of a drug applied to the surface and the degree of invasion due to the stimulation of the sense of pain, it is more preferable that the bottom diameter φ be within the range of 80 μm to 120 μm, and the height h be within the range of 200 μm to 400 μm. Further, as in  FIG. 1B , in addition to the conical shape, the shape of the needle portions  4  may be so-called pencil-like, having a cylindrical column shape with a conical upper portion, or may also be a polyangular pyramid whose section is triangle, quadrangle, or the like. 
     A method for producing the microneedle array  1  is explained with reference to  FIGS. 2A and 2B .  FIG. 2A  is a schematic diagram of a production apparatus  11  for the microneedle array  1  of this embodiment. The production apparatus  11  comprises a conveyor belt  12 , heaters  13   a  to  13   e  provided along the transferring surface of the conveyor belt  12 , a nozzle  14  provided in a predetermined position on the upstream portion of the conveyor belt, a substrate feeder  15  provided in a position downstream the nozzle  14 , and a roll  16  provided downstream the substrate feeder  15  so as to pressurize the transferring surface of the conveyor belt  12 . 
     First, on the conveyor belt  12 , a mold  17  for forming the microneedle  2  is installed. As shown in  FIG. 2B , the mold  17  is obtained by forming needle-forming portions  18  in a metal material by a known method such as photolithography, dry etching, or the like. 
     Next, a solution or a cutting block of medical-grade PLA  19 , a product of Birmingham Polymers Inc., is fed onto the mold  17  from the nozzle  14 . At this time, the temperature of the heater  13   a  is set at the melting point (hereinafter referred to as “Tm”) of PLA  19  or higher. 
     As moving on the conveyor belt  12 , the mold  17  is heated with the heater through the belt, whereby the PLA  19  is heated to the temperature range (° C.) expressed by the equation (1) below and is spread out over the entire surface of the mold  17  to obtain the shape of the large number of needle portions  4  integrated at the sheet portion  5  (microneedle formation process). At this time, the temperature of the heater  13   b  is set at the Tm of PLA. 
       Tm+X (X is 2 or more and less than 50, and preferably 2 or more and less than 10)  (1) 
     Subsequently, the mold  17  moves on the conveyor belt  12 , and a substrate  3  is installed on the mold  17  from the substrate feeder  15 . Although the substrate  3  is made of PMMA as mentioned above, a copolymer of butyl acrylate and methacrylate or the like is also suitable. Further, other plastic materials are also usable. In addition, alumina and metal, which are porous materials, may also be used. At this time, the temperature of the heater  13   c  is set at a temperature higher than the Tm of PLA by about 20° C., and is adjusted to be in the temperature range of the equation (1) when PLA reaches the heater  13   c.    
     At least the processes from the feeding of PLA onto the mold to the formation of microneedle are to be performed under reduced pressure or vacuum. 
     The integrated substrate  3  and mold  17  are pressurized by the roll  16  and thus closely adhered, and, as shown in  FIG. 2B , the substrate  3  and the sheet portion  5  are thermally fused (fusion process). At this time, the temperature of the roll  16  is set within the range of the above equation (1) (Tm is the melting point of PLA). 
     Subsequently, while moving on the conveyor belt  12 , the temperature of the substrate  3  and the mold  17  are gradually lowered to about 70° C. by the heaters  13   d  and  13   e . After cooling, the substrate  3  integrated with the microneedle  2  is removed from the mold  17 , and is punched into a desired shape, thereby giving the microneedle array  1  of this embodiment. To the surface of the needle portions  4  of the obtained microneedle array  1 , insulin, estradiol, or a like hormone drug, nitroglycerin, or a like desired drug is applied in the form of a spray or a gel to form a drug layer. Thus, the microneedle array  1  can be used in transcutaneous administration of the drug. 
     According to the microneedle array  1  of the invention, the needle portions  4  are sufficiently adhered to the substrate  3  made of PMMA at the sheet portion  5 , and thus have sufficient strength to resist plastic deformation even under a load of 5 kgf/cm 2  or less. Accordingly, when puncturing through the skin or a like biological surface, the needle portions satisfactorily reach the body tissue without plastic deformation. Further, the needle portions do not break in the body tissue. Even if they break, PLA that forms the needle portions  4  is decomposed in the body and disappears, and this thus causes no harm to the patient. 
     Further, because only the microneedle  2  is made of medical-grade PLA, as compared with the case where the entire microneedle array (i.e., the microneedle  2  and the substrate  3 ) is made of medical-grade PLA, the amount of the expensive medical-grade PLA to be used can be reduced by about 50% to about 80%. Accordingly, in comparison with conventional microneedle arrays, the manufacturing cost can be greatly reduced, while maintaining comparable performance. 
     Further, because the substrate  3  is made of flexible PMMA, it sufficiently follows the change in skin shape, and there is no need to worry about the separation of the microneedle  2  from the substrate  3 , etc. 
     The microneedle  2  of this embodiment may have slots  21  formed on the surface thereof, as shown in  FIG. 3A . According to such a structure, when a drug is applied to the surface of the microneedle  2 , the drug is stored in the slots  21 . This allows extension of the drug-releasing time and also enables more accurate control of drug release. 
     Further, as shown in  FIG. 3A , communicating holes (let-out means)  21   a  each extending from a slot  21  and penetrating through the sheet portion  5  may also be provided. In this case, if a drug layer  22  comprising a polymer impregnated with a drug, for example, is provided in the gap between the sheet portion  5  and the substrate  3 , the drug is let out from the drug layer  22  into the microneedle  2  through the communicating holes  21   a  and the release is thus continued even after the whole drug on the microneedle  2  is released. 
     Accordingly, this allows further extension of the drug releasing time. The drug layer  22  may be provided inside the substrate  3 , as shown in  FIG. 3B . In such a case, the microneedle array is structured so that communicating holes  21   a  extend inside the substrate  3  and communicate with the drug layer  22 . However, in the case where the substrate  3  is formed using the above-mentioned porous material, the drug can be let out to the microneedle without communicating holes being formed.  FIGS. 3A and 3B  each shows a section of a part of the substrate  3 , the sheet portion  5 , the drug layer  22 , and the microneedles  2 . 
     Although in the method for producing a microneedle array of this embodiment, a method in which production is performed while the mold and the substrate are moved has been explained, a microneedle array may be produced by heating of a fixed mold, feeding PLA or a like biocompatible material thereto from micro-nozzles provided above the mold in correspondence with needle-forming portions to form a microneedle, and thermally fusing it with a substrate. 
     Next, a second embodiment of the invention is explained with reference to  FIGS. 4A ,  4 B,  5 A and  5 B. The microneedle array  31  of this embodiment is different from the above first embodiment in that, as shown in  FIG. 4A , the sheet portion  5  present in the microneedle  2  of the first embodiment is not present in a microneedle  32 . The components common with the first embodiment are indicated with the same reference numerals, and duplicate explanations are omitted. 
     A method for producing the microneedle array  31  of this embodiment is explained with reference to  FIGS. 5A and 5B .  FIG. 5A  is a schematic diagram of a production apparatus  41  for the microneedle array  31  of this embodiment. The production apparatus  41  comprises a conveyor belt  42 ; a first roll  43  provided above the conveyor belt  42 ; a second roll  44  provided beneath the conveyor belt  42  to sandwich the conveyor belt together with the first roll  43 , so that the conveyor belt can be pressurized; a nozzle  45  provided in a predetermined position above the first roll; and a knife edge  46  provided in a predetermined position beneath the nozzle  45 , in such a manner that the tip thereof contacts the surface of the first roll. The first roll  43  is an imbricate roll, as shown in  FIG. 5B , which has the above microneedle-forming mold  17  attached thereto in a many-sided manner with the needle-forming portions  18  facing the outer periphery. 
     First, a substrate  3  made of PC is installed on the conveyor belt  42 . Next, medical-grade PLA  19 , which has been heated to the melting temperature or higher, is fed to the surface of the first roll  43  from the nozzle  45 . At this time, the first roll  43  has also been heated with a non-illustrated heater or the like to the PLA  19  melting temperature or higher. As the first roll  43  rotates, melted PLA  19  approaches the conveyor belt  42 . During this process, the knife edge  46  removes excessive PLA  19  from the surface of the first roll  43 . For this reason, the sheet portion  5  that is present in the microneedle  2  in the first embodiment is not formed in this embodiment. 
     When the substrate  3  moves on the conveyor belt  42 , and is inserted between the first roll  43  and the second roll  44 , PLA  19  melted on the surface of the first roll  43  is transferred to the surface of the substrate  3  to form microneedles  34 , and, at the same time, the substrate  3  and the microneedles  34  are thermally fused. At this time, the second roll  44  is heated by a non-illustrated heater or the like to a temperature lower than the PLA  19  melting temperature by about 20° C. 
     After passing between the first roll  43  and the second rolls  44 , the substrate  3  is naturally cooled by ambient air while moving on the conveyor belt  42 . The thus-obtained substrate  3  having the microneedles  34  is punched into a desired shape and size, thereby giving the microneedle array  31  of this embodiment. 
     According to the microneedle array  31  of this embodiment, because the sheet portion  5  that is present in the first embodiment is not present in the microneedle  32 , the amount of the medical-grade PLA to be used can be further reduced, thereby enabling reduction of manufacturing cost. 
     Although the microneedles  34  of this embodiment have a flat bottom, the microneedles  34  may each have an anchor portion  35  that digs into the substrate as shown in  FIG. 4B . In such a case, performing production by the above method using a substrate  33  having fine asperities previously formed on the surface thereof can form a microneedle array provided with microneedles  34  having anchor portions  35 . 
     Further, in the method for producing a microneedle array of this embodiment, although explained is the case where the substrate  3  is in the form of a sheet, the substrate may also be a continuous film. Further, by adjusting the distance between the knife edge  46  and the first roll  43 , it is also possible to form a microneedle provided with a sheet portion, as in the first embodiment. 
     Next, a third embodiment of the invention is explained with reference to  FIGS. 6A to 6C  and  7 A to  7 G. A microneedle array  51  of this embodiment is different from the above embodiments, as shown in  FIG. 6A , in that a large number of communicating holes  56  communicating with a substrate  53  are formed in a sheet portion  55 , and that a drug layer  57  is provided beneath the substrate. The components common with the above embodiments are indicated with the same reference numerals, and duplicate explanations are omitted. 
     A method for producing the microneedle array  51  of this embodiment is explained with reference to  FIGS. 7A to 7G . A production apparatus  61  for the microneedle array  51  comprises an outer frame  62 , a mold  63  to be inserted into the outer frame  62 , and a press plate  64 . Unlike the above embodiments, the outer frame  62  and the mold  63  are previously formed into the shape and size of the microneedle array  51  to be produced. 
     The mold  63  is formed by machining a mold produced by almost the same method as that of the first embodiment into a desired shape and size, however, unlike the above mold  17 , the mold  63  has a large number of protruding portions  65  formed thereon for forming the communicating holes  56  in the sheet portion  55 . 
     First, as shown in  FIG. 7A , the mold  63  is inserted into the outer frame  62 , and a block of medical-grade PLA  19  is fed onto the mold  63 . The block then may have any shape, such as the shape of a sphere, a rectangular solid, a cylinder column, or the like. The mold  63  is heated with a non-illustrated heater, etc. PLA  19  is heated by the mold  63  to a temperature T° C. expressed by the following equation (2), and is spread out in needle-forming portions  66  following the shape of the mold  63 . The amount of PLA  19  is an amount to allow the PLA  19  to fill needle-forming portions  66  of the mold  63  and further form the sheet portion  55 . Subsequently, as shown in  FIG. 7B , a pressure of 50 MPa or more is applied by the press plate  64 , then the temperature is lowered, and the press plate  64  is raised (microneedle formation process). At this time, the protruding portions  65  fit into the large number of holes provided in the press surface of the press plate  64 . The resulting microneedle  52  has, in the sheet portion  55 , a large number of communicating holes  56  formed by the protruding portions  65 . 
         Tg+Y&lt;T&lt;Tm+ 50 (Tg is the glass transition temperature, and Y is 2 or more and less than 50, and preferably 20 or more)  (2) 
     Subsequently, as shown in  FIG. 7C , a block of PMMA  67  used as a material of the substrate  53  is fed onto the sheet portion  55 . In place of PMMA  67 , polyethylene (PE) or a like material may also be used. A material having a Tm comparable to or lower than that of the material of the microneedles  54  is preferably used. The amount of PMMA  67  is adjusted so that when the PMMA  67  is spread out uniformly over the sheet portion  55 , the tips of the protruding portions  65  are not buried. Subsequently, while heating PMMA  67  to the temperature T calculated by the above equation (2), the press plate  64  applies a pressure of 50 MPa to compress PMMA  67  as shown in  FIG. 7D , and the substrate  53  is thus formed (substrate formation and adhesion process). 
     After the press plate  64  is raised, the mold  63  is removed from the outer frame  62 . Then, as shown in  FIG. 7E , the drug layer  57  comprising a polymer impregnated with a desired drug is closely adhered onto the substrate  53 . After the close adhesion, as shown in  FIG. 7F , the substrate  53  is removed from the mold  63 . This provides the microneedle array  51  of this embodiment, which has a large number of communicating holes  56  running through the sheet portion  55  and the substrate  53  and communicating with the drug layer  57 .  FIG. 7G  shows an end product formed of the microneedle array  51  incorporated with a patch member  58  coated with an adhesive material. 
     According to the microneedle array  51  of this embodiment, because of the communicating holes  56  formed in the sheet portion  55 , the drug is released through the communicating holes  56  without being influenced by the behavior of the microneedles  54  in the body tissue, and thus, stably released into the body tissue through the holes formed in the biological surface by the puncture of the microneedles  54 . Accordingly, drug release can be controlled more stably. 
     When the amount of charged drug is not large, it is also possible to form the drug layer  57  only in the communicating holes  56 , as shown in  FIG. 6B . Further, in the case where the protruding portions  65  of the mold  63  are provided in the needle-forming portions  66 , the microneedles  54  can be formed into a hollow structure, as shown in  FIG. 6C . In such a case, the drug can be administered into the body tissue more efficiently through the communicating holes  56  formed in the microneedles  54 . 
     Although examples of a two-layer structure of a microneedle and a substrate have been explained above, the invention may be structured so that, as shown in  FIG. 8 , a microneedle  101  and a substrate  102  are formed in a single layer. Such an embodiment is explained hereinafter as a fourth embodiment of the invention. 
     A method for producing a microneedle array of this embodiment is explained with reference to  FIGS. 9A to 9F . First, as shown in  FIG. 9B , medical-grade PLA  19  is fed onto a mold  73  under reduced pressure or vacuum. PLA  19  is heated, and, as shown in  FIG. 9C , is spread out in needle-forming portions  66  following the shape of the mold  73 . The amount of PLA  19  is an amount to allow the PLA  19  to fill the needle-forming portions  66  of the mold  73  and further form a sheet portion  65  with a thickness sufficient for the sheet portion  65  to serve as a substrate. Subsequently, as shown in  FIG. 9D , a downward pressure is applied by a press plate  74 , then the temperature is lowered to cause cooling and solidification, and the press plate  74  is raised, thereby giving a microneedle array  64 . 
     According to the microneedle array  64  of this embodiment, because the microneedle array  64  is formed of a single layer, the number of manufacturing processes can be reduced, and the productivity can be improved. 
     As shown in the third embodiment, it is also possible to provide the mold with protruding portions to form communicating holes in the microneedle. 
     Embodiments of the invention have been explained thus far. However, the technical scope of the invention is not limited to the above embodiments, and various modifications may be made without deviating from the spirit of the invention. 
     For example, although the microneedle is made of medical-grade PLA in the above embodiments, insofar as the medical grade is satisfied, PLGA, chitin, chitosan, hyaluronic acid, collagen, glucose, cellulose, magnesium alloy, and other biocompatible materials may also be used. Further, the microneedle may also be made of a mixed material of the above biocompatible materials and the drug. In such a case, the drug is released by dissolution of the microneedle in the body tissue. 
     Further, although the substrate is made of PMMA in the above embodiments, as mentioned above, a copolymer of butyl acrylate and butyl methacrylate polycarbonate, polyurethane, polypropylene, and other resin materials, metals, ceramics, and the like may also be used. In addition, PLA and like materials of a grade lower than the medical grade are also usable. In view of the conformability with the change in shape of the biological surface, the substrate is preferably made of a highly expansible resin material. Further, it is also possible that a plurality of layers made of the above various materials be integrated to form a substrate. 
     Further, although the substrate and the microneedle are adhered by thermal fusion in the above embodiments, they may be adhered by plasma welding. Further, although the substrate and the microneedle are formed by compression molding in the above embodiment, a common plastic molding technique, such as injection molding or the like, may be used instead to form the substrate and the microneedle. 
     According to the invention, molding is performed under reduced pressure or vacuum, and therefore, a sharp microneedle tip can be obtained. Further, since hydrolysis reaction is suppressed, reduction in the molecular weight is made less prone to occur and maintaining the strength of the microneedle is made possible. In addition, the suppression of reactions can avoid the problem of coloring. 
     Example 1 
     While vacuuming, PLA on a mold was heated to 210° C. The PLA was charged into needle-forming portions, and then cooled and solidified at normal temperature over 1 hour, thereby molding a microneedle array. For the molding of microneedles, the apparatus shown in  FIGS. 9A to 9E  was used. 
     The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, the needle tip portions were sharp, and the tip portions of all the microneedles on the microneedle array had the same shape. 
     Comparative Example 1 
     PLA on a mold was heated to 210° C. without vacuuming. The PLA was charged into needle-forming portions, and then cooled and solidified at normal temperature over 1 hour, thereby molding a microneedle array. For the molding of microneedles, the apparatus shown in  FIGS. 9A to 9E  was used. 
     The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, rounded tip portions were observed in 80 needles out of every 800. The microneedles varied in shape and height. 
     Example 2 
     Chitin was dissolved in chloroform to give a resin fluid. The resin fluid was fed onto the mold, and vacuuming was performed while increasing the temperature to 60° C. After 1 hour, at the time when the organic solvent chloroform evaporated, the temperature was lowered to normal temperature, whereby only a chitin molded product was left on the mold. A chitin microneedle array was thus obtained. For the molding of microneedles, the apparatus shown in  FIGS. 9A to 9E  was used. 
     The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, the needle tip portions were sharp, and all the microneedle tip portions on the microneedle array had the same shape. 
     Reference Example 2 
     Chitin was dissolved in chloroform to give a resin fluid. The resin fluid was fed onto the mold, and charged into the mold while increasing the mold temperature to 60° C. 
     After 1 hour, the temperature was lowered to normal temperature, thereby molding a microneedle array. For the molding of the microneedle array, the apparatus shown in  FIGS. 9A to 9E  was used. 
     The obtained microneedle array contained the organic solvent chloroform remaining therein, and thus was unusable for puncturing through a biological surface. 
     Example 3 
     Chitosan, a protein preparation, and water were mixed to give a resin fluid. The resin fluid was fed onto the mold, and the mold was heated to 40° C. Vacuuming was performed, and the mold was maintained at 40° C. and left to stand for 1 hour in this state. Subsequently, the temperature was lowered to normal temperature, whereby only a chitosan molded product was left on the mold. A chitosan microneedle array was thus obtained. For the molding of the microneedle array, the apparatus shown in  FIGS. 9A to 9E  was used. 
     The molded microneedle array was removed, and the shape of the needle tip portions was observed. As a result, the needle tip portions were sharp, and all the microneedle tip portions on the microneedle array had the same shape. 
     Comparative Example 3 
     Chitosan, a protein preparation, and water were mixed to give a resin fluid. The resin fluid was fed onto the mold. The mold was heated to 40° C. and left to stand for 10 hours in this state. After 10 hours, the mold temperature was lowered to normal temperature, and molding was thus performed. For the molding of microneedles, the apparatus shown in  FIGS. 9A to 9E  was used. 
     In Comparative Example 3, solidification into the microneedle array shape took time ten times longer than time required when vacuuming was included. 
     The invention can be used as a microneedle array for medical applications.