JP7786938B2 - Manufacturing method of hollow protruding tool, and hollow protruding tool - Google Patents

Description

The present invention relates to a method for manufacturing hollow protrusions.

In the medical and cosmetic fields, microneedle technology is known, which allows for painless delivery of agents by inserting tiny needles into shallow layers of the skin. Various methods for manufacturing such microneedles have been investigated. For example, Patent Document 1 discloses a technique in which a protrusion-forming section is inserted into one side of a base sheet to form non-penetrating hollow protrusions, and laser light is applied from the other side of the base sheet to form openings. Patent Document 2 also discloses a technique in which a multi-material laminate section, in which a base sheet made from a first material and a second material are laminated, is provided with a convex shape to form micro-hollow protrusions. Patent Document 3 also discloses a technique in which a needle-shaped object having a substrate and protrusions formed on one side of the substrate is irradiated with laser light from the other side of the substrate to form through-holes that penetrate both the substrate and the protrusions.

Japanese Patent Application Laid-Open No. 2019-50927 Japanese Patent Application Laid-Open No. 2019-205767 International Publication No. 2015-125475

In the technology described in Patent Document 1, the opening area of the outer surface of the side wall of the hollow protrusion is larger than the opening area of the inner surface of the side wall. Therefore, in the microneedle manufactured by the technology described in the document, the agent that passes through the opening and comes out of the opening on the outer surface of the side wall is released over a wide area, making it difficult to inject the agent in a pinpoint manner into a desired site, such as a specific layer in the skin.
In the technology described in Patent Document 3, through-holes are formed along the protruding direction of the protrusions, so the agent released from the through-holes spreads in the protruding direction, making it difficult to inject the agent precisely into the desired area.
Patent Document 2 does not describe at all the formation of openings in the fine hollow projections.
Therefore, an object of the present invention is to provide a hollow protruding tool that allows for pinpoint injection of liquid into a desired area, and a method for manufacturing the same.

The present invention relates to a method for manufacturing a hollow protrusion tool, which includes a hole forming step of forming holes penetrating the side walls of minute hollow protrusions by a non-contact hole forming means.
The method for manufacturing the hollow protrusion tool includes a sheet laminating step of laminating a base sheet containing a thermoplastic resin and a molding auxiliary sheet having a higher absorption rate of energy applied by the perforation means than the base sheet to form a laminated sheet;
a protrusion forming step of contacting a convex mold portion having a heating portion with the laminate sheet from the molding auxiliary sheet side, and piercing the convex mold portion into the laminate sheet toward the base sheet side while softening the contacting portion of the laminate sheet by heat;
a release step of pulling out the convex portion from the laminated sheet;
the hole forming step performed after the release step;
It is preferable to include a separation step of separating the hollow protrusions from the molding aid sheet after the hole forming step.

The present invention also relates to a hollow protruding tool having a fine hollow protruding portion with an opening.
The aperture preferably penetrates the side wall of the hollow projection.
It is preferable that the area of one of the openings located on the outer surface of the side wall is smaller than the area of the other opening located on the inner surface of the side wall.

The hollow protrusion device manufacturing method and hollow protrusion device of the present invention can provide a hollow protrusion device that can inject liquid precisely into the desired area.

FIG. 1 is a perspective view showing an example of a hollow protrusion device (microneedle array) manufactured by the manufacturing method of the present invention. FIG. 2 is a perspective view of one hollow protrusion shown in FIG. FIG. 3(a) is a cross-sectional view taken along line III-III shown in FIG. 2, and FIG. 3(b) is an explanatory diagram showing a method for measuring the tip diameter of the hollow protrusion. FIG. 4 is a cross-sectional view that schematically shows a state in which the hollow protruding portion of the hollow protruding device shown in FIG. 1 has been inserted into the skin. FIG. 5 is a diagram showing the overall configuration of a preferred embodiment for manufacturing the hollow protruding tool shown in FIG. FIG. 6 is an explanatory diagram showing a method for measuring the tip diameter and tip angle of the convex portion. 7(a) to 7(g) are diagrams illustrating a manufacturing method for manufacturing the hollow protrusion tool shown in FIG. 1 using the manufacturing apparatus shown in FIG. 8(a) to 8(d) are diagrams illustrating the mechanism by which an opening is formed in a hollow protrusion when a laser is irradiated onto a laminated protrusion.

The present invention will now be described based on preferred embodiments with reference to the drawings. First, one embodiment of a hollow protrusion tool obtained by the manufacturing method of the present invention will be described with reference to Figures 1 to 4.

[First embodiment]
FIG. 1 shows a microneedle array 1 (hollow protrusion device), which is one embodiment of a hollow protrusion device having fine hollow protrusions. The microneedle array 1 of this embodiment has a sheet-like base 2 and a plurality of hollow protrusions 3, with openings 8 provided in the sidewalls 31 of the hollow protrusions 3. The hollow protrusions 3 protrude from the base 2 and are hollow inside. The openings 8 are formed in a portion that surrounds the hollow portion of the hollow protrusion 3 and is located closer to the base 2 than the apex of the hollow portion. The microneedle array 1 opens on the opposite side of the base 2 from the portion where the hollow protrusions 3 are formed, and an opening 7 (see FIG. 3(a)) is formed. The opening 7 is connected to the internal space V of the hollow protrusions 3 (see FIG. 3(a)). The internal space V of the hollow protrusions 3 is formed in a conical shape corresponding to the external shape of the hollow protrusions 3. That is, the inner peripheral surface of the hollow protrusion 3 has a shape corresponding to the outer peripheral surface of the hollow protrusion 3. The shape of the hollow protrusion 3 can be any shape, such as a cone, a truncated cone, a cylinder, a prism, a pyramid, or a truncated pyramid.

The microneedle array 1 has a plurality of truncated cone-shaped hollow protrusions 3 arranged in an array (matrix or matrix) on the upper surface of the base 2. Specifically, nine hollow protrusions 3 are arranged in an array, with three rows in direction Y along direction Y1 (the longitudinal direction of the base sheet 20) in which the base sheet 20 described below is transported, and three columns in direction X perpendicular to direction Y. Direction X is the direction perpendicular to direction Y1 in which the base sheet 20 is transported (the width direction of the base sheet 20). There are no particular limitations on the number and arrangement of hollow protrusions 3, and any number and arrangement may be used.

When applying the microneedle array 1 to the skin, it is preferable that the tips of the hollow protrusions 3 can penetrate as deeply as the stratum corneum at the shallowest point and as deeply as the dermis or subcutaneous tissue. From this perspective, the protrusion height H1 of the hollow protrusions 3 (see FIG. 3(a)) is preferably 0.01 mm or more, more preferably 0.02 mm or more, and also preferably 10 mm or less, more preferably 5 mm or less, and also preferably 0.01 mm to 10 mm, more preferably 0.02 mm to 5 mm. The protrusion height H1 is the distance between the upper surface 2U of the base 2 from which the hollow protrusions 3 protrude and an imaginary line P1 passing through the apex P of the hollow protrusions 3, and the upper surface 2U. If the upper surface 2U is not flat but has wavy irregularities, the height direction Z of the hollow protrusions 3 is aligned vertically, and the imaginary line P1 is a line passing through the apex P and parallel to the horizontal direction. The distance between the imaginary line P1 and the top of the convex portion of the unevenness on the upper surface 2U is defined as the protrusion height H1. The distance between the imaginary line P1 and the upper surface 2U (protrusion height H1) is measured by observing the hollow protrusion 3 under magnification using a scanning electron microscope (SEM) or microscope.

The thickness T1 of the hollow protrusion 3 (see Figure 3(a)) may be constant along the height direction Z of the hollow protrusion 3, or may vary. For example, the thickness T1 of the hollow protrusion 3 may gradually decrease from the base 2 side toward the tip side in the height direction Z.

The thickness T1 of the hollow protrusion 3 is determined by the following method. In a longitudinal section including the apex P of the hollow protrusion 3 and along the height direction Z, the distance between the outer surfaces at the same position in the height direction Z is defined as the outer diameter r1, and the distance between the inner surfaces at the same position in the height direction Z is defined as the inner diameter r2. The outer diameter r1 and the inner diameter r2 are measured at a position in the height direction Z of the hollow protrusion 3 where the inner diameter r2 is greater than 0, and the thickness T1 is determined by the following formula (1).
Thickness T1 = (r1 - r2) / 2 (1)
r1: outer diameter r2: inner diameter

The thickness T2 of the base portion 2 (see Figure 3(a)) is preferably 0.01 mm or more, more preferably 0.02 mm or more, and preferably 1.0 mm or less, more preferably 0.7 mm or less, and preferably 0.01 mm or more and 1.0 mm or less, more preferably 0.02 mm or more and 0.7 mm or less. Thickness T2 is also the thickness of the substrate sheet 20, which will be described later.

The hollow protrusion 3 has an aperture 8. The aperture 8 penetrates the side wall 31 of the hollow protrusion 3. The aperture 8 communicates with the internal space V of the hollow protrusion 3 (see Figure 3(a)) and can be formed at any position on the outer surface of the hollow protrusion 3. One opening 8a of the aperture 8 is located on the outer surface 31a of the side wall 31. The other opening 8b of the aperture 8 is located on the inner surface 31b of the side wall 31.

The pair of openings 8a, 8b of the aperture 8 have different opening areas. Specifically, the area Sa of one opening 8a located on the outer surface 31a of the side wall 31 is smaller than the area Sb of the other opening 8b located on the inner surface 31b of the side wall 31. The advantages of the aperture 8 being formed in the side wall 31 and the area Sa of the opening 8a and the area Sb of the opening 8b being in this relationship are as follows.
For example, as shown in FIG. 4, when the hollow protrusions 3 of the microneedle array 1 are inserted into the epidermis S1 of the skin S and an agent is injected into the epidermis S1, the agent enters the openings 8 through the openings 8b, which have a relatively large opening area, and is released through the openings 8a, which have a relatively small opening area. The relatively small opening area of the openings 8a, which serve as the outlet for the agent release, makes it difficult for the released agent to spread, allowing the agent to be delivered precisely into the epidermis S1. While FIG. 4 shows an example of delivering an agent to the epidermis S1, the site to which the agent is delivered is not limited to the epidermis S1 and may be, for example, the dermis S2, subcutaneous tissue S3, subcutaneous fat (not shown), muscle, or vein (not shown). If, as in the case of the through-holes of the protrusions of Patent Document 3, one opening is located on the side wall of the protrusion and the other opening is located at the base, the through-holes are formed along the protrusion direction of the protrusions, and the agent released from the through-holes spreads in the protrusion direction, making it difficult to deliver the agent to the desired site with pinpoint accuracy.

From the viewpoint of enabling more pinpointed supply of the agent, the ratio Sa/Sb of the area Sa of the opening 8a located on the outer surface 31a of the side wall 31 to the area Sb of the opening 8b located on the inner surface 31b of the side wall 31 is preferably 1 or less, more preferably 0.9 or less, and even more preferably 0.8 or less. From the viewpoint of ensuring the strength of the side wall 31 around the opening 8, it is preferably 0.001 or more, more preferably 0.004 or more, and even more preferably 0.01 or more. From the viewpoint of achieving both of these, it is preferably 0.001 to 1, more preferably 0.004 to 0.9, and even more preferably 0.01 to 0.8.

The inner diameter of the opening 8 of the hollow protrusion 3 may decrease in stages from the inner surface 31b of the side wall 31 toward the outer surface 31a. However, from the perspective of enabling even more pinpointed supply of the agent, it is preferable that the inner diameter gradually decrease from the inner surface 31b of the side wall 31 toward the outer surface 31a.

In addition, in this embodiment, the angle α between the central axis L1 of the hollow protrusion 3 and the opening 8 is preferably 15 degrees or greater, more preferably 25 degrees or greater, even more preferably 30 degrees or greater, and preferably 90 degrees or less, more preferably 80 degrees or less, even more preferably 65 degrees or less, and preferably 15 degrees or greater but 90 degrees or less, more preferably 80 degrees or greater but 65 degrees or less, even more preferably 30 degrees or greater but 65 degrees or less. By setting each α within the above range, the agent released from the opening 8 is more likely to spread in a direction perpendicular to the protruding direction of the hollow protrusion 3, allowing for more pinpoint injection of the agent. The angle α refers to the angle between the central axis L1 and the imaginary line L2 connecting the centroid Qa of opening 8a and the centroid Qb of opening 8b.

The tip diameter L of the hollow protrusion 3 (see Figure 3(b)) is preferably 0.001 mm or more, more preferably 0.005 mm or more, and preferably 0.5 mm or less, more preferably 0.3 mm or less, and preferably 0.001 mm or more and 0.5 mm or less, more preferably 0.005 mm or more and 0.3 mm or less. The tip diameter L of the hollow protrusion 3 is measured as follows.

[Measurement of the tip diameter of the hollow protrusion 3]
The tip of the hollow protrusion 3 is observed under magnification using a scanning electron microscope (SEM) or a microscope. For the tip of the hollow protrusion 3 being observed, an imaginary straight line ILa is extended along the straight line portion of one of the two sides 1a, 1b, 1a, as shown in FIG. 3 . Similarly, an imaginary straight line ILb is extended along the straight line portion of the other side 1b. Next, on the tip side, the point where one side 1a deviates from the imaginary line ILa is determined as the first tip point 1a1, and the point where the other side 1b deviates from the imaginary line ILb is determined as the second tip point 1b1. The length L of the straight line connecting the first tip point 1a1 and the second tip point 1b1 thus determined is measured, and this is defined as the tip diameter L of the hollow protrusion 3.

Next, a preferred embodiment of the method for manufacturing hollow protrusion devices of the present invention will be described with reference to Figures 5 to 7, using the above-mentioned method for manufacturing the microneedle array 1 as an example. Figure 5 shows the overall configuration of a manufacturing apparatus 100 of one embodiment used to carry out the manufacturing method of this embodiment. As mentioned above, each hollow protrusion 3 of the microneedle array 1 is very small, but for ease of explanation, each hollow protrusion 3 of the microneedle array 1 is depicted very large in Figure 5.

As shown in Figure 5, the manufacturing apparatus 100 includes a sheet stacking unit 40 that stacks a base sheet 20 and a molding aid sheet 21 (described later) to form a laminated sheet 4, a protrusion forming unit 50 that has a convex portion 51 for forming hollow protrusions 3 in the base sheet 20, and an aperture forming unit 60 that has a non-contact aperture opening means 6A for forming apertures 8 that penetrate the hollow protrusions 3.

The manufacturing method for the microneedle array 1 using the manufacturing apparatus 100 includes an aperture forming step in which apertures 8 penetrating the sidewalls 31 of the minute hollow protrusions 3 are formed using a non-contact aperture forming means 6A. The manufacturing method for the microneedle array 1 also includes a sheet lamination step, a protrusion forming step, a release step, and a separation step. In this embodiment, the aperture forming step is performed after the release step. The separation step is performed after the aperture forming step.

In this embodiment, as shown in FIG. 5, first, a strip-shaped base sheet 20 containing a thermoplastic resin is unwound from a raw roll of the base sheet 20 and conveyed in the conveying direction Y. Separately, a strip-shaped forming aid sheet 21 is unwound from a raw roll of the forming aid sheet 21 and conveyed in the conveying direction Y. The method of conveying the base sheet 20 and the forming aid sheet 21 may be intermittent conveyance, in which conveyance is stopped once the base sheet 20 has been fed to a predetermined position and then resumed, or continuous conveyance, in which conveyance continues without being stopped. Known conveyance means such as a conveyor roll or a conveyor can be used as the conveying means.

The portion of the base sheet 20 other than the portion where the hollow protrusions 3 are formed constitutes the base 2 of the microneedle array 1 .
Examples of the thermoplastic resin contained in the base sheet 20 include polyfatty acid ester, polycarbonate, polypropylene, polyethylene, polyester, polyamide, polyamideimide, polyetheretherketone, polyetherimide, polystyrene, polyethylene terephthalate (PET), polyvinyl chloride, nylon resin, acrylic resin, and combinations thereof, and polyfatty acid ester is preferably used from the viewpoint of biodegradability. Specific examples of polyfatty acid ester include polylactic acid (PLA), polyglycolic acid, and combinations thereof.

The base sheet 20 may be formed from a mixture containing hyaluronic acid, collagen, starch, cellulose, etc. in addition to a thermoplastic resin. The thickness of the base sheet 20 is equal to the thickness T2 of the base portion 2 of the microneedle array 1.

The base sheet 20 is preferably formed primarily from a thermoplastic resin. "Mainly made of a thermoplastic resin" means that it contains 50% or more by mass of thermoplastic resin. The base sheet 20 preferably contains 50% or more by mass of thermoplastic resin, more preferably 90% or more by mass, and even more preferably the thermoplastic resin content is 100% by mass. A base sheet 20 mainly made of a thermoplastic resin is usually in the form of a film.

The forming aid sheet 21 has a higher absorption rate of the energy applied by the perforation means 6A than the base sheet 20. The energy absorption rate can be measured, for example, by the following method.
<Method for measuring energy absorption rate>
When the sheet to be measured is irradiated with light of the same wavelength as that irradiated by the perforation means, the absorbed energy is the energy incident on the sheet minus the energy reflected by the sheet and the energy transmitted through the sheet. The energy absorptance is calculated as the ratio of the energy absorbed by the sheet to the energy incident on the sheet. For example, when the incident energy is UV light, the absorptance is measured using a spectrophotometer or the like.

Next, in the manufacturing method of this embodiment, as shown in Figures 5 and 7(a), a sheet lamination process is performed in which the base sheet 20 and the molding aid sheet 21 are laminated to form the laminated sheet 4. The sheet lamination process is performed in the sheet lamination unit 40. As shown in Figure 5, the sheet lamination unit 40 has a pair of opposing rolls 41, 42. In the manufacturing method of this embodiment, the base sheet 20 and the molding aid sheet 21 are inserted between the pair of rolls 41, 42 to form the laminated sheet 4 in which the two are laminated. In the sheet lamination process, the molding aid sheet 21 may be laminated over the entire base sheet 20, or may be laminated over only a portion of the base sheet 20.

Next, a protrusion forming step is carried out in a protrusion forming section 50 having a convex portion 51 as shown in FIG.
The convex portion 51 has a convex bottom portion 52 and a plurality of convex portions 53 protruding from the convex bottom portion 52. That is, the convex portion 51 has a support (convex bottom portion 52) that serves as a base, and portions (convex portions 53) protruding at a plurality of locations from one surface of the support. The convex portion 51 is not limited to this form, and may have a structure consisting only of the protruding portions (convex portions 53).

The convex shapes 53 provided on the convex portion 51 correspond to the shape of the internal space V of the hollow protrusion 3 in the microneedle array 1. The outer peripheral surface 54 on the tip side of the convex shape 53 (see Figure 6) has a shape that follows the inner surface 31b of the side wall 31 of the hollow protrusion 3. The number and arrangement of the convex shapes 53 on the convex portion 51 correspond to the number and arrangement of the hollow protrusions 3 in the microneedle array 1.

A variety of known heating units can be used for the convex portion 51. In this embodiment, the heating unit is an ultrasonic vibration device equipped with an ultrasonic oscillator and an ultrasonic horn that vibrates at a predetermined ultrasonic amplitude and oscillation frequency in response to an ultrasonic signal transmitted from the ultrasonic oscillator. The ultrasonic vibration device is provided on the convex bottom portion 52 of the convex portion 51, and the vibration of the ultrasonic horn causes the convex portion 53 to vibrate.

In the protrusion formation process, as shown in Figures 5 and 7(b), a convex portion 51 having a heating portion is brought into contact with the laminate sheet 4 from the molding auxiliary sheet 21 side, and the contacting portion of the laminate sheet 4 with the convex portion 51 is softened by heat while the convex portion 51 is inserted into the laminate sheet 4 toward the base sheet 20 side. More specifically, the convex portion 53 of the convex portion 51 is brought into contact with the laminate sheet 4, and the contacting portion of the laminate sheet 4 with the convex portion 53 is softened by heat while the convex portion 53 is inserted into the laminate sheet 4.

The convex mold 53 heats the laminate sheet 4 that it contacts using the ultrasonic vibration device described above, softening the contacting portion and making it more susceptible to deformation. The softened portion of the laminate sheet 4 is stretched as the convex mold 53 penetrates, deforming along the outer surface of the convex mold 53 to form the laminate protrusion 44. The laminate protrusion 44 has a structure in which a molding aid sheet 21 is laminated on the inner side of the base sheet 20, and the portion of the laminate protrusion 44 made of the base sheet 20 becomes a hollow protrusion 3 through subsequent processes.

Next, the release process is performed. In this process, as shown in Figure 7(c), the convex portion 51 is pulled out from the laminated sheet 4. More specifically, the convex portion 53 is pulled out from the inside of the laminated projection 44. In this embodiment, a molding aid sheet 21 is arranged so as to fit along the inner surface of the hollow projection 3 formed in the release process.

Next, the aperture formation process is performed. In this process, apertures 8 penetrating the sidewalls 31 of the hollow protrusions 3 are formed using a non-contact aperture forming means 6A. This process is performed in the aperture formation unit 60, as shown in FIG. 5. As shown in FIG. 5, the aperture formation unit 60 is equipped with a non-contact aperture forming means 6A on the substrate sheet 20 side of the laminate sheet 4. Examples of non-contact aperture forming means 6A include processing devices that use a heat source, such as a laser device that emits laser light, a hot air emitter that emits hot air, or a halogen lamp emitter that emits infrared light. The manufacturing apparatus 100 uses a laser device 6A because of its ability to focus light and provide high-precision energy control, which are necessary for micromachining. As shown in FIG. 5, the laser device 6A has an irradiation head 61, which is a galvanometer scanner that freely scans laser light 6L. The irradiation head 61 is positioned on the substrate sheet 20 side of the laminate sheet 4, spaced a certain distance above the substrate sheet 20 in the thickness direction. In this way, when laser light 6L is irradiated onto the non-penetrating hollow protrusions 3 from the irradiation head 61 located on the base sheet 20 side of the laminated sheet 4 to form openings 8 in the hollow protrusions 3, burrs are less likely to form around the openings 8 on the outer surface 31a of the hollow protrusions 3. Furthermore, because openings 8 can be easily formed at any position in the hollow protrusions 3, it is easy to freely control the position relative to the skin surface to which a liquid agent or the like is to be supplied.

As shown in FIG. 5 , the irradiation head 61 includes a lens 63 that focuses the irradiated laser beam 6L, two mirrors 62 that freely scan the focused laser beam 6L, and a protective lens 66. The protective lens 66 may or may not be provided, but is preferably provided to prevent dust and dirt from entering the optical system. The mirror 62 is attached to the motor shaft. The mirror 62 includes a mechanism for moving the irradiation point of the laser beam 6L, where the laser beam 6L strikes the lamination protrusion 44 on the laminate sheet 4, in the conveying direction Y of the base sheet 20 and a mechanism for moving the irradiation point in the direction X perpendicular to the conveying direction of the laminate sheet 4, thereby enabling the laser beam 6L to be freely scanned. The lens 63 is movable in the optical axis direction and includes a mechanism for focusing the laser beam 6L to maintain a constant spot diameter at the irradiation point of the laser beam 6L striking the lamination protrusion 44, and a mechanism for moving the irradiation point of the laser beam 6L in the thickness direction Z of the base sheet 20. The irradiation head 61, which has a mirror 62 and a lens 63, is capable of adjusting the irradiation point of the laser light 6L three-dimensionally in the X, Y, and Z directions. Therefore, by three-dimensionally coordinating the desired irradiation position of each of the nine laminated protrusions 44, the laser light 6L can be irradiated with a predetermined spot diameter at the desired irradiation position of each laminated protrusion 44. It is preferable to use laser light 6L that can be absorbed by the hollow protrusions 3 that form the openings. When the substrate sheet 20 forming the hollow protrusions 3 is a sheet such as a film mainly made of a thermoplastic resin, it is preferable to use a _CO2 laser, excimer laser, argon laser, YAG laser, LD laser (semiconductor laser), _YVO4 laser, fiber laser, etc. as the laser light 6L.

In the aperture formation process of this embodiment, as shown in FIG. 7(d), laser light 6L is irradiated onto the lamination projection 44 to form apertures 8 in the sidewalls 31 of the hollow projection 3. This will be described in more detail with reference to FIG. 8. In this embodiment, as described above, the molding aid sheet 21 has a higher energy absorption rate than the base sheet 20. Therefore, when laser light 6L is irradiated onto the lamination projection 44 from the base sheet 20 side as shown in FIG. 8(a), the molding aid sheet 21 absorbs more energy than the base sheet 20, and therefore melts before the base sheet 20 as shown in FIG. 8(b). Then, as shown in FIG. 8(c), the melting heat of the molding aid sheet 21 melts the base sheet 20. The melting heat of the molding aid sheet 21 is transferred to the base sheet 20 via the contact area between the molding aid sheet 21 and the base sheet 20. Therefore, the portion of the base sheet 20 closest to the molten portion of the forming aid sheet 21, i.e., the inner surface 31b of the side wall 31 of the base sheet 20, receives more melting heat energy than the portion of the base sheet 20 farther from the molten portion of the forming aid sheet 21, i.e., the outer surface 31a of the side wall 31 of the base sheet 20. Therefore, as shown in FIG. 8(d), the inner surface 31b of the side wall 31 of the base sheet 20 melts over a wider area than the outer surface 31a. As a result, of the apertures 8 formed in the base sheet 20, one opening 8a located on the outer surface 31a of the side wall 31 has a smaller opening area than the other opening 8b located on the inner surface 31b.

Next, a separation step is carried out. In the separation step, the hollow protrusions 3 with the openings 8 formed therein are separated from the molding auxiliary sheet 21, as shown in Figure 7(g). This results in a continuous sheet with fine hollow protrusions 3 with openings 8 formed therein.
The manufacturing method of this embodiment may include a cutting step of cutting the obtained continuous sheet into predetermined areas after the separating step. In the cutting step, the continuous sheet is cut by a cutting device. This produces the microneedle array 1. The cutting device may be, for example, one equipped with an anvil and a Thomson blade.

Thus, according to this embodiment, a microneedle array 1 can be manufactured in which the area Sa of one opening 8a located on the outer surface 31a of the side wall 31 of the hollow protrusion portion 3 is smaller than the area Sb of the other opening 8b located on the inner surface 31b of the side wall 31, thereby providing a hollow protrusion device that can inject liquid precisely into the desired location.
Furthermore, in this embodiment, since the hole forming step is performed after the release step, when the hole 8 is formed in the hollow protrusion 3, the convex portion 51 can be prevented from being damaged by the hole forming means 6A.
Furthermore, in this embodiment, the convex portion 51 is inserted into the laminate sheet 4 from the side of the molding auxiliary sheet 21 to form the laminate projection 44, so that even after the convex portion 51 is pulled out of the laminate projection 44, the molding auxiliary sheet 21 remains disposed so as to fit along the inner surface of the hollow projection 3. Therefore, even if a through-hole is formed by the hole-opening means 6A in the laminate projection 44 after the convex portion 51 has been pulled out, the shape of the hollow projection 3 is likely to be maintained.
In this way, the manufacturing method of this embodiment can prevent the convex portion 51 from being damaged, and also has excellent formability for the hollow protrusion portion 3.

In this embodiment, the non-contact hole-opening means 6A is preferably laser light irradiation, as this reduces the likelihood of burrs forming around the hole 8 and makes it easier to form the hole 8 at any position in the hollow protrusion 3. To achieve this effect more significantly, it is preferable to use a material for the forming aid sheet 21 that has a higher absorption rate for laser light than the material for the base sheet 20.

In this embodiment, the means for heating the laminated sheet 4 in the protrusion forming process is not particularly limited, but it is preferable to heat the laminated sheet 4 by ultrasonically vibrating the convex portion 51. This makes it possible to change the amount of heat depending on the degree to which the convex portion 51 is inserted, and in this case, the response to the change in heat amount is good, making it easy to form hollow protrusions 1 of the desired shape.

From the viewpoint of forming the hollow protrusions 3, the heating temperature of the laminated sheet 4 by heating the convex portions 51 is preferably equal to or higher than the glass transition temperature but lower than the melting temperature of the base sheet 20 or the forming auxiliary sheet 21 used, and particularly preferably equal to or higher than the softening temperature but lower than the melting temperature. More specifically, the heating temperature is preferably equal to or higher than the glass transition temperature but lower than the melting temperature of the base sheet 20 and equal to or higher than the melting temperature of the forming auxiliary sheet 21, and more preferably equal to or higher than the softening temperature but lower than the melting temperature of the base sheet 20 and equal to or higher than the melting temperature of the forming auxiliary sheet 21.
More specifically, the heating temperature is preferably 30°C or higher, more preferably 40°C or higher, and preferably 300°C or lower, more preferably 250°C or lower. Specifically, it is preferably 30°C or higher and 300°C or lower, more preferably 40°C or higher and 250°C or lower. When the laminate sheet 4 is heated using an ultrasonic vibration device, this applies to the temperature range of the portion of the forming aid sheet 21 that is in contact with the convex mold 53. On the other hand, when the laminate sheet 4 is heated using a heater device instead of an ultrasonic vibration device, the heating temperature of the convex mold portion 51 can be adjusted within the above-mentioned range. The glass transition temperature (Tg) is measured by the following method, and the softening temperature is measured in accordance with JIS K-7196 "Test method for softening temperature by thermomechanical analysis of thermoplastic plastic films and sheets."

[Method for measuring glass transition temperature (Tg)]
The calorific value is measured using a DSC measuring device to determine the glass transition temperature. Specifically, a differential scanning calorimeter (Diamond DSC) manufactured by Perkin Elmer is used as the measuring device. A 10 mg test piece is taken from the substrate sheet. The measurement conditions are as follows: after maintaining at 20°C for 5 minutes, the temperature is increased from 20°C to 320°C at a rate of 5°C/min, and a DSC curve is obtained with temperature on the horizontal axis and calorific value on the vertical axis. The glass transition temperature Tg is then determined from this DSC curve.

The "glass transition temperature (Tg) of the base sheet" means the glass transition temperature (Tg) of the constituent resin of the base sheet, and when there are multiple constituent resins and the glass transition temperatures (Tg) of the multiple resins are different from each other, the heating temperature of the base sheet by the heating means is preferably at least equal to or higher than the lowest glass transition temperature (Tg) of the multiple glass transition temperatures (Tg), and more preferably equal to or higher than the highest glass transition temperature (Tg) of the multiple glass transition temperatures (Tg). The same applies to the "glass transition temperature (Tg) of the molding aid sheet."
The "softening temperature of the base sheet" is similar to the glass transition temperature (Tg), that is, when the base sheet is made of multiple resins with different softening temperatures, the heating temperature of the base sheet by the heating means is preferably equal to or higher than the lowest softening temperature of the multiple softening temperatures, and more preferably equal to or higher than the highest softening temperature of the multiple softening temperatures. The same applies to the "softening temperature of the molding aid sheet."
Furthermore, when the base sheet or the molding aid sheet is composed of two or more resins with different melting points, it is preferable that the heating temperature of the laminated sheet 4 by the heating means be lower than the lowest melting point among those multiple melting points.

For example, when polylactic acid (PLA) is used as the thermoplastic resin contained in the base sheet 20, possible constituent materials of the molding aid sheet 21 include polyethylene terephthalate (PET), polycarbonate, polyether ether ketone, polyetherimide, polystyrene, nylon resin, etc. Of these, PET is preferred from the perspective of high recyclability, as the molding aid sheet 21 does not become a final product.

To ensure that the molding aid sheet 21 can be easily separated from the hollow protrusions 3 during the separation process, it is preferable to use a molding aid sheet 21 that is not thermally welded to the base sheet 20. For example, when polylactic acid (PLA) is used as the thermoplastic resin contained in the base sheet 20, examples of materials that are not thermally welded to the base sheet 20 include polyethylene terephthalate (PET), polycarbonate, polystyrene, nylon resin, etc.

In this embodiment, it is preferable to use a thermoplastic resin contained in the forming aid sheet 21 whose melting point is higher than that of the thermoplastic resin contained in the base sheet 20. It is also preferable to use a thermoplastic resin contained in the forming aid sheet 21 whose glass transition point is higher than that of the thermoplastic resin contained in the base sheet 20. By ensuring that the melting points or glass stain points of the thermoplastic resins contained in the forming aid sheet 21 and the base sheet 20 have the above-mentioned relationship, even if the hollow protrusions 3 may be prone to bending or curving due to the influence of the heat of fusion during through-hole formation, the shaped protrusions 33 can suppress deformation of the hollow protrusions 3.

If the insertion speed of the convex portion 51 into the base sheet 20 is too slow, the resin will be overheated and softened, and if it is too fast, it will not be heated enough. Therefore, from the perspective of efficiently forming the hollow protrusions 3, the insertion speed is preferably 0.1 mm/sec or more, more preferably 1 mm/sec or more, and preferably 1000 mm/sec or less, and even more preferably 800 mm/sec or less. Specifically, the insertion speed is preferably 0.1 mm/sec or more and 1000 mm/sec or less, and even more preferably 1 mm/sec or more and 800 mm/sec or less.

From the viewpoint of efficiently forming hollow protrusions 3, the penetration depth of the convex portion 51 pierced into the base sheet 20 is preferably 0.01 mm or more, more preferably 0.02 mm or more, and preferably 10 mm or less, even more preferably 5 mm or less. Specifically, it is preferably 0.01 mm or more and 10 mm or less, even more preferably 0.02 mm or more and 5 mm or less. Here, "penetration depth" refers to the distance between the apex of the convex portion 51 and the upper surface 2U of the base sheet 20 on the laminate sheet 4 when the convex portion 53 of the convex portion 51 is pierced to the deepest extent into the laminate sheet 4. Therefore, the penetration depth in the protrusion formation process refers to the distance from the upper surface 2U to the apex of the convex portion 53 when the convex portion 53 is pierced to the deepest depth during the protrusion formation process and emerges from the upper surface 2U of the base sheet 20.

With regard to the ultrasonic vibration of the convex portion 51 by the ultrasonic vibration device, from the viewpoint of forming the hollow protrusions 3, the frequency is preferably 10 kHz or more, more preferably 15 kHz or more, and preferably 50 kHz or less, even more preferably 40 kHz or less, specifically, preferably 10 kHz or more and 50 kHz or less, even more preferably 15 kHz or more and 40 kHz or less. Furthermore, with regard to the ultrasonic vibration of the convex portion 51, from the viewpoint of forming the hollow protrusions 3, the amplitude is preferably 1 μm or more, more preferably 5 μm or more, and preferably 60 μm or less, even more preferably 50 μm or less, specifically, preferably 1 μm or more and 60 μm or less, even more preferably 5 μm or less and 5 μm or less.

The shape of the tip end of the convex portion 51 may be a shape corresponding to the outer shape of the hollow protrusion 3 of the hollow protrusion tool 1 to be manufactured. The convex shape 53 of the convex portion 51 is formed so that its height is the same as or slightly higher than the protrusion height H1 (see FIG. 3(a)) of the hollow protrusion 3 of the hollow protrusion tool 1 to be manufactured, and is preferably 0.01 mm or more, more preferably 0.02 mm or more, and preferably 30 mm or less, and more preferably 20 mm or less, specifically, preferably 0.01 mm or more and 30 mm or less, and more preferably 0.02 mm or more and 20 mm or less. The tip diameter D1 (see FIG. 6) of the convex shape 53 of the convex shape portion 51 is preferably 0.001 mm or more, more preferably 0.005 mm or more, and preferably 1 mm or less, and more preferably 0.5 mm or less, and specifically, preferably 0.001 mm or more and 1 mm or less, and more preferably 0.005 mm or more and 0.5 mm or less. The tip diameter D1 of the convex shape 53 of the convex shape portion 51 is measured as follows.
The protruding portion 53 of the protruding portion 51 has a base diameter D2 of preferably 0.1 mm or more, more preferably 0.2 mm or more, and preferably 5 mm or less, even more preferably 3 mm or less, specifically preferably 0.1 mm or more and 5 mm or less, even more preferably 0.2 mm or more and 3 mm or less. From the viewpoint of easily obtaining sufficient strength, the protruding portion 53 of the protruding portion 51 has a tip angle β of preferably 1 degree or more, more preferably 5 degrees or more. From the viewpoint of obtaining a hollow protrusion 3 having an appropriate angle, the tip angle β is preferably 60 degrees or less, more preferably 45 degrees or less, specifically preferably 1 degree or more and 60 degrees or less, even more preferably 5 degrees or more and 45 degrees or less. The tip angle β of the protruding portion 51 is measured as follows.

[Measurement of the tip diameter of the convex mold 53 of the convex mold portion 51]
The tip of the convex mold 53 of the convex portion 51 is observed under a predetermined magnification using a scanning electron microscope (SEM) or a microscope. Next, as shown in FIG. 6 , an imaginary line ILc is extended along the straight line portion of one side 11a of both side sides 11a and 11b, and an imaginary line ILd is extended along the straight line portion of the other side side 11b. Then, on the tip side, the point where one side 11a deviates from the imaginary line ILc is determined as the first tip point 11a1, and the point where the other side side 11b deviates from the imaginary line ILd is determined as the second tip point 11b1. The length D1 of the line connecting the first tip point 11a1 and the second tip point 11b1 thus determined is measured using the scanning electron microscope or the microscope, and the measured length of the line is defined as the tip diameter of the convex mold 53.

[Measurement of tip angle β of convex mold 53 of convex mold portion 51]
The tip of the convex shape 53 of the convex shape portion 51 is observed at a predetermined magnification using a scanning electron microscope or a microscope, as shown in the image in Fig. 6. Next, as shown in Fig. 6, an imaginary line ILc is extended along the straight line portion of one side 11a of both side sides 11a, 11b, and an imaginary line ILd is extended along the straight line portion of the other side 11b. The angle formed by the imaginary lines ILc and ILd is then measured using the scanning electron microscope or the microscope, and this measured angle is defined as the tip angle β of the convex shape 53 of the convex shape portion 51.

The convex portion 51 is made of a high-strength material that is difficult to break. Examples of materials for the convex portion 51 include metals such as steel, stainless steel, aluminum, aluminum alloy, nickel, nickel alloy, cobalt, cobalt alloy, copper, copper alloy, beryllium copper, and beryllium copper alloy, as well as ceramics.

In this embodiment, an aperture 8 may be formed at the tip of the hollow protrusion 3. However, from the viewpoint of preventing damage to the tip of the hollow protrusion 3 and facilitating puncturing the skin, it is preferable to form the aperture 8 in the aperture formation step by irradiating the laser light 6L at a position offset from the center of the tip of the non-penetrating hollow protrusion 3. From the viewpoint of forming the aperture 8 by irradiating the side wall of the hollow protrusion 3 with laser light 6L using less irradiation energy and from the viewpoint of suppressing the effects of the irradiation energy of the laser light 6L and maintaining the strength around the formed aperture 8, it is preferable to form the aperture 8 in the aperture formation step by irradiating the non-penetrating hollow protrusion 3 with laser light 6L from the irradiation head 61 of the laser device 6A in a direction ILf that is inclined relative to the insertion direction ILe of the convex mold 53 of the convex mold portion 51, as shown in FIG. 7(d). From the same viewpoint, the angle θ between the insertion direction ILe of the convex mold 53 and the inclined direction ILf in which the laser light 6L is irradiated is preferably 5 degrees or more, more preferably 10 degrees or more, and particularly preferably 15 degrees or more, and is preferably 85 degrees or less, more preferably 80 degrees or less, and particularly preferably 75 degrees or less. Specifically, it is preferably 5 degrees or more and 85 degrees or less, more preferably 10 degrees or more and 80 degrees or less, and particularly preferably 15 degrees or more and 75 degrees or less. From the same viewpoint, the irradiation time of the laser light 6L is preferably 0.001 ms or more, more preferably 0.005 ms or more, and preferably 5 ms or less, and more preferably 3 ms or less. Specifically, it is preferably 0.001 ms or more and 5 ms or less, and more preferably 0.005 ms or more and 3 ms or less. From the same perspective, the laser output of the laser light 6L is preferably 0.5 W or more, more preferably 1 W or more, and is preferably 100 W or less, more preferably 50 W or less; specifically, it is preferably 0.5 W or more and 100 W or less, more preferably 1 W or more and 50 W or less.

The present invention has been described above based on the preferred embodiment, but the present invention is not limited to the embodiment and can be modified as appropriate.

For example, in the manufacturing method of this embodiment, after inserting the convex portion 51 into the laminate sheet 4 to form the laminate projection 44, a cooling step may be performed to cool the laminate projection 44. The cooling step can be performed, for example, by using a cold air blower provided in the manufacturing apparatus 100 to blow cold air onto the laminate projection 44 while the convex portion 53 of the convex portion 51 is inserted into the interior of the laminate projection 44. Note that when the heating means for the convex portion 51 is ultrasonic vibration, as in the manufacturing apparatus 100, a cold air blower is not necessarily provided; cooling can also be achieved by turning off the vibration of the ultrasonic vibration device. In this regard, using ultrasonic vibration as the heating means is preferable because it simplifies the device and facilitates high-speed manufacturing of the microneedle array 1. Furthermore, heat is less likely to be transmitted to the portions of the laminate sheet 4 that are not in contact with the convex portion 51. Furthermore, turning off the ultrasonic vibration allows for efficient cooling, which has the advantage of reducing deformation of areas other than the formed portion.

When performing the cooling process, the softening time, which is the time required to stop the temperature rise of the heated convex portion 51 and to perform the next cooling process while the convex portion 51 remains inserted inside the hollow protrusion 3, will result in overheating if it is too long. However, from the perspective of compensating for insufficient heating, the softening time is preferably 0 seconds or more, more preferably 0.1 seconds or more, and preferably 10 seconds or less, and even more preferably 5 seconds or less. Specifically, it is preferably 0 seconds or more and 10 seconds or less, and even more preferably 0.1 seconds or more and 5 seconds or less.

In relation to the above-described embodiment, the present invention further discloses the following hollow protrusion device and manufacturing method thereof.

The present invention will be explained in more detail below using examples. However, the scope of the present invention is not limited to these examples.

(1) Preparation of convex mold portion 51 provided in manufacturing apparatus A convex mold portion 51 having one conical convex mold 53 was prepared as the convex mold portion 51. The convex mold 53 had a height (height of the tapered portion) H2 of 2.5 mm, a tip diameter D1 of 15 μm, a base diameter D2 of 0.5 mm, and a tip angle β of 11 degrees.
(2) Preparation of Perforation Means 6A in the Manufacturing Apparatus A UV laser device was used as the perforation means 6A, and UV laser light with a wavelength of 355 nm was irradiated.

Example 1
The hollow protrusion tool of Example 1 was manufactured in the order shown in Figures 7(a) to (g). A 0.4 mm thick sheet made of PLA was used as the base sheet 20. A 0.4 mm thick sheet made of PET was used as the molding aid sheet 21. In the hole formation process, the position from the tip of the laminated protrusion 44 was 300 µm, the laser output of the laser light 6L was 2 W, the irradiation time of the laser light 6L was 2 milliseconds, and the angle θ between the insertion direction ILe and the inclined direction ILf was 30 degrees.

Comparative Example 1
In the protrusion forming step, a 0.4 mm thick sheet made of PET was used as the base sheet 20 in the laminated sheet 4. A 0.4 mm thick sheet made of PLA was used as the molding auxiliary sheet 21. In other words, in the protrusion forming step of Comparative Example 1, the sheets used as the base sheet 20 and the molding auxiliary sheet 21 were reversed from those in Example 1. Other than these, hollow protrusion tools were manufactured in the same manner as in Example 1.

Comparative Example 2
In Example 1, a 0.4 mm thick sheet made of PLA was used as the molding auxiliary sheet 21. That is, in the sheet lamination process of Comparative Example 2, sheets with the same energy absorption rate were stacked. In addition, in the hole formation process, the irradiation time of the laser light 6L was changed to 20 milliseconds. In the separation process, the molding auxiliary sheet 21 located on the inner side of the protrusions formed in the protrusion formation process was separated from the base sheet 20 located on the outer side of the protrusions.

The hollow protrusion devices of Example 1, Comparative Example 1, and Comparative Example 2 were observed using a microscope to confirm the shape of the apertures 8 formed in the side walls of the hollow protrusions. The results are shown schematically in Table 1. In the enlarged cross-sectional views of the apertures in Table 1, the left side of the cross-section is the inner surface 31b of the side wall 31, and the right side of the cross-section is the outer surface 31a of the side wall 31.

The ease of separation in the separation step was evaluated according to the following criteria. The results are shown in Table 1.
(Evaluation criteria for ease of separation)
◯: When the hollow protrusion tool and the molding aid sheet could be separated without any traces of welding to the molding aid sheet on the inner surface of the hollow protrusion tool. ×: When the hollow protrusion tool and the molding aid sheet could be separated, but when there were traces of welding to the molding aid sheet on the inner surface of the separated hollow protrusion tool, or when the hollow protrusion tool and the molding aid sheet could not be separated.

As shown in Table 1, the hollow protrusion device of Comparative Example 1 had through holes formed in the side wall of the hollow protrusion device that gradually increased in size from the inner surface 31b of the side wall 31 toward the outer surface 31a. In other words, the area of the opening 8a located on the outer surface 31a of the side wall 31 was larger than the area of the opening 8b located on the inner surface 31b of the side wall 31. Therefore, it was found that the hollow protrusion device of Comparative Example 1 made it difficult to supply agent to the desired location with pinpoint accuracy.

In the hollow protrusion device of Comparative Example 2, similar to the hollow protrusion device of Comparative Example 1, the through holes formed in the side wall of the hollow protrusion device gradually increased in size from the inner surface 31b of the side wall 31 toward the outer surface 31a, and the area of the opening 8a located on the outer surface 31a of the side wall 31 was larger than the area of the opening 8b located on the inner surface 31b of the side wall 31 (see Table 1). Therefore, it can be seen that the hollow protrusion device of Comparative Example 2 makes it difficult to supply agent to a desired location with pinpoint accuracy.
In addition, in Comparative Example 2, the evaluation result for ease of separation was "x". More specifically, the interface between the base sheet 20 and the molding auxiliary sheet 21 was heat-fused, making it difficult to peel the sheets 20, 21 from each other. Furthermore, traces of welding to the molding auxiliary sheet 21 were found on the inner surface of the peeled base sheet 20, and it was confirmed that the inner surface was rough (see the cross-sectional view of line A-A of Comparative Example 2 in Table 1). Furthermore, traces of welding to the base sheet 20 were found on the outer surface of the peeled molding auxiliary sheet 21, and it was confirmed that the outer surface was rough (see the front view and left side view of Comparative Example 2 in Table 1).

As shown in Table 1, the hollow protrusion device of Example 1 had openings 8 formed in the side wall 31 of the hollow protrusion portion 3 that gradually decreased in size from the inner surface 31b of the side wall 31 toward the outer surface 31a. In other words, the area of the openings 8a located on the outer surface 31a of the side wall 31 was smaller than the area of the openings 8b located on the inner surface 31b of the side wall 31. This demonstrates that the hollow protrusion device of Example 1 can deliver agent to the desired location with pinpoint accuracy. Furthermore, as shown in Table 1, Example 1 received a rating of "Good" for ease of separation, demonstrating that the hollow protrusion device can be easily manufactured.

1. Microneedle array (hollow protrusion device)
2 base portion 3 hollow protrusion portion 31 side wall 6A non-contact hole-forming means 6L laser light 7 opening 8 hole 20 base sheet 21 forming auxiliary sheet 51 convex portion 52 convex bottom portion 53 convex mold 100 manufacturing device V internal space Y1 conveyance direction Z height direction

Claims (4)

A method for manufacturing a hollow protrusion tool, comprising a hole forming step of forming holes penetrating a side wall of a fine hollow protrusion portion by a non-contact hole forming means,
The hollow protrusion tool to be manufactured comprises a minute hollow protrusion portion having an opening, the opening penetrates a side wall of the hollow protrusion portion, and the area of one opening located on the outer surface of the side wall is smaller than the area of the other opening located on the inner surface of the side wall ;
a sheet laminating step of laminating a base sheet containing a thermoplastic resin and a forming auxiliary sheet having a higher absorption rate of energy applied by the perforation means than the base sheet to form a laminated sheet;
a protrusion forming step of contacting a convex mold portion having a heating portion with the laminate sheet from the molding auxiliary sheet side, and piercing the convex mold portion into the laminate sheet toward the base sheet side while softening the contacting portion of the laminate sheet by heat;
a release step of pulling out the convex portion from the laminated sheet;
the hole forming step performed after the release step;
a separation step of separating the hollow protrusions from the molding aid sheet after the hole forming step,
the non-contact hole-opening means is irradiation of laser light,
a constituent material of the forming aid sheet having a higher absorptivity for the laser light than a constituent material of the base sheet;
A method for manufacturing hollow protrusion tools , wherein the thermoplastic resin contained in the molding aid sheet has a melting point higher than the melting point of the thermoplastic resin contained in the base sheet . The method for manufacturing a hollow protrusion tool according to claim 1, wherein the forming aid sheet is one that is not thermally welded to the base sheet. 3. A method for manufacturing a hollow protrusion tool according to claim 1 or 2 , wherein the thermoplastic resin contained in the molding aid sheet has a glass transition point higher than the glass transition point of the thermoplastic resin contained in the base sheet. The method for manufacturing a hollow protrusion tool according to any one of claims 1 to 3 , wherein the laminated sheet is heated by ultrasonically vibrating the convex portion.