JP2013154042A - Method for manufacturing needle shape body and the needle shape body - Google Patents

Abstract

PROBLEM TO BE SOLVED: To solve the problem that warping occurs in a base body by reducing moisture in a needle shape body in a drying process when manufacturing the needle shape body consisting of water-soluble polymers.SOLUTION: A method for manufacturing a needle shape body includes: a needle shape body material preparation process for preparing a needle shape body material containing water-soluble polymers; a filling process for filling a mold 201 having recessed parts 203 formed of recess/projection inversion pattern of a needle shape body form and being made of at least two or more kinds of materials, with the needle shape body material; a drying process for drying the needle shape body material filled in the mold 201 and obtaining the needle shape body; and a mold releasing process for releasing the mold 201 from the needle shape body. In the method for manufacturing the needle shape body, a part other than the recessed parts 203 in the mold 201 is formed of a material with higher adhesion to the needle shape body material compared with a material to be used for the recessed parts 203. Thus, warpage is restrained from occurring in a needle shape body substrate.

Description

  The present invention relates to a method for producing an acicular body for subcutaneous administration of a drug and the acicular body.

  The percutaneous absorption method, which is a method of infiltrating a drug from the skin and administering the drug into the body, is used as a method for easily administering the drug without causing pain to the human body. Some drugs are difficult to administer by transdermal absorption. As a method for efficiently absorbing these drugs into the body, attention has been drawn to a method of perforating the skin using microscopic needle-like bodies and directly administering the drug into the skin. According to this method, it is possible to easily administer a drug subcutaneously without using a special medication device (see, for example, Patent Document 1).

  The shape of the fine needle-like body used at this time is required to have a sufficient fineness and tip angle for piercing the skin, and a sufficient length for penetrating the drug solution under the skin, The diameter is about several μm to several hundred μm (specifically, for example, about 1 μm to 300 μm), the length is a length that penetrates the stratum corneum that is the outermost layer of the skin and does not reach the nerve layer, specifically Is preferably about several tens of μm to several hundreds of μm (specifically, for example, about 10 μm to 1000 μm).

It is known to use various materials as the material for the needle-shaped body described above. For example, a method for producing a needle-shaped body by filling a mold with an aqueous solution of a water-soluble polysaccharide such as glycogen or dextrin and drying the mold. It is disclosed (for example, see Patent Document 2).
Furthermore, as a method for producing a needle-like body, it has been proposed to prepare an original using an etching method, form a template from the original, and perform transfer processing molding using the template (for example, Patent Document 3). reference).

However, when a needle-shaped body is produced using a template, the water existing between the molecular chains of the water-soluble polymer evaporates when the aqueous solution of the water-soluble polymer is filled into the template and then dried. There is a problem that the agglomeration and shrinkage of the substrate occur and the needle-like substrate warps.
As a means for solving the above-described problems, a method of drying the needle-shaped material filled in the mold by blowing in an environment of temperature and humidity corresponding to the temperature of the prepared solution of the needle-shaped material is considered ( For example, see Patent Document 4).

JP-A-48-93192 International Publication No. 2006/080508 Pamphlet International Publication No. 2008/004597 Pamphlet JP 2009-241357 A

However, in the method disclosed in Patent Document 4, it is necessary to adjust the preparation solution of the needle-shaped body material and the drying environment temperature. Further, in the drying process of the needle-shaped body material, equipment for generating wind at a constant speed under a constant temperature and humidity environment is required.
Therefore, the present invention does not require the temperature control of the water-soluble polymer solution of the needle-shaped body material, the equipment for maintaining the temperature and temperature and humidity environment, and without increasing the number of manufacturing processes of the needle-shaped body. An object of the present invention is to provide a method for manufacturing a needle-like body and a needle-like body that can suppress the warpage of the substrate.

  In order to solve the above-mentioned problem, the present invention according to claim 1 includes a needle-shaped material preparation step of preparing a needle-shaped material containing a water-soluble polymer, and the needle-shaped material is formed into a needle-shaped body. A filling step of filling a mold made of at least two kinds of materials with a concave portion having a concave / convex pattern, and drying the needle-shaped material filled in the mold into a needle-shaped body A method for producing a needle-like body comprising: a drying step for obtaining a mold; and a release step for releasing the mold from the needle-like body.

  The present invention according to claim 2 is such that the concave portion of the mold and the portion other than the concave portion are aluminum, nickel, stainless steel, titanium, silicon, alumina, aluminum nitride, machinable ceramics, glass, polycarbonate, polyacetal, polystyrene, acrylic resin. The method according to claim 1, wherein a mold made of at least two kinds of materials selected from the group consisting of fluororesin and silicone resin is used.

  The present invention according to claim 3 is characterized in that the portion other than the concave portion of the mold is made of a material having higher adhesion to the needle-shaped body material as compared with the material used for the concave portion having the concave-convex inverted pattern. It is a manufacturing method of the needlelike object according to claim 2.

  The present invention according to claim 4 is the method for producing a needle-shaped body according to claim 3, wherein the needle-shaped body material contains chitin / chitosan.

  The present invention according to claim 5 includes a base and a protrusion protruding from the base, and the base and the protrusion are made of a needle-shaped body material containing a water-soluble polymer. A needle-shaped body manufactured by the method for manufacturing a needle-shaped body described in any one of the above.

  The method for producing a needle-shaped body according to the present invention is characterized in that a needle-shaped body is produced using a mold made of at least two kinds of materials, and an ionicity generated at the interface between the needle-shaped body material and the mold material. By utilizing the intermolecular interaction, it is possible to improve the adhesion between the needle-shaped body material and the portion of the mold that does not have a concave portion, and to suppress warping of the needle-shaped body.

  Therefore, according to the present invention, the needle can be used without using a facility for maintaining a constant temperature and humidity environment, without increasing the number of manufacturing steps of the needle-like body, and without impairing the peelability of the projection of the needle-like body and the mold. It becomes possible to suppress warping of the body.

It is the schematic which shows an example of the acicular body produced using the manufacturing method of the acicular body which concerns on embodiment of this invention, (a) is a top view of an acicular body, (b) is the figure (a). It is the II sectional view taken on the line of the acicular body shown in FIG. It is the schematic which shows an example of the casting_mold | template of this invention, (a) is a top view of a casting_mold | template, (b) is the II sectional view taken on the line of the casting_mold | template shown to the same figure (a). (A), (b) is a top view which shows the modification of the casting_mold | template shown to Fig.2 (a), respectively. An example of the outline process for explaining the manufacturing method of the needlelike object of the present invention is shown, (a) is a sectional view of a mold, (b) is a sectional view showing the state where a mold was filled with a needlelike object material (C) is sectional drawing which shows the state which dried the acicular material. 4D is a schematic cross-sectional view showing a state where the mold is released from the needle-like body in the schematic steps for explaining the method for producing the needle-like body of the present invention shown in FIG. 4B, and (f). FIG. 3 is a cross-sectional view of a needle-like body released from a mold.

  Hereinafter, embodiments of the present invention will be described in detail. Note that the shape will be described with reference to the drawings, but the same or similar functions are denoted by the same reference numerals throughout the drawings, and redundant description will be omitted. Moreover, each figure is a schematic diagram, and the scale of each part does not correspond with the actual.

The shape and arrangement of the needles according to the present invention will be described with reference to FIG.
Fig.1 (a) is a top view which shows typically the acicular body 101 which concerns on this invention, FIG.1 (b) is the II sectional view taken on the line of the acicular body 101 shown to Fig.1 (a). It is. As shown in FIGS. 1A and 1B, the needle-like body 101 includes a base 103 and a protrusion 105 that protrudes from the first surface of the base 103. The material of the needle-like body 101 may be a water-soluble polymer, and specifically, for example, alginate, curdlan, chitosan, glucomannan, polymalic acid, or the like can be used.

  Further, the needle-like body 101 of the present invention may contain a delivery product. Examples of the delivery product include physiologically active substances and cosmetic compositions. In addition, when a material having a fragrance is used as a delivery product, an odor can be imparted during use, which is preferable for use as a beauty product. In addition, a delivery thing shall also contain a biologic. Here, the biologic refers to a classification of drugs using raw materials or materials derived from human or animal cells or cell tissues.

The delivery material may be dispersed in the material of the needle-like body 101 and encapsulated inside the needle-like body. Moreover, you may apply | coat and hold a delivery material on the needle-shaped body surface.
In addition, when the delivery object is administered by the needle-like body 101, the delivery article may be applied onto the target skin before or after the needle-like body 101 is punctured into the skin. At this time, the delivery material may be arranged on the surface or inside of the needle-like body 101, and the delivery material may be applied to the target skin surface.

Further, the needle-like body 101 of the present invention may be used in a technique of being used by being buried in the body.
The needle-like body 101 may include one protrusion 105 on the base 103, and may include a plurality of protrusions 105 on the base 103. In the case where the plurality of protrusions 105 are provided, it is preferable that the plurality of protrusions 105 are erected on the base 103 and arranged in an array. Here, the “array shape” indicates a state in which the protrusions 105 are arranged, and includes, for example, a pattern such as a lattice arrangement, a close-packed arrangement, a concentric arrangement, and a random arrangement.

  The shape of the protrusion 105 is not limited to the form shown in FIGS. 1A and 1B, and the shape and dimensions may be freely designed depending on the application. For example, when the shaped needle 101 is used for the purpose of promoting percutaneous absorption of a delivery product or for the purpose of percutaneously extracting a substance in a living body to the outside of the living body, from the viewpoint of skin puncture performance, the protrusion 105 The tip has a sharp cone shape, the base width is several μm to several hundred μm, and the length is about several tens μm to several hundred μm.

Further, a constriction or a step may be formed on the side wall of the protrusion 105.
In particular, when the depth of perforation by the protrusion 105 is set to “depth that penetrates the stratum corneum and does not reach the nerve layer”, the delivery product or the cosmetic composition can be delivered to a deeper position than the stratum corneum. . Since the perforations formed in the stratum corneum are closed over time, the delivered product and the cosmetic composition delivered under the stratum corneum are retained in the living body in a state of being barriered to the stratum corneum from the outside. For this reason, the delivery product and the cosmetic composition can reduce the exfoliation due to the metabolism of the stratum corneum and washing such as skin care, and can maintain the makeup state for a long period of time.

  In particular, when the depth of perforation by the protrusion 105 is kept “in the stratum corneum”, the delivery product and the cosmetic composition can stay in the stratum corneum. Since the stratum corneum is constantly generated newly by metabolism, the deliverables and cosmetic compositions in the stratum corneum are discharged out of the body with time. For this reason, for example, the makeup state and the applied state can be easily canceled by washing the skin or peeling the skin.

  In particular, when the depth of the perforation by the protrusion 105 is kept at “a length that penetrates the stratum corneum and does not reach the nerve layer”, the length of the protrusion 105 is more preferably 200 μm or more and 700 μm or less, more preferably. Is preferably in the range of 200 μm to 500 μm, more preferably 200 μm to 300 μm.

In particular, when the perforations are retained in the stratum corneum, the length of the protrusion 105 is specifically 30 μm or more and 300 μm or less, more preferably 30 μm or more and 250 μm or less, and further preferably 30 μm or more and 40 μm or less, It is preferable to be within a range of about.
Further, when the protrusions 105 according to the present invention are arranged in an array on the base 103, the lengths of the protrusions 105 may or may not be the same.

When the length of the protrusion 105 is different, for example,
(1) By making the long projection only on the outer periphery of the array shape, it is possible to suitably contact the curved surface.
(2) The mechanical strength of the needle-like body at the outer peripheral portion that is easily damaged can be reinforced by making the protrusions only short at the outer periphery of the array.
There are advantages such as.

When the protrusion 105 has a shape having a tip angle such as a cone shape,
(1) When penetrating the stratum corneum, the tip angle is preferably in the range of 5 ° to 30 °, more preferably 10 ° to 20 °,
(2) When perforation is retained in the stratum corneum, the tip angle is preferably 30 ° or more, more preferably 45 ° or more.

  In addition, the base 103 and the protrusion 105 constituting the needle-like body 101 may be formed of materials having the same composition, or may be formed of materials having different compositions. By forming the base 103 and the protrusion 105 with the composition having the same composition, the base 103 and the protrusion 105 can be suitably formed by integral molding.

Next, a manufacturing method for manufacturing the needle-like body 101 will be described.
2A and 2B show examples of a mold used for manufacturing the needle-like body 101 in the needle-like body manufacturing method of the present invention. 2A is a top view of the mold 201, and FIG. 2B is a cross-sectional view taken along line II of the mold 201 shown in FIG.

  The mold 201 includes a concave portion 203 having a concave / convex pattern of protrusions, a concave region 205 having a concave portion 203 formed on the first surface, and a non-recessed portion having a concave portion 203 on the first surface. An area 207 is included. FIG. 2 shows an example of a mold 201 in which a non-recessed area 207 made of a different material is formed so as to surround the recessed area 205.

The shape of the mold 201 is not particularly limited as long as it has a shape capable of holding the needle-shaped body material. Specifically, for example, it may be a polygon such as a quadrangle, a triangle, a circle, an ellipse, or the like, and may be any assumed shape.
The first surface of the mold 201 is not particularly limited as long as it has the recess 203. Specifically, for example, a flat surface, a curved surface, a step structure, or the like may be used.

In addition, the first surface of the mold 201 may be subjected to surface processing suitable for the acicular material used and the manufacturing process state.
The material of the mold 201 is not particularly limited as long as the mold 201 has heat resistance, heat conduction, mechanical strength, and shape followability as the mold 201. For example, metals and resins, such as (1) silicon, (2) metal materials such as nickel, aluminum, stainless steel and titanium, (3) ceramics and glass such as alumina, aluminum nitride, machinable ceramics, (4) polyacetal Synthetic resins such as polycarbonate, polystyrene, acrylic resin, fluorine resin, and silicone resin may be used.

In particular, as for the material of the first surface of the mold 201, it is preferable that the region in contact with the needle-shaped body material is composed of at least two kinds of materials.
Further, it is preferable to use at least one material having better adhesion to the needle-shaped body material than the material of the recessed region 205 of the mold 201 as the material of the non-recessed region 207 of the mold 201. Adhesion is considered to be controlled by ionic intermolecular interactions occurring at the interface between the needle-shaped body material and the template material.

  In selecting a material having better adhesion to the needle-like body than the material of the recessed region 205 as the material of the non-recessed region 207, the material having a surface pure water contact angle smaller than that of the surface of the recessed region 205 is used. Is selected as the material of the non-recessed region 207. Furthermore, when silicone resin or fluororesin is selected as the recessed region 205, silicon, aluminum, or glass can be suitably selected as the material of the non-recessed region 207 having better adhesion than the material of the recessed region 205.

Therefore, the needle-like body 101 (see FIG. 1) can be suitably manufactured by using the mold 201 produced by combining materials suitable for the needle-like body material to be used.
In addition, the recessed area 205 and the non-recessed area 207 of the mold 201 may each use two or more materials.

  Further, as a means for forming the recess 203 in the mold 201, a publicly known fine processing technique may be appropriately selected and used. Examples of such a fine processing technique include a lithography method, a wet etching method, and a dry etching method. Method, sandblasting method, laser processing method and precision machining method.

FIGS. 3A and 3B are top views showing molds in different cases from the mold shown in FIG.
In the present embodiment, as shown in FIG. 3A, it is possible to form the non-recessed region 207 made of a different material without surrounding the recessed region 205. In the example shown in FIG. 3A, non-recessed regions 207 made of different materials are formed outside only two sides of the four sides of the outer periphery of the recessed region 205.

  Further, as shown in FIG. 3B, it is also possible to form a non-recessed region 207a made of another material further outside the non-recessed region 207 made of a different material. In FIG. 3B, the recessed region 205 and the non-recessed region 207a formed on the outermost side may be the same material or different materials.

Hereinafter, a manufacturing method for manufacturing the needle-like body 101 shown in FIG. 1 will be described with reference to FIGS. 4A and 4B.
The manufacturing method of the needlelike object concerning the present invention has the following five processes.

<Mold making process>
First, as shown in FIG. 4A (a), a concave portion 203 formed of a concave-convex pattern of needles is formed on the first surface of the substrate to produce a mold 201. The material of the mold 201 may be any of the materials described above, and any of the methods described above may be used as the means for forming the recess 203.

<Needle body material preparation process>
Next, the needle-shaped body material 301 is prepared.
The acicular material 301 may be a water-soluble polymer. For example, alginate, curdlan, chitosan, glucomannan, polymalic acid, etc. may be used specifically. The concentration of the needle-shaped body material 301 is preferably about 1 to 20% by weight.

<Filling process>
Next, as shown in FIG. 4A (b), the needle-shaped body material 301 is filled in the mold 201.
There is no particular limitation on the filling method of the needle-shaped body material 301. For example, as a filling method, an injection molding method, an extrusion molding method, an imprint method, a casting method, or the like may be used.

<Drying process>
Next, the needle-shaped body material 301 filled in the mold 201 is dried as shown in FIG.
There is no restriction | limiting in particular about the drying method of the said acicular material. For example, heat drying, ventilation drying, vacuum drying, or the like may be used. Thereby, the acicular body 101 which consists of the base | substrate 103 and the projection part 105 is obtained.

<Release process>
Next, as shown in FIGS. 4B (d) and (e), the mold 201 is released from the needle-like body 101.
There is no restriction | limiting in particular about the mold release method of the said acicular body. When the adhesion between the non-recessed area 207 of the mold and the needle-shaped body material 301 is strong, as shown in FIG. 4B (e), a state where a part 101a of the needle-shaped body 101 remains on the mold 201. The mold 201 may be released from the mold.

As a result, a needle-like body 101 made of a water-soluble polymer is obtained as shown in FIG. 4B (f).
According to the manufacturing method described above, the problem in the prior art, that is, the problem that the base 103 is warped when the moisture of the needle-like body 101 is reduced can be solved.
As mentioned above, the manufacturing method of the acicular body of this invention can be implemented.

  In addition, the manufacturing method of the acicular body of this invention is not limited to the said embodiment, The method including the other process, modification, and change which those skilled in the art can guess by each process is also contained in the scope of the present invention. .

<Example 1>
Hereinafter, an example of a method for producing a needle-shaped body according to the present invention will be described in Examples. As a matter of course, the method for producing the needle-shaped body of the present invention is not limited to the following examples, and may include additional steps that can be inferred by those skilled in the art, and may be partially modified or omitted. Such a manufacturing method is also within the scope of the present invention.

1. Production of mold First, by using precision machining, 100 protrusions in which a regular quadrangular pyramid (height: 150 μm, bottom surface: 60 μm × 60 μm) is arranged on a silicon substrate in a grid of 10 columns and 10 rows at intervals of 1 mm are used. Formed. The 100 protrusions were arranged in a square region having a side of about 9 mm.

Next, the concavo-convex pattern of the protrusions was transferred to the needle-like body formed of the silicon substrate with a silicone resin to form a concave region of the mold.
Next, the concave region of the mold made of silicone resin was adhered to a glass plate having a larger area than the concave region to obtain a mold as shown in FIG.
Thereby, the casting_mold | template which comprises the recessed part which consists of a silicone resin and glass and which is an uneven | corrugated inversion pattern of a projection part was produced.

2. Adjustment of needle-shaped body material Next, the needle-shaped body material was adjusted.
After dissolving in water so that the concentration of chitosan was 5% by weight and glyoxylic acid was 2.5% by weight, deaeration was performed under vacuum.

3. Next, the chitosan aqueous solution was supplied onto the mold, and the recesses were filled by spin coating. This was left to stand in a normal temperature and humidity environment and dried, and then peeled off from the mold to obtain a needle-like body composed of a substrate and protrusions. Assuming that the needle-shaped material filled in the mold before drying is 100% by weight, the moisture content of the needle-shaped body after drying was 0.1% by weight or less, but warping of the base body of the needle-shaped body was observed. There wasn't.

  The needle-shaped body manufacturing method of the present invention makes it possible to manufacture a needle-shaped body with reduced warpage.

  The acicular body of the present invention can be used in various fields that require fine acicular bodies. For example, application can be expected as a needle-like body used for MEMS devices, optical members, sample jigs, drug discovery, cosmetics, medical uses, cosmetic uses, and the like.

  DESCRIPTION OF SYMBOLS 101 ... Acicular body, 101a ... A part of acicular body, 103 ... Base | substrate, 105 ... Projection part, 201 ... Mold, 203 ... Recessed part, 205 ... Recessed area, 207, 207a ... Non-recessed area, 301 ... Acicular body material.

Claims (5)

A needle-shaped body material preparation step of preparing a needle-shaped body material containing a water-soluble polymer;
A filling step of filling the needle-like material with a mold made of at least two kinds of materials, the needle-like body material having a concave portion made of a concave-convex inverted pattern of a needle-like shape;
A drying step of obtaining a needle-like body by drying the needle-like body material filled in the mold;
A mold release step of releasing the mold from the needle-shaped body;
A method for producing a needle-like body comprising:   The concave portion formed of the concave / convex pattern of the mold and the portion having no concave portion are aluminum, nickel, stainless steel, titanium, silicon, alumina, aluminum nitride, machinable ceramics, glass, polycarbonate, polyacetal, polystyrene, acrylic resin, fluorine. The method for producing a needle-shaped body according to claim 1, wherein a mold made of at least two kinds of materials selected from the group consisting of a resin and a silicone resin is used.   The portion of the mold that does not have a concave portion made of a concave / convex reversed pattern is made of a material having higher adhesion to the needle-shaped body material than a material used for the concave portion made of the concave / convex reversed pattern. The manufacturing method of the acicular body of Claim 2.   The needle-shaped body manufacturing method according to claim 3, wherein the needle-shaped body material includes chitin / chitosan. A base and a protrusion protruding from the base;
The needle-shaped body, wherein the base and the protrusion are made of a needle-shaped body material containing a water-soluble polymer, and are manufactured by the method for manufacturing a needle-shaped body according to any one of claims 1 to 4. .

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