JP2007130030A - Micro-needle, micro-needle assembly, and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a micro-needle and the assembly which are suitable for transdermally administering medication and are hard to be broken and to be bent, and to provide their manufacturing method. <P>SOLUTION: The micro-needle formed by a film which shows crystallization enthalpy ΔHcc of 0-10 mJ/mg in a temperature rising process (a rate of temperature increase: 2°C/min) when differential scanning calorimetry (DSC) is measured and a turbidity change of 30%-99% when the film with a thickness of 200 μm is heated at a glass transition temperature of Tg+70°C for 30 minutes and the micro-needle assembly are introduced. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a microneedle or a microneedle assembly for transdermal administration of a drug, and particularly to a resin-made microneedle or a microneedle assembly. Moreover, it is related with the manufacturing method of this microneedle or a microneedle aggregate.

  In general, drugs that cannot be administered orally are administered by injection. Administration with a syringe causes severe skin damage and is painful. On the other hand, transdermal administration such as a patch is convenient, and further, it is possible to control the drug delivery for locally delivering the drug. It is also said that side effects of drugs can be reduced or avoided. However, when transdermal patches are used, it takes time to develop the drug effect, and the types of drugs that can be administered are greatly limited.

  Such a technique has been developed that overcomes the obstacle that it takes time to develop the drug effect and the types of drugs to be administered are limited. Iontophoresis is a method in which a voltage is applied to the periphery of the skin to be administered, and the charged drug is actively percutaneously absorbed by an electrochemical potential. Sonophoresis is a technique for enhancing the transdermal absorbability of a drug by applying ultrasonic waves to the skin through a medium such as an aqueous solution. Electroporation is a method of introducing a drug by applying a high voltage to a cell membrane to reversibly form small pores. In iontophoresis, the current value can be increased to increase the efficiency of drug absorption, but irritation to the skin is a concern. Since sonophoresis and electroporation directly reduce the barrier action of the skin, there are concerns about damage to the skin and associated damage, restoration of the barrier function against infection, and the like. The drugs that can be indicated by any method are limited. That is, iontophoresis requires the drug to be charged in an aqueous solution, sonophoresis and electroporation have low reactivity with the skin, and the molecular weight of the drug must be small.

  In the transdermal administration of drugs, it is known that the obstacle to drug delivery is the stratum corneum in the surface layer of the skin. In recent years, in order to overcome the obstacles, development of microneedles and microblades that deliver drugs while avoiding the stratum corneum has been actively performed (see Patent Documents 1 and 2).

  A microneedle is generally a micro needle having a length of several hundreds μm and a diameter of several tens of μm, and has a large aspect ratio.

  Microneedles are known to be used as devices for drug delivery and body fluid sampling. The microneedle has a length enough to penetrate the stratum corneum in the upper layer of the skin but does not reach the pain point. Therefore, there is an advantage that it is not necessary to feel pain associated with skin penetration during application. Since the diameter of the microneedle is as small as several tens of μm, the damage to the skin is much smaller than when an injection needle or a microblade is applied.

  Several reports have been made that microneedles can be an alternative to injection (see Non-Patent Document 1).

  Conventional microneedles have been proposed by a method using optical lithography (see Patent Document 3) or a method using deep reactive ion etching (see Patent Document 4).

  Many of the materials used for the microneedles are metal or silicon (see Non-Patent Document 1). Since the metal or silicon microneedles are excellent in rigidity, it is easy to ensure the rigidity necessary for penetrating the stratum corneum even with a microneedle having a thickness of several tens of microns. However, the microneedle has a problem in toughness. When the microneedle is applied, there is a risk that a part of the tip of the microneedle is broken in the living body or the microneedle is broken from the base, so that metal or silicon is placed in the body.

A microneedle using a resin such as polyamide or polyester has also been proposed (see Patent Document 5). There is a possibility that microneedles produced using a resin are safer than metal or silicon microneedles. This is because resin is superior in toughness compared to metal, and resin-made microneedles have the property of being difficult to break.
Special Table 2002-517300 Special table 2000-512529 Japanese translation of PCT publication No. 2004-526581 Special table 2004-538106 gazette Japanese translation of PCT publication No. 2003-501161 D. V. McAllister et al., “Microfabricated needles for transnational deliberation of macromolecules and nanoparticulates: Fabrication methods and transport studies, Proceedings of transport and studies.” 100, no. 24, p. 13755-13760

  Microneedles are dosing devices that are characterized by painlessness when applied and little damage to the skin. In addition, resin-made microneedles have the advantage of being hard to break because they are superior in toughness compared to metal.

  However, since the rigidity of the resin is smaller than that of metal or silicon, the conventional resin microneedles tend to be bent and not pierce the skin.

  It is not appropriate to make the microneedle thick in order to compensate for the low rigidity of the resin. This is because if the microneedle is thickened, it may be painless during adaptation and may lose the characteristic of little damage to the skin.

  Further, among resins, resins having relatively high rigidity generally do not have sufficient moldability. Therefore, it is difficult to produce a high aspect ratio such as a microneedle using a highly rigid resin.

  Therefore, with the conventional technology, it has not been possible to realize a resin-made microneedle that is excellent in toughness and rigidity, is not easily broken, and is not easily bent.

  An object of the present invention is to provide a microneedle and an assembly thereof which are suitable for transdermal administration of a drug and which are difficult to bend and which are difficult to bend, and a method for producing them.

  In order to solve the above problems, the present invention has the following configuration.

  The present invention relates to a microneedle and a microneedle assembly molded by a film, and the film is obtained by differential scanning calorimetry (hereinafter also referred to as DSC) in a temperature rising process at a temperature rising rate of 2 ° C./min. The crystallization enthalpy ΔHcc is 0 to 10 mJ / mg, and the turbidity change when a film having a thickness of 200 μm is heated at a glass transition temperature Tg + 70 ° C. for 30 minutes is 30% to 99%.

  The microneedle of the present invention preferably has a polygonal column shape or cylindrical shape having a height of 10 μm to 1000 μm and a protrusion width of 1 μm to 300 μm, or a height of 10 μm to 1000 μm, a bottom width of 1 μm to 300 μm, and a tip width. It is a polygonal frustum shape or a truncated cone shape of 0 μm to 100 μm.

  The manufacturing method of the microneedle and the microneedle assembly of the present invention is characterized by molding using imprint processing. Preferably, the temperature of the film during imprinting is a glass transition temperature Tg + 30 ° C. to Tg + 80 ° C.

  According to the present invention, it is possible to obtain a resin microneedle that perforates the skin without bending and without bending when the drug is transdermally administered. Furthermore, according to the manufacturing method of the present invention, it is possible to easily manufacture such microneedles.

  The present inventors have intensively studied microneedles and microneedle assemblies that have high mechanical strength and are difficult to bend, and solved the above problems by molding a film having specific physical properties. It is.

  That is, the microneedle and the microneedle assembly of the present invention are molded by a film, and the film is obtained by differential scanning calorimetry, and is crystallized in the temperature rising process at a temperature rising rate of 2 ° C./min. The enthalpy ΔHcc is 0 to 10 mJ / mg, and the turbidity change when a film having a thickness of 200 μm is heated at a glass transition temperature Tg + 70 ° C. for 30 minutes is 30% to 99%.

  The microneedle and the microneedle assembly of the present invention are characterized in that the crystallization enthalpy ΔHcc in the temperature rising process (temperature rising rate: 2 ° C./min) obtained by differential scanning calorimetry is 0 to 10 mJ / mg. It is formed from a film to be made. More preferably, it is 0-5 mJ / mg, More preferably, it is 0-3 mJ / mg. The crystallization enthalpy ΔHcc here is a value obtained according to JIS K7122 (1999), and in the differential scanning calorimetry chart obtained when scanning at a heating rate of 2 ° C./min, an exothermic peak accompanying crystallization. It is a value obtained from the area. In the film used for molding the microneedle and the microneedle assembly of the present invention, if the crystallization enthalpy ΔHcc is larger than this range, the resin constituting the film quickly crystallizes at the time of temperature rise when forming on the surface. , Film deformation is less likely to occur during shaping. For this reason, when the high-aspect ratio microneedle is formed, the resin is insufficiently filled in the mold, resulting in a decrease in transfer accuracy, or in-plane pressure imbalance resulting in a decrease in in-plane uniformity of transfer. It is not preferable for reasons such as. In the film used for molding the microneedle and the microneedle assembly of the present invention, by setting the crystallization enthalpy ΔHcc within the range of the present invention, a shape having a large aspect ratio can be molded satisfactorily.

  The film used for molding the microneedle and the microneedle assembly of the present invention has a turbidity change of 30% to 99% when a film having a thickness of 200 μm is heated at a glass transition temperature Tg + 70 ° C. for 30 minutes. It is characterized by that. Preferably they are 40%-99%, More preferably, they are 50%-99%. Here, the glass transition temperature Tg is a value obtained according to JIS K7122 (1999), and is a bent portion deviated from the base line in the DSC curve obtained when scanning at a heating rate of 2 ° C./min. This is the temperature at which the slope is maximum.

Turbidity means the percentage (Ht) of the amount of light scattered and transmitted off the incident light beam while the incident light passes through the sample from a light source (preferably a standard light source, see JIS Z-8720). It is obtained by the formula.
Ht = 100 × (Td / Tt)
Here, Td is the diffuse transmittance, Tt is the total light transmittance, and when the linear transmittance is Tp, it is expressed by the following relational expression.
Tt = Td + Tp
The turbidity change referred to in the present invention means a value obtained by subtracting the turbidity before heating from the turbidity after heating a 200 μm thick film at a glass transition temperature Tg + 70 ° C. for 30 minutes.

  In addition, in the film used for molding the microneedle and the microneedle assembly of the present invention, if the change in turbidity is below the above range, it can be molded well, but the microneedle after molding is There is a possibility that the rigidity becomes insufficient and the bending becomes easy. In the film used for molding the microneedle and the microneedle assembly of the present invention, by making the turbidity change within the scope of the present invention, crystallization can proceed without lowering the moldability during the molding process. As a result, it is possible to obtain a microneedle that has high rigidity and was difficult to bend while maintaining moldability.

  Moreover, it is preferable that the glass transition temperature Tg of the film used in order to shape | mold the microneedle and microneedle assembly of this invention is the range of 40-160 degreeC. More preferably, it is 60-150 degreeC. If the glass transition temperature Tg falls below this range, the pattern may be deformed when the high aspect ratio microneedles and microneedle aggregates are released, and the shape may change over time even if release is possible. This is not preferable. If the temperature exceeds this range, the forming temperature is high and energy is inefficient, and the volume fluctuation during heating / cooling of the film increases, so that the film can bite into the mold and cannot be released. Even if the mold can be formed, it is not preferable because the transfer accuracy of the microneedle and the microneedle assembly is lowered, or the needle is partially missing, resulting in a defect. In the film used for molding the microneedle and the microneedle assembly of the present invention, good transferability and releasability can be obtained by setting the glass transition temperature Tg of the film within this range.

  In addition, to the film used for molding the microneedle and the microneedle assembly of the present invention, a component that is cured by electromagnetic wave irradiation, for example, a compound having a substituent such as an acryloyl group, a methacryloyl group, and an epoxy group is added. It doesn't matter. In this case, the mechanical strength can be improved by irradiating the cured microneedles and microneedle assembly with electromagnetic waves and curing them.

  Moreover, the film used in order to shape | mold the microneedle and microneedle assembly of this invention can add various additives within the range which does not lose the effect of this invention. Examples of additives that can be added and blended include, for example, organic fine particles, inorganic fine particles, dispersants, dyes, fluorescent brighteners, antioxidants, weathering agents, antistatic agents, polymerization inhibitors, mold release agents, Examples include thickeners, pH adjusters, inorganic salts, and organic salts.

  The film used for molding the microneedle and the microneedle assembly of the present invention may be a sheet made of a single resin or a laminate made of a plurality of resin layers. In the case of a laminated body, compatibility between moldability and mechanical strength can be further enhanced as compared with a single sheet. Thus, when the film is a laminate comprising a plurality of resin layers, the crystallization enthalpy ΔHcc as a whole film, the glass transition temperature Tg, and each change in turbidity when a 200 μm film is heated to Tg + 70 ° C. Although it is preferable to satisfy the above-mentioned requirements, even if the entire film does not satisfy the above-mentioned requirements, it is sufficient that at least a layer satisfying the above-mentioned requirements is formed on the surface layer, and in this case, the surface is easily shaped. be able to.

  Moreover, the film used for molding the microneedle and the microneedle assembly of the present invention may be stretched uniaxially or biaxially. However, depending on the material used, orientation crystallization proceeds by stretching at a high magnification and as a result, moldability may deteriorate. Therefore, it is preferable to perform stretching while appropriately controlling in accordance with changes in physical property values.

  The thickness of the film used for molding the microneedle and the microneedle assembly of the present invention is preferably 100 μm to 500 μm from the viewpoint of moldability at the time of imprinting and handling of the molded microneedle, and 200 μm. ˜500 μm is more preferable from the viewpoint of film formability.

  The film used for molding the microneedle and the microneedle assembly of the present invention is preferably composed of a thermoplastic resin as a main component. Specific examples of the thermoplastic resin include polyethylene resins such as polyethylene terephthalate, polyethylene-2, 6-naphthalate, polypropylene terephthalate, and polybutylene terephthalate, polyethylene, polystyrene, polypropylene, polyisobutylene, polybutene, and polymethylpentene. Examples thereof include polyolefin resins, polyamide resins, polyimide resins, polyether resins, polyesteramide resins, polyetherester resins, acrylic resins, polyurethane resins, polycarbonate resins, and polyvinyl chloride resins. Among them, especially from polyester resins, polyolefin resins, polyamide resins, acrylic resins, or mixtures thereof because of the variety of monomer types to be copolymerized and the ease of adjusting the material properties. It is preferable that the thermoplastic resin selected is mainly formed.

  As a film in which the film used for molding the microneedle and the microneedle assembly of the present invention has a thermoplastic resin as a main component, it is preferable that the thermoplastic resin is composed of 50% by weight or more. It is preferably composed of 90% by weight or more.

  In addition, the film used for molding the microneedle and the microneedle assembly of the present invention is more preferably a resin composition having a polyester resin as a main component among the thermoplastic resins. Polyester resins can be suitably used because of the variety of monomer types to be copolymerized and the ease of adjusting the material properties. In particular, a copolymer of a dicarboxylic acid or an ester-forming derivative thereof and a diol is preferably used.

  Such dicarboxylic acid components include malonic acid, succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, dodecanedioic acid, dimer acid, eicosandioic acid, pimelic acid, azelaic acid, methylmalonic acid, ethylmalonic acid. Aliphatic dicarboxylic acids such as adamantane dicarboxylic acid, norbornene dicarboxylic acid, isosorbide, cyclohexane dicarboxylic acid, decalin dicarboxylic acid, terephthalic acid, isophthalic acid, phthalic acid, 1,4-naphthalenedicarboxylic acid, 1 , 5-naphthalenedicarboxylic acid, 2,6-naphthalenedicarboxylic acid, 1,8-naphthalenedicarboxylic acid, 4,4′-diphenyldicarboxylic acid, 4,4′-diphenyletherdicarboxylic acid, 5-sodium sulfoisophthalic acid, phenylene Dunge Representative examples include aromatic dicarboxylic acids such as rubonic acid, anthracene dicarboxylic acid, phenanthrene dicarboxylic acid, 9,9′-bis (4-carboxyphenyl) fluorenic acid, or ester derivatives of these dicarboxylic acids. Not. Any compound having two carboxyl groups in the molecule can be appropriately selected and used. Moreover, these may be used independently or may be used in multiple types as needed. In addition, compounds obtained by condensing or adding oxyacids such as L-lactide, D-lactide, and hydroxybenzoic acid, derivatives thereof, or compounds obtained by condensing a plurality of these oxyacids to these dicarboxylic acids are also preferably used.

  Examples of the diol component include aliphatic diols such as ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,2-butanediol, and 1,3-butanediol. Alicyclic diols such as cyclohexanedimethanol, spiroglycol and isosorbide, bisphenol A, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 9,9′-bis (4-hydroxyphenyl) fluorene, etc. Aromatic diols can be used as representative examples, and diol compounds obtained by condensing any plurality of these diols into ethers can also be used, but are not limited thereto. Any compound having two hydroxyl groups in the molecule can be appropriately selected and used. In addition, these diols may be used alone or in combination as necessary.

  Here, the polyester resin used for molding the microneedle and the microneedle assembly of the present invention can be obtained by appropriately selecting the above-mentioned dicarboxylic acid component and diol component and copolymerizing them. In order to satisfy the physical properties, the dicarboxylic acid component and the diol component described above are copolymerized so as to include at least one having a bulky skeleton, a bent skeleton, or the like and capable of disturbing the ordered structure. Can be obtained at

  For example, as a polyester resin, from the viewpoint of moldability and rigidity, a copolymer containing terephthalic acid as the dicarboxylic acid component and ethylene glycol as the diol component is preferably used.

  In this case, examples of the dicarboxylic acid component of the copolymer component that can disturb the ordered structure include alicyclic dicarboxylic acids such as adamantane dicarboxylic acid, norbornene dicarboxylic acid, isosorbide, cyclohexane dicarboxylic acid, decalin dicarboxylic acid, and isophthalic acid. Phthalic acid, 1,4-naphthalenedicarboxylic acid, 1,5-naphthalenedicarboxylic acid, 2,6-naphthalenedicarboxylic acid, 1,8-naphthalenedicarboxylic acid, 4,4′-diphenyldicarboxylic acid, 4,4′- Aromatic dicarboxylic acids such as diphenyl ether dicarboxylic acid, 5-sodium sulfoisophthalic acid, phenylendane dicarboxylic acid, anthracene dicarboxylic acid, phenanthrene dicarboxylic acid, 9,9′-bis (4-carboxyphenyl) fluorenic acid, or esters of these dicarboxylic acids Although such ether derivatives as a typical example, but not limited to. Any compound having two carboxyl groups in the molecule can be appropriately selected and used. Moreover, these may be used independently or may be used in multiple types as needed.

  Examples of the diol component of the copolymer component that can disturb the ordered structure include alicyclic diols such as cyclohexanedimethanol, spiroglycol and isosorbide, 1,2-cyclohexanedimethanol, 1,3 -Cycloaliphatic diols such as cyclohexanedimethanol and 1,4-cyclohexanedimethanol, bisphenol A, 1,3-benzenedimethanol, 1,4-benzenedimethanol, 9,9'-bis (phenoxyethanol) fluorene, etc. Aromatic diols, or a diol compound obtained by condensing any plural number of these diols into an ether can be used.

  The carboxylic acid component capable of disturbing such an ordered structure is preferably 5 to 90 mol in 100 mol of all carboxylic acid components, and 5 to 90 mol in diol components in 100 mol of all diol components. It is more preferable to include an appropriate amount according to the type of the acid component or diol component. As a more preferable example, in the case of using polyethylene terephthalate, which is a copolymer of ethylene glycol and terephthalic acid, as a monomer capable of disturbing the ordered structure, when cyclohexanedimethanol as a diol component is used, It is preferable that 10-40 mol is contained in 100 mol of diol components. When spiroglycol as a diol component is used, it is preferable that 5 to 20 mol is contained in 100 mol of all diol components. In addition, when isophthalic acid as a carboxylic acid component is used as a monomer capable of disturbing the ordered structure, it is preferable that 20 to 50 mol is contained in 100 mol of all carboxylic acid components. Moreover, when 2,5-naphthalenecarboxylic acid which is a carboxylic acid component is used, it is preferable that 10-30 mol or 70-90 mol is contained in 100 mol of all the carboxylic acid components. If the above-mentioned range is not satisfied, there is a possibility that the molded microneedle is not sufficiently rigid and it is difficult to perforate the skin, or conversely, the rigidity becomes too high to accurately mold the needle-like projection. Therefore, it is not preferable. In the polyester resin used for molding the microneedle and the microneedle assembly of the present invention, by setting the ratio of the monomer capable of disturbing the ordered structure within the above-mentioned range, the moldability and the rigidity of the needle-like projections are improved. It can be compatible.

  The resin constituting the film used for molding the microneedle and the microneedle assembly of the present invention can be obtained, for example, by appropriately selecting and copolymerizing the above-mentioned dicarboxylic acid and diol, and as a polymerization method therefor May be known techniques such as transesterification, direct polymerization, solution polymerization, and interfacial polymerization.

  In addition, various additives may be added to the resin constituting the film used for molding the microneedle and the microneedle assembly of the present invention at the time of polymerization or after polymerization within the range where the effects of the present invention are not lost. Can do. Examples of additives that can be added and blended include, for example, organic fine particles, inorganic fine particles, dispersants, dyes, fluorescent brighteners, antioxidants, weathering agents, antistatic agents, mold release agents, thickeners, Plasticizers, pH adjusters, inorganic salts, organic salts and the like can be used.

  The film used for molding the microneedle and the microneedle assembly of the present invention is a film obtained by forming the above-described polyester resin into a sheet. As an example of the production method, the above-described polyester resin can be heated and melted in an extruder, extruded from a die cooled onto a cast drum and processed into a sheet (melt cast method). As another method, a sheet forming material is dissolved in a solvent, and the solution is extruded from a die onto a support such as a cast drum or an endless belt to form a film, and then the solvent is dried and removed from the film layer to form a sheet. A method of processing into a solution (solution casting method) or the like can also be employed.

  The microneedle and the microneedle assembly of the present invention can be obtained by molding a film. A specific example of the manufacturing method is imprint processing. The imprint processing is a method of processing the surface shape of the workpiece by pressing the mold against the workpiece while heating. The details are as follows.

  The film and a mold having irregularities in which the shape of the needle to be transferred is inverted are heated within a temperature range not less than the glass transition temperature Tg of the film and less than the melting point Tm, and the film and the mold are brought close to each other and pressed at a predetermined pressure as it is. Hold for hours. Next, the temperature is lowered while maintaining the pressed state. Finally, the press pressure is released to release the film from the mold.

  Further, as a method for producing the microneedle and the microneedle assembly of the present invention, in addition to the above-described method for pressing a lithographic mold (lithographic press method), a roll-shaped mold having irregularities formed on the surface is used. It may be a roll-to-roll continuous molding which is molded into a film and obtains a roll-shaped molded body. In the case of roll-to-roll continuous molding, the productivity is superior to the lithographic press method.

  In the manufacturing method of the microneedle and the microneedle assembly of the present invention, the heating temperature and the press temperature T1 are preferably in the range of Tg + 15 ° C. to Tg + 80 ° C., more preferably in the range of Tg + 30 ° C. to Tg + 80 ° C. . If the thickness is less than this range, the film is not sufficiently softened, and the microneedle may be transferred at a lower height than the designed one. If it exceeds this range, the mold and the film are in close contact with each other, the microneedles are stretched at the time of release, and the height of the microneedles becomes higher than the designed height, which may reduce the mechanical strength. In the manufacturing method of the microneedle and the microneedle assembly of the present invention, good transfer accuracy can be obtained by setting the heating temperature and the press temperature T1 within these ranges.

  In the manufacturing method of the microneedle and the microneedle assembly of the present invention, the pressing pressure depends on the film to be used, but is preferably 0.5 MPa to 20 MPa. More preferably, it is 1 MPa to 10 MPa. If it is less than this range, the microneedle may be transferred at a lower height than designed. If this range is exceeded, the mold and the film are in close contact, the microneedles are stretched at the time of release, and the height of the microneedles exceeds the designed height, which may reduce the mechanical strength. In the manufacturing method of the microneedle and the microneedle assembly of the present invention, good transfer accuracy can be obtained by setting the press pressure within this range.

  In the method for producing the microneedle and the microneedle assembly of the present invention, the press pressure holding time depends on the film used, but is preferably 10 seconds to 10 minutes. If it is less than this range, the microneedle may be transferred at a lower height than designed. If this range is exceeded, the mold and the film are in close contact, the microneedles are stretched at the time of release, and the height of the microneedles exceeds the designed height, which may reduce the mechanical strength. In the manufacturing method of the microneedle and the microneedle assembly of the present invention, by setting the holding time within this range, good transfer accuracy and mechanical strength can be obtained.

  In the manufacturing method of the microneedle and the microneedle assembly of the present invention, the press pressure release temperature T2 is preferably within a temperature range of 25 ° C. to Tg + 20 ° C. and lower than the press temperature T1. More preferably, it is Tg-20 degreeC-Tg + 20 degreeC. Exceeding this range is not preferable because the fluidity of the resin at the time of pressure release is high, and the transfer accuracy is lowered due to deformation of the needle. In the method of manufacturing the microneedle and the microneedle assembly of the present invention, good transfer accuracy can be obtained by setting the press pressure release temperature T2 within this range.

  In the manufacturing method of the microneedle and the microneedle assembly of the present invention, the mold release temperature T3 is preferably within a temperature range of 25 to T2 ° C. More preferably, it is the temperature range of 20-T2-20 degreeC. Exceeding this range is not preferable because the flowability of the resin at the time of mold release is high, and the needle is deformed and the accuracy is lowered. In the manufacturing method of the microneedle and the microneedle assembly of the present invention, the mold can be released with high pattern accuracy by setting the temperature at the time of releasing within this range.

  FIGS. 1A to 1D illustrate cross-sectional views of a mold used in the method for producing the microneedle and the microneedle assembly of the present invention. As the shape of the mold convex portion 11 observed in the cross section of FIG. 1, a rectangular shape (FIG. 1 (a)), a trapezoid shape (FIG. 1 (b)), or a modified one (FIG. 1 (c), ( d)) and a mixture thereof are preferably used, but other shapes can also be used. That is, in addition to FIG. 1A in which the side surface of the mold convex portion 11 is substantially perpendicular to the sheet surface in the cross-sectional view, forms such as FIGS. 1B to 1D are also included. FIG. 1 shows an example in which flat portions are formed between adjacent mold convex portions 11, but the adjacent mold convex portions 11 may not be flat, and the skirts of the adjacent mold convex portions 11 are connected. You may do it. As for the shape of the mold recess 12, a shape such as a rectangle, a trapezoid, a triangle, a bell shape, or a shape obtained by deforming them can be preferably used as in the case of the mold protrusion 11.

  2A to 2E are cross-sectional views schematically showing the arrangement of the mold convex portions 11 and the mold concave portions 12 in a cross section when the mold is cut in parallel with the surface thereof. As shown in FIGS. 2A to 2E, the shape of the mold recess 12 may be selected from a substantially triangular shape, a substantially rectangular shape, a substantially hexagonal shape, other polygons, a circle, an ellipse, a star shape, and the like. Good. 2A shows a case where the mold recess 12 has a circular cross section, FIG. 2B shows a triangular shape, FIGS. 2C and 2E show a square shape, and FIG. ) Exemplifies the case of a hexagonal shape. The mold recesses 12 may be aligned as shown in FIG. 2, or may be randomly arranged, or different shapes may be mixed.

  Here, the width of the recess 12 is represented by the length of the recess width t in the case of FIG. When the length unit varies depending on the position as shown in FIG. 1B or the like, it is represented by three types of values, that is, an entrance width t1, a bottom width t2, and an average value ta.

  The mold used in the method for producing the microneedle and the microneedle assembly of the present invention has a recess width t (or ta) of 1 μm to 300 μm, preferably 20 μm to 80 μm, more preferably 40 μm to 60 μm, and a depth H of 10 μm to 1000 μm, Preferably it is 50 micrometers-200 micrometers, More preferably, it is 75 micrometers-150 micrometers, Moreover, the aspect-ratio H / t of the mold recessed part 12 is 0.1-25, Preferably it is 1-15.

  Moreover, when the cross section of the recessed part 12 has a taper, as a preferable range of entrance width t1 and bottom part width t2, entrance width t1 is 1-300 micrometers, More preferably, it is 20-80 micrometers, More preferably, it is 40-60 micrometers. . The bottom width t2 is 1 to 100 μm, more preferably 1 to 40 μm, and most preferably 1 to 10 μm. Further, the depth H is 10 μm to 1000 μm, preferably 50 μm to 200 μm, and more preferably 75 μm to 150 μm.

  Here, the recess width t of the mold is the unit length of the mold recess 12 as shown in FIG. In the case where the mold recess 12 is circular as shown in FIG. 2 (a), the diameter thereof is used. In the case of an ellipse, the short diameter thereof is used. As shown in FIGS. The diameter of the circumscribed circle may be the recess width t.

  Moreover, in this arrangement | sequence of the mold recessed part 12, it is preferable that the density of the mold recessed part 12, ie, the number of the mold recessed parts 12 per unit area, is 1 to 1000 per square centimeter. Moreover, in the arrangement | sequence of this mold recessed part 12, the area ratio of the mold convex part 11 and the mold recessed part 12 is arbitrary.

  The mold used in the method for producing the microneedle and the microneedle assembly of the present invention can be produced by a known technique such as cutting, laser processing, sandblasting, etching, photolithography, etc. The LIGA method is particularly preferable from the viewpoints of shape reproducibility and microneedle surface smoothness. The LIGA method is an abbreviation derived from German lithography (Lithographie), electroplating (Galvanformung), and molding (Abformung), and uses a synchrotron radiation to produce a fine structure with higher accuracy and higher aspect ratio. This is a precision processing technique using lithography. In this method of preparing a template using the LIGA method, the surface of polymethyl methacrylate (PMMA) is selectively irradiated with synchrotron radiation, the irradiated portion is decomposed, and developed to prepare a PMMA mold. . Next, after electroforming based on the mold, the PMMA mold is dissolved to obtain a mold. The synchrotron radiation that is the exposure light source used here is preferably one having a wavelength of 0.6 nm or less. If this range is exceeded, there is a limit in the depth of processing to PMMA, and there is a possibility that it cannot be processed into the designed shape.

  In the mold production by the above-described method, in order to make the cross-sectional shape of the mold recess 12 not a rectangle but a taper shape such as a trapezoid, the mask may be moved during exposure to PMMA. For example, a method disclosed in Japanese Patent No. 3380878 can be used.

  The material of the mold is not particularly limited as long as it is a metal used for electroforming replication, but it is particularly preferable to use nickel having excellent durability as a main component.

  Although the above-mentioned material may be used as it is for the mold, it is preferable to treat the surface of the mold with a surface treatment agent in order to impart easy slipperiness. The contact angle of the surface layer of the mold by the surface treatment is preferably 80 ° or more, more preferably 100 ° or more.

  Surface treatment methods include fixing the surface treatment agent on the mold surface using chemical bonds (chemical adsorption method), and physically adsorbing the surface treatment agent on the mold surface (physical adsorption method). Is mentioned. Among these, the surface treatment is preferably performed by a chemical adsorption method from the viewpoint of repeated durability of the surface treatment effect and prevention of contamination of the molded product.

  Preferable examples of the surface treatment agent used in the chemical adsorption method include a fluorine-based silane coupling agent. Surface treatment methods using this include cleaning methods such as ultrasonic cleaning in organic solvents (acetone and ethanol), boiling cleaning in acids such as sulfuric acid, and peroxides such as hydrogen peroxide. After the mold surface is cleaned, it is treated with a fluorine-based silane coupling agent. One example of the treatment method is to immerse the mold in a solution in which a fluorinated silane coupling agent is dissolved in a fluorinated solvent. It is also preferable to heat the solution during immersion.

  The microneedle of the present invention is a film having one needle-like projection on the surface, whereas the microneedle assembly of the present invention is a film having two or more needle-like projections on the surface.

  A cross-sectional view of the microneedle and the microneedle assembly of the present invention is shown in FIG. The shape of the needle-like protrusion 32 observed in the cross section of FIG. 3 is rectangular (FIG. 3 (a)), trapezoid (FIG. 3 (b)), or a modified one (FIG. 3 (c), ( d)) and a mixture thereof are preferably used, but other shapes can also be used. That is, in addition to FIG. 3A and the like in which the side surface of the needle-like protrusion 32 is substantially perpendicular to the sheet surface in the cross-sectional view, forms such as FIGS. 3B to 3D are also included. Here, a shape having a taper as shown in FIGS. 3B to 3D is preferable so that the skin can be easily perforated. Further, FIG. 3 shows an example in which flat portions are formed between adjacent molded product convex portions, but the gap between adjacent molded product convex portions may not be flat, and further, the skirt of the adjacent molded product convex portions. May be connected. In addition, as for the shape of the concave portion of the molded product, a shape such as a rectangle, a trapezoid, a triangle, a bell shape, or a deformed shape thereof can be preferably used similarly to the above-described convex portion of the mold.

  4A to 4E schematically show the arrangement of the needle-like protrusions 32 and the recesses 31 in a cross section when cut in parallel with the surfaces of the microneedle and the microneedle assembly of the present invention. It is sectional drawing shown. As shown in FIGS. 4A to 4E, the needle-like protrusion 32 has a shape selected from a substantially triangular shape, a substantially rectangular shape, a substantially hexagonal shape, a polygonal shape, a circle, an ellipse, a star shape, and the like. Also good. 4A shows a case where the cross-section of the needle-like protrusion 32 is a circular shape, FIG. 4B shows a case where the needle-like protrusion 32 has a triangular shape, FIG. 4C and FIG. d) each illustrates the case of a hexagonal shape. The needle-like protrusions 32 may be aligned as shown in the figure, may be arranged at random, or may have different shapes mixed together.

  Here, the width of the needle-like protrusion 32 is represented by the length of the protrusion width S ′ in the case of FIG. When the length unit varies depending on the position as shown in FIG. 3B or the like, it is expressed by three kinds of values, that is, the tip width S'1, the bottom width S'2, and the average value S'a.

  The shape of the needle-like protrusion 32 of the microneedle and the microneedle assembly of the present invention is such that the protrusion width S ′ (or S′a) is 1 μm to 300 μm, preferably 20 to 80 μm, more preferably 40 to 60 μm, and the height H ′. Is 10 μm to 1000 μm, preferably 50 μm to 200 μm, more preferably 75 μm to 150 μm. The aspect ratio H ′ / S ′ of the needle-like protrusion 32 is 0.1 to 25, preferably 1 to 15.

  More preferably, the needle-like protrusion has a tapered shape as shown in FIGS. 3B to 3D so that the skin can be easily perforated, and the tip width S of the needle-like protrusion 32 in that case is suitable. As a preferable range of '1, bottom width S'2, the tip width S'1 is 1 to 100 μm, more preferably 1 to 40 μm, and most preferably 1 to 10 μm. The bottom width S′2 is 1 to 300 μm, more preferably 20 to 80 μm, and more preferably 40 to 60 μm.

  Here, the protrusion width S ′ of the needle-like protrusion is a unit length of the needle-like protrusion 32 as shown in FIG. When the needle-like protrusion 32 is circular as shown in FIG. 4A, the diameter is indicated. When the needle-like protrusion 32 is elliptical, its short diameter is indicated. As shown in FIGS. In this case, the diameter of the circumscribed circle may be the needle width S ′.

  The microneedle density of the microneedle assembly of the present invention, that is, the ratio of the number of microneedles per unit area is preferably 1 to 1000 per square centimeter. Beyond the above range, a dense bundle of microneedles is undesirable because it pushes the skin as a surface rather than a point, reducing the probability of piercing the skin and making it difficult to pierce the skin. In the microneedle assembly of the present invention, it is possible to penetrate the skin satisfactorily by setting the microneedle density within the above range.

  The microneedle and microneedle assembly of the present invention can be used as a perforation device for sampling biological fluids such as blood. In order to perform sampling, the skin is perforated by pressing the needle-like projections of the microneedle or the microneedle assembly for 1 to 5 minutes on a part of the body fluid to be sampled, and the body fluid discharged from the perforated part is collected. Good. The pressing force is preferably such that a force within the range of 0.1 gf to 5 gf is applied to each needle-like protrusion from the viewpoint of the rigidity of the needle-like protrusion and the elasticity of the skin. A force in the range of 2.0 gf is more preferred. Below this range, the skin may not be sufficiently perforated. In addition, if this range is exceeded, the needle-like projections may be deformed during perforation, and the skin may be damaged when the needle-like projections are pulled out from the skin.

  When the microneedle and the microneedle assembly of the present invention are used, it is possible to introduce a drug into the body. As a method for introducing the drug, the drug can be attached to the needle-like protrusion 32 and then the needle-like protrusion side is pressed against the skin to penetrate the upper stratum corneum of the skin. The force for pressing the microneedle or the microneedle assembly to which the drug is applied is a force within the range of 0.1 gf to 5 gf per needle-like protrusion from the viewpoint of the rigidity of the needle-like protrusion and the elasticity of the skin. It is preferable to do so, and a force in the range of 0.3 gf to 2.0 gf is more preferable. Below this range, the skin may not be sufficiently perforated and the drug may not penetrate subcutaneously. In addition, if this range is exceeded, the needle-like projections may be deformed during perforation, and the skin may be damaged when the needle-like projections are pulled out from the skin.

  Examples of drugs that can be used include antibiotics, antiviral agents, anti-inflammatory agents, antitumor agents, analgesics, anesthetics, antidepressants, anti-arthritic agents, appetite suppressants, proteins, peptides, vaccines (DNA vaccines And adjuvant), but is not limited to these and can be used.

  In addition, as a method of attaching the drug to the needle-like protrusion 32 of the microneedle and microneedle assembly of the present invention, a method of attaching the drug after forming the microneedle and microneedle assembly of the present invention, Examples of the method include forming a microneedle and a microneedle assembly after mixing, coating, and / or impregnation (swelling) in a film for forming the microneedle and the microneedle assembly. However, the present invention is not limited to these, and a method capable of attaching the drug to the needle-like protrusion can be arbitrarily used. As an example of the former method of forming a microneedle and a microneedle assembly according to the present invention, a drug is applied onto the microneedle and the microneedle assembly according to the present invention, and a coating film of the drug is formed on the surface. Formation and / or method of swelling drug in needle-like protrusion (coating method), dipping the tip of needle-like protrusion 32 of the microneedle and microneedle assembly of the present invention into the liquid surface of the drug, and the tip surface of needle-like protrusion Examples thereof include, but are not limited to, a method of forming a coating film of the drug and / or a method of swelling the drug into the tip of the needle-like protrusion 32 (stamp method).

  The needle-like projections of the microneedle and the microneedle assembly of the present invention can be used as an acupuncture needle in acupuncture treatment. In the treatment, it is preferable that the force for pressing the needle-like protrusion is applied within the range of 0.1 gf to 5 gf per needle-like protrusion from the viewpoint of the rigidity of the needle-like protrusion and the elasticity of the skin. A force in the range of 0.3 gf to 2.0 gf is more preferable. Below this range, the skin may not be sufficiently perforated. In addition, if this range is exceeded, the needle-like projections may be deformed during perforation, and the skin may be damaged when the needle-like projections are pulled out from the skin.

  Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the following examples.

(Characteristic evaluation method)
A. Crystallization enthalpy ΔHcc and glass transition temperature Tg
The crystallization enthalpy ΔHcc and the glass transition temperature Tg are measured according to JIS K7122 (1999) using a differential scanning calorimeter “Robot DSC-RDC220” manufactured by Seiko Electronics Industries, Ltd. Obtained using. 5 mg of each sheet was weighed into a sample pan and scanned at a rate of temperature increase of 2 ° C./min. The crystallization enthalpy ΔHcc was determined from the area of the crystallization exothermic peak. The glass transition temperature Tg was determined from the temperature at the point where the inclination becomes maximum at the bent portion deviated from the base line in the DSC curve obtained when scanning at a heating rate of 2 ° C./min.

B. Turbidity Turbidity was measured using a fully automatic direct reading haze computer HGM-2DP manufactured by Suga Test Instruments Co., Ltd.

C. Shape Observation Photographs were taken at 1000 and 80 times on the surfaces of the mold and molded product using a scanning electron microscope S-4800 (model name) manufactured by Hitachi High-Technologies Corporation. For the molded product, platinum was vapor-deposited before observation.

D. Skin perforation test The test was performed in the following procedure. The skin of the back of an 8-week-old hairless mouse was removed and fixed in a stretched state without wrinkles on the stage. Next, the microneedle assembly was placed on the skin so that the needle-like projections of the microneedle assembly were on the skin side, and a 300 g weight was gently placed thereon. After standing in that state for one minute, the weight was removed, the microneedle assembly was removed from the skin, and the entire surface of the skin was stained with Evans Blue 2% aqueous solution (Sigma Aldrich Co., Ltd.). Next, in order to remove the stained cells on the skin surface, an operation (tape stripping) of attaching and peeling an adhesive tape on the skin surface was performed twice. After removing the dyed portion of the entire surface by tape stripping, the number of spots stained blue in dots was counted, and the number of perforated holes was obtained. The ratio (%) of needle-like projections that could perforate the skin was determined by the following formula.
Perforation probability (%) = (number of perforated portions / number of needle-like protrusions) × 100
In addition, the shape of the microneedle and the microneedle assembly after the drilling test is observed with a scanning electron microscope, the number of needle-like protrusions bent by the drilling is counted, and the ratio of the number of deformed microneedles (deformation probability) (%) Was determined by the following formula.
Deformation probability (%) = (number of bent needle protrusions / number of needle protrusions) × 100
The condition that the needle-like protrusion is deformed is that the angle formed by the straight line connecting the tip and the bottom of the needle-like protrusion and the vertical direction of the film is 30 ° or more.

(template)
The shapes of the molds used in the examples and comparative examples are as follows.

  FIG. 5A is a schematic view of the produced mold (mold 1), and a total of 400 truncated cone-shaped holes are formed in the mold. FIG. 5B is a cross-sectional view of a portion including the concave portion of the mold. The concave portion has a depth H of 100 μm, an inlet width t1 of 60 μm, a bottom width t2 of 10 μm, and an average width ta of the concave portion of 35 μm. . The dimensions of the mold were 2.2 cm in length, 2.2 cm in width, and 2.0 mm in thickness. FIG. 5C is a schematic view of the mask used for producing the mold 1, and FIG. 5D shows the detailed shape of the masking portion made of gold.

  FIG. 6A is a schematic view of the produced mold (mold 2), and a total of 100 truncated cone holes are formed in the mold. FIG. 6B is a cross-sectional view of the portion including the concave portion of the mold. The concave portion has a depth H of 100 μm, an inlet width t1 of 60 μm, a bottom width t2 of 10 μm, and an average width ta of the concave portion of 35 μm. . The dimensions of the mold were 2.2 cm in length, 2.2 cm in width, and 2.0 mm in thickness. FIG. 6C is a schematic view of the mask used for producing the mold 2, and FIG. 6D shows the detailed shape of the masking portion made of gold.

  FIG. 7A is a schematic view of the produced mold (mold 3). A total of 400 truncated cone holes are arranged in the mold so as to form a hexagon. FIG. 7B is a cross-sectional view of the portion including the concave portion of the mold. The concave portion has a depth H of 100 μm, an inlet width t1 of 60 μm, a bottom width t2 of 10 μm, and an average width ta of the concave portion of 35 μm. . The dimensions of the mold were 2.2 cm in length, 2.2 cm in width, and 2.0 mm in thickness. FIG. 7C is a schematic view of a mask used to produce the mold 3, and FIG. 7D shows a detailed shape of a masking portion made of gold.

  FIG. 8A is a schematic view of the produced mold (mold 4), and a total of 400 triangular columnar holes are formed in the mold. FIG. 8B is a cross-sectional view of a portion including the concave portion of the mold, and the concave portion has a depth H of 100 μm and a concave portion width t (diameter of a circumscribed circle of the triangle) of 60 μm. The dimensions of the mold were 2.2 cm in length, 2.2 cm in width, and 2.0 mm in thickness. FIG. 8C is a schematic view of the mask used for producing the mold 4 and FIG. 8D shows the detailed shape of the masking portion made of gold.

  FIG. 9A is a schematic view of the produced mold (mold 5), and a total of 400 hexagonal columnar holes are formed in the mold. FIG. 9B is a cross-sectional view of the portion including the concave portion of the mold. The depth H of the concave portion is 100 μm, and the width t of the concave portion (diameter of the hexagonal circumscribed circle) is 60 μm. The dimensions of the mold were 2.2 cm in length, 2.2 cm in width, and 2.0 mm in thickness. FIG. 9C is a schematic view of the mask used for producing the mold 5, and FIG. 9D shows the detailed shape of the masking portion of the mask.

FIG. 10A is a schematic view of the produced mold (mold 6), and a total of 400 cylindrical holes are formed in the mold. FIG. 10B is a cross-sectional view of the portion including the concave portion of the mold, where the concave portion has a depth H of 100 μm and a concave portion width t of 60 μm. The dimensions of the mold were 2.2 cm in length, 2.2 cm in width, and 2.0 mm in thickness. FIG. 10C is a schematic view of a mask used for producing the mold 6, and FIG. 10D shows a detailed shape of a masking portion made of gold.

(Reference example)
The mold was produced as follows. Synchrotron radiation having a wavelength of 0.6 nm or less was used as the exposure light source, the exposure time was 1 hour, and the exposure amount was 15.4 amperes / minute. Further, for the production of the molds 1 to 3, during exposure, the mask is rotated and moved in a plane perpendicular to the traveling direction of the radiated light (driving diameter: 25 μm, rotational speed: 1 rotation / second). The exposure was continuously changed to taper. Beryllium was used for the mask membrane and gold was used for the masking material. After exposure, PMMA was developed. The developer used was a mixture of 2-(-butoxyethoxy) ethanol 60% by volume, tetrahydro-1,4-oxazine 20% by volume, aminoethanol 5% by volume, and pure water 15% by volume. The development time was 2 hours. After electroforming with nickel, PMMA was dissolved with a solvent to obtain a mold (samples 1 to 6).

Next, a fluororesin coat was applied to the mold. The coating agent used was Optool DSX (Daikin Chemical Industries, Ltd., 20% solid solution) diluted to 0.2% solids with a fluorine-based solvent (Daikin Chemical Industries, Ltd., demnum solvent).

Example 1
Cyclohexanedimethanol 25 mol% copolymerized polyethylene terephthalate dried at 140 ° C. for 2 hours was heated and melted at 280 ° C. in an extruder, extruded from a die onto a 25 ° C. cast drum, and cooled to prepare a film having a thickness of 200 μm ( Sample 100).

  The crystallization enthalpy ΔHcc of this film was measured and found to be 0.0 mJ / mg. The turbidity before the heat treatment was 0.8%, the turbidity when heated at 140 ° C. for 30 minutes was 91.7%, and the change in turbidity was 90.9%. Moreover, it was 78.7 degreeC when the glass transition temperature Tg of this film was measured.

  The mold 1 was placed on a stage on a lower plate of a press having a heating / cooling function so that the uneven surface of the mold was on the top, and a film (sample 100) cut into a 3 cm square was placed on the mold 1. Next, the upper and lower plates were heated to 140 ° C., and after the temperature reached 140 ° C., the plates were held for 5 minutes. Next, while maintaining 140 ° C., the upper plate was lowered, and the mold and the film were pressed by the upper and lower plates at a pressure of 5.5 MPa. After 4 minutes, the upper and lower plates were cooled to 60 ° C. over 10 minutes while maintaining the press pressure. After cooling to 60 ° C., the press was released, the mold was lowered from the stage without peeling off the film, and air-cooled for 20 minutes. After cooling, the film was released from the mold to obtain a microneedle assembly. A total of 11 microneedle assemblies were produced by the same method (samples 101 to 111).

  When one of the produced microneedle assemblies (sample 101) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. The shape of the microneedle constituting the microneedle assembly is that the tip width S′1 is 10 μm, the bottom width S′2 is 60 μm, and the height H ′ is 99 μm, and the shape of the mold is accurately transferred. I understood it. Photos taken during observation are shown in FIGS.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 102 to 111). The results are shown in Table 1. According to 10 skin piercing tests, the average piercing probability was 78.4%.

Moreover, the deformation | transformation probability of the acicular protrusion of the microneedle aggregate (samples 102-111) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to 10 skin perforation tests, the average deformation probability was 7.1%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 100 have sufficient rigidity for skin perforation.

(Example 2)
Spiroglycol 8 mol% copolymerized polyethylene terephthalate dried at 140 ° C. for 2 hours was heated and melted at 280 ° C. in an extruder, extruded from a die onto a 25 ° C. cast drum, and cooled to prepare a film having a thickness of 200 μm (sample) 200).

The crystallization enthalpy ΔHcc of this film was measured and found to be 0.0 mJ / mg. The turbidity before the heat treatment was 0.5%, the turbidity when heated at 140 ° C. for 30 minutes was 82.3%, and the change in turbidity was 81.8%. Moreover, it was 81.2 degreeC when the glass transition temperature Tg of this film was measured.
According to the procedure of Example 1, microneedle assemblies were prepared using the sample 200 and the template 1 (Samples 201 to 211).

  When one of the produced microneedle assemblies (sample 201) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. The shape of the microneedle constituting the microneedle assembly is that the tip width S′1 is 10 μm, the bottom width S′2 is 61 μm, and the height H ′ is 99 μm, and the shape of the mold is accurately transferred. I understood it.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 202 to 211). The results are shown in Table 1. The average perforation probability by 10 skin perforation tests was 76.1%.

Moreover, the deformation | transformation probability of the acicular processus | protrusion of the microneedle aggregate (samples 202-211) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to ten skin perforation tests, the average deformation probability was 7.4%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 200 have sufficient rigidity for skin perforation.

(Example 3)
Isophthalic acid 20 mol% copolymerized polyethylene terephthalate dried at 140 ° C. for 2 hours was heated and melted at 280 ° C. in an extruder, extruded from a die onto a 25 ° C. cast drum, and cooled to prepare a 200 μm thick film (sample) 300).

  The crystallization enthalpy ΔHcc of this film was measured and found to be 1.2 mJ / mg. Moreover, the turbidity before heat processing was 4.1%, the turbidity when heated at 140 degreeC for 30 minute (s) was 96.3%, and the turbidity change was 92.2%. Moreover, it was 71.3 degreeC when the glass transition temperature Tg of this film was measured.

  According to the procedure of Example 1, microneedle assemblies were prepared using the sample 300 and the mold 1 (Samples 301 to 311).

  When one of the produced microneedle assemblies (sample 301) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. The shape of the microneedle constituting the microneedle assembly is that the tip width S′1 is 10 μm, the bottom width S′2 is 60 μm, and the height H ′ is 99 μm, and the shape of the mold is accurately transferred. I understood it.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 302 to 311). The results are shown in Table 1. According to 10 skin puncture tests, the average puncture probability was 76.8%.

Moreover, the deformation | transformation probability of the acicular processus | protrusion of the microneedle aggregate (samples 302-311) after a piercing | boring test was calculated | required. The results are shown in Table 2. The average deformation probability by 10 skin perforation tests was 10.2%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 300 have sufficient rigidity for skin perforation.

Example 4
According to the procedure of Example 1, microneedle assemblies were prepared using the sample 100 and the template 2 (samples 112 to 122).

  When one of the produced microneedle assemblies (sample 112) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. The shape of the microneedle constituting the microneedle assembly is that the tip width S′1 is 9 μm, the bottom width S′2 is 60 μm, and the height H ′ is 99 μm, and the shape of the mold is accurately transferred. I understood it.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 113 to 122). The results are shown in Table 1. According to 10 skin puncture tests, the average puncture probability was 70.0%.

Moreover, the deformation | transformation probability of the acicular processus | protrusion of the microneedle aggregate (samples 113-122) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to ten skin perforation tests, the average deformation probability was 6.7%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 100 have sufficient rigidity for skin perforation.

(Example 5)
According to the procedure of Example 1, microneedle assemblies were prepared using the sample 100 and the template 3 (samples 123 to 133).

  When one of the produced microneedle assemblies (sample 123) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. Further, the shape of the microneedle constituting the microneedle assembly is that the tip width S′1 is 10 μm, the bottom width S′2 is 60 μm, and the height H ′ is 98 μm, and the shape of the mold is accurately transferred. I understood it.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 123 to 133). The results are shown in Table 1. According to 10 skin puncture tests, the average puncture probability was 79.9%.

Moreover, the deformation | transformation probability of the acicular processus | protrusion of the microneedle aggregate (samples 123-133) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to ten skin perforation tests, the average deformation probability was 7.0%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 100 have sufficient rigidity for skin perforation.

(Example 6)
According to the procedure of Example 1, microneedle assemblies were prepared using the sample 100 and the template 4 (samples 134 to 144).

  When one of the produced microneedle assemblies (sample 134) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. Further, it was found that the microneedles constituting the microneedle assembly had a protrusion width S ′ of 59 μm and a height H ′ of 99 μm, and the shape of the mold was accurately transferred.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 135 to 144). The results are shown in Table 1. The average perforation probability by 10 skin perforation tests was 70.1%.

Moreover, the deformation | transformation probability of the acicular protrusion of the microneedle aggregate (samples 135-144) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to 10 skin perforation tests, the average deformation probability was 4.6%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 100 have sufficient rigidity for skin perforation.

(Example 7)
According to the procedure of Example 1, microneedle assemblies were prepared using the sample 100 and the template 5 (samples 145 to 155).

  When one of the produced microneedle assemblies (sample 144) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. Further, it was found that the microneedles constituting the microneedle assembly had a protrusion width S ′ of 58 μm and a height H ′ of 100 μm, and the shape of the mold was accurately transferred.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 145 to 155). The results are shown in Table 1. The average perforation probability by 10 skin perforation tests was 69.7%.

Moreover, the deformation | transformation probability of the acicular processus | protrusion of the microneedle aggregate (samples 145-155) after a piercing | boring test was calculated | required. The results are shown in Table 2. The average deformation probability by 10 skin perforation tests was 1.0%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 100 have sufficient rigidity for skin perforation.

(Example 8)
According to the procedure of Example 1, a microneedle assembly was prepared using the sample 100 and the template 6 (samples 156 to 166).

  When one of the produced microneedle assemblies (sample 156) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. Further, it was found that the microneedles constituting the microneedle assembly had a protrusion width S ′ of 59 μm and a height H ′ of 99 μm, and the shape of the mold was accurately transferred.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 157 to 166). The results are shown in Table 1. According to 10 skin puncture tests, the average puncture probability was 68.0%.

Moreover, the deformation | transformation probability of the acicular processus | protrusion of the microneedle aggregate (samples 157-166) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to 10 skin perforation tests, the average deformation probability was 2.6%. As a result of observation, no microneedle damaged by perforation was found. From the above, it has been clarified that the needle-like projections of the microneedle assembly produced using the sample 100 have sufficient rigidity for skin perforation.

(Comparative Example 1)
Cyclohexanedimethanol 66 mol% copolymerized polyethylene terephthalate dried at 140 ° C. for 2 hours was heated and melted at 280 ° C. in an extruder, extruded from a die onto a 25 ° C. cast drum, and cooled to prepare a film having a thickness of 200 μm ( Sample 400).

  The crystallization enthalpy ΔHcc of this film was measured and found to be 0.0 mJ / mg. The turbidity before the heat treatment was 1.2%, the turbidity when heated at 140 ° C. for 30 minutes was 8.8%, and the turbidity change was 7.6%. Moreover, it was 71.9 degreeC when the glass transition temperature Tg of this film was measured.

  According to the procedure of Example 1, microneedle assemblies were prepared using the sample 400 and the template 1 (Samples 401 to 411).

  When one of the produced microneedle assemblies (sample 401) was observed with a scanning electron microscope, it was confirmed that the microneedle assemblies were molded. The shape of the microneedle constituting the microneedle assembly is that the tip width S′1 is 10 μm, the bottom width S′2 is 60 μm, and the height H ′ is 99 μm, and the shape of the mold is accurately transferred. I understood it.

  Next, a skin perforation test was performed using the obtained microneedle assembly (samples 402 to 411). The results are shown in Table 1. According to 10 skin puncture tests, the average puncture probability was 15.2%.

Moreover, the deformation | transformation probability of the acicular protrusion of the microneedle aggregate (samples 402-411) after a piercing | boring test was calculated | required. The results are shown in Table 2. According to 10 skin perforation tests, the average deformation probability was 73.9%. As a result of observation, no microneedle damaged by perforation was found. From the above, when a film (sample 400) whose turbidity change by heating is less than 30% is used, there is a possibility that the rigidity of the needle-like protrusions of the produced microneedle assembly is not sufficient for skin perforation. I understood it.

(Comparative Example 2)
Cyclohexanedimethanol 5 mol% copolymerized polyethylene terephthalate dried at 140 ° C. for 2 hours was heated and melted at 280 ° C. in an extruder, extruded from a die onto a 25 ° C. cast drum, and cooled to prepare a film having a thickness of 200 μm ( Sample 500).

  The crystallization enthalpy ΔHcc of this film was measured and found to be 29.8 mJ / mg. The turbidity before the heat treatment was 3.2%, the turbidity when heated at 140 ° C. for 30 minutes was 93.4%, and the change in turbidity was 90.2%. Moreover, it was 73.1 degreeC when the glass transition temperature Tg of this film was measured.

  A microneedle assembly was prepared using the sample 500 and the mold 1 in accordance with the procedure of Example 1 except that the press pressure was 10 MPa (sample 501).

  When the produced microneedle assembly (sample 501) was observed with a scanning electron microscope, it was confirmed that a microneedle assembly having a height of less than 50 μm was molded.

  From the above, it was found that the film (sample 400) exceeding the crystallization enthalpy ΔHcc 10 mJ / mg has low moldability and it is difficult to produce acicular protrusions by imprint processing.

FIGS. 1A to 1D are all cross-sectional views showing a mold used for producing the microneedle and the microneedle assembly of the present invention, and schematically illustrate the shape of the convex portion 11 in the cross-section. Is. 2A to 2E are cross-sectional views in a cross section parallel to the surface of the mold used for producing the microneedle and the microneedle assembly of the present invention, and schematically illustrate the shape of the convex portion 11. To do. FIGS. 3A to 3D are all cross-sectional views showing the microneedle and the microneedle assembly of the present invention, and schematically illustrate the shape of the needle-like protrusion 32 in the cross-section. 4A to 4E are cross-sectional views in a cross section parallel to the surface of the microneedle and the microneedle assembly of the present invention, and schematically illustrate the shape of the needle-like protrusion 32. FIG. . 5 (a) and 5 (b) are schematic diagrams of the mold (mold 1) used in Examples 1, 2, and 3 and Comparative Examples 1 and 2, and FIGS. 5 (c) and 5 (d) are molds (molds). It is the schematic of the mask used in order to produce 1). 6 (a) and 6 (b) are schematic views of the template (template 2) used in Example 4, and FIGS. 6 (c) and 6 (d) are masks used for producing the template (template 2). FIG. FIGS. 7A and 7B are schematic views of the template (template 3) used in Example 5, and FIGS. 7C and 7D are masks used for producing the template (template 3). FIG. 8A and 8B are schematic views of the template (template 4) used in Example 6, and FIGS. 8C and 8D are masks used for producing the template (template 4). FIG. FIGS. 9A and 9B are schematic views of the template (template 5) used in Example 7, and FIGS. 9C and 9D are masks used for producing the template (template 5). FIG. FIGS. 10A and 10B are schematic views of the template (template 6) used in Example 8, and FIGS. 10C and 10D are masks used for producing the template (template 6). FIG. FIG. 5 is twelve scanning electron micrographs that constitute the microneedle assembly (sample 101) produced in Example 1. FIG. 2 is a scanning electron micrograph of one microneedle constituting the microneedle assembly (sample 101) produced in Example 1. FIG.

Explanation of symbols

DESCRIPTION OF SYMBOLS 11 Mold convex part 12 Mold concave part S Mold convex part width H Mold convex part height t Mold concave part width 31 Microneedle and microneedle assembly concave part 32 Needle-like protrusion S 'Needle-like protrusion width H' Height of needle-like projection t ′ Width of concave portion of microneedle and microneedle assembly 501 frustoconical hole 502 circular masking portion by gold 601 frustoconical hole 602 circular masking portion by gold 701 frustoconical shape Hole 702 Circular masking portion made of gold 801 Triangular prism shaped hole 802 Regular triangular masking portion made of gold 901 Hexagonal column shaped hole 902 Regular hexagonal masking portion made of gold 1001 Cylindrical hole 1002 Circular masking portion made of gold

Claims (11)

  A microneedle molded by a film, wherein the film has a crystallization enthalpy ΔHcc of 0 to 10 mJ / mg at a heating rate of 2 ° C./min obtained by differential scanning calorimetry, and has a thickness of 200 μm. A microneedle having a turbidity change of 30% to 99% when heated at a glass transition temperature Tg + 70 ° C. for 30 minutes.   The microneedle according to claim 1, wherein the film contains a polyester resin as a main component.   The microneedle according to claim 1 or 2, wherein the microneedle has a polygonal column shape having a height of 10 µm to 1000 µm and a protrusion width of 1 µm to 300 µm.   The microneedle according to claim 1 or 2, wherein the microneedle has a cylindrical shape having a height of 10 µm to 1000 µm and a protrusion width of 1 µm to 300 µm.   3. The microneedle according to claim 1, wherein the microneedle has a polygonal frustum shape having a height of 10 μm to 1000 μm, a bottom width of 1 μm to 300 μm, and a tip width of 1 μm to 100 μm.   3. The microneedle according to claim 1, wherein the microneedle has a truncated cone shape having a height of 10 μm to 1000 μm, a bottom width of 1 μm to 300 μm, and a tip width of 1 μm to 100 μm.   The microneedle aggregate | assembly containing the microneedle in any one of Claims 1-6.   The microneedle assembly according to claim 7, wherein the microneedle density is 1 to 1000 per square centimeter.   The method for producing the microneedle according to any one of claims 1 to 6 or the microneedle assembly according to claim 7 or 8, further comprising a step of molding using imprint processing.   The microneedle or the micro of claim 9, wherein a mold for molding using imprint processing is manufactured by a LIGA method using synchrotron radiation having a wavelength of 0.6 nm or less as an exposure light source. A method for producing a needle assembly. The method for producing a microneedle or a microneedle assembly according to claim 9 or 10, wherein the temperature (press temperature) of the film during imprinting is a glass transition temperature Tg + 30 ° C to Tg + 80 ° C.