JP2015205094A - Microimplement for dermal administration and manufacturing method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To solve a problem that in a conventional in-skin dissolving type micro needle arranged on a substrate, the whole microneedle cannot be placed in a skin at the time of puncturing so that a medication administration rate does not reach 100%, and a problem that a long painless microneedle with a length of 1 mm or more that reaches a deep site under the skin is not available.SOLUTION: A micropayload with a microhead containing medication in the upper part and a microstem for depth adjustment in the lower part is separated from a stem holder at the time of puncturing, and the microhead moves into the skin so that the microhead reaches deep under the skin and the whole contained medication is placed in the skin, thereby achieving an administration rate of 100%.

Description

The present invention relates to a transdermal administration technique for administering a therapeutic agent or biological substance to the skin, a cosmetic technique for introducing a cosmetic agent into the skin for cosmetic purposes, and a nutritional agent for health. The present invention relates to a transdermal administration technique, a transdermal administration technique for administering a drug for the treatment of an organ deep in the skin, a medical device and a medical dosage form having a fine needle for percutaneous administration common to those techniques. Furthermore, the present invention relates to a micro technology for assembling a minute object on a support base with high-precision control in order to manufacture them.

The expectation of transcutaneous microneedle technology is high, and the target is not limited to the treatment of skin diseases and the treatment and modification of cosmetics, but also to the treatment of immune system diseases related to the deep part of the skin and the whole body. It is highly expected as a painless and minimally invasive medical device. However, in reality, the product technology and production technology are inadequate, and the progress of related technologies has been delayed. The expectation value of a simple microneedle aiming at accurate and high drug administration efficiency is high, and there is high expectation for a medical product having an administration function that reliably reaches the body by a reliable form in reproducible production.

The exact dose is natural for medical instruments, but the microneedles that can be used and the manufacturing method thereof are injection molding for resin processing, machining, laser beam processing, and radiation X-ray beam processing such as synchrotron. However, as a common technique, it is limited to deformation processing of the substrate or its material. Microneedles that apply existing microfabrication are usually processed with a substrate like an integrated electronic circuit called an IC in the case of microfabrication with a length of 100 μm or less, and processing that accompanies the physical properties of the material. Limited to methods. As a result, there has been a problem that the characteristics are moved away from the required characteristics. Although representatives of microneedles utilizing the deformation of the substrate are described in the following documents, there are deficiencies in the administration rate, simple use, and securing of the dosage.

JP 2003-238347 A

In medical administration technology, the certainty of the dosage, which is the administration efficiency, that is, the quantitativeness is the most important. However, there is an administration method using an inorganic or organic coating type microneedle that applies and adheres a drug to the side surface or tip. Yes, or there is an administration method using a mixed microneedle that mixes the drug in the in-body dissolution material, but the coated type cannot reliably administer the drug due to an accident that occurs at the time of insertion. Since it is difficult to insert the drug into the body, it has been difficult to ensure quantitativeness, which means that all drugs are administered accurately.

In the drug-mixed microneedle, it is appropriate to have a process of manufacturing only the needle for mixing the drug independently of the manufacturing of the substrate so that there is no useless drug at the time of administration. However, in the form of bonding as a method for integrating the dollar part and the substrate, it is possible to avoid the waste of the drug entering the substrate, but the situation in which it remains on the substrate due to uneven bonding strength occurs, and the remaining needles The drugs contained in are eventually discarded in vain. Therefore, there has been a demand for a microneedle that can be reliably separated like a bullet.

Since only the skin was the subject of treatment with microneedles, the production of short needles of 1 mm or less was the mainstream, but treatment targeting deeper sites or whole bodies of the skin has increased, and the immune system and diabetes are Included in that subject. The painless administration for such deep sites is necessary even for long microneedles exceeding 1 mm, and the expectation is increasing. However, it was not such a long drug-mixing microneedle.

In a microneedle that is manufactured by separating a needle and a substrate, a manufacturing method in which a needle that is a micro object having a diameter of 1 mm or less and a length of 5 mm or less is independently provided on a substrate or a holder is necessary as a basic mechanism. It is necessary to carry only a small and thin needle formed independently and to assemble the needle into a holder, and it is necessary to handle and mold a very light micro object of about 1 μg. There was no micro transport mechanism and fabrication technology for handling such micro objects.

The percutaneous microneedle, which dissolves the drug in the body, dissolves the needle material at the time of insertion, and has the function to administer the mixed drug. As a result, it was impossible to administer all the drugs, that is, there was a quantitative problem that the administration efficiency did not reach 100%. In order to solve this problem, the needle tip surely pierces the skin surface and reaches the form where it completely enters the needle base, so that the needle part and the substrate are made of different materials and do not come off automatically during use. If it has a function, it is conceivable that the entire needle containing the drug moves away from the substrate and moves into the skin, and then the drug also moves into the skin. However, it can be removed with a uniform needle size, and a stable and fixed amount of drug can be introduced into the skin with good reproducibility, fixed before insertion, and securely attached after insertion. And there was no removable structure. It is an object of the present invention to find and solve a structure capable of exhibiting the above function between the needle and the substrate.

Since the existing microneedles were intended for treatment only on the skin, most of them were short needles of 1 mm or less. In recent years, the expectation for the medical treatment for the deep part of the skin or the whole body has been increased, and immune system diseases and diabetes are included in the target. Long microneedles may also be required. Since there was no such long drug-mixing microneedle, it is an object to obtain a function capable of realizing a long microneedle configuration.

Assembling the microstem of the same size as the micro head from 0.1 mm to 5 mm needs to be performed with an accuracy of 0.01 mm or less, but in this field, there was no such assembling technique. It is an object to obtain a mechanism capable of highly accurate assembly or alignment.

In order to achieve the above object, the present invention provides a means for solving the problem,
(1) A micro-payload having a structure having a columnar micro-stem integrated with the micro-head at the upper part and having a cone-shaped in-body dissolving material micro-head containing a drug at the upper part is inserted into the opening on the upper surface of the stem holder. A microimplement for transdermal drug administration having a structure characterized by:
(2) Triangular pyramid, quadrangular pyramid, cone, bullet shape, polygonal pyramid with a tip size of 0.001 mm or less, a length of 0.02 mm to 5 mm, and a base radius of 0.01 m to 1 mm A micro-implement for transdermal drug administration, characterized by having a micro-head having a cone shape, or a half-shell cone shape that is either a half-shell cone or a half-shell bullet shape, and (3) In-body dissolution having the microhead described in Item 2 at the top, having an upper surface having the same shape as the bottom surface of the microhead, having an outer radius of 0.01 mm to 1 mm and a length of 0.02 mm to 5 mm A microimplement for transdermal administration of a drug characterized by the structure of a micropayload with a solid microstem of material, and
(4) A microimplement for transdermal drug administration characterized by a structure having a cone-shaped microhead containing a drug chip, and (5) two half-shell cones containing pure or drug in a shell together Assembled solid cones, drug-containing cones, drug-containing half-shell cones and solid half-shell cones, and drug-containing half-cone combinations , Solid triangular pyramid and drug-containing triangular pyramid coalescing quadrangular pyramid, drug-containing triangular pyramid coalescing quadrangular pyramid, shell containing together with a drug-containing polygonal pyramid that can flatten the bottom A microimplement for transdermal administration of a drug characterized by having a structure having any one of a combination of polygonal pyramids as a microhead, and (6) the in-vivo soluble agents of claims 1 and 3 are maltose, pullulan, collagen , Hyaluronic acid, other polysaccharides, or a composite material in combination as necessary, and (7) Claims 1 and 3 The solubilized agent in the body is maltose and a microimplement for transdermal administration of a drug characterized by being a mixture with maltose, and (8) the drug according to claims 1 to 7, Vitamins, hyaluronic acid, collagen, protein, DNA, peptides, vaccines, other pharmaceuticals, nutrients, nutritional supplements, cosmetics, antibody testing agents, in-house color materials, in-body metal, in-body metal oxides A micro-implemented drug for transdermal administration, characterized in that it is a body-specific magnetic substance, or a composite combined as necessary And (9) a chip in which one kind or many kinds of the medicine of claim 8 is selected and solidified, or a composite in which one kind or many kinds of the above medicines are mixed with maltose or other sugar material. A microimplement for transdermal administration of a drug, characterized by being a solidified chip, and
(10) The stem holder according to claim 1 has an opening for receiving and supporting the bottom of the micro stem, which is made of maltose, pullulan, hyaluronic acid, cellulose, other sugars, paper material, wood, resin, metal, silk material. A microimplement for transdermal administration of a drug characterized by a structure having a provided microholder or having a plurality of microholders arranged on a substrate surface;
(11) In forming the half-shell cone-shaped microhead including the cone-shape and half-shell cone and the half-shell bullet shape according to claim 2, one side surface of the inverted shape of the cone shape is a rectangular parallelepiped. A micro die for a micro head having one or more concave or concave molds on one side of a rectangular parallelepiped such that the top of the rectangular parallelepiped is coincident with the upper surface which is a flat surface of the rectangular parallelepiped. A method for producing a microimplement for transdermal administration of a drug characterized by
(12) In forming a triangular stem, a quadrangular column, a cylinder, and a half shell cylindrical microstem according to claim 3, the columnar various types are used so that one flat surface of the microstem used matches an upper surface that is one surface of a rectangular parallelepiped. A method for producing a microimplement for transdermal administration of a drug, characterized by using a micro mold for a microstem in which a recess or recess having an inverted shape is provided on an upper surface of a rectangular parallelepiped, and
(13) Cooling and solidification used to form a thermoplastic or wet plastic drug-containing material into a cone shape by a combination of three parts: a micro die for a micro head, a micro die for a macro stem, and a holder. Alternatively, a microimplementation method for transdermal administration of a drug, characterized by mounting a micropayload integrated with the physical properties of dry coagulation as a molding condition on the opening of a stem holder while applying pressure or ultrasonic vibration, And
(14) In the molding method shown in claim 13, in the manufacturing method in which the respective molded products by the two types of micro molds, that is, the micro mold for micro head and the micro mold for micro stem, are separated and taken out, It has a drive function that allows fine adjustment in the upper and lower three-dimensional directions at the same time, and gradually releases at a rate of 0.001 mm or less per second as a vertical component with respect to the release surface of the micro mold. This is a method of manufacturing a microimplement for administration.

As shown in FIG. 1A, the micro-implement has a drug-containing sugar material microhead 2 having a triangular pyramid or a quadrangular pyramid with a sharp tip 1 at the top and a solid sugar material micro head having a triangular pillar or a square plum pillar at the bottom. A sugar material micropayload having a stem 3 in which the bottom surface of the microhead and the top surface of the microstem are integrated to form a sugar material micropayload as shown in FIG. 1B. Since an appropriate opening 5 is provided on the upper surface of the substrate and the structure is mounted by inserting it from the bottom of the microstem, it can be removed from the stem holder as shown in FIG. 2B. Further, by adjusting the length of the microstem, the depth reached by the microhead can be made to correspond to the stratum corneum 6, the dermis layer 7, and the subdermal organ 8 as shown in FIG. 3A. Furthermore, a plurality of micro-implements can be provided by arranging a stem holder on the substrate.

The microimplement equipped with micropayload, which is maltose or other sugar material, can be inserted painlessly into the skin with a sharp micropayload and continues to be inserted until it hits the stem holder, as shown in Fig. 3A. When it is separated from the horny skin, only the micropayload is detached from the stem holder and remains in the skin as shown in FIG. 3B. When the insertion is completed, only the part mounted on the original stem holder is exposed from the skin surface, but most of the micropayload is stuck into the skin from the tip. Since the micropayload has a structure in which a drug-containing microhead is provided in the upper part and a microstem is provided in the lower part, the microhead is completely contained in the skin. The microhead of the micropayload takes several minutes immediately after the insertion, and disappears while dissolving with moisture in the skin as shown in 9 and 10 in FIG. 3C. Since it becomes the osmotic region 11 in the skin, 100% administration efficiency can be achieved, and stable administration can ensure quantitativeness, and the dosage specification can be clarified.

When the sugar material micropayload only targets the skin, a short microstem is employed as shown in FIG. 4A. However, when the skin is painless and deeply inserted, at least the microhead is located under the skin as shown in FIG. 4B. The drug can be administered to a deep site of 1 mm or more, and the treatment using the vaccine for immune diseases and the treatment by the insulin administration for diabetes treatment requiring the systemic circulation are available. Moreover, the volume of the long micropayload itself is increased, and in the microimplement having a plurality of micropayloads, the total volume of the plurality of micros reaches 50 mm cubic, and an increase in dose can be expected. Along with this, it is possible to secure a dose that reaches the weight in mg unit, which has been impossible in the past, and reach the above-mentioned weight range where the immune reaction and insulin can be used.

  The micro payload, which is the integration of the micro head 2 and the micro stem 3, is maltose or sugar depending on the conditions of heating and melting and cooling and solidification by using a micro mold for the micro head in the first stage process. A micro head is molded, and a micro stem is molded using a micro mold for the micro stem under the same conditions in the second stage process, and the above micro molds are combined in the third stage process. The shape of the bottom surface of the microhead and the shape of the top surface of the microstem are aligned and connected while positioning the microstem with high accuracy. Thereafter, by separating the micropayload from both the micro molds, it is possible to take out a molded product of the sharp drug-containing micro payload. By means similar to the above-described molding, the half-shell cone 14 as shown in FIG. 5A and the same half-shell jewel shape 15 as shown in FIG. 5B can be formed. Further, by integration with the half shell cylinder 16 which is a half piece of the cylinder by the same means, the respective payload molded products of the half shell cone and the half shell jewel shape as shown in FIGS. 6A and 6B are obtained. Here, a half-splitting half cone that passes through the apex is called a half-shell cone, and similarly, a half-splitting pearl shape that passes through the apex is called a half-shell jewel shape.

When the half-shell cones are combined and integrated, a cone can be formed. If one is a drug-containing cone microhead 14 and the other is a solid half-shell cone microhead 17, half is pure as shown in FIG. It is possible to make maltose the other with drug-mixed maltose. With this structure, even if it becomes difficult to pierce due to softening due to the mixture of medicines, the strength can be maintained by one pure maltose, which is advantageous as insertion conditions. If necessary, a different drug can be mixed in the other, and a microhead containing two kinds of drugs can also be formed. Further, as shown in FIG. 8, a cone 18 containing the same drug is formed on both, and the drug can be increased by increasing the volume. Similarly, a jewel-shaped drug-containing microhead 19 can be formed. By integrating with the conical microstem 20, a micropayload with a conical microhead as shown in FIG. 8C and a micropayload with a jewel-shaped microhead as shown in FIG. 8D can be formed. As a development system, a jewel shape including a drug chip as shown in FIG. 9 is possible, and a pentagonal pyramid is also possible from a combination of a triangular pyramid and a quadrangular pyramid as shown in FIG.

Since the existing microneedle for drug administration was a fixed type in which the needle was directly connected to the substrate, the portion of the needle that entered the skin at the time of skin penetration was about half of the tip, but it was not used at the root of the needle Since it remained on the substrate, the administration rate was 70% or less, and the remaining 30% was discarded as a useless medicine. In the microimplement of the present invention in which the drug-containing micropayload is fitted and mounted on the stem holder, the micropayload is completely transferred to the skin at the time of insertion, resulting in an effect of a drug administration rate of 100%.

In conventional microneedles for transdermal drug administration, the puncture rate indicating the amount inserted into the skin at the time of puncture is an unstable situation that varies from trial to trial. When the is used, since the micropayload is surely removed when the microstem is removed from the holder at the time of insertion, and the dose is directly determined by the shape of the micropayload, there is an effect that the administration rate becomes constant and the reproducibility can be improved.

  The conventional microneedle for transdermal drug administration has a length of 1 mm or less because the skin was a treatment target, and did not reach the deep part under the skin. Can be used to produce micropayloads with a length of 1 mm or more by combining micro-molds, so that it can be used to administer deeper than 1 mm below the skin and increase the length of the volume. This is effective in increasing immune system diseases and diabetes that could not be achieved in the past.

In the microneedle for transdermal drug administration obtained from the substrate processing, the used part remains on the substrate after use, which was a work load for disposal management after use, but the micropayload according to the present invention is mounted. Since the microimplement is completely transferred into the body after administration of the micropayload, only the stem holder and the substrate remain. Since the residue is only the stem holder of the sugar material and the substrate that does not touch the skin, no special disposal management is required, and the management cost is reduced. Furthermore, if the stem holder or the substrate itself is made water-soluble like sugar material, no waste remains as a water-soluble substance, and an environmental conservation effect is obtained.

(A) It is the outline figure which shows the micro implementation of this invention. (B) It is the outline figure which shows the micropayload of this invention. (A) It is sectional drawing which shows the micro implementation of this invention. (B) It is sectional drawing of the micro implementation of this invention which shows the state from which a micro payload is removed from a stem holder. (A) It is the microimplement of this invention which shows the state which the micropayload penetrated the skin, and sectional drawing of skin. (B) It is sectional drawing of the skin and the microimplement of this invention which shows the state which the micro payload apart from the stem holder penetrated into the skin, and remained. (C) It is sectional drawing which shows the function of this invention which the chemical | medical agent mixed in the micropayload penetrate | invades in skin after the micropayload which penetrated into the skin and melt | dissolved melt | dissolved. (A) It is sectional drawing which shows the state which the micropayload of this invention which provided the chemical | medical agent containing part on the short solid microstem was penetrated shallowly. (B) It is sectional drawing which shows the state which the micropayload of this invention which provided the chemical | medical agent containing part on a long solid microstem penetrated deeply into the skin. (A) It is the schematic which shows the external shape of the chemical | medical agent containing part which is a half-shell cone of this invention. (B) It is the schematic which shows the external shape of the chemical | medical agent containing part which is the half shell jewel of this invention. (A) It is the schematic which shows the external shape of the micropayload of this invention which provided the chemical | medical agent containing part of the half shell cone on the solid micro stem of the half shell. (B) It is the schematic which shows the external shape of the micropayload of this invention which provided the semi-shell jewel-like medicine containing part on the semi-shell cylindrical micro-stem upper surface. (A) It is the schematic which shows the external shape of the solid micropayload of this invention which is a half shell cone. (B) It is the schematic which shows the external shape of the micropayload of this invention which is a cone which combined the chemical | medical agent containing part of the same shape with the non-drug part which is a half shell cone. (A) It is the schematic which shows the external shape of the chemical | medical agent containing part which is a cone of this invention. (B) It is the schematic which shows the external shape of the chemical | medical agent containing part which is the jewel shape of this invention. (C) It is the schematic which shows the external shape of the micropayload of this invention which provided the chemical | medical agent containing part of the cone on the solid microstem. (D) It is the schematic which shows the external shape of the micropayload of this invention which provided the jewel-shaped medicine containing part on the solid solid microstem. It is the schematic which shows the external shape of the micropayload of this invention which is a cone containing the chemical | medical agent chip containing part. It is the schematic which shows the external shape of the chemical | medical agent containing micropayload of this invention which is a pentagonal pyramid. (A) It is the schematic which shows the manufacturing method of this invention which shows the triplane intersection which guide | induces the shape of the triangular pyramid micropayload and the micro die for microheads for shape | molding the vertex. (B) It is the schematic which shows the shape of the micro metal mold | die for microheads used with the manufacturing method of this invention in order to shape | mold a triangular pyramid micropayload. (A) It is the schematic which shows the manufacturing method of this invention which combined the holder with the micro metal mold | die for microheads for shape | molding a triangular pyramid micropayload. (B) It is the schematic which shows the shape of the drug-containing micropayload of the triangular pyramid shape | molded using the micro metal mold | die for microheads by the manufacturing method of this invention. It is the schematic which shows the micro metal mold | die for microheads in the manufacturing method of this invention. It is the schematic which shows the shape of the triangular prism microstem in this invention. It is the schematic which shows the shape of the micropayload of this invention which integrated the medicine containing part of the triangular pyramid, and the microstem of the triangular prism. It is the schematic which shows the shape of the micro implementation which incorporated the micro payload which integrated the triangular pyramid micro pay head and the short triangular prism micro stem in the stem holder. It is the schematic which shows the shape of the micro implementation which incorporated the micro payload which integrated the triangular pyramid micro pay head and the long triangular pyramid micro stem into the stem holder. It is the schematic which shows the function of the micro metal mold | die for micro heads which can be moved up and down, right and left in order to release the micro payload which has a drug-containing micro head of a quadrangular pyramid by the manufacturing method of this invention. It is the schematic which shows the shape of the micro implementation of this invention which incorporated the micropayload provided in the square pyramid containing the medicine chip on the microstem of the square pillar, and was integrated in the stem holder. It is the schematic of the micro implementation of this invention which integrated the chemical | medical-containing square pyramid micropayload and the microstem in the stem holder, and arranged on the board | substrate.

  Although the micro implementation, the manufacturing method, and the embodiment of the present invention will be described below, the present invention is not limited to the following embodiment.

In the form of the micropayload to be mounted on the microimplement of the present invention, the material is maltose, and a triangular pyramid or four containing a drug on an amorphous maltose microstem that is a solid columnar shape capable of adjusting the administration depth under the skin. A micro head made of amorphous maltose with various pyramids such as a pyramid is attached and integrated. In the case of a treatment targeting a shallow part such as the horny surface of the skin surface, the microhead alone can be handled as a micropayload without a microstem. When targeting a deep part under the skin, the bottom is the same shape as the top surface of the microstem on the depth adjustment microstem with a length of 0.2 mm to 5 mm and an outer radius of the cross section of 0.01 mm to 0.5 mm. A micropayload is a form in which drug-containing microheads of various cones having a sharp tip with an outer radius of 0.01 m or less and a length of 0.01 m to 5 mm are mounted and integrated.

In the micro-implementation form of the present invention, the micropayload to be mounted with an opening on the upper surface of the stem holder is integrated with a microhead having a sharp tip of various cones and a microstem that adjusts the length. It functions as a micromedical device that penetrates the skin like a microneedle for transdermal administration, but its main component is amorphous maltose or other sugar material, so moisture in the skin or body like a pharmaceutical dosage form It also has a function to dissolve and disappear. When the sugar microhead contains a drug, the micropayload at the time of skin penetration is completely removed from the holder and remains on the skin, and then the drug is released from the microhead that dissolves in the skin and diffuses into the skin. It can be administered in a penetrating form. If the drug is vitamin, hyaluronic acid, or collagen, the top surface of the holder is a micropayload that integrates a solid microstem with an amorphous maltose or other sugar microhead containing 10% to 90% of the drug. When the micro-implement, which is a structure mounted in the opening of the device, is inserted into the skin by finger operation, the micro-payload is removed from the holder, the micro-head completely enters the skin, and the drug is completely contained under the skin surface. As the microhead dissolves and disappears, the microhead-containing vitamin, hyaluronic acid, or collagen takes an optimal form that is introduced into the skin at an optimal dose rate of 100%.

The microhead in the microimplement of the present invention is a composite material whose component is any one of maltose, pullulan, polysaccharides, collagen, hyaluronic acid, or a combination thereof, and the tip size is within an outer radius of 0.01 mm or less. Triangular pyramid, quadrangular pyramid, half-shell cone, half-shell cone, half-shell jewel shape, whose length is 0.02 mm to 5 mm, the outer radius of the base is 0.02 mm to 5 mm, and can be directly manufactured with a micro mold) What is claimed is: 1. A transdermal administration device characterized by containing a drug in a cone-shaped or bullet-shaped microhead of any one of a polygonal pyramid, and a cone or bullet shaped by combining shellfish shapes Forms. On the other hand, a microhead containing a drug chip has a form as shown in FIG.

The microstem, which is the lower part of the micropayload of the microimplementation according to the present invention, is used for the purpose of deeply introducing the microhead into the skin, so that systemic drugs such as insulin, hormones and prostaglandins can be handled. . The material is preferably the same as the microhead, and maltose, pullulan and other sugar materials, hyaluronic acid, collagen, and mixtures thereof are suitable. Other materials that can be safely dissolved in the skin can be used, and biocompatible materials such as chitin and chitosan and biodegradable materials such as polylactic acid are candidates.

In the shape of the micro die for the micro head for forming the micro head in the micro implement of the present invention, the tip of the micro head is the most important as a penetration function for transdermal administration. In the case of a triangular pyramid microhead, the intersection 27 formed by the three planes of the first plane 24, the second plane 25, and the third plane 26 leads to the minimum point as shown in FIG. The concave surface of the micro mold 28 having the inverted shape or the portion 29 corresponding to the apex of the triangular pyramid having the concave shape is included in the upper surface of the mold, and the two surfaces in the concave mold of the micro mold correspond to the first surface and the second surface. If the third surface is a concave shape and corresponds to a triangle that matches the top surface of the micro mold, and the third surface is a processing surface that includes the tip, a sweep process for flattening is performed. To optimize production methods to derive the head of the form.

In the manufacturing method of the drug-containing microhead and the micropayment in the microimplement of the present invention, when assuming a triangular pyramid microhead, the shape of the triangular pyramid corresponding to the inverted shape is set to one or two or more concave shapes, and a stainless steel rectangular parallelepiped And preparing a micro die for a micro head arranged so that the bottom surface of the micro head coincides with the side surface facing the vertical direction and the one side surface of the concave triangular pyramid coincides with the upper surface triangle of the rectangular parallelepiped. While attaching 30 to the side surface of the micro mold, the maltose mixed with the drug is softened by heating or water-soluble and filled. The two faces of the microhead's triangular pyramid correspond to the two concave faces of the micro mold, and when flattened while removing and sweeping excess filler so that the upper surface of the micro mold and one side of the micro head coincide, The third surface of the head can be formed as a processed surface, and after cooling solidification or dry solidification, it is released to form a microhead. When the microhead is handled as a micropayload without a microstem, the microhead is removed by moving the micro mold horizontally in 0.001mm units with high precision so that it can be pulled out from the bottom. A triangular pyramid micropayload is used as in 12B. To form a micropayload in which the drug-containing microhead and the microstem are integrated, the microhead is formed in the first step and is held in the micro mold, and the microstem shown in FIG. After the microstem 32 of FIG. 14 is formed by the micromold 31 for use, both the micromolds are connected in the third step, and the bottom surface of the microhead and one end of the microstem are attached by heating or moistening to be integrated. . Thereafter, the micropayload is separated by a highly accurate mechanism in the order of the micro mold for the micro stem and the micro mold for the micro head. Here, high-precision mold release means that the filled maltose is hard and brittle, but has micro flexibility, and carefully utilizes the micro mold in 0.001mm increments while utilizing three-dimensional freedom. This is a form of micromachining technology in which the mold is released while being finely shaken up and down and left and right. If necessary, vibration or ultrasonic waves are applied to both micro molds at an appropriate power of 1 W to 10 W, so that the mold release is assured and easy. The two types of micro molds are characterized in that they can be driven with a degree of freedom in a three-dimensional direction in units of 0.001 mm as shown in FIG. 18 and can be heated and cooled at the same time. By this method, a microimplement with a short stem as shown in FIG. 16 and a microimplement with a long stem as shown in FIG. 17 can be formed with an arbitrary length.

In the micro-implementation of the present invention, the drug chip 33 included in the micro head 34 as shown in FIG. 19 includes a pure drug solid, a mixture of drug and micro head material, a micro dosage form containing the drug, a magnetic material, and an electromagnetic wave. Microdosage forms are possible that include microscopic bodies of properties. The drugs include vitamins, collagen, hyaluronic acid, proteins, DNA, pharmaceuticals, nutrients, nutritional supplements, cosmetics, antibody testing agents, color materials, metals, metal oxides, and mixed oval shapes. A medicine chip containing 10% to 90% of any one of a body, a rectangular parallelepiped, a polygonal pyramid, or a selected composite is used as a form.

In the micro implementation of the present invention, the holder for mounting the micropayload is a support base having an opening for inserting and mounting the bottom of the microstem, which is the bottom of the micropayload, before storage and before insertion. Since it is necessary to be surely removed when inserting into the skin in a stable and fixed state, the opening is slightly reduced by 3% to 5% from the bottom surface of the micropayload to make it slightly pressurized, and vibration of 1 kHz to 10 kHz or It is appropriate to push in and mount while applying ultrasonic waves. Also, in the case of a single payload, the shape of a long stem holder such as a rod is easy to handle, and a plurality of micropayloads are arranged on the substrate surface as shown in FIG. A plurality of stem holders are provided. The material of the holder touches the skin at the time of insertion, but it returns after use, so it does not require as strict safety as the residual material in the body, so sugar, paper, wood, resin, metal, maltose, pullulan, hyaluronic acid, One or two or more composites selected from cellulose, solid starch, silk, or biological materials are also possible, but saccharides are preferred for reducing the cost of disposal after use.
Examples of the present invention will be described below, but the present invention is not limited to the following examples.

Microhead with 0.003 mm tip, 0.7 mm long, 0.25 mm square pyramid amorphous maltose containing 17% sodium ascorbate and 0.1% rhodamine 6B A micro-payload integrated with a cuboid pure maltose micro-stem having a length of 0.5 mm and a width of 0.25 is molded into a micro-mount mounted on a stem holder with a length of 1 mm. When 10 were arranged and assembled into an array and inserted into a human skin, it was confirmed by the color of rhodamine 6B that 100% of the microhead drug could be transferred into the skin.

Two hyaluronic acid chips impregnated with rhodamine 6B with a molecular weight of 50,000 to 100,000 in a jewel-shaped microhead that is a circle with a length of 1 mm and a bottom diameter of 0.2 mm and a side of 0.01 mm The chip can be completely transferred into the skin when used on human skin using a micropayload welded onto a cylindrical microstem having a length of 0.5 mm and a diameter of 0.2 mm. The skin became slightly swollen.

Lidocaine, a kind of local anesthetic, is mounted with a microhead containing lidocaine using a micro mold for stainless steel microheads in which 20 concave pyramids with a length of 1 mm and a side of 0.01 mm are arranged in a line. A sample of microimplementation was made and used for animal experiments using rats. As a result of analysis of rat's feet, hands, abdomen, back, neck and blood extracted from high-performance liquid chromatography, it was found to be 0 in plasma. It was found that .003 mg to 0.01 mg of lidocaine was present, which confirmed the penetration of lidocaine throughout the body.

In a microimplement in which a microimplement integrated with a 3 mm long triangular pyramid microhead and a 2 mm long triangular prism microstem is mounted on a 3 mm long stem holder, 50% bovine pancreatic insulin is contained in the microhead. The microimplement with one needle could contain 0.01 mg / insulin. In order to introduce 1 mg into the body, an array type micro-implement having the number of needles of 100 that can be manufactured was ensured by arranging 10 vertical arrays and 10 horizontal arrays on a substrate. If 1 mg is 26 units or 26 IU, it is equivalent to 2.3 mg in diabetic patients who need 60 IU / day, and 80 array micro-implements can be secured 3 times in the morning, noon, and evening, and can be used for treatment. Reached the amount.

  A micropayload equipped with a 1 mm long conical microhead is combined with a half-shell cone containing 1 mg of alprostadil, a stable derivative of prostaglandin, mixed with maltose, and a half-shell cone mixed with rhodamine 6B. When a sample molded to a length of 2 mm was used for a rat, the rhodamine 6B pigment was confirmed throughout the body, and a decrease in blood pressure of 20 mmHg, which meant dilation of blood vessels, was confirmed.

1 mg of collagen content was weighed from human fibroblast-derived collagen aqueous solution, collected into 2 mg of hyaluronic acid chip, and subjected to animal experiments using rats with a sample contained in a 2 mm microimplement contained in a jewel microhead. As a result, 50% of collagen could be transferred into the skin. In addition, when the cross section of the rat skin was observed with a microscope having an individual magnification of 1000 times or more, it was confirmed that the collagen was confined in the matrix region between cells.

Half shellfish with a height of 0.5 mm and a base radius of 0.1 mm using anhydrous amorphous maltose containing 5% by weight of a mixture of titanium oxide and oxidative iron (1: 1 composition ratio) as a cosmetic material 64 micro-implements with a length of 1.5 mm mounted with conical micro-heads are placed on the substrate, and these micro-implements are inserted into the skin surface (within 0.3 mm from the skin surface) where brown spots on the face are present. As a result of the experiment, it was confirmed that the brown stain on the face was lightened and the skin tone was brighter and better.

An elliptical chip (diameter 0.02 mm, maximum diameter 0. 0 mm), which is a kind of protein, mixed with albumin with a limit of heat resistance of about 70 ° C. and anhydrous amorphous maltose (1: 1 composition ratio) and hyaluronic acid. 01 mm), 30% by weight, contained in a microhead with a length of 0.7 mm and a volume of 0.5 mm cubic, and collected into three types of microimplement samples of 1 mm, 2 mm and 3 mm in length. As a result of conducting an insertion experiment using rats, as a result of observation of the cross section of the skin with a microscope, it was confirmed that albumin reached the skin and concentrated to a depth of 1 mm, 2 mm, or 3 mm depending on the length. It was.

0.05 mg of steel oxide powder with an average size of 0.003 mm is mixed in a maltose microhead with a length of 0.5 mm and a triangular pyramid with a side of 0.01 mm, and a pure maltose microstem is mounted and mounted on a 1 mm stem holder Then, after the skin was inserted and the oxidized powder was introduced into the skin, when a magnetic field of 1 mG was applied, it was confirmed with a highly sensitive sensor head that the powder in the skin was magnetized. By grasping the behavior of the magnetic chip (powder), one aspect of biological activity in the skin could be grasped.

The micro-implement and its manufacturing mechanism of the present invention can be used for medical treatment and construction in the beauty field, and the manufacturing method does not use vacuum equipment for microfabrication conventionally obtained only by vacuum equipment or lithography. The cost can be reduced only by machining, and the field of manufacturing a sharp tip of 0.001 mm or less and the element of the three-dimensional machining are included, so that it can be developed in the production process.

1 Tip of micro head
2 Triangular pyramid or quadrangular pyramidal drug-containing sugar micro head 3 Triangular or square pyramid solid sugar micro stem
4 Stem holder 5 Stem holder opening 6 stratum corneum 7 dermis layer 8 layer of lower skin tissue 9 shadow of dissolved microhead 10 dissolved shadow of microstem 11 region of drug diffusion and penetration 12 short microstem 13 long Microstem 14 Half shell conical drug-containing micro head 15 Half shell jewel-shaped drug-containing micro head
16 Solid microstem in a half-shell cylinder 17 Solid microhead in a half-shell cone 18 Conical drug-containing microhead 19 Jewel-shaped drug-containing microhead 20 Cylindrical microstem 21 Jewel-shaped solid microhead 22 Drug microchip 23 Pentagram Microhead 24 containing first agent 25 First plane 25 Second plane 26 Third plane 27 Intersection 28 formed by three surfaces Micro head micro mold 29 Micro mold apex 30 Holder 31 Micro stem micro mold 32 Solid micro Stem 33 Drug microchip 34 Drug microchip-containing microhead 35 Substrate

Claims (14)

A micro-payload with a cone-shaped body-dissolving material microhead containing a drug in the upper part, and a micropayload having a columnar microstem integrated with the microhead in the lower part is inserted into the opening on the upper surface of the stem holder. A microimplement for transdermal drug administration having the structure The tip size is 0.001mm or less, the length is 0.02mm to 5mm, and the base radius is 0.01m to 1mm. A microimplement for transdermal drug administration, characterized by having a structure of a cone, or a half-shell cone that is either a half-shell cone or a half-shell bullet shape as a microhead. An internal body having the microhead according to claim 2 at the top, an upper surface having the same shape as the bottom surface of the microhead, an outer radius of 0.01 mm to 1 mm, and a length of 0.02 mm to 5 mm A microimplement for transdermal administration of drugs characterized by the structure of a micropayload with a solid microstem of dissolved material. Microimplement for transdermal drug administration characterized by a structure with a cone-shaped microhead containing a drug chip Solid or drug-containing two half-shell cones assembled together with shells, solid cones, drug-containing cones, drug-containing half-shell cones and solid half-shell cones, Combination of drug-containing half-cone and drug-containing half-cone, solid triangular pyramid and drug-containing triangular pyramid, quadrangular pyramid of drug-containing triangular pyramid A microimplement for transdermal administration of a drug characterized by having a structure having as a microhead either a drug-containing polygonal cone whose bottom surface can be flattened together or a combination of different drug-containing polygonal pyramids. The in-vivo soluble agent of claim 1 and claim 3 is maltose, pullulan, collagen, hyaluronic acid, other polysaccharides, or a composite material combined as necessary. Micro-implement material for skin administration. 4. The microimplement for transdermal administration of a drug, characterized in that the in-vivo soluble agent of claim 1 and claim 3 is either maltose or a mixture with maltose. The medicines of claims 1 to 7 are vitamins, hyaluronic acid, collagen, proteins, DNA, peptides, vaccines, other pharmaceuticals, nutrients, nutritional supplements, cosmetics, antibody testing agents, in-vivo specifications A micro-implemented drug for transdermal administration, which is a color material, a metal specified in the body, a metal oxide specified in the body, a magnetic material specified in the body, or a composite combined as necessary. A chip in which one kind or many kinds of the medicines of claim 8 are selected and solidified, or a chip obtained by solidifying a composite obtained by selecting one kind or many kinds of the above drugs from maltose or other sugar materials and mixing them. A microimplement for transdermal administration of a drug, characterized in that The stem holder according to claim 1 is a micro provided with an opening for receiving and supporting the bottom of the micro stem made of maltose, pullulan, hyaluronic acid, cellulose, other sugars, paper material, wood, resin, metal, silk material. A microimplement for transdermal administration of a drug characterized by having a structure having a holder or a plurality of microholders arranged on a substrate surface. A microhead having a cone shape and a half shell cone shape including a half shell cone shape and a half shell bullet shape according to claim 2, wherein one side surface of the inverted shape of the cone shape is a plane of a rectangular parallelepiped of a mold. And a micro die for a micro head provided with one or more depressions or depressions on one side of a rectangular parallelepiped such that the top end of the rectangular parallelepiped is included in the upper surface of the rectangular parallelepiped. Of micro-implement for transdermal administration of drugs.   In forming the micro-stem of the triangular prism, quadratic prism, cylinder, and half shell cylinder according to claim 3, the various inverted shapes of the columns are used so that one flat surface of the micro-stem matches an upper surface that is one surface of a rectangular parallelepiped. A method for producing a microimplement for transdermal administration of a drug, comprising using a micro mold for a microstem in which a depression or a recess is provided on an upper surface of a rectangular parallelepiped. Cooling solidification or dry solidification used to form a thermoplastic or wet plastic drug-containing material into a cone shape by a combination of three parts: a micro die for a micro head, a micro die for a macro stem, and a holder. A method for producing a microimplement for transdermal administration of a drug, comprising mounting a micropayload integrated with the physical properties of the above in a stem holder opening while applying pressure or ultrasonic vibration. In the molding method shown in claim 13, in the manufacturing method in which each molded product by two types of micro molds, that is, a micro die for a micro head and a micro die for a micro stem, is separated and taken out, the front and rear, left and right, top and bottom 3 A microscopic device for transdermal administration of a drug having a driving function capable of fine adjustment simultaneously in a dimensional direction and gradually releasing at 0.001 mm or less per second as a vertical component with respect to a releasing surface of a micro mold Implementation method of implementation.