TW202304546A - Microneedle structure production method and microneedle structure - Google Patents

Abstract

The method for producing microneedle structure according to the present invention is a method for producing a microneedle structure 10 provided with, on one surface side of a base material 11 having permeability to liquid in the thickness direction, needle-shaped parts 12 having holes 13, the method involving: a forming step for forming protrusions 5 using a composition 3 for forming a needle part, wherein the composition 3 contains a first water-insoluble material and a first water-soluble material; a bonding step for bonding the composition 3 or the protrusions 5 formed in the forming step to the base material 11; and a removing step for immersing the protrusions 5 and the base material 11 in water to dissolve the first water-soluble material and remove the same, and thereby forming the needle parts 12 and the holes 13 from the protrusions 5. Such a microneedle structure production method provides a microneedle structure provided with a base material and securing flow passages.

Description

Method for producing microneedle structure and microneedle structure

The present invention relates to a method for producing a microneedle structure and a microneedle structure.

In recent years, it has been proposed to supply drugs into the body, collect body fluids from the body, and the like through through holes formed in microneedles. For example, microneedles having a height of 20 μm or more and less than 500 μm and an aspect ratio (h/a) of height h to the maximum length a of the bottom side of 2 are known as microneedles excellent in diffusibility of substances for supplying drugs to the body. The above, and those made of mesoporous materials (Patent Document 1). In addition, in order to understand the patient's symptoms more accurately, an analysis patch with a small burden on the body is proposed, which uses tiny microneedles with a length of less than 1 mm to pierce the patient's skin to collect blood and analyze the blood. In Patent Document 2, the following is disclosed as a low-invasive test patch that can be easily and continuously monitored by the patient himself: a base plate on which microchannels are formed is used as a base material, and needles for forming needles are used on the base plate. The viscous material in the shape part is slowly spewed out from the dispenser to form a plurality of needle parts. This test patch is to puncture the needle-shaped part of the patient, and continuously collect blood from the needle-shaped part through the capillary pump part of the microchannel set on the bottom plate, and use the feeling in the reaction chamber set on the bottom plate Measure the collected blood. [Advanced technical literature] [Patent literature]

[Patent Document 1] Japanese Patent Laid-Open No. 2014-094171 [Patent Document 2] WO2019/176126 Publication

[Problem to be solved by the invention]

It is necessary to form fine capillary pump parts, microchannels, etc. on the substrate used in the above-mentioned inspection patch, but it is desired to manufacture inspection patches, microneedle structures, etc. that ensure channels more cheaply and easily. Moreover, even if it is an inspection patch etc. produced by a simple method, it must form the shape of acicular part as expected and ensure a channel.

The present invention has been made in view of such actual situation, and an object of the present invention is to provide a microneedle structure capable of easily obtaining a microneedle structure securing channels and a method for manufacturing the microneedle structure. [means used to solve a problem]

In order to achieve the above object, first, the present invention provides a method of manufacturing a microneedle structure, which is a microneedle structure having a needle-shaped portion having a hole on one side of a substrate having liquid permeability in the thickness direction. The manufacturing method is characterized by comprising: a forming step of forming protrusions using a needle-shaped portion-forming composition containing a first water-insoluble material and a first water-soluble material; and a subsequent step of making the aforementioned composition or The aforementioned protrusion formed in the aforementioned forming step is bonded to the aforementioned substrate; and a removing step of immersing the aforementioned protrusion and the aforementioned substrate in water to dissolve and remove the aforementioned first water-soluble material, thereby removing the aforementioned protrusion from the aforementioned Forming the aforementioned needle-like portion and the aforementioned hole portion (Invention 1).

In the above invention (Invention 1), since a substrate having liquid permeability in the thickness direction is used, channels can be easily formed in the microneedle structure. Moreover, after bonding such a base material and the composition or the above-mentioned protrusions formed in the forming step, holes are formed in the protrusions in the removal step, so the holes of the protrusions and the holes in the base material The parts are easy to connect, and it is easy to form a channel in the microneedle structure.

In the above invention (Invention 1), it is preferable that the base material having liquid permeability in the thickness direction is a porous base material, and the subsequent step is to combine the protrusion formed by the forming step with the second The sheet of the water-soluble material and the aforementioned porous substrate is subjected to the next step, and the aforementioned removing step is a step of dissolving and removing the aforementioned first water-soluble material and the second water-soluble material (invention 2).

When the porous base material contains the second water-soluble material, when the base material is bonded to the formed protrusions, the base material can be suppressed from absorbing the composition of the protrusions. As a result, since the protruding portion, that is, the needle-shaped portion, especially the root portion, does not form too many voids, the collapse of the needle-shaped portion is suppressed, and the needle-shaped portion having a shape suitable for bonding to the base material that becomes the channel can be formed, and A microneedle structure with good adhesion between the acicular part and the substrate can be produced.

In the above invention (Invention 2), it is preferable that the porous substrate is a substrate composed of a fibrous substance (Invention 3).

In the above inventions (Inventions 2 and 3), it is preferable that the sheet contains the second water-insoluble material (Invention 4).

In the above invention (Invention 4), it is preferable that the first water-insoluble material is the same as the second water-insoluble material (Invention 5).

In the above inventions (Inventions 2 to 5), it is preferable that the sheet is formed by impregnating the base material with a second water-soluble material (Invention 6).

In the above inventions (Inventions 2 to 6), it is preferable that the base material composed of a fibrous substance is a nonwoven fabric, a woven fabric, a knitted fabric, or paper (Invention 7).

In the above invention (Invention 1), it is preferable that the base material is made of a liquid-impermeable material and has through-holes formed along the thickness direction (Invention 8).

Since the base material has liquid impermeability, since the liquid absorption of the base material can be suppressed, the liquid can only pass through the through-holes formed along the thickness direction in the base material. Therefore, the body fluid obtained from the needle-shaped part or the liquid medicine delivered to the needle-shaped part does not seep out of the substrate, and the entire amount can be circulated through the through-hole. Moreover, after bonding such a base material and the composition or the above-mentioned protrusions formed in the forming step, holes are formed in the protrusions in the removing step, so the holes of the protrusions and the through-holes in the base material Easy to connect, easy to form channels in the microneedle structure.

In the above-mentioned inventions (Inventions 1 to 8), it is preferable to include a filling step of filling the above-mentioned needle-shaped portion forming composition into a mold having a concave portion (Invention 9).

In the above invention (Invention 9), preferably, in the filling step, the composition for forming the needle-like portion contains a solvent, and in the forming step, the solvent is evaporated (Invention 10).

In the above inventions (Inventions 1 to 10), it is preferable to include a step of disposing a bodily fluid analysis means and/or a physiologically active substance on the surface of the substrate opposite to the surface on which the needle-like portion is provided. means of storage (invention 11).

Second, the present invention provides a microneedle structure having an acicular portion having a hole on one side of a porous substrate, wherein the acicular portion is formed of a first water It is composed of an insoluble material, and is directly provided on the aforementioned porous substrate, and the aforementioned porous substrate contains a second water-insoluble material (Invention 12). [Efficacy of the invention]

According to the manufacturing method of the microneedle structure of the present invention, it is possible to provide a microneedle structure in which the needle-shaped portion ensuring the channel can be easily obtained, and at the same time the needle-shaped portion can be formed in a desired shape, and the needle-shaped portion and Channel engagement is good.

[Mode for Carrying Out the Invention]

Embodiments of the present invention will be described below. [Microneedle structure] Fig. 1 shows a microneedle structure 10 according to an embodiment of the present invention. The microneedle structure 10 includes a plurality of needle-shaped portions 12 separated from each other at predetermined intervals on one side of a substrate 11 . The microneedle structure 10 can be used as an inspection patch for absorbing interstitial fluid from the skin through the needle-shaped part 12 and using the obtained interstitial fluid for examination; Drug administration patches for skin administration into the body, etc.

(1) Needle-shaped portion The shape, size, formation interval, formation number, etc. of the needle-shaped portion 12 can be appropriately selected according to the intended use of the microneedle. Examples of the shape of the needle-like portion 12 include a cylindrical shape, a prismatic shape, a conical shape, and a pyramidal shape. In this embodiment, it is a pyramidal shape. The largest diameter or cross-sectional dimension of the needle-like portion 12 is, for example, 25 to 1000 μm, the diameter of the tip or the size of the cross-section of the tip is 1 to 100 μm, and the height of the needle-like portion 12 is, for example, 50 to 2000 μm. In addition, the needle-shaped part 12 is provided in a plurality of rows in one direction of the base material 11, and a plurality of needle-shaped parts 12 are formed in each row at the same time, and are arranged in a matrix.

The needle-shaped portion 12 is composed of a first water-insoluble material that is insoluble in water contained in a cleaning solution used in a removal step described later. In consideration of ease of handling in the manufacturing steps, the first water-insoluble material is preferably a water-insoluble resin. The water-insoluble resin is preferably a water-insoluble resin whose melting point is higher than normal temperature and lower than 250°C, more preferably a water-insoluble resin whose melting point is higher than 40°C and lower than 200°C, particularly preferably a melting point higher than 45°C And the water-insoluble resin below 150°C is particularly preferred as a water-insoluble resin whose melting point is higher than 45°C and below 80°C. Since the melting point is higher than normal temperature, the water-insoluble resin becomes solid at normal temperature to form the needle-like portion 12, and if the melting point is lower than 150°C, the degree of freedom in the selection of the material that can be used as the base material increases. , and at the same time workability is also improved.

In addition, such a water-insoluble resin is preferably a water-insoluble biodegradable resin that hardly affects the human body. As the biodegradable resin, it is preferable to use aliphatic polyester and its derivatives. Furthermore, examples include polylactic acid, polyglycolic acid, polycaprolactone, and copolymers of monomers constituting them. At least one of the group consisting of copolymers and the like. In addition, biodegradable resins such as polybutylene succinate, aliphatic aromatic copolyester, and polyhydroxybutyrate can also be used. Also, a mixture of two or more of these biodegradable resins may be used. Most preferably, the first water-insoluble material is polycaprolactone, which is a biodegradable resin with a melting point of 60° C., or a copolymer of caprolactone and monomers constituting other biodegradable resins. The molecular weight of the water-insoluble resin is usually 5,000-300,000, preferably 7,000-200,000, more preferably 8,000-150,000.

Each needle-like portion 12 has a hole 13 formed on its surface and inside. The hole 13 is formed by removing the first water-soluble material in the removal step described later, and body fluids, medical solutions, etc. pass through the hole 13 . The hole portion 13 is formed in the needle portion 12 as a porous structure. If the needle-shaped portion 12 is formed in a porous structure, a channel through which body fluid or medical fluid passes is relatively formed inside as the hole portion 13, so it is not necessary to mechanically form a nanoscale channel, which is preferable. In addition, since body fluid or medical fluid can pass through the entirety of the portion of the needle-like body formed with the porous structure, the amount of flow can be increased compared to simple communication holes. Furthermore, when the needle-shaped portion 12 is formed in such a porous structure, if the porous structure does not cover part or all of the side surface of the needle-shaped portion, the hole 13 will also open on the side surface of the needle-shaped portion 12 . In this case, compared with the case where only the tip of the needle-shaped portion 12 is opened, the flow rate of the liquid can be increased. The hole portion 13 extends to the base material 11 side according to the formed hole portion 13 as shown in its cross section. The size of the opening of the hole 13 is determined according to the use of the test patch using the microneedle structure 10, etc., but the size of the opening is preferably 0.1 to 50.0 μm in terms of ease of liquid penetration. More preferably, it is 0.5-25.0 μm, and even more preferably, it is 1.0-10.0 μm. In addition, in the present invention, the term "body fluid" includes blood, lymph fluid, interstitial fluid, and the like.

(2) Substrate The substrate 11 is not particularly limited as long as it has liquid permeability in the thickness direction. The base material 11 is preferably a porous material in which minute base material holes penetrating from one side to the other side are formed therein. As such a porous substrate 11, known substrates can be used, for example, substrates made of foam materials such as foamed polyurethane resin, porous materials such as porous ceramics, or substrates made of fibrous substances. The base material formed. The porous substrate 11 is usually insoluble in water, or is formed of a material that is hardly soluble in water. It is preferably a substrate made of fibrous substances that are easy to handle. Here, the fibrous substance in the present invention means fibers such as natural fibers and chemical fibers. Examples of the substrate composed of fibrous materials include nonwoven fabrics, woven fabrics, knitted fabrics, paper, and the like composed of such fibers.

The substrate pore portion of the porous substrate 11 communicates with the pore portion 13 of the needle-like portion 12 to form a communicating hole. The shape of the substrate hole is determined according to the material of the substrate. The porous substrate 11 preferably has a porosity of 1 to 70%, more preferably 5 to 50%, and particularly preferably 10 to 30%, due to the pores of the substrate. When the porosity is within this range, the body fluid absorbed by the needle-shaped portion 12 can be sufficiently absorbed. As will be described later, the porous substrate 11 preferably contains the second water-insoluble material, and substrate pores are maintained in the substrate 11 containing the second water-insoluble material. In addition, the needle-like portion 12 is directly attached to the base material 11 here. For example, when the base material 11 and the needle-shaped portion 12 are bonded by an adhesive layer or the like, a gap is generated between the base material 11 and the needle-shaped portion 12, and a liquid leaks out, or the base material 11 is damaged due to the adhesive layer. The passage of the liquid between the needle-shaped part 12 and the needle-shaped part 12 may be hindered, but by directly adhering the base material 11 and the needle-shaped part 12, it is easy to connect the passages of both.

Also, as the base material having liquid-permeability in the thickness direction, not only the base material 11 itself can be adopted which is made of a material having liquid-permeability, but also one which is formed in the following manner: It is made of permeable material, and through the through hole formed in the base material 11, the liquid can pass through the thickness direction of the base material 11. Since the base material 11 has liquid impermeability, the base material 11 can be prevented from absorbing liquid, so the liquid in the base material 11 can only pass through the through holes. Therefore, the body fluid obtained from the needle-shaped part 12 or the liquid medicine delivered to the needle-shaped part 12 does not seep out of the base material 11, and the entire amount can be circulated through the through-hole. Thereby, when the microneedle structure 10 is used as an inspection patch, since the body fluid can quickly pass through the substrate 11, rapid analysis can be made possible, and even if the microneedle structure 10 is used When the drug is administered to the patch, the drug solution does not leak out, and the entire amount of the drug solution can be quickly supplied to the skin.

Examples of such liquid-impermeable materials include resin films, metal foils, and glass films, and resin films are preferably used. The shape of the through-hole is not particularly limited, but from the viewpoint of generating capillarity and securing a sufficient flow rate, a structure having a plurality of through-holes with a small diameter is preferable. The diameter of the through hole is, for example, 2 mm or less, preferably 0.05 to 1 mm, more preferably 0.1 to 0.8 mm. The through holes can be formed by punching, laser drilling, or the like. Examples of the resin used for the resin film include polybutylene terephthalate, polyethylene terephthalate, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, vinyl chloride, acrylic acid Resin, polyurethane, polylactic acid, etc. The substrate 11 may be a laminated substrate obtained by laminating a resin film provided with through holes and a porous substrate.

In the case where an adhesive layer is provided on the surface of the substrate 11 on which the needle-shaped portions 12 are formed, the bonding step described later can be performed at room temperature, or the adhesiveness between the substrate 11 and the needle-shaped portions 12 can be improved. In this case, due to the presence of the adhesive layer, a gap is generated between the base material 11 and the needle-shaped portion 12, and the liquid leaks out, or the passage of the liquid between the base material 11 and the needle-shaped portion 12 is restricted due to the adhesive layer. risk of hindrance. Therefore, it is preferable to provide the adhesive layer in the base material 11 so as to include the region through which the liquid should pass, and to provide the non-formation region of the adhesive layer in the central part.

In this way, the microneedle structure 10 of this embodiment forms the needle-like portion 12 in a desired shape, and the liquid in the channel formed by the hole 13 of the needle-like portion 12 and the base material hole of the base material 11 is formed. Good penetrability means good bonding between the needle-like portion 12 and the base material 11 .

[Inspection patch] Preferably, the microneedle structure 10 is used in an inspection patch 20 that absorbs body fluid from the skin through the needle-like portion 12 and performs an inspection using the obtained body fluid. As shown in FIG. 2 , the inspection patch 20 has a microneedle structure 10, and has an analysis piece on the side of the base material 11 opposite to the surface on which the needle-shaped part 12 is provided (hereinafter, sometimes referred to as "back surface"). 21 and film 22. In addition, the microneedle structure 10 can also be used as a drug delivery patch for injecting a drug from the skin into the body through the needle-shaped part 12 from the base material 11 . In this case, the drug administration patch can be constructed in such a way that a sheet containing a physiologically active substance can be provided on the back side of the base material 11 of the microneedle structure 10, and the The physiologically active substance from the tablet containing the physiologically active substance is administered into the skin.

The analysis sheet 21 is used for analyzing and examining body fluids such as blood and interstitial fluid obtained from the subcutaneous area, and is provided on the back side of the substrate 11 . When the needle-shaped part 12 is punctured on the subject's skin, the bodily fluid flows into the hole 13 of the needle-shaped part 12 and is absorbed by the base material 11 and reaches the analysis sheet 21 through the hole of the base material. The analysis sheet 21 can be appropriately selected according to desired test contents, and one formed by including components as analysis means in a base material such as paper can be used. As such an analysis sheet 21 , for example, a glucose measuring paper that changes color according to the glucose concentration in the body fluid can be mentioned. In the case of using a glucose measurement paper as the analysis sheet 21, it can be used as a test patch 20 for blood glucose value measurement, and the analysis sheet 21 of the test patch 20 for blood glucose value measurement absorbs 10. The interstitial fluid is collected and discolored, and the degree of discoloration is used to measure the blood sugar value over time.

Adhesive film 22 is made of material with living body safety. If considering the followability of the attached skin, it is preferably made of material with softness, stretchability, and even shrinkage, but it is not subject to any restrictions. limited to this material. As a preferred material of the adhesive film 22, stretchable woven fabrics can be cited, and those known in the past can be used.

[Method for Manufacturing Microneedle Structure] (Filling Step) FIG. 3 shows a method for manufacturing a microneedle structure 10 according to an embodiment of the present invention. In this embodiment, as shown in FIG.3(a), the liquid composition 3 is filled in the mold (mold) 2 in which the several recessed part 1 was formed (filling process). The recess 1 is filled with the filled liquid composition 3 .

The material of the mold 2 is not particularly limited, but for example, it is preferably formed of polysiloxane, which is easy to make a correct mold and the solidified liquid composition 3 is easy to peel off. In this embodiment, it is made of polysiloxane. Composed of methyl siloxane. The concave portion 1 is used to form the needle-shaped portion 12 shown in FIG. 1 , and is configured to form the needle-shaped portion 12 of a desired shape. In the mold 2, a plurality of such recesses 1 are spaced apart from each other and arranged in a plurality of rows at designated positions.

The liquid composition 3 includes: the aforementioned first water-insoluble material (shown schematically as a light gray circle in Figure 3(a)), the first water-soluble material (in Figure 3(a) Schematically shown as dark gray circles) and solvent. In addition, in the drawings, for the sake of explanation, each material is schematically described in the form of particles, and is shown as being dispersed in a solvent. The liquid composition 3 only needs to have at least one of the first water-insoluble material and the first water-soluble material (composition for forming the needle-shaped part) dissolved in the solvent. From a viewpoint, it is preferable that at least the first water-insoluble material is dissolved. The liquid composition 3 preferably has a viscosity of 0.1 to 1000 mPa·s, more preferably 0.5 to 100 mPa·s, particularly preferably 1.0 to 10 mPa·s. With this range, the liquid composition 3 can be injected into the mold 2 with good workability, and the composition in the filling step has good filling ability to the concave portion 1, so that the desired needle-shaped portion 12 can be formed.

As the first water-soluble material, it is preferably a water-soluble material with a melting point higher than normal temperature. The water-soluble material may be organic or inorganic, and examples thereof include sodium chloride, potassium chloride, Glauber's salt, sodium carbonate, potassium nitrate, alum, sugar, and water-soluble resins. The water-soluble resin is preferably a water-soluble thermoplastic resin, and preferably has a melting point higher than normal temperature. Examples of the water-soluble thermoplastic resin include hydroxypropyl cellulose, polyvinylpyrrolidone, and the like in addition to the biodegradable resins described below. In further consideration of the impact on the human body, the water-soluble thermoplastic resin is more preferably a biodegradable resin. Such biodegradable resins include at least one selected from the group consisting of polyolefin glycols such as polyethylene glycol and polypropylene glycol, polyvinyl alcohol, collagen, and mixtures thereof, particularly preferably poly ethylene glycol. The molecular weight of polyethylene glycol is, for example, preferably from 200 to 4,000,000, more preferably from 600 to 500,000, particularly preferably from 1,000 to 100,000.

The first water-insoluble material and the first water-soluble material are preferably mixed at a mass ratio of 9:1 to 1:9, more preferably 8:2 to 2:8, particularly preferably 7:1 3～3:7 for mixing. By constituting the liquid composition 3 in this ratio, the needle-shaped portion 12 having a desired porosity is formed, and it becomes easy to achieve both the liquid permeability and the strength of the needle-shaped portion 12 .

In this embodiment, the liquid composition 3 contains a solvent in order to contain each material and be liquid. The solvent may be water or an organic solvent, but in the case of dissolving the first water-insoluble material, the liquid composition 3 preferably contains an organic solvent. The organic solvent should just be an organic solvent which can dissolve or disperse the said 1st water-insoluble material and 1st water-soluble material. For example, aliphatic hydrocarbons such as hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride and ethylene chloride, methanol, ethanol, Propanol, butanol, 1-methoxy-2-propanol and other alcohols, acetone, methyl ethyl ketone, 2-pentanone, isophorone, cyclohexanone and other ketones, ethyl acetate, butyl acetate, etc. Cellosolve solvents such as esters and ethyl cellosolve, etc.

The total content of the first water-insoluble material and the second water-insoluble material in all components of the liquid composition 3 is preferably at most 40%, more preferably at most 35%, and most preferably at most 30% by mass. By containing the composition in this range with respect to the entire amount of the liquid composition 3, the liquid composition 3 can be formed with a desired viscosity that facilitates the manufacture of the needle-like portion 12 of the microneedle structure 10, and as a result, it is possible to The needle-like portion 12 is formed in a desired shape.

In addition, the liquid composition 3 may contain not only the above-mentioned first water-insoluble material, which is the resin and the first water-soluble material, but also other materials as non-volatile solid components.

In this embodiment, although the liquid composition 3 obtained by dissolving or dispersing each material in a solvent is used, the liquid composition 3 may be composed only of a composition that does not contain a solvent, and the liquid composition 3 may further include a dispersant. For example, in order to further increase the strength of the needle-shaped portion, a water-insoluble material other than resin such as silica filler may be included. When filling a mold with a composition not containing a solvent, it is preferable to heat and fluidize the composition.

(Vibration Step) Next, as a vibration step, it is preferable to place the mold 2 on an ultrasonic cleaning device and subject the mold 2 to ultrasonic vibration. The means for imparting vibration is not limited to an ultrasonic cleaning device as long as it can impart fine vibration to the mold 2 . By performing such a vibration step, as shown in FIG. 3( b ), the filling of the recess 1 with the liquid composition 3 is promoted, and the first water-insoluble material and the first water-soluble material in the recess 1 are further filled into the recess. 1 in every corner. This filling eliminates defects caused by air bubbles, and enables the formation of needle-shaped portions 12 with high transferability in accordance with the shape of the recessed portion 1, and the strength of the needle-shaped portions 12 is improved.

When performing ultrasonic treatment as a vibration step, heating may be carried out at the same time. In this case, heating is carried out at a temperature above a temperature that can promote evaporation/drying (for example, above 45° C.), and it is particularly preferred to use the first water-insoluble Heating is performed at least one of the melting point of the material and the first water-soluble material (for example, 60° C. or higher). By heating at this temperature, the solidification of the surface of the liquid composition 3 is suppressed, the evaporation/drying of the organic solvent is promoted, and the first water-insoluble material and the first water-soluble material in the liquid composition 3 are accelerated to the concave portion. 1 padding. In particular, by heating at 60° C. or higher, the evaporation/drying of the organic solvent is further promoted, and the filling of the concave portion 1 with the first water-insoluble material and the first water-soluble material is further promoted.

The frequency in the vibrating step is preferably selected from a low frequency range with a high filling acceleration effect, preferably 10-200kHz, more preferably 20-150kHz, particularly preferably 30-80kHz. Also, in the vibration step, the time for ultrasonic treatment is preferably 0.5 to 10 minutes, more preferably 2 to 7 minutes. By vibrating the mold 2 in this range, the filling of the concave portion 1 with the first water-insoluble material and the first water-soluble material in the liquid composition 3 is further promoted.

(Degassing step) It is preferable to perform a degassing step next to the shaking step. Thereby, the air contained in the concave portion 1 can be degassed, the filling of the concave portion 1 with the first water-insoluble material and the first water-soluble material can be further promoted, and at the same time, the evaporation/drying of the organic solvent can be promoted. The degassing step is preferably carried out at 0.01 to 0.05 MPa and 20 to 25° C. in the case of using ethyl acetate as a solvent, for example, as in the examples described later. By degassing in this pressure range, the solidification of the liquid composition 3 on the surface is suppressed, the organic solvent is easily evaporated/dried, and the filling of the recess 1 with the first water-insoluble material and the first water-soluble material can be further promoted .

(Heating Step) After that, it is preferable to perform a heating step of heating at 80 to 120°C. Thereby, as shown in FIG. 3( c ), in the case where the evaporation/drying of the solvent is further promoted while having been heated above the melting point of any one of the first water-insoluble material and the first water-soluble material, the material becomes The melted state promotes the filling of the recess 1 with the first water-insoluble material and the first water-soluble material. In addition, in this embodiment, although a heating process is performed after a degassing process, you may perform a heating process first.

Afterwards, the solvent is evaporated/dried, and the first water-insoluble material and the first water-soluble material contained in the liquid composition 3 are fully filled into the recess 1, and in the state where the protrusion 5 has been formed in the recess 1, as shown in the figure 3( d ), the sheet 4 is placed on the mold 2 . In this way, by sufficiently filling the concave portion 1 with the first water-insoluble material and the first water-soluble material, in this embodiment, the needle-shaped portion 12 can be provided in a desired shape, and the needle-shaped portion 12 and the base material 11 can be formed in a desired shape. The adhesion is also good. Thus, in this embodiment, the forming process of forming the protrusion part 5 is performed by the filling process, the subsequent vibration process, the degassing process, and the heating process. Also, the vibration step and/or the degassing step may be omitted. Alternatively, the protrusion 5 can be formed without performing the heating step by drying the solvent at room temperature.

(Sheet) The sheet 4 is formed by containing a water-soluble second water-soluble material and a water-insoluble second water-insoluble material in the aforementioned porous base material 11. Because the mold 2 is heated in the step before this, the first water-insoluble material and the first water-soluble material in the recess 1 are in a melted state. If the sheet 4 is placed, the melted first The protrusion 5 formed by the water-insoluble material and the first water-soluble material will directly bond the sheet 4 . In this case, since the sheet 4 includes the second water-insoluble material and the second water-soluble material, it is possible to suppress the substrate 11 from absorbing the melted composition in the concave portion 1 . As a result, even if the microneedle structure 10 has a porous base material 11 and is formed using a liquid material, excessive voids are not formed in the protrusions 5, especially at the bases, so that the collapse of the needle-shaped parts 12 is suppressed. situation. Therefore, the needle-like portion 12 having a shape suitable for bonding to the base material 11 can be formed, and the microneedle structure 10 with good bonding between the needle-like portion 12 and the base material 11 can be manufactured. Furthermore, because the sheet 4 not only includes the second water-soluble material but also includes the second water-insoluble material, the first water-insoluble material that has melted in the concave portion 1 and the second water-insoluble material included in the sheet 4 are heated. Sealing, and the adhesion between the sheet 4 and the protrusion 5 is further improved.

As the second water-soluble material, those listed for the first water-soluble material can be used, but as described later, in order to easily impregnate the porous base material 11 with the second water-soluble material, a water-soluble resin is preferred, and a water-soluble resin is preferred. It is preferably a water-soluble thermoplastic resin, and more preferably a water-soluble biodegradable resin. Preferably, the second water-soluble material is the same as the first water-soluble material. Since the second water-soluble material is the same as the first water-soluble material, it becomes easy to remove the second water-soluble material and the first water-soluble material in the subsequent removal step, and the desired hole portion of the needle-shaped portion 12 can be formed. 13.

The second water-insoluble material can use those listed for the first water-insoluble material, but preferably the second water-insoluble material is the same as the first water-insoluble material. Since the second water-insoluble material is the same as the first water-insoluble material, the heat-sealing between the second water-insoluble material and the first water-insoluble material becomes easier, and the adhesion between the protrusion 5 and the sheet 4 is improved.

Also, as the second water-insoluble material, as described later, a water-insoluble resin is preferable in order to facilitate impregnation of the porous base material 11 with the second water-soluble material. The water-insoluble resin is preferably a water-insoluble resin whose melting point is higher than normal temperature and lower than 250°C, more preferably a water-insoluble resin whose melting point is higher than 40°C and lower than 200°C, particularly preferably a melting point higher than 45°C And water-insoluble resin below 150℃. The resin used as the second water-insoluble material is also preferably biodegradable.

The sheet 4 may optionally contain the second water-soluble material and the second water-insoluble material, but as long as the sheet 4 does not absorb moisture from the recess 1 from the surface side of the substrate 11 that is in contact with the protruding portion 5 (acicular portion 12 ), The form of the first water-insoluble material and the first water-soluble material only needs to contain at least the second water-soluble material. That is, the sheet 4 only needs to be constituted in such a manner that it contains at least the second water-soluble material, and the second water-soluble material can block at least a part of the base material pores of the porous base material 11, so that the second water-soluble material can be suppressed. A water insoluble material is absorbed with a first water soluble material. For example, a layer including the second water-soluble material and the second water-insoluble material may be laminated on the surface of the porous substrate 11 on the side adjacent to the protrusion 5 . Preferably, the porous substrate 11 is impregnated with the second water-soluble material and the second water-insoluble material. As a method of impregnating the porous substrate 11 with the second water-soluble material and the second water-insoluble material, for example, the porous substrate 11 is immersed in a solution having the second water-soluble material and the second water-insoluble material. That's it. In addition, the solution having the second water-soluble material and the second insoluble material can be coated on the porous substrate 11 by means of inkjet or the like. The solution having the second water-soluble material and the second water-insoluble material immersed in the porous substrate 11 is dried, so that the second water-soluble material and the second insoluble material remain in the substrate pores of the substrate 11, which is It is better because of the simple impregnation method. The solution may have not only the second water-soluble material and the second water-insoluble material, but also a solvent. In all the components of the solution, the total concentration of the second water-soluble material and the second water-insoluble material is preferably 1 to 35%, more preferably 3 to 30%, and most preferably 5 to 25% by mass. %. Preferably, the solution contains the second water-soluble material and the second water-insoluble material at a mass ratio of 9:1 to 1:9. Within this range, it becomes easy to obtain the effect of restoring the substrate hole portion of the substrate 11 in the removal step described later, and it becomes easy to improve the adhesiveness between the substrate 11 and the needle-like portion 12 .

When the porous base material 11 is immersed in the solution containing the second water-soluble material and the second water-insoluble material, for example, after the base material 11 is immersed in the solution at 10-60°C for 1-60 minutes, the solvent is evaporated , the substrate 11 can be impregnated with the second water-soluble material and the second water-insoluble material by drying. In particular, when the base material 11 is made of a fibrous substance, the second water-soluble material and the second water-insoluble material can be easily and sufficiently absorbed by immersion in a solution to impregnate the base material 11 .

In this embodiment, the sheet 4 is configured to contain the second water-insoluble material, but it is not limited thereto. The sheet 4 may not contain the second water-insoluble material. Because the mold 2 is heated, the first water-insoluble material and the first water-soluble material in the recess 1 are in a melted state. The protrusion 5 formed by the melted first insoluble material and the first water-soluble material will adhere to the surface of the placed sheet 4 . In the case where the sheet 4 does not contain the second water-insoluble material, for example, by providing any bonding means on the surface of the sheet 4 on which the mold 2 is placed, such as a bonding portion using a known adhesive agent, the sheet can be improved. 4 Adhesion with the protruding part 5.

(Pressing Step) Next, as shown in FIG. 3(e), a pressing step of applying pressure to the sheet 4 is performed. The pressurization method is not particularly limited, and a known method can be used. In the pressurization step, a heating step of heating at 60 to 120° C. may be performed simultaneously. Adhesiveness can be further improved by also performing a heating process simultaneously. Thereafter, by maintaining the low temperature state of -10 to 3° C., the protrusions 5 in the recess 1 are solidified, and at the same time, the bonding of the protrusions 5 and the sheet 4 is completed. In this manner, in the present embodiment, the step of adhering the protrusions 5 and the sheet 4 is performed by the heating step, the subsequent pressurization step, and the curing of the protrusions 5 . In addition, the protrusion 5 and the sheet 4 may be bonded only by the heating step without performing the pressurizing step. Alternatively, the protrusion 5 and the sheet 4 may be bonded by the above-mentioned bonding means without any one of the heating step and the pressurizing step. Like this embodiment, when the liquid composition 3 contains a solvent, by evaporating the solvent after the filling step, the shape of the composition for forming the needle-shaped portion starts to be fixed (forming step). Therefore, it is impossible to carry out the step of following the composition for forming the needle-shaped part and the substrate 11 before the forming step, and the following step must be carried out after the forming step. However, in the present invention, since the sheet 4 contains a water-soluble material, it can Absorption of the needle-shaped portion-forming composition by the substrate 11 is suppressed, and the needle-shaped portion can be obtained in a desired shape.

(Removal step) After the next step is completed, as shown in FIG. 3(f), a removal step is performed, which separates the protruding portion 5 and the sheet 4 that are subsequently cured from the mold 2, and removes the protruding portion 5 and the sheet 4. water-soluble materials.

The cleaning solution in this removal step contains water, and the removal step is performed by, for example, placing the protruding portion 5 and the sheet 4 in the cleaning solution. By standing still in the washing liquid containing water, the parts communicating with the outside among the first water-soluble material and the second water-soluble material contained in the protrusions 5 and the sheet 4 are dissolved and flow into the water to be removed. In addition, the cleaning liquid may also be a mixed solvent of water and alcohol. By this removal, the hole part 13 is formed in the protrusion part 5 as shown in FIG.3(g), and is formed as the needle-shaped part 12. Thereby, the microneedle structure 10 was obtained. In the removing step, by removing the second water-soluble material, the substrate hole portions of the substrate 11 blocked by the second water-soluble material are at least partially restored, and thus the sheet 4 becomes to exhibit good liquid permeability. In addition, when the sheet 4 contains the second water-soluble material and the second water-insoluble material, the substrate 11 contains the second water-insoluble material and the pores of the substrate have been restored. In this case, by dissolving the part of the first water-soluble material in contact with the second water-soluble material, the second water-insoluble material remains in the substrate 11, and the needle-like portion 12 extends to the substrate 11 side. The hole portion 13 is further connected to the base material hole portion of the base material 11 . The pores 13 connected to the pores of the base material constitute liquid passages. Thereby, in the microneedle structure 10 , liquid can easily pass through the interface between the needle-shaped portion 12 and the base material 11 .

(Modification of Protrusion Forming Means) In the present embodiment, the liquid composition 3 is filled in the concave portion 1 to form the needle-shaped portion 12, but it is not limited thereto. For example, the forming step may be performed by preparing a liquid composition 3 with a high viscosity, and dropping the high-viscosity liquid composition 3 onto the porous substrate 11 using a dispenser or the like, Thereby, the needle-like portion 12 is formed. Even in this case, by including at least the first water-soluble material in the base material 11 , it is possible to prevent the liquid composition 3 from being absorbed into the base material 11 and preventing the needle-shaped portion 12 from obtaining a desired shape.

In the present embodiment, although the concave portion 1 is filled with the liquid composition 3 containing the first water-insoluble material, the first water-soluble material soluble in water, and the solvent to form the needle-shaped portion 12, it is also possible to form the needle-shaped portion 12 by using The composition containing the first water-insoluble material and the first water-soluble material that is soluble in water and does not contain a solvent is filled into the recess 1 while being melted, thereby forming the protrusion 5 . Specifically, first, such a composition is molded into an appropriate shape (for example, a disc shape) to produce a solid composition. Then, an adhesive layer is provided on the sheet 4 in advance, and the adhesive layer of the sheet 4 is bonded to one surface of the solid composition. Thereby, the bonding step of bonding the composition before the formation of the needle-like portion 12 and the base material 11 is carried out at room temperature. Thereafter, the surface of the solid composition with the base material opposite to the side on which the base material is pasted faces the recess 1, and the solid composition is filled into the recess 1 while being heated to melt, and thereafter, Protrusions 5 are formed by cooling. In the microneedle structure 10, if the obtained needle-shaped portion 12 has a porous structure, the bonding area of the needle-shaped portion 12 to the substrate 11 becomes smaller, which becomes disadvantageous for the adhesion between them, but in In such a state where the base material 11 and the solid composition are bonded, the adhesion between the needle-like portion 12 and the base material 11 can be improved by heating in the forming step.

[Manufacturing method of inspection patch] By disposing the analysis sheet 21 at a predetermined position on the back side of the substrate 11 of the obtained microneedle structure 10 (installation step), and laminating the adhesive film so as to cover the analysis sheet 21 22, and inspection patches can be manufactured. As the lamination method, a conventionally known method can be used. For example, after the analysis sheet 21 has been placed on the back side of the substrate 11, a generally used rubber-based adhesive, acrylic adhesive, polymer adhesive, etc. are laminated. The adhesive film 22 formed by forming an adhesive layer such as silicone adhesive on the adhesive film substrate can be used to manufacture inspection patches. Drug administration patches can also be produced by the same method.

[Modification of microneedle structure and its manufacturing method] In the above-mentioned embodiment of the microneedle structure and its manufacturing method, although a plurality of needle-like parts 12 are directly provided on the base material 11, the needle-like parts 12 There may also be a base, and each needle-shaped portion 12 is provided on the base material 11 through the base, wherein the base becomes the base of each needle-shaped portion 12, and has holes similarly to each needle-shaped portion 12 department. In this case, as long as the base is made of the same material as that described for the needle-shaped part 12, or is formed by the same steps, the needle-shaped part 12 and the base material 11 can also be obtained through the base. continuity. In the above-mentioned filling step, in order to form the base, it is only necessary to fill the mold 2 with the liquid composition 3 in excess of the volume corresponding to the concave portion 1 and let it overflow from the concave portion 1 . In this case, the base can be formed by providing a wall portion on the surface of the mold 2 where the concave portion 1 is formed, which is equivalent to providing a liquid storage portion, and the liquid composition overflowing from the concave portion 1 is stored in the liquid storage portion.

In the present embodiment, although the porous base material 11 contains the second water-soluble material which is soluble in water and the second water-insoluble material which is insoluble in water, the sheet 4 may be used instead of this case. The resin film provided with the through hole is bonded to the protrusion 5 . In this case, by dissolving the first water-soluble material in the removal step, the hole portions 13 extending to the base material 11 side of the needle-shaped portion 12 are further connected to the through holes of the base material 11 . The hole portion 13 connected to the through hole constitutes a liquid passage. Accordingly, in the microneedle structure 10 , the liquid easily passes from the needle-shaped portion 12 through the through-hole of the substrate 11 to reach the surface of the substrate 11 opposite to the surface on which the needle-shaped portion 12 is provided.

Hereinafter, the present invention will be described in more detail by means of examples. [Example] Blend 100 parts by weight of polyethylene glycol (molecular weight 4000, melting point 40°C) as the first water-soluble material, and 100 parts by weight of polycaprolactone (molecular weight 10,000, melting point 40°C) as the first water-insoluble material. 60° C.), 800 parts by weight of ethyl acetate as a solvent (organic solvent), and a liquid composition having a solid content concentration of 20%.

0.7 ml of the liquid composition was poured into a mold made of polydimethylsiloxane having a concave portion having the following shape and the like. The size of the region of the mold filled with the liquid composition was a square with four sides of 15 mm, and a liquid storage part was provided above the surface where the concave part was formed. The liquid composition is filled up to the upper side of the concave portion formation surface, and the needle-shaped portion has a base. ・Shape of recessed part: Square weight shape with square cross section ・Length of one side of the largest cross section of the concave part: 500μm ・Height of concave part: 900μm ・Interval between recesses: 1000μm ・Number of recesses: 13 per wale, 169 in total in 13 rows ・Arrangement of concave parts: Square lattice shape

Next, the mold was placed on an ultrasonic cleaning device (ultrasonic cleaning machine AU-10C/manufactured by Aiwa Medical Industry Co., Ltd.), and ultrasonic treatment was performed for 1 minute in an environment at a temperature of 23°C.

Next, as a degassing step, vacuum drying was performed for 30 minutes in a reduced-pressure atmosphere at a temperature of 23° C. and a pressure of 0.05 MPa. Thereafter, heating was performed for 30 minutes at 110° C. in an environment without adjusting the humidity.

On the other hand, 100 parts by weight of polyethylene glycol (the same as the first water-soluble material) as the second water-soluble material, and 100 parts by weight of polycaprolactone (the same as the first water-soluble material) as the second water-insoluble material were blended. One water-soluble material is the same), 1800 parts by weight of ethyl acetate as a solvent (organic solvent), and a solution with a solid content concentration of 10% is prepared. In addition, filter paper (WHATMAN FILTER PAPER GRADE4/GE Healthcare Life Sciences Co., Ltd.) as a porous substrate was immersed in the above solution, taken out, and dried at 23° C. for 60 minutes to prepare a sheet.

The sheet was placed on the exposed surface of the base provided above the protrusion of the recess formed in the heated mold, and a weight (500 g) was placed on the placed sheet, whereby A pressurization step is performed. Thereafter, after keeping it at a low temperature of 3°C for 10 minutes, peel off the protrusion, base, and sheet from the mold, and immerse in purified water at 23°C for 24 hours to dissolve and remove the protrusion, base, and sheet. The first water-soluble material and the second water-soluble material.

Thereafter, the first water-soluble material and the second water-soluble material are dissolved and removed, and the protruding portion, the base portion, and the sheet are bonded and left standing for 24 hours at 23° C. and a relative humidity of 50% to evaporate the water and carry out After drying, a microneedle structure is produced.

As a comparative example, a microneedle structure was produced in the same manner as in the examples except that the step of immersing the porous base material in the solution was not performed.

For the microneedle structures obtained in Examples and Comparative Examples, the root of the needle-shaped part was peeled off from the base material with tweezers, and the interior of the needle-shaped part was observed with an optical microscope (magnification: 50 times and 100 times). In the case of the microneedle structure of the example, the resin was filled almost without gaps in the base of the needle-shaped part, but in the microneedle structure of the comparative example, there were gaps, cavities, etc., and the filling was not sufficient. .

Next, in Examples and Comparative Examples, the protrusions were formed by cooling the composition, and the protrusions were observed with an optical microscope (magnification: 50 times and 100 times) after peeling off from the mold and before immersing in purified water, and the needles were calculated. The amount of shape parts remaining on the substrate. The ratio of this number of residues to the total number of designed needles was calculated as the transfer rate. In the microneedle structure obtained in the example, if the transfer rate is more than 50%, the transferability is good, while the transfer rate of the microneedle structure obtained in the comparative example is less than 50%, and the transferability is low. [Industrial Utilization]

The microneedle structure of the present invention can be used as an inspection patch, for example, by arranging an analysis sheet on the back side and laminating it with an adhesive film.

1: Concave 2: Mold 3: liquid composition 4: piece 5: Protrusion 10: Microneedle structure 11: Substrate 12: Acicular part 13: Hole 20: Check the patch 21: Analysis sheet 22: film

FIG. 1 is a schematic partial cross-sectional view of the microneedle structure of the present invention. Fig. 2 is a cross-sectional view of an inspection patch using the microneedle structure of the present invention. FIG. 3 is an explanatory diagram showing the flow of a method of manufacturing a microneedle structure.

10: Microneedle structure

11: Substrate

12: Acicular part

13: Hole

Claims (12)

A method of manufacturing a microneedle structure, which is a method of manufacturing a microneedle structure having an acicular portion having a hole on one side of a substrate having liquid permeability in the thickness direction, characterized in that it comprises: a forming step of forming a protrusion using a needle-shaped portion-forming composition containing a first water-insoluble material and a first water-soluble material; a subsequent step of adhering the aforementioned composition or the aforementioned protrusion formed in the aforementioned forming step to the aforementioned substrate; and A removing step of immersing the protrusion and the base material in water to dissolve and remove the first water-soluble material, thereby forming the needle-shaped portion and the hole portion from the protrusion. The method for manufacturing a microneedle structure according to claim 1, wherein the substrate having liquid permeability in the thickness direction is a porous substrate, The aforementioned adhering step is a step of adhering the aforementioned protrusion formed in the aforementioned forming step to a sheet comprising the second water-soluble material and the aforementioned porous base material, The aforementioned removing step is a step of dissolving and removing the aforementioned first water-soluble material and the second water-soluble material. The method for manufacturing a microneedle structure according to claim 2, wherein the porous substrate is a substrate composed of a fibrous substance. The method of manufacturing a microneedle structure according to claim 2 or 3, wherein the sheet contains a second water-insoluble material. The method for manufacturing a microneedle structure according to claim 4, wherein the first water-insoluble material is the same as the second water-insoluble material. The method for producing a microneedle structure according to claim 2 or 3, wherein the sheet is obtained by impregnating the base material with a second water-soluble material. The method for manufacturing a microneedle structure according to claim 3, wherein the base material composed of fibrous material is non-woven fabric, woven fabric, knitted fabric or paper. The method for manufacturing a microneedle structure according to claim 1, wherein the base material is a base material made of a liquid-impermeable material, and has through holes formed along the thickness direction. The method for manufacturing a microneedle structure according to claim 1, wherein the forming step includes a filling step of filling the needle-shaped portion-forming composition into a mold having concave portions. The method for producing a microneedle structure according to claim 9, wherein, in the filling step, the composition for forming the needle-like portion contains a solvent, In the aforementioned forming step, the aforementioned solvent is evaporated. The method for manufacturing a microneedle structure according to claim 1, further comprising: a step of providing a bodily fluid analysis means and/or on the surface of the base material opposite to the surface on which the needle-like portion is provided. Means of storage of physiologically active substances. A microneedle structure having an acicular portion having a hole on one side of a porous base material, characterized in that: The above-mentioned needle-shaped part is made of the first water-insoluble material, and is directly arranged on the above-mentioned porous substrate, The aforementioned porous substrate contains a second water-insoluble material.

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