JP2018134195A - Uneven structure, percutaneous administration device, and percutaneous administration device set - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an uneven structure capable of controlling dissolution easily; and to provide a percutaneous administration device, and a percutaneous administration device set.SOLUTION: An uneven structure includes a substrate 21 having a first surface 21S, and a projection part 22 projecting from the first surface 21S. The uneven structure has a part containing polysaccharide, as a principal component, manifesting solubility into water by being cooled to a lower temperature than room temperature. The polysaccharide contains one or more polysaccharides selected from a group comprising hydroxypropylchitosan and hydroxybutylchitosan.SELECTED DRAWING: Figure 8

Description

  The present invention relates to a concavo-convex structure having minute protrusions, a transdermal administration device including the concavo-convex structure as an administration part, and a transdermal administration device set.

  As a method of administering a drug from the skin to a drug administration target, a method using a transdermal administration device is known. The transdermal administration device includes an administration part that is a concavo-convex structure having a minute protrusion for perforating the skin and a base body that is a part that supports the protrusion. For example, a microneedle, which is an example of an administration unit, has a protrusion having a needle shape that is sharpened toward the tip. In the method of administering a drug using a transdermal administration device, a hole is formed in the skin by pressing the protrusion against the skin, and the drug is fed into the body of the administration target from this hole.

  In one example of such an administration part, the administration part is made of a material having solubility in water, and the drug is contained in the protrusion. And the chemical | medical agent enters a body, when the projection part stuck in the skin melt | dissolves due to the surface of the skin and the water | moisture content inside (for example, refer patent document 1).

International Publication No. 2008/020632

  When the administration part has solubility in water as described above, the administration part starts dissolution immediately after the protrusion is stabbed into the skin, and the speed of dissolution can vary depending on the amount of moisture in the skin. The amount of moisture in the skin varies depending on the individual to be administered, and even in the same individual, the amount of moisture in the skin varies depending on the surrounding environment such as humidity. Therefore, it is difficult to artificially control the mode of dissolution of the administration part, that is, the timing at which the administration part starts to dissolve and the speed of dissolution.

  It is also proposed that the solubility of a part of the administration part is different from that of the other part, for example, the solubility of the protrusion and the substrate is different, and this difference in solubility is used for effective drug administration. Has been. However, even in such a case, it is difficult to independently control the start timing of dissolution between the protrusion and the base, and the difference in the speed of dissolution between the protrusion and the base is due to the amount of moisture in the skin. Can vary. Therefore, there is a limit in controlling the dissolution of the administration part.

  It is an object of the present invention to provide a concavo-convex structure, a transdermal administration device, and a transdermal administration device set that can be easily controlled for dissolution.

  The concavo-convex structure that solves the above problem is a concavo-convex structure including a base having a first surface and a protrusion protruding from the first surface, and the concavo-convex structure is formed at a temperature lower than room temperature. It has a portion containing as a main component a polysaccharide that exhibits solubility in water by cooling.

  According to the said structure, the part which contains the said polysaccharide as a main component starts melt | dissolution by cooling. Therefore, about the part which contains the said polysaccharide as a main component, the timing of a melt | dissolution start can be controlled by controlling the timing of cooling. Therefore, compared with the case where the whole administration part is made of a material having solubility in water at room temperature, dissolution control is easier.

In the concavo-convex structure, the polysaccharide preferably contains one or more polysaccharides selected from the group consisting of hydroxypropyl chitosan and hydroxybutyl chitosan.
According to the said structure, in the part which contains the said polysaccharide as a main component, the structure which expresses the solubility to water at temperature lower than normal temperature is implement | achieved suitably.

The transdermal administration device which solves the said subject is equipped with the said uneven structure body as an administration part, and the said projection part contains a chemical | medical agent.
According to the above configuration, a transdermal administration device in which the dissolution of the administration part can be easily controlled is realized.

In the transdermal administration device, both the base and the protrusion may include the polysaccharide as a main component.
According to the above configuration, by controlling the cooling timing of the transdermal administration device, it is possible to control the timing of the start of dissolution of the entire administration unit, and the timing of the start of diffusion of the drug into the body. Adjustment is also possible.

In the transdermal administration device, only the protruding portion of the base body and the protruding portion may contain the polysaccharide as a main component.
According to the above configuration, by controlling the cooling timing of the transdermal administration device, it is possible to control the timing of starting the dissolution of the protrusion, and adjusting the timing at which the diffusion of the drug into the body is started Is also possible. Moreover, the freedom degree of the material selection about a base | substrate is raised.

In the transdermal administration device, the substrate may include the polysaccharide as a main component, and the protrusion may include a polymer material having solubility in water at room temperature as a main component.
According to the above configuration, by controlling the cooling timing of the transdermal administration device, it is possible to dissolve only the base prior to the protrusion and leave the protrusion in the skin. Therefore, a configuration suitable for the purpose of administration is to diffuse the drug contained in the protrusions into the body for a long time.

  A transdermal administration device set that solves the above problems is a dosing unit that includes a base having a first surface, and a projection that protrudes from the first surface and includes a drug, and is at room temperature. A transdermal administration device including the administration unit having a portion containing a polysaccharide that exhibits water solubility as a main component by cooling to a low temperature, and a cooling member for cooling the administration unit.

  By using the transdermal administration device set having the above-described configuration, the drug can be administered to the administration subject while accurately controlling the dissolution of the administration part by cooling the administration part with the cooling member.

  According to the present invention, dissolution control in the concavo-convex structure and the transdermal administration device can be facilitated.

The perspective view which shows the perspective structure of a transdermal administration device about one Embodiment of a transdermal administration device. Sectional drawing which shows the cross-section of the transdermal administration device of one Embodiment. The figure which shows the structure of the intaglio used for manufacture of the transdermal administration device of one Embodiment. The figure which shows the manufacturing process of the transdermal administration device of one Embodiment, Comprising: The figure which shows the state with which the intaglio was filled with the material solution of the administration part. The figure which shows the manufacturing process of the transdermal administration device of one Embodiment, Comprising: The figure which shows the administration part which is the molded product peeled from the intaglio. The figure which shows the usage method of the transdermal administration device of one Embodiment, Comprising: The figure which shows the state which fixed the transdermal administration device to the skin of administration object. The figure which shows the usage method of the transdermal administration device of one Embodiment, Comprising: The figure which shows the state which is cooling the transdermal administration device. The figure which shows the usage method of the transdermal administration device of one Embodiment, Comprising: The figure which shows the state which the administration part melt | dissolved by cooling. Sectional drawing which shows the cross-section of the transdermal administration device of a modification. Sectional drawing which shows the cross-section of the transdermal administration device of a modification. Sectional drawing which shows the cross-section of the transdermal administration device of a modification. Sectional drawing which shows the cross-section of the transdermal administration device of a modification. Sectional drawing which shows the cross-section of the transdermal administration device of a modification. Sectional drawing which shows the cross-section of the transdermal administration device of a modification. It is a figure which shows the usage method of the transdermal administration device of a modification, Comprising: The figure which shows the state which the base | substrate of the administration part melt | dissolved by cooling. The figure which shows the usage method of the transdermal administration device of a modification, Comprising: The figure which shows the state which peeled the adhesive sheet after melt | dissolution of a base | substrate.

With reference to FIGS. 1-8, one embodiment of a concavo-convex structure, a transdermal administration device, and a transdermal administration device set is described.
[Configuration of transdermal administration device]
The shape of the transdermal administration device will be described with reference to FIGS. 1 and 2.

As shown in FIG. 1, the transdermal administration device 10 includes a microneedle 20 and an adhesive sheet 30. The microneedle 20 is an example of an administration unit that is an uneven structure.
The microneedle 20 includes a base 21 having a plate shape and a protrusion 22 protruding from the base 21. The base 21 has a first surface 21S that is a surface on which the protrusions 22 are arranged, and a second surface 21T that is a surface opposite to the first surface 21S, and the first surface 21S is the surface of the protrusions 22. Supports the proximal end. That is, the protrusion 22 protrudes from the first surface 21 </ b> S of the base 21. The outer shape of the base body 21 as viewed from the direction facing the first surface 21S is not particularly limited, and the outer shape of the base body 21 may be circular, elliptical, or rectangular.

  The shape of the protrusion 22 may be a pyramid shape or a conical shape. Further, the protruding portion 22 may have a shape with a sharp tip, such as a cylindrical shape or a prismatic shape. Further, the protruding portion 22 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 22 may have any shape that can pierce the skin. Further, a constriction or a step may be formed on the side wall of the protrusion 22, or a groove or a hole may be formed.

  The number of the protrusions 22 is not particularly limited as long as it is 1 or more. When the microneedle 20 has a plurality of protrusions 22, the plurality of protrusions 22 may be regularly arranged on the first surface 21S of the base 21 or may be irregularly arranged. For example, the plurality of protrusions 22 are arranged in a lattice shape or a concentric shape.

  The pressure-sensitive adhesive sheet 30 includes a base material sheet 31 and a pressure-sensitive adhesive layer 32 that covers one of the two surfaces of the base material sheet 31. The surface of the pressure-sensitive adhesive layer 32 opposite to the surface in contact with the base material sheet 31 is the pressure-sensitive adhesive surface of the pressure-sensitive adhesive sheet 30, and the second surface 21 </ b> T of the substrate 21 is attached to this pressure-sensitive adhesive surface.

  When viewed from the direction facing the first surface 21S, the outer shape of the pressure-sensitive adhesive sheet 30 is larger than that of the base 21, and the pressure-sensitive adhesive layer 32 protrudes outside the base 21 over the entire outer periphery of the base 21 so that the pressure-sensitive adhesive surface is exposed. Yes. The outer shape of the adhesive sheet 30 viewed from the direction facing the first surface 21S is not particularly limited, and the outer shape of the adhesive sheet 30 may be circular or elliptical, or may be rectangular.

  Note that the transdermal administration device 10 may be provided with a concavo-convex structure, and may be provided with a concavo-convex structure alone without the adhesive sheet 30. Further, the transdermal administration device 10 may include other members in addition to the administration unit and the adhesive sheet 30 or instead of the adhesive sheet 30. For example, the transdermal administration device 10 may include a protective sheet that covers the adhesive surface of the adhesive sheet 30.

  As shown in FIG. 2, the length H of the protrusion 22 is from the first surface 21S to the tip of the protrusion 22 in the thickness direction of the base 21, that is, in the direction orthogonal to the first surface 21S of the base 21. Length. The length H of the protruding portion 22 is preferably 10 μm or more and 1000 μm or less, and the length H of the protruding portion 22 is a depth necessary for a hole formed in the object to be drilled by the protruding portion 22 within this range. It is decided accordingly. When the target of perforation is human skin and the bottom of the hole is set in the stratum corneum, the length 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 length 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 of the hole reaches the dermis, the length H is preferably 200 μm or more and 500 μm or less. When the depth of the hole reaches the epidermis, the length H is preferably 200 μm or more and 300 μm or less.

  The width D of the protrusion 22 is the maximum value of the length of the protrusion 22 in the direction along the first surface 21S of the base body 21, that is, in the direction parallel to the first surface 21S. For example, when the protrusion 22 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 22 on the first surface 21S of the base 21 is the width D of the protrusion 22. It is. For example, when the protrusion 22 has a conical shape or a cylindrical shape, the diameter of a circle defined by the bottom of the protrusion 22 is the width D of the protrusion 22. The width D of the protrusion 22 is preferably 1 μm or more and 300 μm or less.

The aspect ratio A (A = H / D), which is the ratio of the length H to the width D of the protrusion 22, is preferably 1 or more and 10 or less.
When the protrusion 22 is formed to have a sharp tip and a hole having a depth penetrating the stratum corneum is formed by the protrusion 22, the tip angle θ of the protrusion 22 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 22 in the cross section along the thickness direction of the base 21. For example, when the projecting portion 22 has a regular quadrangular pyramid shape, the tip angle θ of the projecting portion 22 is an apex angle of a triangle having a square diagonal line defining the bottom of the projecting portion 22 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 22 are determined according to the volume required for the hole formed by the protrusion 22. If the length H, the width D, the aspect ratio A, and the tip angle θ are within the above ranges, the shape of the protrusion 22 is a shape suitable for forming a hole in the skin. In addition, the thickness of the base | substrate 21, ie, the shortest length from the 1st surface 21S to the 2nd surface 21T, is not specifically limited.

Subsequently, materials of respective parts constituting the transdermal administration device 10 will be described.
The microneedle 20 is preferably composed of a biocompatible material. And the base | substrate 21 and the projection part 22 contain the polysaccharide which expresses the solubility to water at the temperature lower than normal temperature as a main component. The normal temperature is, for example, 20 ° C., and the polysaccharide is preferably a material that exhibits solubility in water at 10 ° C. or lower. Examples of the polysaccharide having such temperature responsiveness include hydroxypropyl chitosan and hydroxybutyl chitosan. Each of the base body 21 and the protrusions 22 may contain two or more of these polysaccharides, and the base body 21 and the protrusions 22 may contain different polysaccharides.

  The main component of the base 21 is a component having the highest content among the components constituting the base 21, for example, a component having a content of 50% by mass or more in the base 21. Similarly, the main component of the protrusion 22 is a component having the highest content among the components constituting the protrusion 22, for example, a component having a content of 50% by mass or more in the protrusion 22. is there.

  Moreover, the protrusion part 22 contains the chemical | medical agent. The type of drug is not particularly limited as long as it is a substance that functions by being administered intradermally. Examples of the drug include various proteins, pharmacologically active substances, cosmetic compositions, and the like, and are selected according to the purpose.

  Examples of the pharmacologically active substance include vaccines such as influenza, analgesics for cancer patients, insulin, biologics, gene therapy drugs, injections, oral preparations, and preparations for skin application. In the administration method using the transdermal administration device 10, a drug is administered to a hole formed in the skin. Therefore, the administration method using the transdermal administration device 10 can be used for administration of pharmacologically active substances requiring subcutaneous injection in addition to the pharmacologically active substances used for conventional transdermal administration. In particular, the administration method using the transdermal administration device 10 is suitable for administration of injections such as vaccines to children because it does not give pain to the patient during administration. Moreover, since the administration method using the transdermal administration device 10 does not require the patient to take a drug at the time of administration, it is suitable for the administration of the oral agent to a child who is difficult to take the oral agent.

  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 fragrant material is used as the cosmetic composition, it is possible to impart an odor to the transdermal administration device 10, so that the transdermal administration device 10 suitable for cosmetics is obtained.

  The drug may also be contained in the substrate 21. If each of the base 21 and the protrusion 22 contains a drug and the composition of the base 21 and the protrusion 22 is the same, the base 21 and the protrusion 22 can be formed integrally, so that the microneedle 20 can be easily manufactured. is there. On the other hand, if only the protrusion 22 contains a drug, the drug is concentrated on the portion of the microneedle 20 to be inserted into the skin, so that the drug can be used efficiently. In addition, the amount of drug required for forming the microneedle 20 can be reduced.

  The material of the pressure-sensitive adhesive sheet 30 is not particularly limited. As the base material sheet 31, for example, a resin film made of polyethylene terephthalate or the like is used, and the pressure-sensitive adhesive layer 32 is formed of, for example, an epoxy-based or acrylic pressure-sensitive adhesive. The The pressure-sensitive adhesive sheet 30 is preferably configured to have flexibility that can be deformed along the shape of the skin to be administered. Moreover, it is preferable that the adhesive sheet 30 is comprised so that it may be hard to inhibit the heat conduction between the exterior and the microneedle 20.

[Method of manufacturing transdermal administration device]
With reference to FIGS. 3-5, the manufacturing method of the transdermal administration device 10 is demonstrated.
First, an original plate having the same shape as that of the desired microneedle 20 is formed. The original plate may be formed by a known method according to the shape of the original plate, for example, using 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.

  As shown in FIG. 3, an intaglio 50 having a recess 51 having a shape obtained by inverting the irregularities of the original is then formed from the original. The intaglio 50 is formed by a known shape transfer method. Examples of the shape transfer method include a method of forming an Ni intaglio by Ni electroforming, a method of performing transfer molding using a molten resin, and the like. Thereby, the intaglio 50 which has the recessed part 51 containing the hollow of the shape which follows the projection part 22 of manufacture object is formed.

  As shown in FIG. 4, subsequently, the material solution containing the forming material of the microneedle 20 is filled in the recess 51 of the formed intaglio 50. That is, the above-described temperature-responsive polysaccharide is dissolved in cold water at a temperature at which the polysaccharide dissolves, and the drug solution is mixed with the solution to prepare the material solution. The fluidity of the material solution is preferably adjusted to such an extent that the material solution can be smoothly filled in the intaglio 50 by appropriately adjusting the amount of the solute. When the composition of the base 21 and the composition of the protrusion 22 are different, for example, when only the protrusion 22 contains a drug, or when the polysaccharide contained in the base 21 and the polysaccharide contained in the protrusion 22 are different The material solution for forming the base 21 and the material solution for forming the protrusion 22 may be adjusted separately according to the composition of the base 21 and the protrusion 22.

  The method for supplying the material solution to the intaglio 50 may be appropriately selected from known methods in consideration of the shape and size of the recess 51. For example, as a method for supplying the material solution, a spin coating method, a method using a dispenser, a casting method, an ink jet method, or the like can be used. The supply of the material solution to the intaglio 50 may be performed under normal pressure. However, in order to fill the material solution into the recess 51 more smoothly, the supply is preferably performed under reduced pressure or under vacuum. The material solution filled in the recess 51 is dried and solidified, whereby a molded product that becomes the microneedle 20 is formed.

  When the composition of the base 21 and the composition of the protrusion 22 are different, first, a material solution for forming the protrusion 22 is filled in a portion corresponding to the shape of the protrusion 22 in the recess 51, and this material solution is After being dried, the material solution for forming the substrate 21 is further filled and dried on the dried filling.

  As FIG. 5 shows, the microneedle 20 is obtained by releasing the molded product formed by drying and solidifying the material solution from the intaglio 50. The outer shape of the microneedle 20 may be adjusted by punching the molded product by machining.

The transdermal administration device 10 is formed by affixing the adhesive sheet 30 to the microneedle 20 thus formed.
[How to use transdermal administration device]
With reference to FIGS. 6-8, the usage of the transdermal administration device 10 and its effect | action are demonstrated with the structure of a transdermal administration device set.

The transdermal administration device set includes a transdermal administration device 10 and a cooling member for cooling the microneedles 20.
When a drug is administered to an administration target using the transdermal administration device 10, first, the first surface 21S of the base 21 of the microneedle 20 is directed to the site where the drug is administered, that is, the tip of the protrusion 22 is the skin. The microneedle 20 is pressed against the skin. Then, the adhesive surface of the adhesive sheet 30 protruding outside the base 21 is attached to the skin.

As a result, as shown in FIG. 6, the transdermal administration device 10 is fixed to the administration target in a state where the protrusion 22 is stuck in the skin Sk of the administration target.
Subsequently, as shown in FIG. 7, the cooling member 40 cooled to a predetermined temperature is pressed against the transdermal administration device 10 from the base material sheet 31 of the adhesive sheet 30.

  The material of the cooling member 40 is not particularly limited, but is preferably a material that can easily maintain a low temperature state. As the cooling member 40, for example, a metal block or a Peltier element is used. Alternatively, various cryogens may be used as the cooling member 40. Moreover, the temperature of the cooling member 40 should just be set to the temperature which the microneedle 20 expresses solubility according to the material which comprises the microneedle 20. FIG. For example, the cooling member 40 is cooled to 10 ° C. or lower.

  The microneedles 20 are cooled by the cooling member 40 via the adhesive sheet 30. As a result, as shown in FIG. 8, the microneedles 20 exhibit solubility, and the surface of the skin, the moisture in the inside, the microneedles The base 21 and the protrusion 22 are dissolved due to the water contained in the water 20, for example, water derived from the solvent of the material solution or water generated by moisture absorption of the microneedles 20. Thus, the protrusion 22 or the drug contained in the protrusion 22 and the base body 21 enters the body of the administration target through the hole formed in the skin Sk by the protrusion 22.

  The method for cooling the transdermal administration device 10 is not limited to the use of the cooling member 40. Instead of the cooling member 40, the transdermal administration device 10 may be cooled by spraying a cooling gas having a temperature of, for example, 10 ° C. or less onto the transdermal administration device 10 from the base material sheet 31 of the adhesive sheet 30. . That is, the transdermal administration device 10 can be used without being limited to being used as a transdermal administration device set.

  In the above configuration, since the microneedle 20 exhibits solubility in water by cooling to a temperature lower than normal temperature, even after the transdermal administration device 10 is fixed to the skin Sk to be administered, Before the cooling of the transdermal administration device 10 is started, the microneedles 20 have not started to dissolve. Then, when the microneedles 20 are cooled to a temperature at which the solubility is exhibited by the cooling of the transdermal administration device 10, the microneedles 20 start to dissolve. Therefore, by controlling the cooling timing of the transdermal administration device 10, it is possible to control the start timing of the dissolution of the microneedles 20, and it is possible to adjust the timing at which the diffusion of the drug into the body is started. It is.

Moreover, the structure which consists of each polysaccharide of the above-mentioned hydroxypropyl chitosan and hydroxybutyl chitosan has the tendency to melt | dissolve rapidly by being cooled at 10 degrees C or less.
When the microneedle is made of a water-soluble material at room temperature as in the past, depending on the material, it may take a long time of about 1 to 3 hours to dissolve the protrusion. For example, it is possible to accelerate the dissolution of the protrusions made of such a material by supplying water to the microneedles fixed to the skin. However, such a method is complicated, and the supplied water Due to the fact that the drug spreads on the skin surface, the drug contained in the microneedle may spread on the skin surface without entering the skin.

  In addition, among materials that are water-soluble at room temperature, if a low-molecular material is used, it is possible to realize a protrusion with a high dissolution rate, but a protrusion made of a low-molecular material is made of a polymer material. Since the strength is lower than that of the projected portion, there is a problem that the projected portion is easily deformed and is not easily stuck in the skin.

  On the other hand, if the microneedle 20 of the present embodiment is composed mainly of the above-mentioned temperature-responsive polysaccharide, a good dissolution rate can be obtained by cooling without supplying water. It is also possible to suppress the strength of the portion 22 from becoming excessively low.

[Modification]
The microneedle 20 should just have the part which has the said temperature-responsive polysaccharide as a main component in at least one part.

  For example, as shown in FIG. 9, only the protrusion 22 is a temperature response part RA that is a part mainly composed of the temperature-responsive polysaccharide, and the substrate 21 is the temperature-responsive polysaccharide. The non-temperature response part RB which is a part which has a different material as a main component may be sufficient.

Conversely, as shown in FIG. 10, only the base 21 may be the temperature response portion RA, and the protrusion 22 may be the non-temperature response portion RB.
Further, as shown in FIG. 11, the tip portion of the protrusion 22 is a temperature response portion RA, and a portion of the microneedle 20 excluding the tip portion, that is, the base end portion of the protrusion 22 and the base 21 are formed. The non-temperature response unit RB may be used.

Conversely, as shown in FIG. 12, the base end portion of the protrusion 22 and the base body 21 may be the temperature response portion RA, and the tip portion of the protrusion 22 may be the non-temperature response portion RB.
Further, as shown in FIG. 13, the portion located on the first surface 21 </ b> S side in the thickness direction in the protrusion 22 and the base body 21 is the temperature response portion RA, and the thickness direction in the base body 21 is the first in the thickness direction. The portion located on the second surface 21T side may be the non-temperature response part RB.

  On the other hand, as shown in FIG. 14, the portion located on the second surface 21 </ b> T side in the thickness direction in the base body 21 is the temperature response portion RA, and the protrusion 22 and the base body 21 in the thickness direction are in the thickness direction. The portion located on the first surface 21S side may be the non-temperature response part RB.

  Further, the boundary between the temperature response portion RA and the non-temperature response portion RB of the microneedle 20 may be different from the configuration shown in FIGS. 9 to 14. In short, at least a part of the microneedle 20 is important. However, what is necessary is just the temperature response part RA. In addition, the form demonstrated using the above-mentioned FIGS. 1-8 is a form in which the whole microneedle 20 is the temperature response part RA.

  The temperature response part RA is made of the material mentioned as the material constituting the microneedle 20 in a form in which the entire microneedle 20 is the temperature response part RA. Non-temperature response part RB is comprised from the material which has the solubility to water at normal temperature, and the material which does not have the solubility to water irrespective of temperature, for example, specifically, for example, water-soluble polymer Or a thermoplastic resin. Examples of the polymer material having solubility in water at room temperature include carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohol (PVA), polyacrylic acid polymer, poly Examples include acrylamide (PAM), polyethylene oxide (PEO), pullulan, alginate, pectin, chitosan, chitosan succinamide, oligochitosan, trehalose, maltose and the like. Examples of the thermoplastic resin include polyglycolic acid (PGA), polylactic acid, polyethylene, polypropylene, polystyrene, polyamide, polycarbonate, cyclic polyolefin, polycaprolactone, acrylic, urethane resin, aromatic polyether ketone, and epoxy. Examples thereof include resins. However, the material which comprises non-temperature response part RB is not limited to these materials.

  When the microneedle 20 is manufactured, the temperature response in the microneedle 20 is adjusted by adjusting the order and filling ratio of the material constituting the temperature response portion RA and the material constituting the non-temperature response portion RB to the intaglio 50. The part where the part RA and the non-temperature response part RB are located can be adjusted.

  As shown in FIGS. 9, 11, and 13, the microneedle 20 is divided into a temperature response portion RA and a non-temperature response portion RB along a direction orthogonal to the first surface 21S, and the tip of the protrusion 22 In the configuration in which the part including the temperature response part RA is, the following effects are obtained. That is, when the transdermal administration device 10 is cooled during the administration of the drug, the portion including the tip of the protrusion 22 is dissolved, so that the protrusion containing the drug is controlled by controlling the cooling timing of the transdermal administration device 10. The start timing of the dissolution of the part 22 can be controlled. Therefore, it is possible to adjust the timing at which the drug is diffused into the body.

  In the configuration in which the portion including the tip of the protrusion 22 is the temperature response portion RA, the non-temperature response portion RB, that is, the degree of freedom of material selection for the portion including at least the second surface 21T of the base body 21 in the microneedle 20. Therefore, characteristics such as rigidity and strength that are difficult to realize when the entire base body 21 is the temperature response portion RA can be imparted to the microneedle 20.

  On the other hand, as shown in FIGS. 10, 12, and 14, the microneedle 20 is divided into a temperature response portion RA and a non-temperature response portion RB along a direction orthogonal to the first surface 21 </ b> S. In the configuration in which the portion including the second surface 21T is the temperature response portion RA, the following effects are obtained. That is, by controlling the cooling timing of the transdermal administration device 10, the temperature response portion RA is dissolved before the non-temperature response portion RB, and the tip portion of the protrusion 22 which is the non-temperature response portion RB is placed in the skin. The drug contained in the protrusion 22 can be diffused into the body for a long time.

  Specifically, for example, when only the substrate 21 is the temperature response unit RA, when the transdermal administration device 10 is cooled during the administration of the drug, the substrate 21 is dissolved as shown in FIG. In this case, for example, a polymer material that is soluble in water at room temperature and has a slow dissolution rate is used as the main component of the protrusion 22 and gradually diffuses into the body as a drug over a long period of time. Therefore, it is possible to use a drug that exhibits a high effect.

  In general, a material having solubility in water at room temperature is difficult to dissolve at a low temperature. Therefore, when the transdermal administration device 10 in which only the base 21 is the temperature response portion RA is cooled and the base 21 is dissolved, the protrusions are formed. The part 22 remains in the skin in a state where it is not completely dissolved. And after the base | substrate 21 melt | dissolves, as FIG. 16 shows, even if it peels the adhesive sheet 30 from the skin Sk, the protrusion part 22 will remain in skin and will melt | dissolve gradually after that.

  As described above, in the configuration in which the portion including the second surface 21T of the base body 21 is the temperature response portion RA, at least the tip portion of the projection portion 22 is left in the skin as the non-temperature response portion RB. The drug contained in can be diffused in the body for a long time. When the protrusion 22 is configured so that the dissolution rate is slow according to the function of the medicine, the transdermal administration device 10 with the adhesive sheet 30 attached to the skin until the dissolution of the protrusion 22 is completed. It may be burdensome and uncomfortable for the user of the transdermal administration device 10 to be fixed on the skin. For example, such a burden or discomfort tends to increase particularly when the site where the drug is administered is a conspicuous site such as the face. On the other hand, if the temperature response part RA melt | dissolves by cooling as mentioned above and the peeling of the adhesive sheet 30 is possible, leaving the at least front-end | tip part of the protrusion part 22 in the skin, the adhesive sheet 30 is stuck Even if it is not continued, the diffusion effect of the drug can be obtained for a long time.

  As shown in FIG. 14, in the configuration in which the portion on the first surface 21S side of the protrusion 22 and the base body 21 is the non-temperature response part RB, a part of the base body 21 also remains on the skin. In the method of manufacturing the microneedles 20, the thinner the base 21 is, the more difficult it is to peel off the molded product from the intaglio 50. Therefore, there is a limit to making the base 21 thinner. It is also possible to reduce the burden and discomfort of the user by reducing the thickness of the portion of the substrate 21 that remains on the skin during administration of the drug while securing the thickness of the substrate 21 at the time. In addition, since the microneedle 20 is temporarily fixed to the skin by the adhesive sheet 30, it is easy to set the administration site of the drug, that is, the position of the microneedle 20 with respect to the skin.

  As described above, even in the configuration in which the portion including the second surface 21T of the base body 21 is the temperature response portion RA, at least the second surface 21T of the base body 21 is controlled by controlling the cooling timing of the transdermal administration device 10. The timing of the start of dissolution of the containing part can be controlled. Therefore, the timing at which the adhesive sheet 30 can be peeled can be adjusted.

  Thus, if the microneedle 20 has a temperature response portion RA, that is, a portion having the temperature-responsive polysaccharide as a main component, the cooling timing of the temperature response portion RA is set. By controlling, the timing of the start of dissolution can be controlled. In the configuration in which the portion including the tip of the protrusion 22 is the temperature response portion RA by controlling the timing of the dissolution start of the temperature response portion RA, the timing at which the diffusion of the drug into the body can be adjusted. In addition, in the configuration in which the portion including the second surface 21T of the base body 21 is the temperature response portion RA, the timing at which the adhesive sheet 30 can be peeled can be adjusted. Therefore, compared with the case where the whole microneedle 20 is comprised from the material which has the solubility to water at normal temperature, control of melt | dissolution of the microneedle 20 is easy. Even when the temperature response unit RA is located in a portion not in contact with the skin when the transdermal administration device 10 is used, the temperature response unit RA is based on the cooling of the temperature response unit RA. It can be dissolved due to the moisture contained in it.

  In the embodiment and the modification, the shape of the protrusion 22 included in the administration unit is needle-shaped, that is, the length in the thickness direction of the base 21 is longer than the length in the direction along the first surface 21S of the base 21. It is not limited to shape. The shape of the protrusion 22 is blade-shaped, that is, the length in one extending direction, which is the direction along the first surface 21S of the base 21, is longer than the length in the thickness direction of the base 21. The tip may be formed in a linear shape extending in a direction different from the direction orthogonal to the first surface 21S of the base body 21, for example, in a direction along the extending direction. For example, the protrusion 22 has a triangular prism shape extending along the extending direction, and one of three rectangular side surfaces of the triangular prism is in contact with the base body 21 and the side that divides the other two side surfaces is formed. You may have the shape which functions as a front-end | tip of the projection part 22. FIG.

  Furthermore, the concavo-convex structure provided with the base 21 and the protrusion 22 is not limited to being used as the administration part of the transdermal administration device 10, but is used for various applications utilizing the fact that the shape of the structure collapses due to dissolution. May be. One such application is, for example, a cell culture sheet that uses the protrusion 22 as a support for culturing cells. Specifically, a method of using a sheet for cultivating cells fixed at the protrusions of the concavo-convex structure and detaching the sheet by dissolving the concavo-convex structure by cooling after cell culture is exemplified. Moreover, the usage method which culture | cultivates a cell on an uneven structure, dissolves an uneven structure by cooling, and detach | desorbs the cultured cell is illustrated. In such a case, the base | substrate 21 and the projection part 22 do not need to contain the chemical | medical agent, and the projection part 22 should just have a shape and arrangement | sequence according to a use.

As described above, according to the present embodiment, the following effects can be obtained.
(1) Since the concavo-convex structure has a part containing as a main component a polysaccharide that exhibits solubility in water by cooling to a temperature lower than room temperature, the part containing the polysaccharide as a main component is cooled by cooling. Start lysis. Therefore, about the part which contains the said polysaccharide as a main component, the timing of a melt | dissolution start can be controlled by controlling the timing of cooling. Therefore, compared with the case where the whole administration part is made of a material having solubility in water at room temperature, dissolution control is easier. And the uneven structure body provided with such a base | substrate 21 and the projection part 22 is used as an administration part for administration of the chemical | medical agent in the transdermal administration device 10, Therefore The control of dissolution of an administration part is easy. Is realized. In addition, by using a transdermal administration device set composed of the transdermal administration device 10 and the cooling member 40, the drug is administered to the administration target while accurately controlling the dissolution of the administration part by cooling the administration part by the cooling member 40. Can be administered.

  (2) According to the structure in which the polysaccharide includes one or more polysaccharides selected from the group consisting of hydroxypropyl chitosan and hydroxybutyl chitosan, the portion containing the polysaccharide as a main component is more than normal temperature. A configuration that exhibits solubility in water at a low temperature is suitably realized.

  (3) In the case where both the base body 21 and the protrusion 22 contain the polysaccharide as a main component, the timing of starting the dissolution of the entire administration unit is controlled by controlling the cooling timing of the transdermal administration device 10. It is also possible to adjust the timing at which diffusion of the drug into the body is started.

  (4) Of the base body 21 and the protrusion 22, in the structure in which only the protrusion 22 includes the polysaccharide as a main component, the dissolution of the protrusion 22 is controlled by controlling the cooling timing of the transdermal administration device 10. The start timing can be controlled, and the timing at which the diffusion of the drug into the body can be adjusted. Moreover, the freedom degree of the material selection about the base | substrate 21 is raised.

  (5) In the configuration in which the base 21 includes the polysaccharide as a main component and the protrusion 22 includes a polymer material having solubility in water at room temperature as a main component, by cooling the transdermal administration device 10, Only the base body 21 can be dissolved before the protrusions 22 to leave the protrusions 22 in the skin. Therefore, a configuration suitable for a case where the purpose of administration is to diffuse the drug contained in the protrusion 22 into the body for a long time.

[Example]
The concavo-convex structure and the transdermal administration device described above will be described using specific examples.

Example 1
<Formation of intaglio>
A microneedle master serving as an administration portion 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 by plating. Then, using a potassium hydroxide aqueous solution heated to 90 ° C. and having a weight percent concentration of 30%, the silicon original was removed by wet etching to form a nickel intaglio.

<Preparation of material solution>
Hydroxypropyl chitosan was dissolved in cold water to prepare a hydroxypropyl chitosan aqueous solution having a weight percent concentration of 5%. And rhodamine B was added to this hydroxypropyl chitosan aqueous solution as a chemical | medical agent, and the material solution for formation of a microneedle was adjusted.

<Production of transdermal administration device>
After filling the intaglio with the material solution, the material solution filled in the intaglio was naturally dried in an environment of 5 ° C. to dry and solidify the material solution. After the solidified molded product was peeled off from the intaglio, the molded product was punched into a 12 mmφ circle to obtain a microneedle that was a concavo-convex structure of Example 1. In the microneedle of Example 1, both the base and the protrusions contain as a main component a polysaccharide that exhibits solubility in water at a temperature lower than room temperature.

An adhesive sheet was affixed to the obtained microneedle substrate to obtain a transdermal administration device of Example 1.
<Confirmation test>
The transdermal administration device of Example 1 was fixed to the pig skin by piercing the pig skin with a protrusion and attaching an adhesive sheet to the pig skin. Thereafter, a cooling member, which is a metal block cooled to 10 degrees, was pressed onto the transdermal administration device from the pressure-sensitive adhesive sheet for 1 minute.

  Thereafter, the transdermal administration device was peeled from the pig skin, and the pig skin was observed with a confocal microscope. As a result, fluorescent coloration of rhodamine B was confirmed in the skin of pig skin. This suggests that the microneedles were dissolved by cooling the transdermal administration device, and rhodamine B was diffused into the skin of pig skin.

(Example 2)
<Formation of intaglio>
An intaglio was produced in the same manner as in Example 1.

<Preparation of substrate material solution>
Hydroxybutyl chitosan was dissolved in cold water to prepare a hydroxybutylchitosan aqueous solution having a weight percent concentration of 5%, and this aqueous solution was used as a material solution for forming a substrate.

<Adjustment of material solution for protrusions>
Hydroxypropylcellulose was dissolved in water to prepare a hydroxypropylcellulose aqueous solution having a weight percent concentration of 10%. And Evans blue was added as a chemical | medical agent to this hydroxypropyl cellulose aqueous solution, and the material solution for formation of a projection part was adjusted.

<Production of transdermal administration device>
After filling the portion corresponding to the shape of the protrusion in the concave portion of the intaglio with the material solution of the protrusion, the material solution is dried by placing the intaglio filled with the material solution on a hot plate set at 40 ° C. Solidified. From the solidified filling, the substrate material solution was filled into the intaglio and the substrate material solution was lyophilized. After the solidified molded product was peeled off from the intaglio, the molded product was punched into a 12 mmφ circle to obtain a microneedle that was a concavo-convex structure of Example 2. In the microneedle of Example 2, only the base contains a polysaccharide that exhibits solubility at a temperature lower than room temperature as a main component.

An adhesive sheet was affixed to the obtained microneedle substrate to obtain the transdermal administration device of Example 2.
<Confirmation test>
The transdermal administration device of Example 2 was fixed to the pig skin by piercing the pig skin with a protrusion and attaching an adhesive sheet to the pig skin. Thereafter, a cooling member, which is a metal block cooled to 10 ° C., was pressed onto the transdermal administration device from the adhesive sheet for 2 minutes.

  Thereafter, the transdermal administration device was peeled from the pig skin, and the pig skin was observed with a stereomicroscope. As a result, it was confirmed that a blue protrusion was embedded in the skin of pig skin. Further, a part of the dissolved substrate was adhered to the adhesive sheet peeled from the pig skin. This suggests that the substrate was dissolved by cooling of the transdermal administration device, and the protrusions were left in the skin of pig skin.

  DESCRIPTION OF SYMBOLS 10 ... Transdermal administration device, 20 ... Microneedle, 21 ... Base | substrate, 21S ... 1st surface, 21T ... 2nd surface, 22 ... Projection part, 30 ... Adhesive sheet, 31 ... Base material sheet, 32 ... Adhesive layer, 40 ... cooling member, RA ... temperature response part, RB ... non-temperature response part.

Claims (7)

A concavo-convex structure comprising a substrate having a first surface and a protrusion protruding from the first surface,
The concavo-convex structure has a concavo-convex structure having a polysaccharide as a main component that exhibits solubility in water by cooling to a temperature lower than room temperature. The uneven structure according to claim 1, wherein the polysaccharide includes one or more polysaccharides selected from the group consisting of hydroxypropyl chitosan and hydroxybutyl chitosan. The concavo-convex structure according to claim 1 or 2 is provided as an administration part,
A transdermal administration device, wherein the protrusion includes a drug. The transdermal administration device according to claim 3, wherein both the base and the protrusion include the polysaccharide as a main component. The transdermal administration device according to claim 3, wherein, of the substrate and the protrusion, only the protrusion includes the polysaccharide as a main component. The substrate contains the polysaccharide as a main component,
The transdermal administration device according to claim 3, wherein the protrusion includes a polymer material having solubility in water at room temperature as a main component. A substrate having a first surface, and a protrusion that protrudes from the first surface and includes the protrusion containing a drug, and has a solubility in water by cooling to a temperature lower than room temperature. A transdermal administration device comprising the administration unit having a portion containing a polysaccharide as a main component to be expressed;
A cooling member for cooling the administration part;
A transdermal administration device set comprising: