JP5090032B2 - 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 producing the needle-shaped body.

  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 for transdermal administration of a physiologically active substance, a method of transdermal administration using a fine needle-like body has attracted attention. By perforating the stratum corneum with high barrier properties using fine needles, it is possible to form a passage route for physiologically active substances and improve the efficiency of transdermal administration. It has the advantage that not only the fat-soluble physiologically active substance used but also a water-soluble physiologically active substance can be applied to transdermal administration. At this time, by designing the fine needle-like body 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 a fine needle-like body is used for the purpose of transdermal administration, the fine needle-like body penetrates through the stratum corneum, which is thin enough to perforate the skin, and the tip corner, the outermost layer of the skin, It is desirable that the needle does not reach the nerve layer. Specifically, the diameter of the needle-like body is about several to 100 μm, the tip angle of the needle-like body is 30 ° or less, The length is preferably about several tens of μm to several hundreds of μm.

  Many of the fine acicular bodies used for the purpose of transdermal administration include a flow path formed on the surface of the acicular body or inside the acicular body, and a solution containing a physiologically active substance (hereinafter referred to as a drug solution) , And applied through the flow path. In addition, a method has been proposed in which fluid transport is enhanced by imparting hydrophilicity to a path for transporting a chemical solution contained in a needle-like body (see Patent Document 1).

  Further, a method is disclosed in which a physiologically active substance is applied to the surface of a needle-like body by a method of supplying a chemical solution to the surface of the needle-like body and forming a dry film. In this case, a uniform dry film can be formed by performing a treatment for improving wettability on the surface of the needle-like body. Examples of the surface treatment include chemical pre-etching, plasma treatment, heat treatment, cleaning with an alkaline detergent, and cleaning with a wetting agent (see Patent Document 2).

  In addition, the material constituting the fine needle-shaped body is preferably a material that does not adversely affect the human body even if the damaged needle-shaped body remains in the body. In addition, biocompatible materials such as maltose, polylactic acid, and dextran are considered promising (see Patent Document 3).

In addition, as a method for manufacturing the fine needle-like body described above, a manufacturing method has been proposed in which an original plate of a needle-like body is created by machining, a duplicate plate is made from the original plate, and transfer processing is performed (Patent Document 4). reference).
JP-T-2005-514179 JP-T-2006-500794 gazette JP 2005-021677 A JP-T-2006-513811

  A needle-like body that is used by adding a chemical solution to the surface of the needle-like body in advance does not require a channel for supplying the chemical solution or a mechanism for feeding the chemical solution, and can be produced relatively easily. . Therefore, the manufacturing cost of the needle-like body can be suppressed. However, the chemical solution added to the surface of the needle-like body is not completely delivered into the living body, and a considerable part of the chemical solution remains on the surface of the needle-like body, especially on the substrate even after use. Depends on the puncture status of the needle-like body and the skin condition. Therefore, there is a problem that the dose of the physiologically active substance to be strictly controlled is unstable. In addition, since the amount of the physiologically active substance remaining in the needle-like body after use is expected in advance, it is necessary to add more physiologically active substance to the needle-like body than is actually required. When using a substance, there has been a problem that the cost burden on the patient is increased.

  The present invention has been made to solve the above-described problems, and it is easy to control the amount of a chemical solution to be added, and can selectively hold the chemical solution at a site where the chemical solution is delivered into the living body with high efficiency. The object is to provide a possible needle-like body.

The present invention according to claim 1 is a fine needle-like body, comprising a substrate and a protrusion provided on the substrate, wherein the tip of the protrusion is a region exhibiting hydrophilicity, The base of the protrusion and the substrate surface are regions that exhibit hydrophobicity, the chemical solution is retained in the region that exhibits hydrophilicity, and the region that exhibits hydrophilicity is hydrophilized by ozone treatment. This is a needle-like body.
In the present specification, the term “needle-like body” is not limited to the case where there is a single protrusion, but also includes a structure in which a plurality of protrusions are regularly arranged (for example, arranged in an array). Define as including.

  The present invention according to claim 2 is the needle-shaped body according to claim 1, wherein the water contact angle is less than 90 degrees for the hydrophilic region, and the water region is hydrophobic. A needle-like body having a contact angle of 90 degrees or more.

The present invention described in claim 3 is the needle-shaped body according to claim 1 or 2 , wherein the protrusion is made of polylactic acid.

According to a fourth aspect of the present invention, in the method for manufacturing a fine needle-like body, the step of forming a protrusion on the substrate, and the length of the protrusion on the substrate on which the protrusion is formed A step of disposing a mask having a short film thickness; a step of modifying the tip of the protrusion that penetrates the mask to hydrophilicity by ozone treatment; a step of removing the mask; and the modification to the hydrophilicity And a step of holding a chemical solution in the region.

  The needle-like body of the present invention is characterized in that the tip of the protrusion is an area showing hydrophilicity, and the base of the protrusion and the substrate surface are areas showing hydrophobicity. Thereby, the solution containing a physiologically active substance can be selectively held in the hydrophilic region including the tip of the protrusion that reaches the deepest part by skin puncture. Therefore, it becomes possible to deliver the retained physiologically active substance into the living body with high efficiency without waste.

Hereinafter, the acicular body according to the present invention will be described (FIG. 1).
The needle-shaped body of the present invention is
A substrate,
A protrusion provided on the substrate,
The tip of the protrusion is a hydrophilic region,
The base of the protrusion and the substrate surface are regions that exhibit hydrophobicity.

  The substrate is provided to support the protrusion. The substrate is not particularly limited as long as it has mechanical strength to support the protrusions. Although it may be formed from the same material as the protrusions or a material different from the protrusions, it is preferably a material that is less irritating to the living body. Moreover, it is preferable to have flexibility so that the surface can be uniformly pressed against the curved surface.

  In the needle-like body of the present invention, the shape of the protrusion, the dimension of the protrusion, the material constituting the protrusion, and the like are not limited. When a fine needle-like body is used for the purpose of transdermal administration, it is desirable that the protrusion has a diameter of several μm to several hundred μm and a length of about several tens μm to several hundred μm.

  The material for forming the protrusion is not particularly limited, but when the needle-like body is used on the skin of a living body, the protrusion is preferably formed of a material that does not adversely affect the living body. Biocompatible materials such as medical silicone resins, maltose, polylactic acid, dextran, Mg-based compounds, and Ti-based compounds are preferably used.

The needle-shaped body of the present invention is characterized in that the tip of the projection is a region showing hydrophilicity, and the surface of the projection and the substrate surface excluding the tip of the projection have a region showing hydrophobicity.
For example, specifically, for the hydrophilic region, the contact angle of water is preferably less than 90 degrees, and more preferably less than 50 degrees. In the hydrophobic region, the water contact angle is preferably 90 degrees or more, and more preferably 130 degrees or more.
In the needle-shaped body of the present invention, the hydrophobic region surrounding the hydrophilic region has an effect of suppressing the outflow of the chemical solution held in the hydrophilic region, and the hydrophilic region and the hydrophobic region water The larger the contact angle difference, the greater the effect of retaining the chemical solution.

  The needle-like body according to the present invention can selectively hold a chemical solution in a desired region by selectively arranging a region in which the wettability of the surface is controlled. After supplying a desired amount of the chemical solution, a treatment for strengthening the state of holding the chemical solution on the surface may be performed. For example, the chemical solution adhesion state on the surface of the needle-shaped body may be reinforced by taking advantage of the fact that the viscosity of the chemical solution itself is increased by performing a treatment for releasing the solvent in the chemical solution to some extent. As a measure for releasing the solvent in the chemical solution to some extent, for example, decompression or heating may be performed.

  In the schematic view of the needle-shaped body of the present invention shown in FIG. 1, an example in which the region including the tip is a hydrophilic surface in all the protrusions is shown, but a hydrophilic surface is not necessarily formed in all the protrusions. It does not have to be. It is also possible to control the amount of drug solution retained in the entire needle-like body by changing the ratio of the protrusions forming the hydrophilic surface. Moreover, it is also possible to provide the same chemical liquid holding amount controllability by controlling the area of the hydrophilic region formed on the protrusion.

  The needle-like body of the present invention cannot obtain the effects of the invention when the chemical solution is oil-based. In this case, by selectively changing the arrangement of the hydrophilic region and the hydrophobic region of the present invention, the selective retention effect of the chemical solution in the region including the tip of the protrusion is obtained, similar to the present invention.

  The method for supplying the chemical solution to the fine needles according to the present invention is not particularly limited. You may selectively supply a chemical | medical solution to a hydrophilic area | region, and you may supply a chemical | medical solution uniformly to the surface in which the projection part was formed. In this case, since the chemical solution added to the hydrophobic region tries to maintain a substantially spherical shape by the surface tension, it is easily removed from the substrate by tilting the substrate or simply blowing nitrogen or air. The removed chemical solution is preferably collected and used for addition to another needle-like body.

Hereinafter, the manufacturing method of the needle-shaped body of the present invention will be specifically described with reference to FIG.
The method for manufacturing a needle-shaped body of the present invention is characterized in that the method for manufacturing the needle-shaped body of the present invention is characterized in that a mask is applied to the needle-shaped body and the surface outside the mask is subjected to surface processing to be hydrophilic / hydrophobic. .

  For the production of the fine needle-shaped body shown in FIG. 2A, a known production method may be used as appropriate according to the shape of the needle-shaped body. At this time, as a fine processing technique, for example, a lithography method, a wet etching method, a dry etching method, a sand blast method, a laser processing method, a precision machining method, or the like may be used. It is also possible to produce a mother die by the fine processing technique, and to produce a fine needle-like body by a transfer molding method using the mother die and the molding material. It is also possible to produce a replica mold from the mother mold and to produce a fine needle-like body by a transfer molding method using the replica mold and the molding material. As the transfer molding method, a known production method may be used as appropriate. For example, an injection molding method, an extrusion molding method, an imprint method, a casting method and the like can be suitably used.

  In order to selectively perform surface treatment on a desired area on the surface of the needle-like body, a mask having an opening corresponding to the desired area is prepared. The material and form of the mask are not particularly limited. It suffices that the pattern portion and the shielding portion have sufficient selectivity for the surface treatment for modifying the needle-like body surface to be hydrophilic or hydrophobic. For example, after preparing a mask having an opening corresponding to a region to be subjected to hydrophilic treatment, and arranging the mask at a predetermined position on the protrusion as shown in FIG. 2B, as shown in FIG. By applying a hydrophilic treatment to the film, a hydrophilic region can be formed only in a region corresponding to the opening of the mask illustrated in FIG. If a material that can be easily punctured by the needle-like body is used, it is possible to expose only the tip of the projection from the mask without forming an opening in a desired region. For example, a silicon resin that can be easily punctured with a needle-like body is prepared, the needle-like body is pierced and penetrated into the silicon resin, and only the tip region of the protrusion is exposed from the silicon resin. In this case, for example, in order to expose a height of only 50 μm from the tip of the protrusion with respect to the protrusion having a height of 150 μm from the silicon resin, the difference between the height of the protrusion and the height of the tip to be exposed is 100 μm. A silicon resin having a thickness of 1 mm is prepared, and the silicon resin is completely penetrated by the protrusion, and the tip of the protrusion can be exposed by 50 μm from the silicon resin.

  It is also possible to form a hydrophobic region only in a desired region by preparing a mask corresponding to the region to be subjected to the hydrophobic treatment and performing the hydrophobic treatment. In this case, as shown in FIG. 3, the protrusion may be punctured with a desired depth into silicon resin to provide a mask, and the base of the protrusion and the substrate surface may be subjected to a hydrophobic treatment. For example, when only 50 μm at the tip of the protrusion is protected from the hydrophobic treatment with respect to the protrusion having a height of 150 μm, the protrusion may be punctured with silicon resin to a depth of 50 μm and subjected to the hydrophobic treatment.

  As a method for modifying the surface of the needle-like body to be hydrophilic or hydrophobic, a known treatment method may be appropriately used depending on the desired surface characteristics. At this time, for example, ozone irradiation, electromagnetic wave irradiation such as ultraviolet rays or X-rays, electron beam irradiation, plasma irradiation, addition of a property modifying substance to the surface, addition of a photocatalyst, etc. can be suitably used as the surface treatment method.

  In a fine needle-shaped body made from polylactic acid, a biocompatible material, ozone treatment is performed on the desired area on the surface where the protrusions are formed, so that the treated area can be contacted with water. It can be easily modified to hydrophilicity with an angle of 90 degrees or less. On the surface not subjected to the surface treatment, the hydrophobic surface of polylactic acid having a water contact angle of about 100 degrees is maintained, and the acicular body according to the present invention is obtained.

  The surface hydrophilic treatment can also be carried out by adding a substance that promotes hydrophilicity. By this method, the present invention can be applied to a substance that is difficult to add hydrophilicity by surface modification. However, when the protrusion is used on the skin of a living body, the substance that promotes hydrophilicity is desirably a substance that does not adversely affect the living body. A method for adding the hydrophilic substance is not particularly limited, and a known treatment method may be used as appropriate. At this time, for example, a spray coating method, a spin coating method, a dip coating method, a vapor deposition method, a graft polymerization method and the like can be suitably used. Examples of the substance that promotes hydrophilicity include polyvinyl alcohol and phospholipid compounds.

  It is also possible to carry out the surface hydrophilic treatment by the photocatalytic effect. By adding a photocatalyst typified by titanium oxide to a desired region on the surface of the acicular body and irradiating with excitation light, the hydrophilicity of the desired region can be improved. Alternatively, a selective hydrophilic treatment can be applied to a desired region by adding a photocatalyst to the entire surface of the needle-like body and limiting the irradiation region of the excitation light using a mask. At this time, the mask needs to satisfy the performance of shielding the excitation light.

  It is also possible to apply a hydrophobic treatment to a desired region. For example, when a hydrophobic region for an aqueous chemical solution is provided, surface fluorination by a fluorine-based gas treatment can be used. The fluorinated surface is hydrophobic to aqueous chemicals.

  The surface of the fine acicular body formed from quartz shows hydrophilicity. Similarly, because of the natural oxide film present on the surface, the surface of fine needles made of silicon also exhibits hydrophilicity. When modifying the hydrophilicity of the silicon surface with quartz or natural oxide film to hydrophobicity, for example, surface treatment with a hexamethyldisilazane solution can give a methyl group to the surface to obtain a hydrophobic surface. It is. Further, for example, by treating the silicon surface on which the natural oxide film is formed with a hydrofluoric acid aqueous solution, the natural oxide film on the surface is removed, dangling bonds of silicon atoms on the surface are terminated with hydrogen atoms, and hydrophobic It is also possible to obtain a neutral surface. Therefore, the hydrophobic region can be selectively formed by performing the above-described hydrophobic treatment on a desired region using a mask.

  After performing the surface modification treatment on a desired region through the mask as described above, the mask is removed to obtain the needle-like body according to the present invention as shown in FIG.

  Hereinafter, as an example of an embodiment of the method for producing a needle-shaped body of the present invention, a description will be given with reference to FIG. Naturally, the manufacturing method of the needle-shaped body of the present invention is not limited to the following examples, and includes other manufacturing methods that can be analogized. Further, the needle-like body of the present invention is not limited to the needle-like body produced in the following examples.

  First, using precision machining, a needle-like shape in which 25 square pyramidal projections (height: 150 μm, bottom: 60 μm × 60 μm) are arranged in a grid of 5 rows and 5 rows at 1 mm intervals on a silicon substrate. Formed body. The 25 protrusions were arranged in a square area having a side of about 4 mm.

Next, a nickel conductive layer having a thickness of 100 nm was formed on the acicular body formed of the silicon substrate by sputtering. This conductive layer becomes a seed layer in the subsequent electrolytic plating.
Next, a nickel film having a thickness of 500 μm was formed on the seed layer by electrolytic plating.
Next, the silicon substrate was wet-etched with a potassium hydroxide aqueous solution having a weight percent concentration of 30% heated to 90 ° C. to completely remove it, thereby producing a needle-like replica mold made of nickel.
Next, using the replica mold, needle-like body transfer molding to polylactic acid was performed by an imprint method, and the replica mold was peeled from the polylactic acid.

  As a result, the acicular body 10 made of polylactic acid composed of the substrate 1 and the protrusion 2 shown in FIG. 2A was obtained. The needle-like body 10 has a square quadrangular pyramid (height: 150 μm, bottom: 60 μm × 60 μm) projections 2 on a square substrate 1 having a side of about 8 mm in a grid of 5 columns and 5 rows at 1 mm intervals. It was prepared in the form of 25 lines.

  Next, in order to investigate the surface state of the needle-like body 10, the contact angle was measured. As a result of measuring the needle-like body 10 on a horizontal stage and dropping pure water thereto, the contact angle of water with the surface of the needle-like body 10 was about 100 degrees.

  Next, a mask was prepared. A silicon resin with a side of 10 mm and a thickness of 100 μm is prepared as a mask, and as shown in FIG. 2B, the silicon resin 4 is punctured by the protrusion 2, and the tip of the protrusion 2 is exposed from the silicon resin 4. I let you. At this time, the height 3 of the protrusion 2 exposed from the silicon resin 4 was about 50 μm.

Next, as shown in FIG. 2 (c), ozone treatment 5 which is one of the surface hydrophilization means is selectively performed on the tip of the protrusion 2 exposed from the silicon resin 4, and FIG. ), A hydrophilic region 56 was formed at the tip of the protrusion.
Next, the silicon resin 4 was removed from the needle-like body 10, and as shown in FIG. 2E, the needle-like body 11 according to the present invention in which the hydrophilic region 56 was formed at the tip of the protruding portion was obtained.

  Subsequently, in order to confirm the effect of the present invention, the needle-like body 11 was completely immersed in an aqueous chemical solution in which fluorescent particles were dispersed. After 1 minute, the needle-like body 11 was pulled up from the chemical solution. Thereafter, when the surface of the needle-like body 11 was observed with an optical microscope while irradiating the excitation light of the fluorescent particles, fluorescence emission was intensively confirmed in an area of about 50 μm from the tip of the protrusion 2, while in the other areas Fluorescence emission was not confirmed. From this result, it was confirmed that the chemical solution was selectively held in the region of about 50 μm at the tip of the protrusion 2.

  Next, two polylactic acid flat plate samples prepared through the same steps as the needle-like body 11 were prepared, and one of them was subjected to a hydrophilic treatment with ozone. As a result of placing these samples on a horizontal stage and measuring by dropping pure water, the contact angle of water on the surface of the sample subjected to ozone treatment is about 40 degrees, and the surface of the sample not subjected to ozone treatment The contact angle of water was about 100 degrees. From this result, in the needle-shaped body 11 produced according to the present example, the hydrophilic region formed at the tip of the protrusion exhibits hydrophilicity with a water contact angle of about 40 degrees, while the other region is water. The contact angle was measured to exhibit hydrophobicity of about 100 degrees.

It is the schematic which shows an example of the acicular body of this invention. It is a general | schematic fragmentary sectional view for demonstrating an example of the manufacturing process of the acicular body by embodiment of this invention with time. It is a schematic fragmentary sectional view which shows an example of the mask arrangement | positioning in the manufacturing process of the acicular body by embodiment of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Board | substrate 2 ... Projection part 3 ... Height of the base part of the projection part exposed from the mask 4 ... Mask 5 ... Surface modification means 6 ... Modified surface 10 ... Needle-like body 11 ...... Needle

Claims (4)

In fine needles,
A substrate,
A protrusion provided on the substrate,
The tip of the protrusion is a hydrophilic region,
The base of the protrusion and the substrate surface are regions showing hydrophobicity, and
A chemical solution is retained in the hydrophilic region , and
The needle-like body, wherein the hydrophilic region is hydrophilized by ozone treatment . The acicular body according to claim 1,
For the region showing hydrophilicity, the contact angle of water is less than 90 degrees,
A needle-like body having a contact angle of water of 90 degrees or more with respect to a hydrophobic region. The needle-shaped body according to claim 1 or 2 ,
A needle-like body characterized in that the protrusion is made of polylactic acid. In the method for producing fine needles,
Forming a protrusion on the substrate;
Placing a mask having a film thickness shorter than the length of the protrusion on the substrate on which the protrusion is formed;
A step of modifying the tip of the protruding portion penetrating the mask to be hydrophilic by ozone treatment ;
Removing the mask;
Holding the chemical in the hydrophilically modified region;
A needle-shaped body manufacturing method comprising:

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