JP5874303B2 - Needle-like body and method for producing needle-like body - Google Patents

Description

  The present invention relates to a needle-shaped body and a method for manufacturing a needle-shaped body suitable for manufacturing the needle-shaped body.

  The percutaneous absorption method, which is a method of injecting a delivery product such as a drug from the skin and administering the delivery product into the body, is used as a method capable of easily administering the delivery product without causing pain to the human body. .

  In the field of transdermal administration, a method has been proposed in which skin is perforated using a needle-like body on which a needle of the order of μm is formed, and a drug or the like is administered into the skin (see Patent Document 1).

  Further, as a method for producing a needle-like body, it has been proposed to prepare an original plate using machining, form a transfer plate from the original plate, and perform transfer processing molding using the transfer plate (Patent Document 2). reference).

  In addition, as a method for producing a needle-like body, it has been proposed to prepare an original plate using an etching method, form a transfer plate from the original plate, and perform transfer processing molding using the transfer plate (Patent Document 3). reference).

  Further, it is desirable that the material constituting the acicular body is a material that does not adversely affect the human body even if the damaged acicular body remains in the body. For this reason, biocompatible materials such as chitin and chitosan have been proposed as acicular materials (see Patent Document 4).

  Chitin is a component contained in shells of crustaceans such as crabs and shrimps, and chitosan is a deacetylated product. Although there is no clear boundary line between chitin and chitosan, generally, chitin having a deacetylation of 70% or more is called chitosan.

  Chitin / chitosan is characterized by being dissolved in an acidic aqueous solution. Therefore, by preparing an aqueous solution in which chitin / chitosan is dissolved in an acidic aqueous solvent, filling the aqueous solution into a transfer plate having a needle-like shape, and evaporating water from the aqueous solution, Can be produced.

JP-A-48-93192 International Publication No. 2008/013282 Pamphlet International Publication No. 2008/004597 Pamphlet International Publication No. 2008/020632 Pamphlet

  The needle-shaped body is required to be insoluble in the living body depending on the use, such as a drug to be delivered and a prescription for symptoms.

  However, a needle-shaped body prepared from an acidic aqueous solution of chitin / chitosan has no water resistance, and dissolves when contacted with water or immersed in water. For this reason, a needle-shaped body prepared from an acidic aqueous solution of chitin / chitosan is dissolved in the living body, has a high load on the living body, and cannot maintain a fine needle-shaped body shape after puncturing. There was a problem.

  Further, since the needle-like body is used by puncturing skin that is never flat, it is preferable that the needle-like body has a certain degree of flexibility. A needle-shaped body prepared from an acidic aqueous solution of chitin / chitosan has poor flexibility, and there is a problem in that the protrusion is damaged when the skin is punctured.

  Accordingly, the present invention has been made to solve the above-described problems, and has a low load on a living body, can maintain a fine needle-like body shape after puncturing the skin, and has flexibility. It is an object of the present invention to provide a needle-like body.

In order to solve the above-mentioned problem, the invention according to claim 1 is provided with a protrusion having a needle-like shape and a support substrate for supporting the protrusion, and the needle-like material used for the protrusion is at least chitosan. A needle-like body characterized by containing glyoxylic acid.
The invention described in claim 2 is characterized in that the chitosan contains one or more materials selected from the group consisting of chitosan, chitin / chitosan, chitin / chitosan derivatives, glucosamine, and glucosamine derivatives. It was set as the acicular body of item 1.
According to a third aspect of the present invention, the glyoxylic acid is selected from glyoxylic acid and glyoxylic acid hydrate. The needle-shaped body according to the first or second aspect is provided.
According to a fourth aspect of the present invention, there is provided the acicular body according to any one of the first to third aspects, wherein the protrusion and the support substrate are made of an acicular body material having the same composition. .
As the invention of claim 5, wherein the needle-like shape, the needle-like body according to any one of claims 1 to 4, characterized in that the height 10μm or more 1000μm following needles shape It was.
According to a sixth aspect of the present invention, there is provided a method for manufacturing a needle-like body comprising a protrusion having a needle-like body shape and a support substrate for supporting the protrusion, comprising a recess having a needle-like body shape. A step of preparing an intaglio, a step of preparing chitosan and glyoxylic acid in a liquid state to form a liquid needle-shaped body material, a step of filling the intaglio with the liquid needle-shaped body material, and the liquid needle-shape Heating the body material in a state of being filled in the intaglio and solidifying the needle-shaped body material; and separating the solidified needle-shaped body material from the intaglio to form a needle-shaped body. It was set as the manufacturing method of the acicular body to do.

  By using the needle-shaped body of the present invention, the shape can be maintained in the living body even after puncturing the skin with high water resistance, and the needle-shaped body having a low load on the living body can be obtained. . It was possible to push a fine three-dimensional structure having flexibility on the order of μm along the skin, and to obtain a needle-like body that was not damaged when punctured into the skin.

FIG. 1 is a schematic cross-sectional view of the acicular body of the present invention. FIG. 2 is an explanatory view of the method for producing a needle-shaped body of the present invention.

  Hereinafter, the acicular body of the present invention will be described. FIG. 1 shows a schematic cross-sectional view of the needle-shaped body of the present invention.

  The acicular body 1 of the present invention includes a protrusion 2 having a needle shape and a support substrate 3 that supports the protrusion. The needle-like body of the present invention is characterized in that at least the needle-like material used for the protrusion includes at least chitosan and glyoxylic acid or a hydrate thereof.

  As a result of intensive studies, the present inventor has made a needle-like body by adding glyoxylic acid or its hydrate to chitosan, so that the shape can be maintained in vivo, and the skin can be punctured without being broken. The inventors have found that a three-dimensional structure having a fine order can be obtained, and have completed the present invention.

  Glyoxylic acid contains an aldehyde group and a carboxyl group in one molecule. Glyoxylic acid is thought to act as a crosslinking agent in chitosan. The chitosan amino group reacts with the aldehyde group and carbonyl group of glyoxylic acid, and the chitosan molecules cross-link with each other, so the amino group of chitosan is lost and biocompatible chitosan cannot form a salt even in an acid solution. Since it becomes difficult to dissolve in water and the flexibility can be improved, it is considered that the shape can be maintained in vivo and the skin can be punctured without being damaged.

  The acicular body of the present invention is insoluble in an aqueous solvent. Here, “the needle-like body is insoluble in an aqueous solvent” means “the volume of the needle-like body decreased after being immersed in a pH 7.5 phosphate buffer solution (PBS) for 24 hours. Is 5% or less of the volume before immersion. "

  The chitosan used as the needle-shaped body material of the present invention has biocompatibility, and is one or more selected from the group consisting of chitosan, chitin / chitosan, chitin / chitosan derivatives, glucosamine, and glucosamine derivatives. Materials may be included. Although there is no clear boundary line between chitin and chitosan, generally, chitin having a deacetylation of 70% or more is called chitosan. Deacetylation can be appropriately performed by a known method.

Chitosan / chitin / chitosan, chitin / chitosan derivatives and glucosamine derivatives with biocompatibility are derived from crustaceans, shrimp and other crustaceans, from hyphae / microbe-produced plants, and from those as starting materials Etc. can be used. Chitosan, chitin, chitosan and chitin-chitosan derivatives are bactericidal effect with illustrating cosmetic effects against skin, since it has an antibacterial effect, it can be preferably used as the needle-shaped material used for the needle-shaped body of the present invention.

  The glyoxylic acid used as the needle-shaped material of the present invention is selected from glyoxylic acid and glyoxylic acid hydrate. Glyoxylic acid and glyoxylic acid hydrate are used as materials for cosmetics, pharmaceuticals, and fragrances, and as pH adjusters for cosmetics, and these can be used.

In the needle-like body of the present invention, the shape of the protrusion 2 may be any shape as long as it is suitable for puncturing the skin, and may be designed as appropriate. For example, specifically, a cone, a pyramid, a cylinder, a prism, a pencil shape (the body portion is a columnar shape, and the tip portion is a cone shape) may be used. Further, either (1) a shape with one protrusion on the support substrate or (2) a shape with a plurality of protrusions on the substrate may be used.

  In addition, when a plurality of protrusions stands on the support substrate 3, it is preferable that the protrusions are arranged in an array. Here, “array shape” indicates a state in which the unit needle-like bodies are arranged, and includes, for example, patterns such as a lattice arrangement, a close-packed arrangement, a concentric arrangement, and a random arrangement. Shall be.

  In addition, the needle-shaped support substrate of the present invention is preferably made of a needle-shaped material having the same composition as the protrusion. By forming the support substrate and the protruding portion with the composition having the same composition, the supporting substrate portion and the protruding portion portion can be suitably formed by integral molding.

The support substrate 3 may have a multilayer structure in which a material different from the needle-like material is laminated in the lower layer. By laminating a plurality of types of materials, it is possible to obtain a support substrate 3 utilizing the physical properties of the plurality of materials. For example, it can be bent when the upper layer is formed by the composition of the projections having the same composition lower using the supporting substrate with a rich material flexible, suitably supporting substrate into a roll (1). Similarly, (2) when using a substrate in which the upper layer is made of a material having higher malleability than the lower layer, the support substrate can be suitably bent into a roll shape. Moreover, also when (3) the board | substrate which made the upper layer of the support substrate the material whose shrinkage is smaller than a lower layer is used, a board | substrate can be suitably bent in roll shape. Moreover, (4) By making the lowest layer of a support substrate into a layer which has a softness | flexibility, when a needle-shaped body is accumulated and stored, damage to a projection part can be suppressed.

  In the prescription using the needle-like body, an applicator for fixing the insertion position and direction can be used.

  In the needle-shaped body of the present invention, a hole may be provided in the protrusion. At this time, the hole may be a through hole or a non-through hole up to the back surface of the support substrate. Moreover, the needle-shaped body of the present invention may be provided with holes in the support substrate. At this time, the hole may be a through hole or a non-through hole up to the back surface of the support substrate.

  Next, the preferable shape of the projection part of the needlelike object of the present invention is explained with reference to FIG.

  The protrusions of the needle-shaped body of the present invention preferably have a size and length suitable for forming a puncture hole in the skin. Specifically, the height H of the protrusion is preferably in the range of 10 μm or more and 1000 μm or less. The width D of the protrusion is preferably in the range of 1 μm to 300 μm. The aspect ratio is preferably in the range of 1 to 10. The aspect ratio A is defined by A = H / D using the length H and width D of the protrusion.

  In the acicular body of the present invention, the height H of the protrusion is preferably in the range of 10 μm or more and 1000 μm or less. The height H of the projection is the distance from the support substrate to the tip of the projection.

  The height H of the protrusion of the needle-like body is preferably determined in consideration of how deep the puncture hole formed when the needle-like body is punctured is formed in the skin.

  In particular, when the puncture hole formed when the needle-like body is punctured is held in “in the stratum corneum”, the height H of the protrusion of the needle-like body is specifically within the range of 10 μm to 300 μm, More preferably, it is in the range of 30 μm or more and 200 μm or less.

  In addition, when the puncture hole formed when the needle-like body is punctured is “length that penetrates the stratum corneum and does not reach the nerve layer”, the height H of the protrusion of the needle-like body is 200 μm or more and 700 μm. Within the following range, more preferably within the range of 200 μm to 500 μm, and further preferably within the range of 200 μm to 300 μm.

  Further, when the puncture hole formed when the needle-like body is punctured is “the length that the puncture hole reaches the dermis”, the height H of the projection of the needle-like body is in the range of 200 μm or more and 500 μm or less. It is preferable to do. When the puncture hole formed when the needle-like body is punctured is “the length that the puncture hole reaches the epidermis”, the height H of the projection of the needle-like body is in the range of 200 μm or more and 300 μm or less. It is preferable.

  The width D of the protrusion is preferably in the range of 1 μm to 300 μm. It is preferably determined in consideration of how deep the puncture hole formed when puncturing the needle-like body is formed in the skin.

  The width D of the protrusion is the maximum length of the protrusions in contact with the support substrate when the protrusion is projected in parallel with the substrate surface. The diameter of the circle of the surface in contact with the protrusion and the support substrate is the width D when the protrusion is conical, and the square of the surface in contact with the protrusion and the support substrate when the protrusion is a regular pyramid. The diagonal line is the width D. In addition, when the protrusion is a cylinder, the diameter of the circle in contact with the protrusion and the support substrate is the width D, and when the protrusion is a square prism, the surface is in contact with the protrusion and the support substrate. The diagonal of the square is the width D.

  When the needle-like body shape has a tip angle such as a cone shape, when penetrating the stratum corneum, the tip angle θ of the protrusion is in the range of 5 ° to 30 °, more preferably 10 ° to 20 °. It is preferable to be within the range of 0 ° or less. Note that the tip angle θ indicates the maximum angle (vertical angle) when the protrusion is projected in parallel with the substrate surface.

  Hereinafter, the production of the needle-shaped body of the present invention will be described. In the method for producing a needle-shaped body according to the present invention, a step of preparing an intaglio plate having a concave portion having a needle-shaped body shape, and adjusting the liquid state of chitosan and glyoxylic acid or its hydrate, A step of making the body material, a step of filling the intaglio with the liquid needle-shaped body material, and heating the liquid needle-shaped body material while the intaglio is filled to solidify the needle-shaped body material. And a step of peeling the solidified needle-like material from the intaglio plate to form a needle-like body.

<Process for preparing intaglio>
As the intaglio, an original plate for determining the shape of the needle-like body is prepared, and an intaglio plate in which the desired shape of the needle-like body is inverted from the original plate is produced. As a method for producing the original plate for determining the shape of the needle-like body, a known production method can be appropriately used according to the shape of the needle-like body. At this time, it may form an original using microfabrication techniques, as microfabrication techniques, for example, Rukoto using lithography, wet etching method, dry etching method, a sandblasting method, a laser processing method, and precision machining method Can do. As a method for forming the intaglio from the original plate, a known shape transfer method may be used as appropriate. For example, (1) Ni intaglio is formed by Ni electroforming, and (2) transfer molding using a molten resin.

<Process of preparing chitosan and glyoxylic acid in a liquid state to form a liquid needle-like body material>
Next, biocompatible chitosan used as a needle-shaped body material is dissolved in an aqueous glyoxylic acid solution to prepare a solution. Biocompatible chitosan is known to be soluble in acid, and glyoxylic acid is known to be soluble in water, and is preferably prepared as an aqueous acid solution. In addition, here, the liquid state is sufficient as long as it has fluidity that can flow into the intaglio, and may be in a gel form.

<Step of filling needle material>
Next, the adjusted liquid needle-shaped body material is filled into the intaglio. About a filling method, you may select a well-known method suitably according to the shape and dimension of an intaglio. For example, as a filling method, a spin coating method, a method using a dispenser, a casting method, or the like can be used. In addition, when filling, the environment around the intaglio may be under reduced pressure or under vacuum.

<Step of solidifying the needle-shaped body material>
Next, the filled acicular body material is solidified. The solidification of the needle-shaped body material is completed even at room temperature, but if the heat treatment is performed, the molding time can be shortened. The heating temperature and time at this time are preferably set to temperatures at which chitosan molecules react with each other by the reaction of the amino group of chitosan with the aldehyde group and carbonyl group of glyoxylic acid. Specifically, the heating temperature is preferably in the range of 50 ° C. or more and 100 ° C. or less. Any known heating means may be used as long as desired heating can be performed. For example, as the heating means, there is a means for placing an intaglio filled with a needle-shaped body material on a hot plate.

<Step of peeling the needle-like body from the intaglio>
Next, the acicular body material solidified from the intaglio is peeled to obtain the acicular body.
As a method for peeling, a method such as peeling by physical force or chemical dissolution of the intaglio can be used.

  In the method for manufacturing a needle-shaped body according to the present invention, the needle-shaped body material used for the protrusion is formed by solidifying a material obtained by mixing at least chitosan and glyoxylic acid. As a result of intensive studies, the inventor has found that a fine three-dimensional structure in the order of μm that is insoluble in water and the living body can be manufactured by dissolving chitosan in a glyoxylic acid aqueous solution and forming a needle-like body. The headline and the present invention have been completed. By mixing biocompatible chitosan and glyoxylic acid, a non-dissolvable fine three-dimensional structure on the order of μm is obtained, and elution of the material into the living body is eliminated, and the delivery material applied on the skin is administered. Therefore, it was possible to provide a needle-like body that can be safely provided with a puncture hole.

<Example 1>
<Manufacture of needles>
Hereinafter, the needle-like body of the present invention and a specific method for producing the needle-like body will be specifically described. In addition, the manufacturing method of the acicular body of this invention and a acicular body is not limited to a present Example. FIG. 2 is an explanatory view of the needle-shaped body of the present invention.

  First, by using precision machining on a silicon substrate, an acicular body original plate in which 36 square squares (height: 150 μm, bottom surface: 60 μm × 60 μm) are arranged in a grid of 6 columns and 6 rows at 1 mm intervals is used. Formed.

Next, a nickel film having a thickness of 500 μm is formed on the acicular body original plate formed of the silicon substrate by plating, and the silicon substrate is heated with a 30% by weight potassium hydroxide aqueous solution heated to 90 ° C. is removed by wet etching to prepare a intaglio 11 made of nickel (FIG. 2 (a)).

Next, the acicular material 12 was prepared. In this example, chitosan was dissolved in a glyoxylic acid solution as the acicular body material 12 to prepare a material solution (FIG. 2 (a)).

Then, using a spin coating method to fill the needle material 12 to the intaglio 11 (Figure 2 (b)).

Next, the intaglio 11 needle-like material 12 is filled with a heat source 13 90 ° C., then heated for 10 minutes, the needle-shaped material 12 dried and solidified (Figure 2 (c)). Here, a hot plate is used as the heat source 13.

Next, the solidified acicular material 12 was peeled from the intaglio 11 to obtain the acicular body 1 (FIG. 2 (d)).

<Reference Example 1>
A needle-like body was produced in the same manner as in Example 1. However, the acicular material was a solution in which chitosan was dissolved in a 5% acetic acid solution.

<Confirmation test 1>
The acicular body obtained in Example 1 and Reference Example 1 was subjected to a confirmation test for insolubilization using a pH 7.5 phosphate buffer solution (PBS) and artificial skin. The needle-like body was immersed in PBS for 24 hours, and after the needle-like body was sufficiently dried, it was confirmed by a microscope whether the needle-like body was dissolved.

<Confirmation test 2>
The needle-like body obtained in Example 1 and Reference Example 1 was stabbed into the side surface of a polyurethane cylinder having R (radius) = 25 mm, and it was confirmed whether the needle-like body substrate could be aligned without being damaged.

Table 1 shows the measurement results of Confirmation Test 1 and Confirmation Test 2.

  From Table 1, it was confirmed from the results of Confirmation Test 1 that the needle-shaped body produced in Example 1 produced by mixing chitosan and glyoxylic acid did not dissolve in PBS. On the other hand, the acicular body produced in Reference Example 1 produced only with chitosan was dissolved in PBS, and the acicular body shape of the protrusions could not be maintained. Further, the volume of the needle-like body prepared in Example 1 before being immersed in a pH 7.5 phosphate buffer solution (PBS) for 24 hours and the volume after being immersed for 24 hours were measured. The volume before the immersion of the needle-shaped body produced in the above was 5% or less. In addition, when the needle-shaped body prepared in Example 1 was punctured into the artificial skin, it was confirmed that the needle-shaped body manufactured in Example 1 did not dissolve even when punctured into the artificial skin for 3 hours.

  Moreover, from the result of the confirmation test 2, in the acicular body produced in Example 1 manufactured by mixing chitosan and glyoxylic acid, it was able to follow without causing a substrate crack on the cylindrical side surface of R = 25 mm. On the other hand, when the acicular body produced in Reference Example 1 produced only with chitosan was placed along the side of the cylinder with R = 25 mm, the substrate cracked.

  In addition, the acicular body of this invention can be utilized for the various field | areas which require a fine acicular body. For example, it can be expected to be applied as a needle-like body used for MEMS devices, optical members, sample jigs, drug discovery, medical use, cosmetics, cosmetic use and the like.

DESCRIPTION OF SYMBOLS 1 ... Acicular body 2 ... Protrusion part 3 ... Support substrate 11 ... Intaglio 12 ... Acicular body material 13 ... Heat source (hot plate)

Claims (6)

A protrusion having a needle-like shape;
A support substrate for supporting the protrusion,
The acicular body material used for the protrusion includes at least chitosan and glyoxylic acid.   The acicular body according to claim 1, wherein the chitosan includes one or more materials selected from the group consisting of chitosan, chitin / chitosan, chitin / chitosan derivatives, glucosamine, and glucosamine derivatives.   The acicular body according to claim 1 or 2, wherein the glyoxylic acid is selected from glyoxylic acid and glyoxylic acid hydrate.   The acicular body according to any one of claims 1 to 3, wherein the protrusion and the support substrate are made of an acicular body material having the same composition. The needle-shaped body according to any one of claims 1 to 4, wherein the needle- shaped body is a needle-shaped body having a height of 10 µm or more and 1000 µm or less. A method for manufacturing a needle-like body comprising a protrusion having a needle-like shape and a support substrate that supports the protrusion,
Preparing an intaglio with a recess having a needle-like body shape;
Adjusting the liquid state of chitosan and glyoxylic acid to form a liquid needle-shaped body material;
Filling the intaglio with the liquid needle-shaped body material;
Heating in a state where the liquid needle-shaped body material is filled in the intaglio, and solidifying the needle-shaped body material;
Peeling the solidified needle-like body material from the intaglio plate to form a needle-like body.

Images