JP2010184465A - Method for manufacturing needle-like article and needle-like article duplicate plate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for manufacturing a needle-like article by which a plurality of numbers of transcription processing can be suitably performed. <P>SOLUTION: The method for manufacturing a duplicate plate for the needle-like article comprises a step to fill a filling material into the needle-like forming side of a needle-like article original plate in which a needle-like shape is formed; a step to cure the filling material; the step to peel off the cured filling material from the needle-like article original plate to obtain a duplicate plate for the needle-like article; and a step to irradiate the needle-like article duplicate plate with ionizing radiation irradiating the side where the needle-like shape is formed. Furthermore, a method for manufacturing the needle-like article by duplicating the needle-like article using the duplicate plate is disclosed. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a needle-like body duplication plate used for duplicating a fine needle-like body.

  The fine acicular body is used for the percutaneous absorption method in which the stratum corneum and epidermis of the skin are punctured using the acicular body, and the drug applied to the surface of the acicular body is directly administered into the skin. It has been. The percutaneous absorption method using a needle-shaped body is advantageous in that a drug can be easily administered without causing pain to the human body, and bleeding and secondary infection are small (see Patent Document 1).

  The shape of the needle part of the fine needle-like body used at this time must have a thinness and a tip angle for puncturing the skin, and a length for allowing the drug solution to reach a desired subcutaneous site. The diameter is several μm to several hundred μm, the length is a length that penetrates the stratum corneum, which is the outermost layer of the skin, and does not reach the nerve layer, specifically a cone of about several tens μm to several hundred μm It is desirable to have a shape.

  More specifically, it is required to penetrate the stratum corneum that is the outermost skin layer. The thickness of the stratum corneum varies slightly depending on the site, but is about 20 μm on average. In addition, an epidermis having a thickness of about 200 μm to 350 μm exists under the stratum corneum, and further, a dermis layer in which capillaries are stretched exists under the epidermis. For this reason, in order to penetrate the stratum corneum and penetrate the chemical solution, a needle length of at least 350 μm or more is required.

  In order to inject a predetermined amount of medicine into the body, a plurality of needle-like bodies are generally arranged in an array. Further, in order for the recipient to be painless, the length of the needle-like body is preferably less than 500 μm.

  Therefore, as a method for manufacturing an array-shaped acicular body original plate having a desired length, for example, a conical acicular body such as a pyramid or a cone is formed on one surface of a machined steel plate by a wire cutting method. A manufacturing method is cited as a method that reduces production costs and is excellent in productivity (see Patent Document 2).

  In addition, the material constituting the needle-shaped article must be a material that does not adversely affect the human body even if the damaged needle-like body remains in the body. A biocompatible material such as a resin based on resin, maltose, polylactic acid, or dextran is considered promising (see Patent Document 3).

  As a method for producing a needle-like body using the biocompatible resin, a production method using a resin replica is disclosed (see Patent Document 4).

US Pat. No. 6,183,434 Special table 2006-513811 public information Japanese Laid-Open Patent Publication No. 2005-21677 JP 2008-89859 A

  However, when replicated using a resin replica plate, the shape of the needle-shaped body formed on the resin replica plate is impaired by multiple times of transfer processing molding, and the durability of the resin replica plate is deteriorated, resulting in productivity. May decrease.

  Therefore, an object of the present invention is to provide a needle-shaped body manufacturing method capable of suitably performing a plurality of transfer processing moldings.

In order to achieve the above-mentioned object, the invention according to claim 1
A method for producing a fine needle-shaped body,
A step of producing an acicular body original plate in which an acicular body shape is formed;
Filling the needle-shaped body forming side of the needle-shaped body original plate with a filling material, and curing the filling material;
Peeling the cured filling material from the acicular body original plate to form an acicular body replication plate made of the filling material;
Filling the needle-shaped replica plate with a molding material and curing the molding material;
Peeling the cured molding material from the acicular replica, and producing a needle-shaped body made of the molding material,
The filling material is a resin whose internal crosslink density is increased by irradiation with ionizing radiation,
In the step of forming the acicular body replica, the needle-shaped body manufacturing method is characterized by irradiating the needle-shaped body forming side of the filling material with ionizing radiation after peeling the filler material from the acicular body original plate. It is what.

  The invention according to claim 2 is characterized in that the filling material includes one or more resins selected from the group consisting of epoxy resins and silicone resins. It is what.

  The invention according to claim 3 is the needle-shaped body manufacturing method according to claim 1, wherein the ionizing radiation is an electron beam.

The invention according to claim 4 is a needle-like body duplication plate in which a concave portion having a needle-like body shape is formed,
The main component is a resin whose internal crosslink density increases by irradiation with ionizing radiation.
After the formation of the concave portion, the needle-shaped replica plate is irradiated with ionizing radiation.

  In the method for producing a needle-shaped body according to the present invention, the crosslink density of the resin inside the resin replica plate is increased by electron beam irradiation, so that the durability of the resin replica plate can be improved. For this reason, it can suppress that the acicular body shape formed in the resin-made replication plate is impaired by the transfer process molding of multiple times.

(A)-(e) It is process drawing explaining the manufacturing process of the replication plate for acicular bodies which becomes this invention, and the process of replicating an acicular body using it.

    Next, the manufacturing method of this invention is demonstrated.

The step of mass-replicating the needle-shaped body with the biocompatible material includes a step of preparing a needle-shaped original plate serving as a matrix for the resin-made replica plate, a step of preparing a resin-made replica plate (practical version) from the master plate, Although it consists of the process of shape | molding a needle-shaped object with a biocompatible material from a resin replication plate, this invention relates to the process of producing a resin replication plate. First, an overview of all steps will be described.

<Needle body forming process>
First, an acicular original plate is formed. As a method for forming the acicular body original plate, an acicular body manufacturing method using a known fine processing technique may be used as appropriate. For example, (1) a needle-shaped body manufacturing method using fine machining such as grinding or cutting, (2) a needle-shaped manufacturing method using a fine processing technique such as lithography or etching, etc. Is mentioned.
The substrate material for producing the acicular body original plate can be appropriately selected according to the processing method. For example, substrate materials such as carbon, ceramics, silicon, quartz, metal, and resin may be used.

  The shape and dimensions of the needle-shaped body formed on the needle-shaped body original plate may be appropriately designed and determined. For example, specifically, a cone, a pyramid, a cylinder, a prism, a truncated cone, a truncated pyramid, and the like may be used.

Further, the shape of the needle-like body may be a needle-like shape in which a plurality of unit needle-like bodies are erected on the substrate. In the case of a needle-like body shape in which a plurality of unit needle-like bodies stands on the substrate, the length of each unit needle-like body may or may not be the same between the unit needle-like bodies. When the lengths of the unit needles are different, for example, (1) the unit needles that are long only on the outer periphery of the array can be suitably brought into contact with the curved surface. By making the unit needle-like body short only on the outer periphery, the mechanical strength of the needle-like body on the outer peripheral portion that is easily damaged can be reinforced.
The pitch dimension, which is the distance between the unit needles, may be appropriately designed and determined according to the specifications.

  In addition, the size of the needle-shaped body is desirably thin enough to puncture the skin and long enough not to reach the nerve layer. Specifically, the diameter of the needle-shaped body is from several μm. It is desirable that the length of the needle-like body is about several hundred μm and about several hundred μm to several hundred μm.

  In particular, when the perforation is kept at “a length that penetrates the stratum corneum and does not reach the nerve layer”, the length of the needle-like body is specifically 200 μm or more and 700 μm or less, more preferably 200 μm or more and 500 μm or less. In the following, it is further preferable to be in the range of about 200 μm to 300 μm.

  When the depth of perforation by the needle-like body is kept at “depth that penetrates the stratum corneum and does not reach the nerve layer”, the delivery product can be delivered to a position deeper than the stratum corneum.

  In particular, when the perforations are retained in the stratum corneum, the length of the acicular body is specifically 30 μm or more and 300 μm or less, more preferably 30 μm or more and 250 μm or less, and further 30 μm or more and 40 μm or less. It is preferable to be within the range.

  If the depth of perforation by the needles is kept “in the stratum corneum”, the delivery can stay in the stratum corneum. Since the stratum corneum is constantly generated by metabolism, the deliverables in the stratum corneum are discharged out of the body with time. For this reason, it can be used suitably for short-term drug release and for maintaining a short-term makeup state.

<Process for producing a resin replica plate>
Next, a process for producing a resin replica (practical version) will be described. A concave resin duplication plate that is an inverted shape of the desired needle shape is formed by filling a resin material into the concave and convex portions of the needle body original plate formed by the above-described method and peeling the filling layer from the needle body original plate. Form. By using a duplicate plate, a large amount of needles can be produced from the same duplicate plate, so that it is generally unnecessary to remanufacture an expensive original plate, and thus the production cost can be reduced. Become.
Next, ionizing radiation is irradiated to the concave / convex pattern forming surface of the resin replica. By promoting the cross-linking reaction of the resin material by ionizing radiation and increasing the durability, more needle-like bodies can be produced from the same replica plate, so that the productivity can be increased as compared with the prior art.

  At this time, the resin material used for the filling layer is not particularly limited, but a material is selected in consideration of shape followability to the mother die, transferability in transfer processing molding described later, durability, and releasability. For example, a thermosetting resin such as a poxy resin or a silicone resin can be used.

  Moreover, as a method of peeling the filling layer from the needle-shaped body original plate, peeling by a physical peeling force or a selective etching method can be used.

  The ionizing radiation applied to the resinous duplication plate is not particularly limited, and includes gamma rays, X-rays, electron beams, etc. Among them, electron beams are preferably used.

  In the electron beam irradiation, an electron beam generated by an electron beam accelerator is irradiated. Examples of the electron beam irradiation apparatus include electron beam accelerators such as a Cockloft Walton type, a bandegraph type, a resonant transformer type, an insulating core transformer type, or a linear type, a dynamitron type, and a high frequency type. Irradiate an electron beam with a curtain method, a beam scanning method, or the like. Preferably, an apparatus “electro curtain” (trade name) capable of irradiating a uniform electron beam in a curtain form from a linear filament is used.

  The electron beam is irradiated with electrons having an energy of 100 keV to 10 MeV, preferably 1 to 10 MeV, with an irradiation amount of about 5 to 200 kGy. When the irradiation dose is less than 5 kGy, there is a risk that the hardness for obtaining the desired durability may not be obtained. When the irradiation dose exceeds 200 kGy, the crosslinking density increases and the cured binder is often damaged. Therefore, there is a possibility that the hardness for obtaining the desired durability cannot be obtained.

  The atmosphere at the time of irradiation with an electron beam is performed at an oxygen concentration of 500 ppm or less, and is usually preferably performed at about 200 ppm.

  Further, the configuration of the resinous duplication plate may be a multi-sided configuration having a plurality of needle-like patterns. Furthermore, taking advantage of the advantage of being made of resin, it is possible to wrap the duplicated plate around a cylindrical plate and to have a configuration suitable for a roll-to-roll method suitable for mass production.

<Process for forming needle-shaped body>
Finally, a process of filling a resinous replica with a molding material, performing transfer molding, and molding a needle-like body will be described.

When performing the transfer molding process using the resin replication plate of the present invention, the molding material is preferably a biocompatible material. By using a biocompatible material, even if problems such as breakage or chipping occur at the time of puncture, adverse effects on the human body can be suppressed.
Specific examples of the biocompatible material include (1) medical silicone, (2) polysaccharides such as maltose, (3) polylactic acid, (4) chitin / chitosan, and (5) derivatives thereof. Etc.

  As a method for filling the duplication plate with the molding material, a known filling method may be used as appropriate. Examples of the filling method include an imprint method, a hot embossing method, an injection molding method, an extrusion molding method, and a casting method.

  Next, the molding material, which is a needle-like material, is released from the resin replica plate to obtain a transfer-molded needle-like body.

  At this time, in order to improve the peelability of the duplicate plate, a release layer for increasing the mold release effect may be formed on the surface of the duplicate plate before filling with the molding material. As the release layer, for example, a fluorine-based resin can be used.

  Moreover, as a formation method of a mold release layer, thin film formation methods, such as PVD method, CVD method, a spin coat method, a dip coat method, can be used suitably.

  Although the above is the outline of the manufacturing process of the acicular body which becomes this invention, it is not limited to the example of the said description, The other method applicable in each process may be sufficient.

  According to the method for producing a needle-like body of the present invention, the resin cross-linking density inside the resin duplication plate is increased by electron beam irradiation, so that the durability of the resin duplication plate can be improved.

  In particular, in the case of a needle-like body shape having a sharp portion such as a pyramid shape or a conical shape, the deterioration of the resin replication plate is severe in the sharpened portion, and the effect of improving the durability of the resin replication plate according to the present invention. Is enormous.

  Moreover, since the needle-like body can be formed from a biocompatible material by using the above-mentioned resin-made replica plate, even if problems such as folding or chipping occur at the time of puncturing, the human body is not adversely affected. It becomes possible to produce a needle-shaped article.

  Hereinafter, an embodiment of the present invention will be described with reference to FIGS.

  A ceramic substrate having a thickness of 5 mm was prepared as the substrate.

  In processing this substrate, a two-blade ball end mill having a ball radius of 0.01 mm was used. The above-mentioned ball end mill is attached as a cutting tool to an NC control milling machine with XYZ axes, and the tool is revolved from the center of the needle-like body to the outer peripheral direction. Processing was performed.

  At this time, the rotation speed was 50000 rpm and the feed rate was 0.1 mm / s. The diameter of the bottom surface of the cone formed by machining was designed to be 280 μm, the pitch was 500 μm, and the machining depth was 450 μm. Further, the portion without the needle-like body was cut at a depth of 450 μm so that the apex of the needle-like body was the highest on the substrate.

  The needle-shaped body part produced as described above was observed with a scanning electron microscope. As a result, it was confirmed that the needle-like body original plate 11 having a root width of 280 μm and a height of 445 μm and having a conical protrusion having a tip angle of 35 ° could be formed (FIG. 1A).

  Next, a replica plate 14 made of resin was prepared using the above-mentioned acicular body original plate made of ceramic as a matrix.

The acicular body original plate 11 was filled with an epoxy resin as a filler 12, and was subjected to a heat curing treatment at 100 ° C. for 1 hour using a clean oven (FIG. 1B).

  Next, the filler 12 was released from the needle body original plate 11 and the electron beam 13 was irradiated to the filler 12 to produce a resin replica plate 14. The acceleration voltage of the electron beam was 5 MeV, the irradiation amount was 100 kGy, and the oxygen concentration in the atmosphere was 100 ppm (FIG. 1C).

  Next, a needle-like body was produced on the resin replica 14 using an imprint method. As the needle-like body material 15 to be filled, polylactic acid which is a biocompatible material was used (FIG. 1 (d)).

  Finally, the needle-shaped body material 15 is released from the resin replica plate 14 to form a cone-shaped needle-shaped body made of polylactic acid having a root diameter of 280 μm, a height of 445 μm, and a tip angle of 35 °. 16 could be manufactured (FIG. 1 (e)).

  In addition, using the resin replica plate 14 and a resin replica plate (not shown) that has not been subjected to electron beam irradiation treatment, the process of manufacturing the needle-shaped article is repeated 100 times, and the durability is compared. did. When the surface of both resin replica plates was observed with a scanning electron microscope, many cracks were confirmed on the surface of the resin replica plates that had not been subjected to electron beam irradiation treatment. The resin replica plate surface was intact. Thus, the effect of electron beam irradiation was proved.

  In the embodiment of the present invention, a case where gamma rays are used as ionizing radiation will be described.

  The process for producing the filler from the process for preparing the needle plate precursor was the same as that in Example 1.

  A resin duplication plate was produced by irradiating the filler released from the acicular original plate with gamma rays. The gamma rays were irradiated by an apparatus having a radiation source of 37 TBq or less, and the irradiation amount was 50 kGy.

  Using the resin replica plate, a needle-shaped article was manufactured from a biocompatible material. The production process of the needle-shaped article was the same as that of Example 1.

  Using the resin replica plate and the resin replica plate not subjected to the gamma irradiation treatment, the process of producing the needle-shaped article was repeated 100 times, and the same durability comparison as in Example 1 was performed. Many cracks were confirmed on the surface of the resin duplication plate not subjected to the gamma ray irradiation treatment, whereas the surface of the resin duplication plate subjected to the gamma ray irradiation treatment was intact. Thus, the effect of γ-ray irradiation was proved.

  The method for producing a needle-shaped body according to the present invention can be applied not only to medical treatment but also to various fields that require a fine needle-shaped body. For example, a fine needle-shaped body used for MEMS devices, drug discovery, cosmetics, and the like. It is also useful as a production method.

DESCRIPTION OF SYMBOLS 11 ... Acicular body original plate 12 ... Filler 13 ... Electron beam 14 ... Resin replication plate 15 ... Acicular body material 16 ... Acicular body molded product

Claims (4)

A method for producing a fine needle-shaped body,
A step of producing an acicular body original plate in which an acicular body shape is formed;
Filling the needle-shaped body forming side of the needle-shaped body original plate with a filling material, and curing the filling material;
Peeling the cured filling material from the acicular body original plate to form an acicular body replication plate made of the filling material;
Filling the needle-shaped replica plate with a molding material and curing the molding material;
Peeling the cured molding material from the acicular replica, and producing a needle-shaped body made of the molding material,
The filling material is a resin whose internal crosslink density increases upon irradiation with ionizing radiation,
In the step of forming the acicular body replica, the needle-shaped body manufacturing method is characterized by irradiating the needle-shaped body forming side of the filling material with ionizing radiation after peeling the filler material from the acicular body original plate. .   The needle-shaped body manufacturing method according to claim 1, wherein the filling material includes one or more resins selected from the group consisting of epoxy resins and silicone resins.   2. The method for manufacturing a needle-shaped body according to claim 1, wherein the ionizing radiation is an electron beam. It is a needle-like body duplication plate in which a recess having a needle-like body shape is formed,
The main component is a resin whose internal crosslink density increases by irradiation with ionizing radiation.
A needle-shaped replica plate, which is irradiated with ionizing radiation after the formation of the recess.

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