JP2015136422A - Microneedle, and method of producing microneedle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a microneedle which can suppress air bubbles from being contained in the tip of a projection part, and a method of producing a microneedle.SOLUTION: A microneedle 10 has a shape in which a projection part 12 projects from the surface of a substrate 11, and comprises a first portion 22 comprising the tip of the projection part 12, and a second portion 21 comprising the rear face of the substrate 11. A weight average molecular weight of a main component of the first portion 22 is smaller than a weight average molecular weight of a main component of the second portion 21.

Description

  The technology of the present disclosure relates to a microneedle and a method for manufacturing the microneedle.

  A method using a microneedle is known as a method for administering a delivery product such as a drug from the skin into the body. The microneedle has a plurality of protrusions having a needle shape on the surface of the substrate. In the administration method using microneedles, the protrusions perforate the skin when the substrate is pressed against the skin, and the delivery product is fed into the body from the holes formed by the protrusions.

  In such a microneedle manufacturing process, for example, as described in Patent Document 1, first, a liquid containing a microneedle forming material is filled into an intaglio having a recess corresponding to the shape of the microneedle. And the molded object is shape | molded by drying the liquid body with which the intaglio was filled, and a microneedle is obtained by releasing a molded object.

JP 2009-201956 A

  By the way, since the forming material of the microneedle contains a polymer material such as a water-soluble polymer in order to increase the strength of the formed microneedle, the viscosity of the liquid containing the forming material of the microneedle is increased. Cheap. In general, in a liquid having a high viscosity, bubbles generated in the liquid are less likely to disappear than in a liquid having a low viscosity. Therefore, when bubbles are generated in the liquid material when the liquid material is filled in the intaglio, the liquid material is dried in a state where the bubbles are included, and microneedles including the bubbles may be formed. In particular, since the protrusion has a minute shape as it approaches the tip, if the tip of the protrusion contains bubbles, the accuracy of the transfer of the shape from the intaglio to the protrusion of the microneedle is reduced.

  The technique of this indication aims at providing the manufacturing method of a microneedle which can suppress that a bubble is contained in the tip part of a projection part, and a microneedle.

  A microneedle that solves the above problem has a shape in which a protruding portion protrudes from the surface of a base, and includes a first portion that includes the tip of the protruding portion and a second portion that includes the back surface of the base. The weight average molecular weight of the main component of the first part is smaller than the weight average molecular weight of the main component of the second part.

  A method of manufacturing a microneedle that solves the above-described problem is a method of manufacturing a microneedle having a shape in which a protruding portion protrudes from the surface of a base, and a liquid material containing a first forming material is used as a tip of the protruding portion A first forming step of forming a molded product by filling a part of the intaglio having a shape obtained by inverting the irregularities of the microneedles with the portion corresponding to the bottom as a bottom, and a second forming material of the molded product A second forming step of filling the intaglio from above, and the weight average molecular weight of the main component of the first forming material is smaller than the weight average molecular weight of the main component of the second forming material.

According to the said structure, the front-end | tip part of a projection part is formed with a material with a relatively small weight average molecular weight among the formation materials of a microneedle. Therefore, compared with the case where the tip portion of the protrusion is formed of a material having a relatively large weight average molecular weight, the liquid material containing the tip forming material is cured to form the tip portion. The viscosity of is low. As a result, since the liquid material is suppressed from being hardened in a state where bubbles remain in the liquid material, it is possible to suppress the bubbles from being included in the tip portion of the protrusion of the microneedle.
In the microneedle, the first portion and the second portion are preferably layers partitioned in a direction in which the protruding portion extends.

  According to the said structure, the microneedle has a multilayer structure, and the 1st part and the 2nd part are divided as a layer. Therefore, microneedles having different weight average molecular weights in the direction in which the protrusions extend can be easily manufactured.

In the microneedle, the first portion preferably includes a protein as a delivery product intended to be delivered to the inside of a perforation target and a disaccharide.
According to the said structure, the stability of the protein at the time of drying solidifying and becoming a crystal | crystallization is improved by the effect | action of a disaccharide.

  In the microneedle manufacturing method, in the first forming step, the liquid material containing the first forming material is filled in a part of the intaglio by one of an ink jet method and a method using a dispenser. It is preferred that

  According to the above method, the liquid material is supplied little by little directly to the portion of the concave portion of the intaglio plate corresponding to the tip of the protruding portion of the microneedle. Therefore, wasteful consumption of the liquid material can be suppressed as compared with the injection method of removing the excess liquid material after supplying the liquid material collectively to the entire recess. In addition, even when these methods are used, the weight average molecular weight of the molecules contained in the liquid is relatively small, and as a result, the viscosity of the liquid is lowered and the bubbles are suppressed from being included in the liquid. Clogging and intrusion of bubbles in the portion for discharging the liquid material can be suppressed by the apparatus for discharging the liquid material.

  According to the technique of the present disclosure, it is possible to suppress bubbles from being included in the tip portion of the protrusion in the microneedle.

It is a perspective view which shows the perspective structure of the microneedle in one Embodiment in the technique of this indication. It is sectional drawing which shows a part of sectional structure of the microneedle in one Embodiment. It is a figure which shows the manufacturing process of the microneedle in one Embodiment typically, Comprising: It is a figure which shows the intaglio for manufacturing a microneedle. It is a figure which shows typically the manufacturing process of the microneedle in one Embodiment, Comprising: It is a figure which shows filling of the front end layer formation liquid body in the formation process of a front end layer. It is a figure which shows typically the manufacturing process of the microneedle in one Embodiment, Comprising: It is a figure which shows the front end layer formed at the formation process of a front end layer. It is a figure which shows typically the manufacturing process of the microneedle in one Embodiment, Comprising: It is a figure which shows filling of the base end layer formation liquid body in the formation process of a base end layer. It is a figure which shows typically the manufacturing process of the microneedle in one Embodiment, Comprising: It is a figure which shows the base end layer formed at the formation process of a base end layer. It is a figure which shows the manufacturing process of the microneedle in one Embodiment typically, Comprising: It is a figure which shows the released microneedle.

With reference to FIGS. 1-8, one Embodiment of the manufacturing method of a microneedle and a microneedle is described.
[Configuration of microneedle]
With reference to FIG. 1 and FIG. 2, the structure of a microneedle is demonstrated.

  As shown in FIG. 1, the microneedle 10 includes a base body 11 and a plurality of protrusions 12 protruding from the surface of the base body 11. The bottom surface of the protrusion 12 is formed integrally with the surface of the base 11, and the base 11 supports the base ends of the plurality of protrusions 12.

  The shape of the substrate 11 may be a flat plate shape, a curved plate shape, or a rectangular parallelepiped shape. In addition, since the flexibility of the base body 11 is easily obtained, the base body 11 is preferably a flat plate.

  The shape of the protrusion 12 may be a pyramid shape or a conical shape. Further, the protruding portion 12 may have a shape in which the tip is not pointed, such as a columnar shape or a prismatic shape. Further, the protruding portion 12 may have a shape in which two or more solids are combined, such as a shape in which cones are stacked on a cylinder. In short, the protrusion 12 may have any shape that can pierce the skin. In addition, the number of the protrusion parts 12 is arbitrary as long as it is 1 or more.

  The delivery object intended to be delivered to the inside of the perforation target is contained in the microneedle 10, and the delivery part diffuses inside the perforation target by the protrusion 12 being dissolved inside the perforation target. The delivery material may be supplied from the outside of the microneedle 10. Whether the delivery product is contained in the microneedle 10 or supplied from the outside of the microneedle 10 differs depending on the mode of use of the microneedle 10.

  When the delivery product is supplied from the outside of the microneedle 10, the protrusion 12 may be formed with a hole through which the delivery product is passed toward the inside of the perforation target. The hole formed in the protruding portion 12 may be a hole that penetrates from the tip of the protruding portion 12 to the back surface of the base body 11, or may be a hole that does not penetrate. Regardless of whether or not there is a hole, a groove that allows the delivery article to pass toward the inside of the object to be perforated may be formed around the protrusion 12. In addition, a hole through which the delivery material supplied from the outside of the microneedle 10 is directed toward the protrusion 12 may also be formed in the base body 11. The hole formed in the base 11 may be a hole penetrating from the surface of the base 11 to the back surface of the base 11 or may be a hole that does not penetrate.

  Each of the plurality of protrusions 12 may be regularly arranged on the surface of the base 11 or may be irregularly arranged. In addition, the plurality of protrusions 12 may be arranged at a plurality of locations on the surface of the base body 11 in a biased manner. For example, the plurality of protrusions 12 are arranged in a lattice shape or a concentric shape.

  A support layer made of a material different from that of the base body 11 may be laminated on the back surface of the base body 11. For example, if the support layer is formed from a material that is more flexible than the base 11, a material that is more malleable than the base 11, or a material that has a smaller shrinkage rate than the base 11, a support with high hardness is provided. Compared with the structure in which the microneedle is supported by the body, the flexibility of the microneedle is enhanced. And it is also possible to manage a microneedle in the state wound by roll shape.

  When the microneedle 10 is used, the back surface of the base 11 is pressed toward the skin with the tip of the protrusion 12 directed toward the skin. At this time, an applicator for fixing the position and orientation of the microneedle may be attached to the microneedle 10.

  As shown in FIG. 2, the height H of the protrusion 12 is preferably 10 μm or more and 1000 μm or less. The height H of the protrusion 12 is the length from the surface of the base 11 to the tip of the protrusion 12. The height H of the protrusion 12 is determined according to the depth of the hole required for the drilling target. When the target of perforation is human skin and the bottom of the hole is set in the stratum corneum, the height H is preferably 10 μm or more and 300 μm or less, and more preferably 30 μm or more and 200 μm or less. When the bottom of the hole is set to a depth that penetrates the stratum corneum and does not reach the nerve layer, the height H is preferably 200 μm or more and 700 μm or less, more preferably 200 μm or more and 500 μm or less, More preferably, it is 200 μm or more and 300 μm or less. When the depth is set so that the bottom of the hole reaches the dermis, the height H is preferably 200 μm or more and 500 μm or less. When the depth of the hole is set to a depth that reaches the epidermis, the height H is preferably 200 μm or more and 300 μm or less.

The width D of the protrusion 12 is the maximum value of the length of the protrusion 12 in the direction parallel to the surface of the base body 11. The width D of the protrusion 12 is preferably 1 μm or more and 300 μm or less. For example, when the protrusion 12 has a regular quadrangular pyramid shape or a regular quadrangular prism shape, the length of the diagonal line in the square defined by the bottom of the protrusion 12 on the surface of the base 11 is the width D of the protrusion 12. For example, when the protrusion 12 has a conical shape or a cylindrical shape, the diameter of a circle defined by the bottom of the protrusion 12 is the width D of the protrusion 12.
The aspect ratio A (A = H / D), which is the ratio of the height H to the width D of the protrusion 12, is preferably 1 or more and 10 or less.

  When the tip of the projection 12 is formed in a sharp shape and a hole having a depth penetrating the stratum corneum is formed by perforation, the tip angle θ of the projection 12 is preferably 5 ° or more and 30 ° or less. More preferably, the angle is 10 ° or more and 20 ° or less. The tip angle θ is the maximum value of the angle formed by the tip of the protrusion 12 in the cross section orthogonal to the surface of the base 11. For example, when the projecting portion 12 has a regular quadrangular pyramid shape, the tip angle θ of the projecting portion 12 is the apex angle of a triangle having a square diagonal line defined by the bottom of the projecting portion 12 as a base and a vertex of the regular pyramid as a vertex. is there.

  The width D, the aspect ratio A, and the tip angle θ of the protrusion 12 are determined according to the volume required by the hole. If the height H, the width D, the aspect ratio A, and the tip angle θ are within the above ranges, the shape of the protrusion 12 is a shape suitable for forming a hole in the skin.

  The microneedle 10 is composed of a first portion including the tip of the protrusion 12 and a second portion including the back surface of the base body 11. The weight average molecular weight of the main component of the first part is smaller than the weight average molecular weight of the main component of the second part.

  Furthermore, the weight average molecular weight of the main component of the first part is preferably less than 10,000. On the other hand, the weight average molecular weight of the main component of the second portion is preferably in the range of 10,000 to 1,000,000. It may be difficult to mold a material having a weight average molecular weight exceeding 1,000,000 into a microneedle.

  Furthermore, the first part contains a material having a weight average molecular weight of 10,000 or more as a material other than the main component within a range of less than 0.5% by weight, or does not contain a material having a weight average molecular weight of 10,000 or more. Is preferred. In the first part, when the content of the material having a weight average molecular weight of 10,000 or more is less than 0.5% by weight, the effect of the present invention is enhanced.

  The first part and the second part are preferably layers partitioned in the height direction, which is the direction in which the protrusions 12 extend. Hereinafter, an example in which the first portion is partitioned as the distal end layer 22 and the second portion is defined as the proximal end layer 21 will be described.

  The distal end layer 22 and the proximal end layer 21 are stacked along the height direction of the protrusion 12. The distal end layer 22 includes the distal end of the protruding portion 12, and the proximal end layer 21 includes the proximal end of the protruding portion 12 and the base body 11. The weight average molecular weight of the main component of the distal end layer 22 is smaller than the weight average molecular weight of the main component of the proximal end layer 21.

  The main component of the tip layer 22 is a substance having the highest content (mass%) among the substances constituting the tip layer 22. The main component of the base end layer 21 is a substance having the highest content (mass%) among the substances constituting the base end layer 21.

  For example, when both the main component of the distal end layer 22 and the main component of the proximal end layer 21 are water-soluble polymers, examples of the water-soluble polymers include alginate, curdlan, chitin, chitosan, glucomannan, and polymalic acid. Any one selected from the group consisting of collagen, collagen peptide, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, gelatin, chitosan succinamide, trimethylchitosan, oligochitosan, oligochitin, ethylene glycol chitosan, and ethylene glycol chitin Preferably, the weight average molecular weight of the water-soluble polymer that is the main component of the distal end layer 22 is adjusted to be smaller than the weight average molecular weight of the water-soluble polymer that is the main component of the proximal end layer 21. Is done. The main component of the distal end layer 22 and the main component of the proximal end layer 21 may be different types of water-soluble polymers.

  At least one of the distal end layer 22 and the proximal end layer 21 may contain a delivery product, or a mode in which the water-soluble polymer functions as a delivery product or a mode in which the delivery product is supplied from the outside of the microneedle 10. For example, the distal end layer 22 and the proximal end layer 21 may not contain a delivery product separately from the water-soluble polymer.

  When the distal layer 22 or the proximal layer 21 includes a delivery product together with the water-soluble polymer, the delivery product is contained in the distal layer 22 or the proximal layer 21 while being held by the water-soluble polymer. When the perforation target is a human body, the distal end layer 22 and the proximal end layer 21 are dissolved by the moisture of the skin, so that the delivery material is diffused into the body. Since the protrusion 12 is inserted deeper into the object to be perforated at a portion closer to the tip, when the tip layer 22 contains the delivery object, the delivery object can be diffused from a deeper position inside the object to be perforated. In addition, when only the protrusion 12 includes a delivery product, the delivery product concentrates on a portion that is deeply inserted into the perforation target by the microneedle 10, so that the delivery product can be efficiently fed into the perforation target. .

  As a delivery product, a pharmacologically active substance or a cosmetic composition can be used. The type of delivery is selected according to the purpose. When the distal layer 22 and the proximal layer 21 include a delivery product, the distal layer 22 and the proximal layer 21 may include the same type of delivery product or different types of delivery products. May be.

  Examples of the pharmacologically active substance include vaccines such as influenza, pain relieving drugs for cancer patients and the like, biologics, gene therapy drugs, injections, oral preparations, and skin application preparations. In transdermal administration using the microneedle 10, a drug is administered to a hole formed in the skin. Therefore, transdermal administration using the microneedle 10 can be used for administration of pharmacologically active substances that require subcutaneous injection, in addition to the pharmacologically active substances used for conventional transdermal administration. In particular, transdermal administration using the microneedle 10 is suitable for administration of injections such as vaccines to children because it does not cause pain during administration. In addition, transdermal administration using the microneedle 10 is suitable for administration of oral preparations for children who are difficult to take oral preparations, since it is not necessary to drink the drugs at the time of administration.

  A cosmetic composition is a composition used as a cosmetic or a cosmetic. Examples of the cosmetic composition include a moisturizer, a colorant, a fragrance, or a physiologically active substance that exhibits a beauty effect such as an improvement effect on wrinkles, acne, pregnancy lines, and an improvement effect on hair loss. When a material having a fragrance is used as a delivery product, a scent can be imparted to the microneedles 10, so that the microneedles 10 suitable for cosmetics can be obtained.

  The ratio between the delivery product and the water-soluble polymer contained in the microneedle 10 is determined in consideration of the amount of the delivery product that needs to be administered into the body and the amount of the water-soluble polymer that is necessary for forming the microneedle 10. Is done.

  The tip layer 22 preferably contains a disaccharide. Disaccharides include sucrose, lactulose, lactose, maltose, trehalose, cellobiose, cordobiose, nigerose, isomaltose, isotrehalose, neotrehalose, sophorose, laminaribiose, gentibiose, tulanose, maltulose, palatinose, gentiobiose, mannobiose , Melibiose, melibiurose, neolactose, galactosucrose, silabiose, rutinose, rutinose, vicyanose, xylobiose, primeverose, trehalosamine, maltitol, cellobionic acid, lactosamine, lactose diamine, lactobionic acid, lactitol, hyalobiuronic acid, and sucralose It is preferable to use at least one selected from.

  In the case where the microneedle 10 contains a protein as the delivery product exemplified above, the disaccharide has an effect of enhancing the stability of the protein when the aqueous solution of the forming material of the microneedle 10 is dried and solidified to form crystals.

  If the weight average molecular weight of the main component of the distal end layer 22 is smaller than the weight average molecular weight of the main component of the proximal end layer 21, the distal end layer 22 does not contain a water-soluble polymer, The tip layer 22 may include a delivery product and a water-soluble small molecule. Alternatively, the tip layer 22 may include a poorly water-soluble molecule. Further, the base end layer 21 may include a polymer different from the water-soluble polymer such as a poorly water-soluble synthetic resin.

  The boundary between the base end layer 21 and the distal end layer 22 is not particularly limited, but is preferably a position closer to the distal end of the protrusion 12 than the center of the protrusion 12 in the height direction of the protrusion 12. Due to the difference in weight average molecular weight, the proximal end layer 21 has higher strength than the distal end layer 22. Therefore, when the boundary between the proximal end layer 21 and the distal end layer 22 is at the above position, The overall strength is increased.

  Further, the boundary between the proximal layer 21 and the distal layer 22 may not be parallel to the surface of the substrate 11. For example, in the cross section orthogonal to the surface of the substrate 11, the boundary between the base layer 21 and the tip layer 22 may be curved in a mountain shape along the outer shape of the projection 12, or may be valleys that are recessed toward the substrate 11 side. It may be curved into a shape.

[Manufacturing method of microneedle]
With reference to FIGS. 3-8, the manufacturing method of a microneedle is demonstrated. 3 to 8, the number of the protrusions 12 included in the microneedle 10 is simplified.

<Intaglio forming process>
As shown in FIG. 3, in the intaglio forming process, an intaglio 30 having a recess 31 that matches the shape of the microneedle 10 is formed. First, an original plate having a desired microneedle 10 shape is formed. The shape of the original plate determines the shape of the microneedle 10 to be manufactured. The original plate is formed by a method corresponding to the shape of the microneedle 10 included in the original plate. The original plate is formed using, for example, a fine processing technique. Examples of the fine processing technique include a lithography method, a wet etching method, a dry etching method, a sand blasting method, a laser processing method, and a precision machining method.

  Next, an intaglio 30 having a shape obtained by inverting the unevenness of the original is formed from the original. The intaglio 30 is formed by a known shape transfer method. Examples of the shape transfer method include a method of forming an intaglio plate 30 made of Ni by Ni electroforming, a method of performing transfer molding using a molten resin, and the like.

  The intaglio 30 has a concave portion 31 in the shape of the microneedle 10, a portion corresponding to the tip of the protrusion 12 of the microneedle 10 is disposed on the bottom side of the intaglio 30, and the base 11 of the microneedle 10 is disposed on the opening side of the intaglio 30. It has in the direction where the site | part corresponding to a back surface is arrange | positioned.

<Formation process of tip layer>
As shown in FIG. 4, in the formation process of the tip layer 22 which is an example of the first formation process, the tip layer forming liquid material including the formation material of the tip layer 22 which is an example of the first formation material is intaglio 30. Filled. The tip layer forming liquid is filled into a part of the intaglio 30 from the bottom side of the intaglio 30. The tip layer forming liquid is produced by dissolving the above-mentioned forming material of the tip layer 22 in a solvent. The type of the solvent is not limited as long as it can dissolve the forming material. For example, when the main component of the forming material is a water-soluble polymer, water is used as the solvent. The tip layer forming liquid may be a dispersion liquid. Moreover, the tip layer forming liquid material only needs to have fluidity to such an extent that it can be injected into the intaglio 30.

  As a method for injecting the tip layer-forming liquid into the intaglio plate 30, an ink jet method or a method using a dispenser is preferably used. In the ink jet method or the method using a dispenser, the tip layer forming liquid is supplied in small amounts directly to the portion of the recess 31 of the intaglio 30 corresponding to the tip of each projection 12 of the microneedle 10. Therefore, it is possible to suppress wasteful consumption of the tip layer forming liquid compared to the injection method of removing the excess tip layer forming liquid after supplying the tip layer forming liquid to the entire recess 31 in a lump. it can. In particular, since the delivery product is often expensive, when the tip layer forming liquid includes the delivery product, an increase in manufacturing cost due to wasteful consumption of the tip layer forming liquid can be appropriately suppressed. In addition, when injecting the tip layer forming liquid into the intaglio plate 30, the intaglio plate 30 may be disposed in an environment under reduced pressure or under vacuum.

The step of forming the tip layer 22 preferably includes a step of drying the tip layer forming liquid material at normal temperature or in a heating environment after the intaglio 30 is filled with the tip layer forming liquid material. However, since the tip layer forming liquid filled in the intaglio 30 is a small amount, when the solvent evaporates from the tip layer forming liquid immediately after filling, a time for drying the tip layer forming liquid is provided. It does not have to be done.
As shown in FIG. 5, the tip layer 22 is a molded product formed by curing the tip layer forming liquid.

<Formation process of proximal layer>
As shown in FIG. 6, in the formation process of the proximal end layer 21 which is an example of the second formation process, the proximal end layer forming liquid containing the formation material of the proximal end layer 21 which is an example of the second formation material. Is filled in the intaglio plate 30. The base layer forming liquid is filled on the tip layer 22 formed inside the intaglio 30. The base end layer forming liquid is produced by dissolving the above-described forming material of the base end layer 21 in a solvent. The type of the solvent is not limited as long as it can dissolve the forming material. For example, when the main component of the forming material is a water-soluble polymer, water is used as the solvent. The base end layer forming liquid may be a dispersion liquid. Moreover, the base end layer forming liquid body should just have fluidity | liquidity to such an extent that injection | pouring to the intaglio 30 is possible.

  Comparing the tip layer forming liquid and the base layer forming liquid, the weight average molecular weight of the main component of the tip layer forming liquid is smaller than the weight average molecular weight of the main component of the base layer forming liquid. Accordingly, the viscosity of the distal layer forming liquid is lower than the viscosity of the proximal layer forming liquid.

  As a method for injecting the base layer-forming liquid material to the intaglio plate 30, an ink jet method or a method using a dispenser may be used as in the method for injecting the tip layer-forming liquid material, or other methods such as spin A coating method, a casting method, or the like may be used. In addition, when injecting the base layer forming liquid, the intaglio 30 may be disposed in an environment under reduced pressure or under vacuum.

After the base end layer forming liquid is filled in the intaglio plate 30, the base end layer forming liquid is dried to cure the base end layer forming liquid. The base end layer forming liquid may be dried at room temperature or in a heating environment. When the base layer-forming liquid is dried while being heated, the time required for drying can be shortened. In order to suppress the formation of bubbles in the microneedles 10, the heating temperature is preferably a temperature at which the base layer forming liquid does not boil. Specifically, when the base layer forming liquid is an aqueous solution, the heating temperature is preferably 50 ° C. or higher and 90 ° C. or lower. As a heating method, for example, a known heating method such as heating with a hot plate can be used.
As shown in FIG. 7, a molded product formed by curing the base layer forming liquid is the base layer 21.

  The base end layer 21 is not limited to filling the liquid material as described above. For example, a sheet made of a water-soluble polymer formed in a film shape is pressed against the intaglio plate 30 on which the front end layer 22 is formed. It may be formed by filling the intaglio 30.

<Mold release process>
As shown in FIG. 8, in the mold release step, the molded product formed by the tip layer forming step and the base end layer forming step is released from the intaglio plate 30. The molded product released from the intaglio plate 30 is the microneedle 10. As a method of releasing the molded product, for example, a method of peeling the molded product from the intaglio plate 30 by physical force, a method of selectively dissolving the intaglio plate 30 using chemical properties, or the like is used. it can.
The microneedle 10 is manufactured by the above process.

[Action]
The effect | action which the microneedle 10 of this embodiment brings is demonstrated.
In the present embodiment, the tip of the protrusion 12 is formed by filling the intaglio 30 with the tip layer forming liquid. The weight average molecular weight of the main component of the distal layer forming liquid is smaller than the weight average molecular weight of the main component of the proximal layer forming liquid. Therefore, since the tip of the projection 12 is formed of a material having a relatively small weight average molecular weight among the materials for forming the microneedles 10, the tip of the projection 12 is made of a material having a relatively large weight average molecular weight. Compared to the case where it is formed, the viscosity of the tip layer forming liquid is lowered. As a result, since the tip layer forming liquid is prevented from curing in the state where bubbles remain in the tip layer forming liquid filled in the intaglio plate 30, the tip of the protrusion 12 is formed by the formed microneedle 10. It is suppressed that air bubbles are contained in the. Thereby, the precision of the transfer of the shape from the intaglio 30 to the projection part 12 of the microneedle 10 is also improved.

  Moreover, since the microneedle 10 is comprised from the part formed with the material with a relatively small weight average molecular weight, and the part formed with the material with a relatively large weight average molecular weight, the microneedle 10 is a weight average. Compared with the case where it forms only from a material with small molecular weight, the fall of the intensity | strength of the whole microneedle 10 is also suppressed.

  Moreover, when the tip layer forming liquid is low in viscosity, when filling the intaglio 30 with the tip layer forming liquid, a method of discharging the liquid little by little, such as a method using an ink jet method or a dispenser, is provided. Even if it uses, it is suppressed that the nozzle which discharges a liquid material with the apparatus which discharges a liquid material is blocked. Also, since the viscosity of the tip layer forming liquid is low, it is possible to prevent bubbles from being contained in the liquid even in the apparatus for discharging the liquid, so that bubbles enter the nozzle and the liquid is not discharged in a specified amount. Is also suppressed. In particular, when the weight average molecular weight of the main component of the tip layer-forming liquid is less than 10,000, clogging or intrusion of bubbles in the nozzle can be appropriately suppressed.

As described above, according to the present embodiment, the following effects can be obtained.
(1) In the microneedle 10, the weight average molecular weight of the main component of the first part including the tip of the protrusion 12 is smaller than the weight average molecular weight of the main component of the second part including the back surface of the substrate 11. Therefore, since the tip of the protrusion 12 is formed of a material having a relatively small weight average molecular weight, the viscosity of the liquid for forming the tip layer 22 is lowered, and as a result, bubbles are generated at the tip of the protrusion 12. Inclusion is suppressed.

(2) Since the first part and the second part are layers partitioned in the extending direction of the protruding part 12, the microneedles 10 having different weight average molecular weights in the extending direction of the protruding part 12 are easily manufactured. be able to.
(3) When the first part contains a protein as a delivery product and a disaccharide, the stability of the protein when the forming material of the first part is dried and solidified to become a crystal is enhanced.

  (4) In the manufacturing process of the microneedle 10, a liquid body containing a material having a relatively small weight average molecular weight is filled into the intaglio plate 30 by any one of an ink jet method and a method using a dispenser. Therefore, wasteful consumption of the liquid material can be suppressed. Even in the case of using these methods, since the weight average molecular weight of the main component of the liquid material is relatively small, clogging or intrusion of bubbles in the portion for discharging the liquid material in the apparatus for discharging the liquid material may occur. It can be suppressed.

(Modification)
The above embodiment can be implemented with the following modifications.
-The microneedle 10 may be comprised from the layer of 3 or more layers divided in the height direction of the projection part 12. As shown in FIG. In this case, if there is a layer in which the main component of the layer has a weight average molecular weight larger than the weight average molecular weight of the main component of the layer including the tip of the protrusion 12, the effect according to the above (1) can be obtained. Therefore, if the weight average molecular weight of the main component of the layer including the tip of the protrusion 12 is smaller than the weight average molecular weight of the main component of the layer including the back surface of the substrate 11, the effect according to the above (1) is obtained. can get. When the protrusion 12 has a shape that narrows toward the tip, the weight average molecular weight of the main component in each layer decreases from the layer including the back surface of the substrate 11 toward the layer including the tip of the protrusion 12. It is preferable because the accuracy of the transfer of the shape from the intaglio 30 to the protrusion 12 of the microneedle 10 is further improved.

The microneedle 10 does not have a multilayer structure, and its composition gradually changes along the height direction of the microneedle 10, and from the back surface of the base 11 to the tip of the protrusion 12 in the height direction of the protrusion 12. The structure in which the weight average molecular weight of the main component per unit volume gradually decreases may be used. Even in such a configuration, the weight average molecular weight of the main component of the first portion including the tip of the protrusion 12 is smaller than the weight average molecular weight of the main component of the second portion including the back surface of the substrate 11.
In the step of forming the tip layer, the method of injecting the tip layer forming liquid into the intaglio 30 may be a method different from a method using an inkjet method or a dispenser, such as a spin coating method or a casting method. .

(Example)
The manufacturing method of the microneedle mentioned above is demonstrated using a specific Example and a comparative example.

[Example]
<Intaglio forming process>
First, an original microneedle was formed from a silicon substrate by precision machining. The shape of the protrusions was a regular quadrangular pyramid (height: 150 μm, bottom surface: 60 μm × 60 μm), and 36 protrusions were arranged in a grid of 6 columns and 6 rows at 1 mm intervals on the substrate.

  Next, a nickel film having a thickness of 500 μm was formed on the original microneedle by plating. Then, using a 30% by weight potassium hydroxide aqueous solution heated to 90 ° C., the original microneedle made of silicon was removed by wet etching to form a nickel intaglio.

<Formation process of tip layer>
A dextran having a molecular weight of 5000 was dissolved in water to prepare a tip layer forming liquid. Then, the tip layer forming liquid material was filled into the concave portions of the intaglio by an ink jet method. Next, the intaglio plate filled with the tip layer forming liquid was heated at 90 ° C. for 10 minutes to dry and cure the tip layer forming liquid. A hot plate was used as a heat source for heating.

<Formation process of proximal layer>
A pectin having a weight average molecular weight of 80,000 was dissolved in water to prepare a base layer forming liquid. Then, the base layer-forming liquid material was poured into the intaglio plate on which the tip layer was formed, using a dispenser, and the base plate layer-forming liquid material was filled into the intaglio plate. Next, the intaglio plate filled with the base end layer forming liquid was heated at 90 ° C. for 10 minutes, and the base end layer forming liquid was dried and cured. A hot plate was used as a heat source for heating.
<Mold release process>
The molded product was peeled from the intaglio to obtain the microneedle of the example.

[Comparative example]
<Intaglio forming process>
First, an original microneedle was formed from a silicon substrate by precision machining. The shape of the protrusions was a regular quadrangular pyramid (height: 150 μm, bottom surface: 60 μm × 60 μm), and 36 protrusions were arranged in a grid of 6 columns and 6 rows at 1 mm intervals on the substrate.

  Next, a nickel film having a thickness of 500 μm was formed on the original microneedle by plating. Then, using a 30% by weight potassium hydroxide aqueous solution heated to 90 ° C., the original microneedle made of silicon was removed by wet etching to form a nickel intaglio.

<Microneedle formation process>
A liquid material was prepared by dissolving pectin having a weight average molecular weight of 80,000 in water. Then, the liquid material was poured into the intaglio using a dispenser, and the intaglio was filled with the liquid. Next, the intaglio plate filled with the liquid material was heated at 90 ° C. for 10 minutes to dry and cure the liquid material. A hot plate was used as a heat source for heating.
<Release process>
The molded product was peeled from the intaglio to obtain a microneedle of a comparative example.

<Evaluation>
The microneedle of the example and the microneedle of the comparative example were observed with a stereoscopic microscope. In the microneedle of the example, bubbles were not observed at the protrusions. On the other hand, in the microneedle of the comparative example, bubbles were observed at the protrusions. Moreover, in the microneedle of the comparative example, chipping at the tip of the protrusion due to the liquid material not entering the tip of the recess was observed.

  DESCRIPTION OF SYMBOLS 10 ... Microneedle, 11 ... Base | substrate, 12 ... Protrusion part, 21 ... Base end layer, 22 ... Tip layer, 30 ... Intaglio, 31 ... Recessed part

Claims (5)

It has a shape with protrusions protruding from the surface of the base,
A first portion including a tip of the protrusion;
A second part including the back surface of the base body,
The weight average molecular weight of the main component of the first part is
A microneedle smaller than the weight average molecular weight of the main component of the second part. The microneedle according to claim 1, wherein the first portion and the second portion are layers partitioned in a direction in which the protrusion portion extends. The microneedle according to claim 1 or 2, wherein the first portion includes a protein as a delivery product intended to be delivered to the inside of a perforation target and a disaccharide. A method for producing a microneedle having a shape in which a protrusion protrudes from the surface of a substrate,
A liquid material containing a first forming material is filled into a part of an intaglio plate having a shape obtained by reversing the irregularities of the microneedles with a portion corresponding to the tip of the projection as a bottom, thereby forming a molding. 1 forming step;
Filling a second forming material into the intaglio from above the molding, and
The method for producing microneedles, wherein the weight average molecular weight of the main component of the first forming material is smaller than the weight average molecular weight of the main component of the second forming material. The liquid body containing the first forming material is filled in a part of the intaglio by one of an inkjet method and a method using a dispenser in the first forming step. Manufacturing method of microneedle.

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