JP5303256B2 - Needle-like body provided with a projection having a constriction in the body portion, and method for manufacturing the same - Google Patents

Description

  The present invention relates to a method for manufacturing a needle-shaped body and a needle-shaped body manufactured thereby.

  As a method for supplying a physiologically active substance into a living body, parenteral administration is widely used. In addition, transdermal administration is known as parenteral administration. When a physiologically active substance is supplied by a transdermal route, the skin permeability of the physiologically active substance is reduced by the barrier function of the stratum corneum.

  For this reason, a percutaneously absorbable physiologically active substance having a relatively high skin permeability is selected, and it is considered difficult to apply a physiologically active substance having a low skin permeability to a percutaneously absorbable physiologically active substance. Yes.

  In recent years, as a method of transdermally administering a physiologically active substance, a method of transdermal administration using a needle-like body having fine protrusions has attracted attention.

  Perforation of the stratum corneum having a high barrier property using a needle-like body having fine protrusions can form a passage route for physiologically active substances and improve the efficiency of transdermal administration. In addition, there is an advantage that not only a fat-soluble physiologically active substance used for transdermal administration but also a water-soluble physiologically active substance can be applied to the transdermal administration.

  At this time, by designing the projection so as not to penetrate the stratum corneum and reach the capillaries and nerves, it is possible to prevent bleeding and pain during use.

  When the needle-like body having the protrusion is used for the purpose of transdermal administration, the protrusion is sufficiently thin to pierce the skin, and the tip angle penetrates the stratum corneum which is the outermost layer of the skin. However, it is desirable to have a length that does not reach the nerve layer.

  Therefore, it is desirable that the diameter of the protrusion is about several μm to 100 μm, the tip angle is 30 ° or less, and the length is about several tens μm to several hundred μm.

Conventionally, the function of skin or skin stratum corneum in daily life for the purpose of chemically improving or altering the alteration or discoloration of the skin so that they are not visually perceived. That is, in order to greatly improve the convenience, safety, and efficiency in the skin function regenerating action in a painless state when imparting coloring, beautification, UV protection, etc., a needle-shaped body and a method for producing the needle-shaped body Is provided. (Patent Document 1)
In addition, the neck portion of the protrusion is formed through an X-ray lithography process in which an X-ray photosensitive resin containing polymethyl methacrylate (PMMA) is formed by irradiating synchroton radiation X-rays. A needle-like body having a protrusion with a constriction at the body is realized by irradiating X-rays with high straightness a plurality of times from different angles.
JP 2003-238347 A

  However, the X-ray lithography process shown in Patent Document 1 requires a synchrotron radiation facility for obtaining highly straight X-rays, and there is a problem that the apparatus is expensive and large. Further, it is considered that the number of exposures is at least 4 times, which is not easy. Thus, a method for manufacturing a similar needle-like body provided with a constriction is performed without an X-ray lithography process, and it is a problem that it can be easily performed at low cost.

  Accordingly, an object of the present invention is to provide a method for producing a needle-like body having a constricted protrusion at a low cost and in a simple manner.

The present invention described in claim 1
A method of manufacturing a needle-like body comprising a base and a protrusion that protrudes from the first surface of the base and has a constriction on its body,
This is a method comprising forming a constriction on the body of the protrusion by selectively applying an etching solution to the protrusion provided on the first surface of the substrate by a dispensing method and etching.

The present invention according to claim 2 further includes applying an etching protective agent to the protrusion and curing the protrusion before applying the etching solution.
Removing the cured etch protectant from the tip to the constricted position to be formed;
It is the method which comprises.

  The present invention according to claim 3 is a method characterized in that the removal of the cured etching protective agent is performed by an ashing method.

  The present invention according to claim 4 is the method according to any one of claims 1 to 3, wherein the selective application of the etching solution and the etching are performed a plurality of times.

The present invention according to claim 5 provides:
By making the needle-shaped body manufactured by the method according to any one of claims 1 to 4 as a mother die, making a duplicate plate from the mother die, and performing transfer processing molding,
This is a method of manufacturing a needle-like body having a base and a protrusion protruding from the first surface of the base and having a constriction at the body.

The present invention according to claim 6 provides:
6. The method according to claim 5, wherein a biocompatible material is used as a molding material for transfer processing molding.

The present invention according to claim 7 provides:
A reinforcing material is further applied by a dispensing method to the constriction of the protrusion of the needle-shaped body manufactured by the manufacturing method according to any one of claims 1 to 6. , A method of producing a needle-like body comprising a base body and a protruding portion protruding from the first surface of the base body and having a constriction in the body portion thereof.

The present invention according to claim 8 provides:
It is the acicular body manufactured by the manufacturing method of any one of Claims 1-7.

  ADVANTAGE OF THE INVENTION According to this invention, the method which can manufacture the acicular body which comprises the protrusion part which has a constriction cheaply and simply is provided.

  Below, the manufacturing method of the acicular body of this invention is demonstrated.

The method according to the invention comprises:
A method of manufacturing a needle-like body comprising a base and a protrusion that protrudes from the first surface of the base and has a constriction on its body,
This is a method comprising forming a constriction on the body of the protrusion by selectively applying an etching solution to the protrusion provided on the first surface of the substrate by a dispensing method and etching.

  In particular, the present invention is characterized in that a needle-like body having a projecting portion having a constriction in a body portion is manufactured by a manufacturing method including a selective application step of an etching solution by a dispensing method.

  The needle-shaped object to be constricted may be produced directly from the needle-forming material by a method known per se, for example, precision machining, and a mold or a duplicate plate is used by a method known per se. Then, it may be manufactured by transfer molding.

  Here, the “body” refers to a portion sandwiched between the base portion and the tip portion of the projection, but the base portion may be included in a portion where the constriction exists.

  The position of the constriction in the trunk portion of the protrusion can be adjusted by using an etching protective agent. For example, when an etching protective agent is not used, it is possible to perform constriction from the trunk portion to the base portion of the projection by etching. By using the etching protective agent, the trunk portion of the protruding portion is protected from etching from the base portion of the protruding portion to a height at which the etching protective agent is present. Therefore, the etching is performed on the protrusion body at a position closer to the tip than the position where the etching protective agent is present. As a result, it is possible to confine the target portion.

  In addition, by controlling either the film thickness condition of the etching protective agent applied to the needle-shaped body or the removal of the etching protective agent, for example, the ashing condition by the ashing treatment method, the protrusion can be placed at a desired position. A constriction can be formed.

  Furthermore, a plurality of constrictions may be formed on the body portion of the protrusion by repeating the etching solution coating and etching steps.

  The needle-like body having the constricted protrusion obtained in this way is used as a mother mold, a replica plate is made from the mother mold, and transfer processing molding is performed using the biocompatible material, thereby constricting the biocompatible material. You may form the provided acicular body.

  When such a needle-like body is punctured into a living body, the protrusion can be easily folded at the constricted position by applying pressure in a direction perpendicular to the height direction of the needle-like body. Thereby, a part of projection part can remain in a skin stratum corneum. When the biocompatible material particularly contains a physiologically active substance or the protrusion is made of a physiologically active substance, the effect of the physiologically active substance is expected to act safely and continuously for several days to several months. The

  Furthermore, the strength of the protrusions can be reinforced by applying a material according to the purpose to the constriction of the needle-like body by the dispensing method. For example, the low-molecular-weight molding material that is easy to dissolve in the living body is applied to the constriction of the protrusion molded by the biocompatible material, so that a certain strength is maintained before puncturing the living body. Since the strength is reduced after puncturing, the added value of improved handling can be expected.

<Process to process the body of the protrusion in a constricted manner>
The body of the protrusion is processed into a constriction.

  It does not specifically limit as a manufacturing method of the acicular body which comprises the protrusion part which performs a constriction, What was manufactured by the existing method can be used.

The material of the needle-like body for processing the constriction from the base portion to the desired position of the body portion is desirably a material that can be etched with an etching solution. For example, specifically, Si, Al, Mo, Ti, Ta, W, Pt, Au, Ag, Cu, SiO ₂ , PSG, BSG, Si ₃ N ₄ , Al ₂ O ₃ or the like is preferably used. it can.

  The needle-shaped body may be produced directly from a needle-shaped body-forming material by a method known per se, for example, precision machining, and is transferred and molded using a mold or a replica plate by a method known per se. May be manufactured.

  For example, in the case of manufacturing by microfabrication technology, examples of such microfabrication technology are not limited to these, but etching such as lithography, wet etching, dry etching, plasma etching, and reactive ion etching, Includes laser processing, focused ion beam, blasting such as sand blasting and precision machining.

  It is only necessary to form a constriction on the body portion by performing an etching process on the needle-like protrusion portion thus obtained.

  Moreover, you may adjust the position of the constriction in the said projection part by using an etching protective agent for the 1st surface with the projection part of the acicular body mentioned above as needed. That is, an etching protective agent is not necessary in the case where a neck portion including the base portion of the protruding portion is formed.

  The etching protective agent may be a high-viscosity liquid, and in addition to being cured in a desired shape, one that is resistant to etching with an etching solution can be used. For example, specifically, a negative resist or a thermosetting resin may be used.

  Moreover, it does not specifically limit as a process of apply | coating the said etching protective agent, According to the etching protective agent to be used, it can select suitably. For example, specifically, a spin coating method, a spray method, a dip method, a dispensing method, or the like can be used.

  The etching protective agent remains in a curved shape at the base of the protrusion in a self-aligning manner due to surface tension. For this reason, it becomes possible to form a uniform curved surface in all the projection parts especially when a plurality of projection parts stand. Further, by controlling the viscosity of the etching protective agent, it is possible to control the film thickness of the tip portion of the protrusion in association with the curvature radius of the curved surface at the base portion. This makes it possible to design and manufacture a desired radius of curvature of the base of the needle state and a protrusion having a film thickness at the tip. At this time, the higher the viscosity of the etching protective agent, the larger the radius of curvature and the film thickness.

  When an etching protective agent is used, the etching protective agent is cured after being applied.

  As a method for curing the etching protective agent, a method appropriate for the etching protective agent to be used may be appropriately used. Further, by controlling the curing conditions of the etching protective agent, the radius of curvature of the curved surface at the base and the film thickness at the tip can be controlled. Thereby, it is possible to design and manufacture a protrusion having a desired radius of curvature and film thickness.

  For example, when the etching protective agent is a thermosetting resin, when the curing temperature is increased, the volume shrinkage returned to room temperature increases, and as a result, the radius of curvature and the film thickness tend to decrease.

  Next, the etching protective agent is removed from the tip of the protrusion to a desired position. The removal may be appropriately selected according to the etching protective agent.

  In the case where a resist or a thermosetting resin is used as the etching protective agent, an ashing treatment method may be used as a step of removing unnecessary resist or thermosetting resin. The ashing treatment method is roughly divided into a wet process using a liquid phase and a dry process using a gas phase. In particular, in the present invention, since the surface energy increase treatment of the exposed surface is also required, an active gas is used. It is desirable to use a dry process.

  When the etching protective agent is removed from the protrusion tip to a desired position by the ashing method, the surface energy of the exposed material can be increased simultaneously by the removal.

  The apparatus used for the ashing treatment method is not particularly limited as long as it uses an active gas. For example, specifically, a photoexcited ashing device or a plasma ashing device can be used.

  As a reaction gas used in the ashing apparatus, oxygen gas can be mainly used. This is excited by light and plasma to cause a chemical reaction with an organic polymer resist or thermosetting resin, thereby proceeding with an ashing treatment.

  Regarding the film thickness distribution of the cured film formed by the etching protective agent formed on the protrusion, the tip of the protrusion tends to be the thinnest and the base of the protrusion tends to be the thickest. Therefore, if the ashing conditions in the ashing process are controlled, the etching protective agent up to the desired part can be selectively removed from the tip part to the body part.

  Next, an etching solution is dropped by a dispensing method, and the body portion is etched from the base portion of the protruding portion to form a constriction. Moreover, at the time of dripping, you may incline a needlelike body as needed.

  The dispenser used in the step of dropping the etching solution by the dispensing method is not particularly limited as long as the device has a performance capable of minutely controlling the discharge amount of the etching solution. For example, specifically, a piezoelectric inkjet dispenser can be used. Further, it is preferable that the inner diameter of the dispenser head is as small as not to make it difficult to discharge.

  As the etchant discharged by the dispenser, an etchant corresponding to the material to be etched can be used as appropriate. In addition, it is important to show high wettability for a material having a high surface energy. For example, specifically, if the material to be etched is Si, the etching solution can be KOH, and if the material to be etched is Al, the etching solution can be HCl. Further, in order to obtain an optimum constricted shape, the etching rate may be optimized by adjusting the concentration of the etching solution in some cases.

  The portion where the etching solution is dropped is preferably a boundary portion between the cured film of the etching protective agent and the material to be etched. As soon as the dropped etchant reaches the boundary, it spreads in the direction of the tip showing high contact on the cured film, and spreads in all directions showing a low contact angle on the material to be etched. Due to the balance with the spreading of the etching solution in the base portion direction due to the weight of the etching solution, it spreads circumferentially around a part of the protrusion.

  Moreover, it is also possible to provide a plurality of constrictions in the same acicular body by using the etching location control by changing the thickness of the cured film of the etching protective agent a plurality of times.

  After the etching process is performed, a rinsing process is performed as necessary, and a sufficient ashing process is performed again, whereby a needle-like body provided with a constriction can be obtained.

<Needle transfer processing molding>
First, a replica plate may be formed by using a needle-like body having a projection provided with the constriction as a matrix.

  At this time, the method for producing the replica plate only needs to have shape followability sufficient to function as a replica plate and flexibility sufficient to release the filled material from the replica plate, for example, molding of organic silicon or the like. Resin etc. can be used. Although there is no restriction | limiting in the thickness of resin to form, It is preferable to form in thickness more than twice the height of a projection part.

  Next, transfer processing molding is performed on various materials using the duplicate plate.

  Using the duplicate plate, the needle-like body is duplicated by an imprint method, a hot embossing method, an injection molding method, a casting method, or the like. The material of the replicated product is not particularly limited, but a needle-like body applicable to a living body can be formed by using a medical silicone resin that is a biocompatible material, maltose, polylactic acid, dextran, or the like.

<Drop of reinforcing material to the constriction of the needle-shaped body>
A needle-like body having a protrusion provided with a constriction has a lower strength against a lateral force than a needle-like body without a constriction, and has poor handling properties. On the other hand, the reinforcement material according to the objective can be dripped collectively by the dispensing method. The reinforcing material is not particularly limited, but silicone resin, maltose, polylactic acid, dextran, or the like can be used if the biocompatible material is reinforced. In addition, when the reinforcing material is dropped by the dispensing method, the needle-like body may be inclined as necessary.

  The reinforcing material dropped on the bundle is applied only to the bundle in a self-aligning manner due to surface tension. If the amount of dripping is adjusted, the constriction of the needle-like body does not appear to be apparent and maintains a certain strength before puncturing the living body, whereas the strength decreases after puncturing the living body. It can also be done. Therefore, in the case of the reinforcing material used for such applications, it is desirable to select a material having a molecular weight lower than that of the needle-shaped body material.

  When the needle-like body according to the present invention is intended to administer a physiologically active substance or the like to the puncture target through the needle-like body, the needle-like body may have a structure including or containing the physiologically active substance or the like. In that case, the physiologically active substance may be encapsulated in a microcapsule or the like and provided in the protrusion. Further, the physiologically active substance may be directly mixed with the member forming the protrusion, and the protrusion may be formed of the physiologically active substance.

  According to the present invention, by using a selective coating process of an etching solution by a dispensing method, a needle-like body having a projection having a constriction on a body similar to the conventional one without passing through a conventional X-ray lithography process. Can be produced inexpensively and easily.

  In addition, when the needle-like body of the present invention is punctured into a living body, by applying pressure in a direction perpendicular to the height direction of the needle-like body, the needle-like body can be easily folded at the neck, Thereby, it can remain in the skin stratum corneum. In particular, when the biocompatible material is a physiologically active substance, it is expected that the effect of the physiologically active substance is safely maintained for several days to several months.

  As mentioned above, although the example of the aspect of the manufacturing method of the acicular body according to this invention was demonstrated, these are not limited to the said aspect, You may add various changes. In the case of the method according to the present invention, any step may be replaced with any replaceable step known per se, and further steps may be added. Such an embodiment is also included in the scope of the present invention.

  Hereinafter, an example of the present invention will be described with reference to FIG.

  First, a silicon wafer was prepared as the substrate 101. The crystal orientation of this silicon wafer is the (1, 0, 0) plane, and the thickness of the wafer is 525 μm. Chromium was formed to a thickness of 100 nm on this silicon wafer by DC magnetron sputtering. At this time, the sputtering pressure is 0.25 Pa and the input power is 1000 W.

  Next, a positive resist OFPR (viscosity: 50 cp) manufactured by Tokyo Ohka Kogyo Co., Ltd. was coated as a 1 μm film thickness as a chromium film etching mask on the chromium film, and a square opening pattern having a side of 30 μm was formed by photolithography. Using this resist pattern as an etching mask, chromium was etched using a mixed solution of perchloric acid and ceric ammonium nitrate to form a chrome pattern 102 having a square opening with a side of 30 μm. (FIG. 1 (a)). After forming the chromium patterning, OFPR was removed with an organic solvent, and the dimension of the chromium pattern was measured. As a result, the dimension of the square opening pattern of chromium was 30 μm on one side.

  Using this chromium pattern 102 as an etching mask, a silicon wafer is patterned by anisotropic wet etching of silicon using an etching rate difference depending on crystal orientation using potassium hydroxide having a weight concentration of 25% and a liquid temperature of 90 ° C. 103 was formed. After the wet etching, chromium was removed with a mixed solution of perchloric acid and ceric ammonium nitrate (FIG. 1B). When the shape of the silicon opening pattern thus formed was confirmed by a scanning electron microscope, the depth of the pattern was about 20 μm and the opening angle of the re-deep part was 70 °.

  The front surface of this substrate is coated with a positive resist OFPR-20cp made by Tokyo Ohka Co., with a film thickness of 50 nm, and a square resist pattern 104 having a side of 30 μm is formed in accordance with the silicon opening pattern (FIG. 1C). Using this resist pattern 104 as an etching mask, etching was performed on the entire wafer surface until the resist 104 on the silicon wafer was completely removed by ICP (Inductively Coupled Plasma) etching using a fluorocarbon-based gas. . As a result of measuring the OFPR under the etching conditions used at this time and the etching rate of silicon, the etching selectivity of OFPR and silicon was 0.15.

  When the sample after the entire surface etching was observed with an operation electron microscope, it was confirmed that a pyramid-shaped protrusion having a side of about 30 μm, a height of about 300 μm, and a tip angle of about 10 ° was formed as a microneedle. did. As a result, a needle-like body 117 having a protruding portion 105 protruding on the first surface of the base body 116 was obtained (FIG. 1D).

  Next, a negative resist OMR-83 manufactured by Tokyo Ohka Co., Ltd. was coated on this original plate. At this time, a spin coating method (rotation speed: 1500 rpm, 180 sec) was used.

  Next, the resist was cured by ultraviolet light. When the shape of the protrusion after curing the resist was confirmed by a scanning electron microscope, the OMR film thickness was 50 nm. In addition, it was confirmed that the root portion of the protruding portion had a gentle curved shape in a state where it was completely covered with OMR, without an acute angle portion where there was a concern about the concentration of mechanical load (see FIG. 1 (e)). As shown in FIG. 1E, the resist functions as an etching protective agent 106.

An ashing process (O ₂ 200 sccm, 800 W, 20 sec) was performed by a plasma ashing apparatus in order to selectively expose only the Si at the tip of the protrusion 105 covered with the resist 106. When the shape of the protrusion after the ashing process was confirmed with a scanning electron microscope, it was confirmed that the exposed surface of Si was in a range of 200 μm from the tip of the protrusion.

  Next, using a piezo-type ink jet dispenser, potassium hydroxide having a weight concentration of 25% and a liquid temperature of 90 ° C. was dropped at the boundary between Si and the resist film. The inner diameter of the dispenser head was 50 μm, and it was confirmed from the stroboscopic image at the tip of the head that one droplet diameter was ejected at 50 μm. When the shape of the protrusions after the wet etching process was confirmed by a scanning electron microscope, it was confirmed that the protrusions 107 having a vertical width of 50 μm were formed at a position of 175 μm from the tip of the protrusions (FIG. 1 (f )).

In order to remove all OMR covered with the protrusions 107, ashing (O ₂ 200 sccm, 800 W, 2000 sec) was performed using a plasma ashing apparatus. When the shape of the protrusion after the ashing process was confirmed with a scanning electron microscope, it was confirmed that the entire protrusion was an exposed surface of Si. In this way, a duplicate plate with the projections and depressions inverted was produced.

  Using this duplicate plate, the shape of a polylactic acid-made projection produced by an imprint method was confirmed with a scanning electron microscope, and it was confirmed that a projection 108 having substantially the same shape as the original plate was formed. (FIG. 1 (g)).

  Finally, a collagen aqueous solution was discharged to the constriction of the protrusions 108 using a piezo-type ink jet dispenser (head inner diameter 50 μm). Since collagen is more easily decomposed in vivo than polylactic acid, if the constriction of the protrusion 108 is covered with a collagen film, the protrusion 108 can be easily folded in the constriction after puncturing the living body. It can remain in the stratum corneum. Conversely, before puncturing the living body, the protrusions are reinforced by the collagen film in the constriction, and the strength to the extent that the handling property is improved can be maintained. After confirming the shape with a scanning electron microscope after the collagen film formation step using the dispenser, it was confirmed that the constriction 109 covered with the collagen film was formed on the protrusion 108. (FIG. 1 (h)).

  The method for producing a needle-like body of the present invention is useful as a method for producing a needle-like body used for, for example, a MEMS device, medical treatment, and drug discovery.

The figure which shows an example of the aspect of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 101 ... Board | substrate 102 ... Resist pattern 103 for perforation pattern formation ... Perforation pattern 104 ... Resist 105 ... Protrusion part 106 ... High-viscosity liquid 107 ... Constriction 108 ... Acicular body 109 formed by transfer processing ... Constriction after reinforcement by reinforcement material 116: Base 117 ... Needle-shaped body

Claims (8)

A method of manufacturing a needle-like body comprising a base and a protrusion that protrudes from the first surface of the base and has a constriction on its body,
A method comprising forming a constriction in a body portion of a protrusion by selectively applying an etching solution to the protrusion provided on the first surface of the substrate by a dispensing method and etching. Furthermore, before applying the etchant, applying an etching protective agent to the protrusions and curing,
Removing the cured etch protectant from the tip to the constricted position to be formed;
The method of claim 1 comprising: The method according to claim 2, wherein removing the cured etching protective agent is performed by an ashing method.   The method according to claim 1, wherein the etching solution is selectively applied and etched a plurality of times. By making the needle-shaped body manufactured by the method according to any one of claims 1 to 4 as a mother die, making a duplicate plate from the mother die, and performing transfer processing molding,
A method of manufacturing a needle-like body comprising a base and a protrusion that protrudes from the first surface of the base and has a constriction in its body.   The method according to claim 5, wherein a biocompatible material is used as a molding material for transfer processing molding.   A reinforcing material is further applied by a dispensing method to the constriction of the protrusion of the needle-shaped body manufactured by the manufacturing method according to any one of claims 1 to 6. A method for producing a needle-like body comprising a base and a protrusion protruding from the first surface of the base and having a constriction at the body.   The acicular body manufactured by the manufacturing method of any one of Claims 1-7.

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