JP5717322B2 - Method for producing needle array master - Google Patents

Description

  The present invention relates to a means for manufacturing an acicular array.

  The acicular array includes a plurality of acicular bodies (generally also referred to as microneedles) that are minute acicular structures. It is mainly used in the fields of medicine, biological phenomena, drug discovery, etc., and in recent years, an increasing number of cases have been used especially in the administration method called trans-Dermal Drug-Delivery System (hereinafter referred to as “TDDS”). ing.

  Administration by TDDS has fewer side effects such as gastrointestinal disorders than oral administration, and can effectively act on the affected area. In addition, the blood concentration of the drug is kept constant by being absorbed through the skin continuously. The percutaneous absorption method in which a drug is administered to a living body by infiltrating the drug from the skin is used as a method by which the drug can be easily administered without causing pain to the subject. However, some drugs are difficult to administer by the transdermal absorption method. As a method for efficiently absorbing such a drug into the body, attention has been drawn to a method of perforating the skin using a micron-order fine needle and administering the drug directly into the skin. According to this method, it is possible to easily administer a drug subcutaneously without using a special device for medication.

  When an acicular body array is used for the purpose of transdermal administration, the acicular body has a sufficient fineness and tip angle to pierce the skin, penetrates the stratum corneum that is the outermost layer of the skin, and enters the nerve layer. Desirably, the needle has a length that does not reach. Specifically, the diameter of the needle-like body is about several μm to 100 μm, the tip angle of the needle-like body is 30 ° or less, and the length of the needle-like body is several tens of meters. It is desirable that the thickness is about μm to several hundred μm.

  On the other hand, when the needle array is intended for blood collection, the required functions are an outer diameter of 200 μm or less to reduce pain, a length of 500 μm or more reaching the capillaries, and a strength of the structure. It is required that no part remains in the body after use.

  In addition, a test chip and a blood analyzer using a needle array have been proposed (for example, Patent Document 1). Patent Document 1 discloses a needle-like array with hollow needle-like bodies obtained by processing a silicon wafer by dry etching and wet etching. This document discloses that this is used as a test chip that punctures a human body and collects blood by capillary action. An apparatus including a system for analyzing blood collected by the test chip is also disclosed.

  Moreover, it is desirable that the material constituting the medical needle array as described above is a material that does not adversely affect the human body even if the damaged needle-like body remains in the body. Biocompatible materials such as silicon resin, maltose, polylactic acid, and dextran are promising (see Patent Document 2).

  On the other hand, the manufacturing technology for needle-shaped object arrays requires selection of a material having the optimum hardness for the puncture target, reduction in manufacturing cost, and improvement in functional reliability. It is essential that the array penetrates the outer skin, and the minimum strength and durability of the acicular body is required.

  Many methods for producing needle arrays have been reported by various research institutes and companies. For example, a method of forming a needle-like body on a silicon substrate by a photolithography method that is one of microfabrication methods (for example, Patent Document 3) or a method of forming a needle-shaped body by wire cutting (for example, Patent Document 4) ) And the like.

  According to Patent Document 3, isotropic etching or crystal anisotropic etching is performed after an etching mask is placed on a silicon wafer used in a semiconductor process, and further anisotropic etching is performed. A method is disclosed for removing the deposited layer and performing wet etching, thereby forming a needle array comprising needles having any desired tip shape.

  According to Patent Document 4, one surface of a parallel hexahedral machined steel plate is machined in two directions of the X direction and the Y direction by high-precision wire cutting, and a quadrangular pyramid shaped needle-like body is formed at a predetermined position of the machined steel plate. A method for producing a master mold comprising:

  However, since the method described in Patent Document 3 is a lithography method, a manufacturing process such as resist coating, drying, exposure, development, etching, and resist stripping is necessary, and the process is many and complicated. In addition, there is a problem that the cost required to manufacture the needle-shaped body array is large, and the time to complete the process is long.

  The manufacturing method described in Patent Document 4 has poor processing fineness, which is a common defect in precision machining including wire cutting. In the needle-like body structure, a particularly sharp tip shape is necessary, but the needle-like body array manufactured by the manufacturing method has a problem that only the tip portion is missing.

  As described above, many manufacturing methods have been proposed, but none of the methods satisfy both quality and cost at the same time. For example, the quality required for an acicular array is typified by the shape, such as the height, root width, tip angle, and surface roughness of the acicular body, and the limit pressure that causes damage when the acicular body is punctured. The quality of the mechanical strength.

  On the other hand, Patent Document 5 discloses a method of manufacturing an inkjet head by processing photosensitive glass. In this method, a photomask for forming a groove pattern to be an ink flow path is formed on the surface of the photosensitive glass, a crystal part is formed by ultraviolet irradiation and heat treatment, and etching is performed to form a groove. Thereafter, the diaphragm and the piezoelectric element are bonded to obtain an ink jet head.

JP 2002-369816 A Japanese Patent Laid-Open No. 2005-21677 JP 2005-199392 A JP-T-2006-513811 Japanese Patent No. 3200881

  An object of the present invention is to provide means for easily forming a needle-like body array having needle-like bodies that satisfy the specifications for shape, such as required height, root width, tip angle, and / or surface roughness. That is.

To achieve the above object, the present invention provides:
(1) A method for producing an acicular body original plate for producing an acicular body array comprising a substrate and acicular bodies formed on the first surface of the substrate,
Forming an exposed portion by exposing the photosensitive glass to energy distribution; and
A step of modifying the exposed portion by heat treatment after exposure to form a modified portion; and
And a step of removing the modified portion by isotropic etching ,
Performing the exposure by continuously and spirally irradiating a laser ;
(2) The manufacturing method according to (1 ) , wherein a tapered non-through hole is formed by removing the modified portion by the isotropic etching ;
It is.

  According to the present invention, there is provided means for easily forming a needle-like body array including needle-like bodies that satisfy the specifications for shape such as required height, root width, tip angle and / or surface roughness.

Schematic which shows the example of the acicular body array according to this invention, and the example of an acicular body array original plate. The schematic sectional drawing which shows the example of the acicular body according to this invention. The schematic sectional drawing which shows the example of the acicular body according to this invention. The schematic sectional drawing which shows the example of the acicular body according to this invention. The schematic sectional drawing which shows the example of the acicular body array according to this invention. The schematic sectional drawing which shows the example of the acicular body array according to this invention. Schematic which shows the example of the acicular body array according to this invention. The figure which shows the example of the exposure pattern with respect to photosensitive glass. The flowchart which shows typically the procedure of the manufacturing method of the acicular body array according to this invention.

  According to the present invention, there are provided a method of manufacturing a needle-shaped object precursor for manufacturing a needle-shaped object array, a needle-shaped object array precursor, and a needle-shaped object array manufactured by them.

1. Acicular body array The acicular body array according to the present invention is schematically shown in FIGS. Fig.1 (a) is a top view of the acicular body array according to this invention, FIG.1 (b) is a cross section which cut | disconnected Fig.1 (a) along line II. As shown in FIGS. 1 (a) and 1 (b), a needle array 1 according to the present invention includes a base body 2 and a plurality of needle bodies 3 provided on the first surface of the base body 2.

  The needle-like bodies according to the present invention are preferably forested on the substrate and arranged in an array. Here, the “array shape” indicates a state where the needle-like bodies are arranged, and includes, for example, a pattern such as a lattice arrangement, a close-packed arrangement, a concentric arrangement, and a random arrangement. .

  Further, when the needle-like bodies according to the present invention are forested on the substrate and arranged in an array, it is particularly preferable that the close-packed arrangement be used. By using the close-packed arrangement, the accumulation rate of microneedles per area can be improved. Here, the “closest packing arrangement” refers to an arrangement in which the other six microneedles are arranged at an equal distance with respect to one microneedle.

  The needle-shaped body array is not limited to the form shown in FIGS. 1A and 1B, and the shape may be freely designed depending on the application. In addition, the needle-like body is not particularly limited in shape, size, constituent material, and the like, and may be appropriately designed according to the use and / or specifications. For example, when it is used for the purpose of promoting percutaneous absorption of a physiologically active substance or for the purpose of taking a substance in a living body percutaneously out of the living body, it is provided in an acicular array from the viewpoint of skin puncture performance. The tip of the needle-like body has a sharp cone shape, the root width is several μm to several hundred μm, the length is about several tens μm to several hundred μm, and there is no constriction or step on the side wall of the needle-like body Is desirable.

  Examples of the shape of the acicular body according to the present invention are shown in FIGS.

  The needle-like body 201 shown in FIG. 2 has (a) a cone shape in which the side wall angle changes midway, (b) a cone shape in which the side wall angle is constant, (c) a columnar shape up to the middle, and a tip shape in a cone shape.

  The needle-like body 301 shown in FIG. 3 has (a) a cone shape in which the left-right asymmetric side wall angle changes midway, (b) a cone shape in which the left-right asymmetric side wall angle is constant, and (c) a column shape up to the middle of the left-right asymmetric side. And the tip is conical.

  The needle-like body 401 shown in FIG. 4 has (a) a cone shape having a hollow portion and (b) a left-right asymmetric cone shape having a hollow portion.

  In the case where the physiologically active substance and / or cosmetic composition is applied onto the surface of the needle-like body according to the present invention, the shape of the needle-like body is such that the physiologically active substance and / or cosmetic composition stays on the surface. It is preferable to have such a shape. Specifically, for example, a shape having a hollow non-through hole, a shape in which the side surface of the needle-like body is curved inward, a shape in which a groove serving as a flow path is formed on the side surface of the needle-like body, etc. good.

  In particular, when the depth of perforation by the needle-like body is kept at “depth that penetrates the stratum corneum and does not reach the nerve layer”, the physiologically active substance or cosmetic composition is delivered to a position deeper than the stratum corneum. I can do it. Since the perforations formed in the stratum corneum are closed over time, the physiologically active substance and cosmetic composition delivered under the stratum corneum are retained in the living body in a state where they are barriered to the stratum corneum from the outside. For this reason, physiologically active substances and cosmetic compositions can reduce exfoliation due to metabolism of the stratum corneum and washing such as skin care, and can maintain a makeup state for a long period of time.

  Since it can maintain a long-term makeup state, it is particularly suitable for delivery of a cosmetic composition at sites where long-term color retention is required, such as the eyebrows, around the eyes, around the lips, etc. I can do it.

  In particular, when the depth of perforation by the needle-like body is kept “in the stratum corneum”, a physiologically active substance or a cosmetic composition can be retained in the stratum corneum. Since the stratum corneum is constantly generated by metabolism, the physiologically active substance and the cosmetic composition in the stratum corneum are discharged out of the body with time. For this reason, for example, the makeup state and the applied state can be easily canceled by washing the skin or peeling the skin.

  In addition, the needle-shaped body array of the present invention desirably has a sufficient thinness for piercing the skin and a length that does not reach the nerve layer. Specifically, the diameter of the needle-shaped body is several. It is desirable that the length of the needle-shaped body is about several μm to several hundred μm.

  In particular, when the perforation is kept at a length that penetrates the stratum corneum and does not reach the nerve layer, the length of the acicular body is specifically 200 μm or more and 700 μm or less, more preferably 200 μm or more and 500 μm or less, More preferably, it is in the range of about 200 μm to 300 μm.

  In particular, when the perforations are retained in the stratum corneum, the length of the acicular body is specifically 30 μm or more and 300 μm or less, more preferably 30 μm or more and 250 μm or less, and further preferably 30 μm or more and 40 μm or less, It is preferable that it exists in the range of a grade.

  When the needle-like bodies according to the present invention are arranged in an array, the lengths of the needle-like bodies may or may not be the same. When the lengths of the needle-like bodies are different, for example, (1) by making the needle-like body long only at the outer periphery of the array shape, it is possible to suitably contact the curved surface. (2) Only the outer periphery of the array-like shape is short By forming the needle-like body, there are advantages such as the mechanical strength of the microneedles on the outer peripheral portion that is easily damaged can be reinforced.

  When the needle-like body has a tip-like shape such as a cone shape, (1) when penetrating the stratum corneum, the tip angle is in the range of 5 ° to 30 °, more preferably 10 ° to 20 °. (2) When perforation is retained in the stratum corneum, the tip angle is preferably 30 ° or more, more preferably 45 ° or more.

  The material for the needle-like body array is not particularly limited as long as it has sufficient mechanical properties to hold the needle-like body. For example, metals such as stainless steel, silicon, Mg-based compounds and Ti-based compounds, for example, inorganic materials such as quartz and ceramics, biocompatible materials such as medical silicone resins, such as polylactic acid, polyglycolic acid, poly Biodegradable materials with biocompatibility, such as lactic acid glycolic acid copolymer, polycitric acid, polymalic acid, polyamino acid, maltose, dextran, chitin and its derivatives, chitosan and its derivatives, and other biocompatible and biodegradable materials Any organic material such as a polymer having decomposability may be used.

  Further, the base and the needle-like body constituting the needle-like body array may be formed of the same composition material or different composition materials. By forming the base body and the needle-shaped body with a composition having the same composition, the base body part and the needle-shaped body part can be suitably formed by integral molding.

  Further, the substrate may be flexible. By using a flexible substrate, it is possible to suitably puncture a flexible object such as a curved surface or biological skin. In addition, when a flexible substrate is used, a roller with a needle-like body can be formed by forming the substrate into a roll shape.

  The substrate may be a sheet-like substrate. By using a sheet-like substrate, the substrate can be stored in a state of being laminated on a cylinder in a roll shape, and the manufacturing process can be continuously performed by a roll-to-roll method.

  The substrate may be a multilayer substrate. By laminating a plurality of types of materials, a substrate utilizing the physical properties of the plurality of materials can be obtained. For example, the following examples of substrates are given. (1) The upper layer may be formed of a composition having the same composition as that of the needle-shaped body, and the lower layer may be made of a material having high flexibility. (2) The upper layer may be made of a material having higher malleability than the lower layer, and in that case, there is an advantage that the substrate can be suitably bent into a roll shape. (3) The base may be a material in which the upper layer has a smaller shrinkage than the lower layer, and in this case, the base can be suitably bent into a roll. Or (4) You may arrange | position the layer which has a softness | flexibility in the lowest layer of a base | substrate. In that case, when accumulating the acicular array, the breakage of the acicular portion can be suppressed.

  Moreover, the acicular body array according to the present invention may be in contact with the skin in the form of a sheet, or may be roll-shaped and mounted on a roller-shaped instrument so as to be in contact with the skin.

  An example of the needle array of the present invention is shown in FIG. FIG. 5A shows the needle-like object array 500 when the base body 501 and the needle-like object 502 constituting the needle-like object array 500 are integrally formed of a material having the same composition.

  The needle-like array 510 shown in FIG. 5B shows an example including a flexible base 511 and a needle-like body 512 protruding on the first surface. Such a needle-shaped body array 510 may be formed by filling a plate with inverted concave and convex portions of a needle-shaped body and molding the needle-shaped body, and then fixing the material to the base material before the material is solidified. You may fix the said acicular body and base material after solidifying.

  The needle-like object array 520 in FIG. 5C is an example including the needle-like objects 524 protruding from the first surface of the base 521. The base body 521 includes a first portion 522 integrally formed of a material having the same composition as the needle-like body 524 and a second portion 523 made of a material having a composition different from that of the needle-like body 524. Such a needle-like array 520 is formed by filling a material in a plate with inverted concavities and convexities of the needle-like body to form the needle-like body and the first portion, and then forming the second portion before the material is solidified. The base material of the part may be fixed, or the base material for the needle and the first part and the second part may be fixed after the material is solidified.

  For example, when the needles according to the present invention are formed of chitin, chitosan and / or derivatives thereof, they perforate the skin and are degraded in vivo. At this time, the decomposed chitin, chitosan and / or a derivative thereof can be expected to have a cosmetic effect such as moisturizing the skin. Solid chitin, chitosan and / or derivatives thereof have sufficient strength to pierce the skin even when formed with microscopic fine dimensions as described above. Providing sufficient mechanical strength to perforate the skin and at the same time exhibiting a moisturizing effect in the skin is an effect produced by forming the perforated needle body itself using chitin, chitosan and / or a derivative thereof It is.

  Further, the needle-like body may be constituted by a plurality of phases having different compositions, or the configuration may be different depending on the part of the needle-like body. As an example, FIG. 6 shows a schematic diagram of a needle-like body array 600 configured to include a larger amount of a physiologically active substance and / or cosmetic composition at the tip than at the base. In FIG. 6, an example of the needle-like body array 600 in which a physiologically active substance and a cosmetic composition are contained in a portion of the tip portion 602 of the needle-like body 601 more than the base portion 603 is shown. FIG. 6 illustrates the case where the needle-like body 601 has two layers. However, the needle-like body 601 is not strictly two layers, but has a configuration in which the concentration of the physiologically active substance and / or cosmetic composition gradually increases toward the tip. Or vice versa.

  The acicular body may contain a plurality of active ingredients such as active substances and / or cosmetic compositions. For example, chitin, chitosan and / or a derivative thereof may form a needle-like body, and the needle-like body may further contain a further active substance. When the physiologically active substance and / or cosmetic composition is contained in the chitin, chitosan and / or derivative thereof forming the needle array, the physiologically active substance and / or cosmetic composition is prepared as a microcapsule, After the microcapsules are kneaded and dispersed with the needle-shaped material, in this case, chitin, chitosan and / or derivatives thereof, the needle-shaped body may be formed. By microencapsulating the physiologically active substance and / or cosmetic composition, the controlled release rate of the physiologically active substance and / or cosmetic composition can be controlled by the physical properties of the substance used for the outer shell of the microcapsule. it can. For this reason, it acts particularly suitably when it is desired to retain the physiologically active substance and / or cosmetic composition for a long period of time.

  When arranging the needle-like bodies in an array, an auxiliary frame may be provided around the needle-like bodies. By changing the height of the auxiliary frame, the puncture site can be controlled by the height of the auxiliary frame even with a needle having a length of 700 μm or more. In addition, when the auxiliary frame is a closed figure as seen from the top view, it is possible to suppress the flow out of the auxiliary frame when a physiologically active substance or a cosmetic composition is applied. For example, such an auxiliary frame may be provided on the base so as to surround the periphery of the forested needle-like body. An example of such a needle array is shown in FIG. The needle-like body array 700 of FIG. 7 is provided with an auxiliary frame 704 so as to surround the needle-like body 701 protruding on the first surface of the base body 702. Such an auxiliary frame can be formed, for example, by forming and using an inverted pattern of the auxiliary frame having a desired shape on the plate for forming the needle-like body and an inverted pattern of the needle-like body. Is possible. The means for forming the reverse pattern of the auxiliary frame on the plate may be a microfabrication technique known per se, such as, but not limited to, lithography, wet etching, dry etching, plasma etching, and reactivity. Etching such as ion etching, laser processing, focused ion beam, blasting such as sand blasting, and precision machining may be used.

  In the following, a method for producing a needle array according to the present invention will be described. However, together with the following method, any conventional means known per se may be used together to produce the needle array.

2. Needle-shaped array master The needle-shaped array is a needle-shaped array original, that is, a step of forming an exposed portion by exposing the photosensitive glass to an energy distribution, and the exposure by heat treatment after the exposure. It is possible to manufacture by using a needle array original plate manufactured by a method including a step of forming a modified portion by modifying a portion and a step of removing the modified portion by isotropic etching. It is. As shown in FIG. 1 (c), the needle array precursor 4 includes a base 5 and a recess 6 formed on the first surface of the base 5. The recess 6 may be provided in the base 5 in a shape obtained by reversing the pattern of the needle-like body 3 provided on the first surface of the target needle-like array 1.

  The step of forming the exposed portion by performing exposure with the photosensitive glass having an energy distribution can be performed using, for example, a laser. As the irradiation energy amount for the photosensitive glass increases, the depth of the recess 6 finally obtained increases. Therefore, it is necessary to perform exposure with an energy distribution corresponding to the depth of the recess 6.

  In order to expose the photosensitive glass with an energy distribution according to the depth of the concave portion 6, the central portion is exposed to the maximum amount by the laser so that the exposure amount decreases from the central portion toward the outside. Irradiation is sufficient. Further, the irradiation may be performed so as to be concentric with the shape of the opening of the concave portion provided in the base, or continuously and spirally so as to connect the opening and the lowest portion of the concave portion. . For example, as shown in FIG. 8A, the original material 801 may be intermittently irradiated with lasers in a plurality of concentric circles. FIG. 8A illustrates an example in which the opening is circular, but the shape of the opening may be any of a circle, an ellipse, and a rectangle. As shown in FIG. 8A, the laser is scanned concentrically and irradiated with the maximum exposure amount at the central portion, and the irradiation amount is gradually decreased from the central portion toward the outer side, so that FIG. It is possible to obtain a recess 802 having a cross section as in b) after etching.

  As a laser light source for performing exposure, a solid laser such as a ruby laser and a YAG laser, a liquid laser such as a dye laser, a gas laser such as a He—Cd laser, an Ar laser and a He—Ne laser, an InGaAsP system, a GaAlAs system, a GaAlInP system, and the like A GaN-based semiconductor laser may be used, and since the resolution can be improved to several hundred nm or less, a femtosecond laser and evanescent light are preferably used.

  After the exposed portion is formed by exposing the photosensitive glass as described above, the exposed portion is modified, that is, crystallized by annealing. The crystallization may be performed by heat treatment performed using a means such as an electric furnace.

  After crystallization, the crystallized portion of the photosensitive glass, that is, the modified portion is removed using an etching solution. Examples of the etching solution used here include hydrofluoric acid aqueous solution and the like. Etching may be performed by immersing photosensitive glass in the etching solution. By such etching, only the crystallized portion of the photosensitive glass can be removed, thereby making it possible to form a large number of concave portions corresponding to desired needle-like bodies in the photosensitive glass as non-through holes. is there.

  The production of the needle array from the needle array original plate manufactured as described above using photosensitive glass is performed by applying the needle array material to the needle array original plate and performing transfer molding. May be. Alternatively, the needle array original plate is used as a first plate, a second plate is produced from the original plate, a third plate is produced from the second plate, and the final product needle is produced from the third plate. You may carry out by manufacturing a solid body array.

3. Manufacturing method of needle-shaped object array An example of the manufacturing method of the needle-shaped object array is shown in FIG. FIG. 9 is a cross-sectional view schematically showing a manufacturing process until the needle array is manufactured. The manufacturing method includes a step of processing a photosensitive glass to produce a first plate (FIG. 9 (1)), a step of producing a second plate by a transfer molding method (FIG. 9 (2)), A step of producing a third plate (FIG. 9 (3)) and a step of producing a needle-like body array from the third plate (FIG. 9 (4)) are provided.

<The process of producing the 1st plate which processed photosensitive glass>
First, the photosensitive glass is exposed to laser light. As shown in FIG. 8B, the exposure amount of the laser beam is the largest at the center so that a non-through hole having a sharp bottom 803 is obtained in the cross-sectional shape of the recess 802 formed after etching. What is necessary is just to carry out so that it may become so small that it goes outside. For example, when the shape of the concave portion 802 is a cone, first, point irradiation is performed on the center of the circle, and then a circle with a small diameter is drawn with a laser beam, and the diameter of the circle is gradually increased. Perform exposure. The output of the laser beam irradiated at this time is the largest at the first point irradiation, and the output is reduced as the diameter of the circle increases.

  The photosensitive glass exposed by such a method is annealed in an electric furnace or the like to crystallize the exposed portion. Thereafter, by immersing in a hydrofluoric acid aqueous solution, only the crystallized portion of the sensitive glass is removed, and a large number of recesses that are non-through holes are formed. Thereby, the acicular body array original plate is produced as the first plate 901 (FIG. 9 (1)).

<Process for producing second plate from first plate>
Next, as shown in FIG. 9 (2), the first plate 901 produced by the above process is filled with a thermosetting resin 903 ((a) in FIG. 9 (2)), followed by heat treatment. Then, the resin 903 is cured and peeled from the first plate 901 ((b) in FIG. 9 (2)) to produce the second plate 904 ((c) in FIG. 9 (2)). The second plate 904 produced in this way is produced by being transferred from the first plate 901, and thus has a sword mountain shape in which many convex needles are formed. That is, the second plate 904 includes a base body 905 and a needle-like body 906 in the same manner as the needle-like array to be finally obtained.

  Preferable examples of the thermosetting resin 903 include, but are not limited to, silicone, acrylic, melamine resin, unsaturated polyester, and polyimide.

<Step of producing a third plate from the second plate>
As shown in FIG. 9 (3), the second plate 904 is filled with a thermosetting resin 907 ((a) of FIG. 9 (3)), and the resin 907 is cured by heat treatment or the like. By peeling ((b) of FIG. 9 (3)), a third plate 908 is produced ((c) of FIG. 9 (3)). The third plate 908 produced in this way is produced by being transferred from the second plate 904. Accordingly, the third plate 908 has the same shape as the first plate 901, that is, includes a base and a recess formed on the first surface of the base.

  Preferable examples of the thermosetting resin 907 include, but are not limited to, silicone, acrylic, melamine resin, unsaturated polyester, and polyimide.

<Process for producing an acicular array from the third plate>
Next, as shown in FIG. 9 (4), the needle-shaped body array material 909 is applied to the third plate 908 and transferred and molded ((a) in FIG. 9 (4)), and cured and peeled off. As a result ((b) of FIG. 9 (4)), the target needle-shaped body array 910 is obtained ((c) of FIG. 9 (4)). The needle-like body array 910 includes a base 911 and a needle-like body 912 provided on the first surface of the base 911.

  The needle array material 909 may be any one of the needle array materials described in the section “1. Needle array” described above. Preferably, for example, a medical silicone resin, polylactic acid is used. And biocompatible resins such as dextran are used.

  The specific contents of the present invention will be described below with reference to the drawings. Of course, the embodiments of the present invention are not limited to the following examples, but should be understood to include other forms that can be inferred.

Example 1
(1) Production of first plate Exposure is performed by irradiating photosensitive glass (product name: CM101, manufactured by Sumita Optical Glass Co., Ltd.) with laser light (device name: CPA-2001, manufactured by Clark-mxr). It was. In order to form a concave portion in the photosensitive glass with a sharp tip of the needle-like body provided in the needle-like body array, which is the final product obtained by transferring the unevenness, the irradiation of the laser becomes closer to the center portion. Laser light was irradiated so as to draw a plurality of concentric circles so as to increase the total energy amount.

Table 1 shows exposure conditions when a conical non-through hole with a diameter of 100 μm is formed as a recess.

  As shown in Table 1, the exposure was performed in a total of 5 steps by changing the laser irradiation method, processing diameter, and output stepwise. First, point irradiation is performed on the portion corresponding to the center of the recess, and then the laser is scanned while concentrically scanning either photosensitive glass or laser so that the processed diameters are 25, 50, 75, and 100 μm, respectively. Exposure was performed by irradiation. At this time, the laser output is the largest at the first point irradiation so that the processed shape becomes a conical shape, and in the circle irradiation, the smaller the diameter of the circle to be scanned, the larger the laser output at the time of exposure, The output was set to decrease as the diameter increased.

  Next, the exposed portion was crystallized by performing heat treatment on the exposed photosensitive glass. In the heat treatment, the temperature was first raised to 510 ° C. at a rate of 0.5 min / ° C., held at 510 ° C. for 1 hour, then raised to 540 ° C. and held at 540 ° C. for 1.5 hours.

  In order to remove only the crystallized portion at the end, it was immersed in a dilute hydrofluoric acid aqueous solution having a concentration of 5% and a volume of 500 ml for 1 hour. As a result, it was possible to produce a first plate in which a large number of non-through holes having a conical shape and a sharp bottom were formed as recesses.

(2) Production of Second Plate After the prepared first plate was filled with a silicone resin that is a thermosetting resin, heat treatment was performed to cure the resin. The heat treatment conditions for curing the resin were a temperature of 130 ° C. and a time of 30 minutes. Since the second plate thus produced is transferred from the first plate, the second plate has a number of conical needles in the form of a sword on the first surface of the substrate. Been formed.

(3) Production of third plate After a silicone resin, which is a thermosetting resin, was poured into the second plate produced in the above procedure, the resin was cured by heat treatment. The heat treatment conditions for curing the resin were the same as when the second plate was produced, and the temperature was 130 ° C. and the time was 30 minutes. Thereafter, the resin was peeled off from the second plate to produce a third plate. The shape of the third plate thus produced was the same as that of the first plate, and a large number of non-through holes with sharp bottoms were formed as recesses on the first surface of the base.

(4) Production of needle-shaped body array Using the third plate produced by the above procedure, transfer was performed to polylactic acid, which is a biocompatible resin, to produce a needle-shaped body array. The shape of the needle-shaped body array produced in this way is the same as that of the second plate, and has a large number of needle-shaped bodies on the first surface of the substrate.

  When the needle-shaped array thus prepared was observed with a scanning electron microscope, the needle-shaped array had a plurality of uniform conical needle-shaped bodies on the first surface of the substrate. Was confirmed.

Example 2
The third plate obtained in Example 1 was transferred using water-soluble chitosan.

  In general, chitin is dissolved in a solvent such as formic acid + dichloroacetic acid, trichloroacetic acid + dichloroethane, dimethylacetamide + lithium chloride, methanesulfonic acid, methanol + calcium chloride dihydrate, 10% aqueous sodium hydroxide.

  In addition, a strong acid can be used to dissolve chitosan, which dissolves in dilute aqueous solutions such as hydrochloric acid, formic acid, acetic acid, lactic acid, and citric acid.

  Hereinafter, as an example, preparation of an aqueous chitosan solution is illustrated.

  First, 7 L of distilled water and raw material chitosan (degree of deacetylation 70%) are added to a jar fermenter and dissolved with 180 g of glacial acetic acid. Bacillus-derived endo-type chitonase was added and subjected to enzyme treatment at pH 5.5 and 40 ° C. for 24 hours. Next, 5 g of enzyme inactivated / powdered activated carbon (manufactured by Nimura) was added at 80 ° C., followed by filtration with filter paper (NoSC manufactured by Advantech). The filtrate was lyophilized to obtain 620 g (yellowish brown) of a dried product. It was redissolved in water to obtain an aqueous chitosan solution. The aqueous chitosan solution described above was poured into the third plate and dried at a temperature of about 30 ° C.

  From the above, the conical needle array of the present invention was manufactured.

Example 3
As in Example 2, an acicular array was produced. In this example, chitosan oligosaccharide and chitosan aqueous solution were used instead of water-soluble chitosan.

  First, a gel solution was prepared by mixing chitosan oligosaccharide, a protein having a cosmetic effect or a pharmaceutical effect, and water. Next, a small amount of the aqueous solution was supplied to such an extent that the entire concave portion of the third plate was not filled. The third plate was loaded with heating to 30 ° C. under reduced pressure, dried, and the tip portion of the third plate was filled with chitosan oligosaccharide. The chitosan aqueous solution prepared in Example 2 was filled in the third plate having chitosan oligosaccharide filled in the tip portion, heated to 30 ° C., and dried.

  From the above, it was possible to produce an acicular array in which only the tip portion was made of chitosan oligosaccharide and the basal portion was made of water-soluble chitosan.

  The acicular array according to the present invention delivers an active ingredient and / or a cosmetic ingredient used medically, nutritionally, or cosmetically to a target site in the medical field such as treatment and prevention, and in the cosmetic field. Can be used conveniently to

1,500,510,520,600,700,910 Needle-like body array 2,5,501,511,521,702,905,911 Base 3,201,301,401,502,512,524,601,701 , 906, 912 Needle-like body 4 Needle-like body array original plate 6, 802 Recessed portion 801 Master material 803 Bottom portion 901 First plate 903, 907 Thermosetting resin 904 Second plate 908 Third plate 909 Needle-like body array material

Claims (2)

A method of manufacturing a needle-shaped body precursor for manufacturing a needle-shaped body array comprising a base and a needle-shaped body formed on a first surface of the base,
Forming an exposed portion by exposing the photosensitive glass to energy distribution; and
A step of modifying the exposed portion by heat treatment after exposure to form a modified portion; and
And a step of removing the modified portion by isotropic etching,
The method for producing an acicular body array original plate, wherein the exposure is performed by continuously and spirally irradiating a laser.   2. The method of manufacturing an acicular body array original plate according to claim 1, wherein a tapered non-through hole is formed by removing the modified portion by the isotropic etching. 3.

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