KR20190123642A - Multi-layer microneedles having excellent skin permeability, patches comprising the same and a method for preparing the patches - Google Patents

Abstract

The present invention relates to a multilayer microneedle excellent in skin permeability, a patch comprising the same and a method of manufacturing the patch. More particularly, the present invention relates to a multilayer microneedle, a patch comprising the same and a method of manufacturing the patch, the microneedle exhibiting improved production efficiency, adhering well to various skin areas and comprising two or more layers including a top layer and a bottom layer, wherein each layer is made of a mixture comprising a biocompatible biodegradable polymer and exhibits different hardness and compressive strength, respectively, so that skin permeability and biodegradability in skin are excellent.

Description

Multi-layer microneedles having excellent skin permeability, patches comprising the same and a method for preparing the patches}

The present invention relates to a multi-layered microneedle excellent in skin permeability, a patch and a method for producing the patch, more specifically, comprising at least two layers comprising a top layer and a bottom layer, each layer is biocompatible Multi-layered microneedle made of a mixture containing biodegradable polymers, each having a different hardness and compressive strength, and having excellent skin permeability and biodegradability in the skin, but which can adhere well to various skin areas and exhibit improved production efficiency. It relates to a patch and a manufacturing method of the patch.

Drug Delivery System (DDS) refers to a series of technologies that deliver drugs to target sites such as cells and tissues to control the absorption and release of drugs to reduce side effects and maximize efficacy.

In addition to the general oral intake, the drug delivery system includes a transdermal permeable delivery system for locally applying drugs, and researches for efficiently and safely administering pharmaceutical substances such as drugs have been continuously conducted. In the case of injection therapy, the method of administration is cumbersome, there is a problem in that there is a limit in control in addition to the method of temporarily injecting drugs may be accompanied by pain depending on the patient.

In order to improve the shortcomings of injection therapy, researches on microstructures (microneedles), which are much smaller and less painful than needles of syringes, have been conducted in various fields such as drug delivery, blood collection, biosensor, and skin care. .

Conventional microneedle manufacturing methods include US Pat. No. 6,364,856 “MICRONEEDLE DEVICES AND METHODS OF MANUFACTURE AND USE THEREOF” and Korean Patent No. 10-0793615, “Biodegradable solid microneedle and its manufacturing method”.

The patent injects a biodegradable viscous material into a micro mold made using a curable polymer, dries and separates it from the mold to produce a microneedle (molding technique), or a biodegradable viscous material for forming a biodegradable solid microneedle. The microneedles are prepared by drawing and drying the biodegradable viscous material coated with a frame patterned with pillars (pillars), drawing and then cutting the drawn biodegradable viscous material (drawing technique).

On the other hand, high hardness is required for skin permeability in the upper layer (tip) of the microneedle, and softness and low hardness are required in order to be able to adhere well to the skin having the curvature in the lower layer. In order to satisfy this demand, additional additional procedures (coating, etc.) have to be performed, and thus the productivity efficiency is lowered. In addition, the microneedle manufactured as described above has a problem of poor physical properties appearing at each site.

Therefore, there has been a demand for microneedles that can satisfy the different hardness and compressive strengths required for each part of the microneedles, while having excellent skin permeability and biodegradability in the skin and exhibiting improved production efficiency.

In order to solve the above problems, the present invention comprises two or more layers comprising a top layer and a bottom layer, each layer is made of a mixture comprising a biocompatible biodegradable polymer, each having a different hardness and compression It is an object of the present invention to provide a multi-layered microneedle, a patch and a method of manufacturing the patch, which exhibit strength and are excellent in skin permeability and biodegradability in the skin, but which can adhere well to various skin parts and exhibit improved production efficiency.

In order to solve the above technical problem, the present invention is a microneedle comprising two or more layers comprising a top layer and a bottom layer, each layer is made of a mixture comprising a biocompatible biodegradable polymer, each with a different hardness And multi-layer microneedle, which exhibits compressive strength.

According to another aspect of the invention, the multilayer microneedle; And a pressure-sensitive adhesive film attached to the lower end of the multilayer microneedles.

According to another aspect of the invention, the first step of injecting a solution containing a biocompatible biodegradable polymer in the intaglio mold having a needle-shaped groove to the desired layer height; Defoaming and drying the injected solution in a vacuum atmosphere; A third step of repeating the first and second steps according to the desired number of layers; And a fourth step of releasing the microneedles from the engraved mold by attaching it to the adhesive film at the lower end of the formed microneedles, wherein the solutions containing the biocompatible biodegradable polymers injected into the respective layers are each different in hardness. And a compressive strength, a method for producing a multilayer microneedle patch is provided.

In the case of using the multilayer microneedle according to the present invention, the high hardness layer constituting the upper end (tip) layer of the needle is excellent in skin permeability, and also the low hardness soft layer constituting the lower needle layer (or base layer). By attaching well to a variety of skin areas having a bent, it is possible to manufacture a multi-layered microneedle patch exhibiting improved production efficiency in the manufacturing process because the manufactured needle patch is not twisted or brittle.

The biocompatible biodegradable polymer having high hardness, which is used for skin permeation at the upper end portion of the needle, has a relatively high molecular weight, so that the biodegradability or dissolving power in the skin is slightly decreased, Since the soft biocompatible biodegradable polymer has a relatively low molecular weight, it is possible to form a microneedle patch structure having excellent skin permeability and excellent biodegradability (solubility) in the skin.

Figure 1 schematically shows a method of manufacturing a multilayer microneedle patch of an embodiment of the present invention.
Figure 2 schematically shows a method of manufacturing a microneedle patch of a comparative example of the present invention.
Figure 3 shows the results of measuring the compressive strength of the coating film dried the high hardness biocompatible biodegradable polymer solution used in the embodiment of the present invention.
Figure 4 shows the compressive strength measurement results of the coating film dried the soft biocompatible biodegradable polymer solution used in the embodiment of the present invention.
Figure 5 shows the comparative results of the needle structure moldability, skin permeability, biodegradability, appearance form and handleability of the microneedle patch prepared in Examples and Comparative Examples of the present invention.

Hereinafter, the present invention will be described in detail.

The multilayer microneedle of the present invention is a microneedle comprising two or more layers including an upper layer and a lower layer, each layer being made of a mixture comprising a biocompatible biodegradable polymer, each having a different hardness and compressive strength. Indicates.

As used herein, the term "upper layer" refers to a layer located on the top of the multilayer microneedle, and the "lower layer" refers to a layer located on the bottom of the multilayer microneedle. If the multilayer microneedles of the present invention comprise three or more layers, there may be additional layers between the top and bottom layers.

Although not particularly limited, the upper layer may include a means capable of delivering a drug or a bioactive material to the skin, for example, a plurality of micropores, and the like, but is not limited thereto.

The upper layer (tip) layer of the multi-layer microneedle of the present invention may have a sufficient hardness enough to pass through the skin keratin layer of 10 to 20 ㎛ thickness, the compressive strength of the upper layer is greater than 10 MPa , At least 15 MPa, at least 20 MPa, at least 25 MPa, at least 30 MPa, at least 40 MPa, or at least 50 MPa, at most 20,000 MPa, at most 15,000 MPa, at most 10,000 MPa, at most 5,000 MPa, at most 3,000 MPa, at most 1,000 MPa. , Less than or equal to 500 MPa, less than or equal to 100 MPa, less than or equal to 80 MPa, or less than or equal to 70 MPa, such as greater than or equal to 20,000 MPa or less, greater than or equal to 10,000 MPa or less, greater than or equal to 5,000 MPa or less, greater than or equal to 1,000 MPa, greater than or equal to 10, more than 500 MPa, It may be greater than 10 100 MPa or less, greater than 10 80 MPa or less, greater than 10 70 MPa or less. When the compressive strength of the upper layer is lower than the numerical range, excellent skin permeability cannot be obtained. On the contrary, when the compressive strength is higher than the numerical range, additional skin permeability cannot be obtained.

In the multilayer microneedle of the present invention, the biocompatible biodegradable polymer used for forming the top (tip) layer has a low viscosity (low viscosity) so that the molding process can be performed quickly and easily. It is preferable to use diluted to have, for example, the viscosity range may be 10 ~ 300 cPs.

Although not particularly limited, the height of the upper layer may occupy 10% to 90% of the total height of the multilayer microneedle based on the depth from the tip of the microneedle.

In the multilayer microneedle of the present invention, the lower end layer (or base layer) of the needle formed by secondary molding after molding the upper end (tip) layer has the flexibility of the film patch constituting the needle array. It can be prepared using biocompatible biodegradable polymers having low hardness softness to add. The lower layer may have a compressive strength of 0.1 MPa or more, 0.3 MPa or more, 0.5 MPa or more, 1.0 MPa or more, 1.5 MPa or more, 2 MPa or more, 3 MPa or more, 4 MPa or more, or 5 MPa or more, and 10 MPa or less, 9.5 It may be MPa or less, 9 MPa or less, 8.5 MPa or less, 8 MPa or less, 7 MPa or less, or 6 MPa or less, for example, 0.1 to 10 MPa, 0.5 to 9 MPa, 1 to 8 MPa. If the compressive strength of the lower layer is higher than the numerical range, flexibility cannot be added to the multilayer microneedle patch. On the contrary, if the compressive strength is lower than the numerical range, additional flexibility cannot be expected.

In the multilayer microneedle of the present invention, the biodegradable (dissolved) to biocompatible polymers used for forming the bottom layer (or base layer) are high viscosity (high viscosity) to enable fast drying after a molding process. It is preferable to use diluted to have, for example, the viscosity range may be 300cp or more.

In the multi-layered microneedle of the present invention, the number of layers forming the multi-layered microneedle structure is not particularly limited. Preferably, the number of layers may be 2-4 in consideration of the efficacy and manufacturing productivity of the microneedle. . In addition, when there are more than two layers in the multilayer microneedle of the present invention, only the layers adjacent to each other may exhibit different hardness and compressive strength.

In the multi-layer microneedle of the present invention, the biocompatible biodegradable polymer is hyaluronic acid and its salt form polymer, polyvinylpyrrolidone (PVP) -based polymer, polyvinyl alcohol (PVA) -based polymer, polyvinylacetate (PVAc ) Polymer, polyethylene glycol (PEG) polymer, polypropylene glycol (PPG) polymer, polyethylene oxide (PEO) polymer, polypropylene oxide (PPO) polymer, polyacrylamide (PAAm) polymer, polymethacryl Acid polymer, cellulose polymer, polypeptide polymer, polylactic acid (PLA) polymer, polylactide (PL) polymer, polyglycolic acid (PGA) polymer, polycaprolactone (PCL) polymer, glucan (starch) ) Polymer, gelatin, collagen peptide (derived from collagen), glycerin, dextran, povidone, carbomer, locust bean gum, xanthan gum, catty gum, guar gum, glucosamine, damma gum At least one selected from the group consisting of alginic acid, chitosan, alginic acid, chitin, pectin, fibrin, agarose, pullulan, polylysine, chondroitin sulfate (derived from chondroitin), carrageenan and a copolymer of monomers forming the polymer. Can be used.

The mixture (solution) containing the biocompatible biodegradable polymer is a substance that can be decomposed or dissolved by water, body fluids, enzymes, or microorganisms in a living body based on an inert material that is not toxic to the human body and is chemically stable. Means a mixture prepared by dissolving with a specific solvent. The solvent is not particularly limited and includes water (purified water), anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms, acetone, ethyl acetate, butyl acetate, propyl acetate, chloroform, 1, 3-butylene glycol, hexane, diethyl Ether and the like can be used as the solvent, and preferably water or lower alcohols can be used.

Although not particularly limited, the mixture including the biocompatible biodegradable polymer may further include one or more drugs or bioactive substances, such as astaxanthin, polyphenol, vitamin, adenosine, anthocyanin, coenzyme Q10. , Lipoic acid, lycopene, tocopherol, retinol, AHA (glycolic acid, lactic acid, citric acid, tartaric acid), BHA (salicylic acid) and the like.

The multilayer microneedles of the present invention are not particularly limited, but may have an aspect ratio of 0.5 or more, a height of 20 μm or more, and a width to diameter of the bottom side of 5 μm or more, for example, an aspect ratio of 0.5 to 5, a height of 20 to 1,000 μm, and a diameter of the base side. 5 to 500 μm.

According to another aspect of the invention, the multilayer microneedle; And a pressure-sensitive adhesive film attached to the lower end of the multilayer microneedles.

Although not particularly limited, the adhesive film is a skin adhesive film having a protective film (liner) covered with an outer portion to protect the adhesive layer, and uses a material such as hydrocolloid gel or polyurethane to make a type of skin adhesive layer. It is not limited to.

According to another aspect of the invention, the first step of injecting a solution containing a biocompatible biodegradable polymer in the intaglio mold having a needle-shaped groove to the desired layer height; Defoaming and drying the injected solution in a vacuum atmosphere; A third step of repeating the first and second steps according to the desired number of layers; And a fourth step of releasing the microneedles from the engraved mold by attaching it to the adhesive film at the lower end of the formed microneedles, wherein the solutions containing the biocompatible biodegradable polymers injected into the respective layers are each different in hardness. And a compressive strength, a method for producing a multilayer microneedle patch is provided.

1 schematically illustrates a method of manufacturing a multilayer microneedle patch according to an embodiment of the present invention, which will be described in more detail with reference to the present invention. In the multilayer microneedle patch according to an embodiment of the present invention, the biocompatible material is injected into each layer. Solutions containing type biodegradable polymers may each exhibit different hardness and compressive strength, such that the top (tip) layer of the microneedle is made of a mixture comprising a high hardness biocompatible biodegradable polymer The lower end layer (or base layer), which abuts against it, is made of a mixture comprising a biocompatible biodegradable polymer having ductility.

The high hardness biocompatible biodegradable polymer and the low hardness ductile biocompatible biodegradable polymer may have a compressive strength as described above.

In the method of manufacturing a multilayer microneedle patch of the present invention, a first step of injecting a solution containing a biocompatible biodegradable polymer into a concave mold having a needle-shaped groove at a desired layer height may be performed. Primary molding or secondary molding of the present specification means the first or second molding is performed, can be repeated according to the desired number of layers, basically the primary molding corresponds to the process of forming the upper end of the microneedle.

The primary molding is to fill the biocompatible biodegradable polymer solution (mixture) into the intaglio mold having the needle-shaped grooves prepared, but the depth is not limited but can be injected to the desired layer height, preferably the intaglio needle Do not fill more than the height of the groove.

In this case, the coating method for filling the biocompatible biodegradable polymer solution (mixture) into the needle-shaped recess groove includes dipping coating, spray coating, silk printing, ink jet coating, spin coating, slit coating, bar coating, and gravure. Coating or the like can be used, but is not limited thereto.

In addition, the intaglio mold having the needle-shaped groove may be made of at least one material selected from the group consisting of silicon-based polymers, fluorine-based polymers, UV-curable polymers, thermosetting polymers, thermoplastic polymers, ceramic oxides, and metallic inorganic materials. This is not restrictive.

In addition, in order to improve release or wetting of the polymer solution filled in the intaglio mold having the needle-shaped grooves used, the intaglio mold having the needle-shaped grooves may be plasma treated, a self-assembly monolayer. ) And one or more surface treatment processes selected from the group consisting of surface deposition. Specifically, hydrophilic surface treatment by plasma treatment and hydrophobic release treatment by SAM treatment may be performed on the intaglio mold having a needle-shaped groove.

In the manufacturing method of the multilayer microneedle patch of the present invention, a second step of defoaming and drying the injected solution in a vacuum atmosphere may be performed.

After primary molding, the polymer solution may be left in a vacuum atmosphere to remove the bubbles and dry the polymer solution. At this time, the conditions of the vacuum atmosphere is left for 10 minutes or more at 10torr or less, the atmosphere is left within the temperature range in which the drug or nutrients are not damaged, preferably not more than 40 ℃. In some cases, after degassing in a vacuum atmosphere, the drying may be performed by a blowing method instead of a vacuum drying method, and is not limited to any drying method.

In the method of manufacturing a multilayer microneedle patch of the present invention, a third step of repeating the first and second steps may be performed according to the desired number of layers.

When the high hardness needle upper end (tip) layer is formed and dried through the primary molding, a soft biocompatible biodegradable polymer solution (mixture) corresponding to the lower end of the final needle is applied to the upper layer and The degassing and drying process may be performed by leaving it in a vacuum atmosphere. If it is desired to form three or more layers, a corresponding biocompatible biodegradable polymer solution (mixture) may be injected to form the corresponding layer.

In one embodiment, when the multilayer microneedle of the present invention is three or more layers, the upper end (tip) layer of the microneedle is made of a high hardness biocompatible biodegradable polymer solution (mixture), and the adjacent intermediate layer It may be composed of soft biodegradable to biocompatible polymers, and the lowermost lower layer (ie, base or base layer) may use a biocompatible biodegradable polymer selected to have a high or low hardness or compressive strength unlike an intermediate layer. Can be.

In the method of manufacturing a multilayer microneedle patch of the present invention, a fourth step of releasing the microneedle from the intaglio mold may be performed by attaching the lower end of the formed microneedle to the adhesive film.

In this step, the microneedle layer may be supported by attaching the adhesive film to the lower end of the formed microneedle. The adhesive film is a skin adhesive film having a protective film (liner) covered with an outer portion to protect the adhesive layer, and a film made of a material such as hydrocolloid gel or polyurethane may be used. It does not specifically limit.

Hereinafter, the present invention will be described in detail with reference to Examples. However, the embodiments according to the present invention are not limited to the embodiments described herein and may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art, but are provided to sufficiently convey the spirit of the present invention to those skilled in the art.

EXAMPLE

Preparation of the Multilayer Microneedle Patch of the Present Invention

After preparing the biocompatible biodegradable polymer solution (mixture) as shown in Table 1 and Table 2, respectively, the following description and the process described in Figure 1 was carried out to produce a multilayer microneedle. The contents of the compositions described in the table below are expressed in weight (wt%).

First, a high hardness biocompatible biodegradable polymer solution prepared as shown in Table 1 is dispensed into a silicon mold having an intaglio needle structure prepared in advance, and then filled in a groove of the intaglio needle structure, and 60% of the intaglio needle groove Filled to depth. Then, degassed under reduced pressure to 10 torr in a vacuum oven, and dried at 40 ℃ for 3 hours.

As can be seen in Figure 3, it was confirmed that the compressive strength of the coating film dried the high hardness biocompatible biodegradable polymer solution composition was measured to 65MPa.

Thereafter, a soft biocompatible biodegradable polymer solution prepared in the composition of Table 2 is dispensed and applied onto the high hardness biocompatible biodegradable polymer layer formed by the primary molding, and then, in a vacuum oven to 10 torr. After degassing under reduced pressure, the mixture was dried at 40 ° C. for 6 hours. Thereafter, the final dry molded multilayer microneedle was released and separated from the silicone mold using a hydrocolloid adhesive film.

As can be seen in Figure 4, the soft biocompatible biodegradable polymer solution composition was confirmed that the compressive strength of the coating film after drying was measured to 4.2MPa.

ingredient High hardness biocompatible biodegradable polymer solution (wt%) Poly (lactic acid) 2 Crosslinked-HA (Sodium hyaluronate) 1300kDa 0.5 DMC 90 Purified water 7.5 EGF  10 ppm to 100% by weight of the total amount

* EGF: Epidermal Growth Factor

DMC: Dimethyl Carbonate

ingredient Flexible biocompatible biodegradable polymer solution (wt%) Low Molecular Weight-Sodium hyaluronate (HA) 50kDa 6 glycerin One Gelatin (M.W2000) 3 Purified water 90 EGF  10 ppm to 100% by weight of the total amount

Preparation of Microneedle Patch of Comparative Example

The high hardness biocompatible biodegradable polymer solution prepared as shown in Table 1 is dispensed into a silicon mold having a previously prepared intaglio needle structure to be filled in the indentation needle structure, and the intaglio needle groove is filled to overflow. It was. Thereafter, the mixture was degassed under reduced pressure in a vacuum oven to 10 torr, dried at 30 ° C. for 2 hours, and further dried at 40 ° C. for 8 hours. Thereafter, the final dry molded microneedle was released from the silicone mold using a hydrocolloid adhesive film.

For the comparison of the microneedle patches prepared in Examples and Comparative Examples, the experiment was carried out as follows. First, each patch was measured with an optical microscope for needle structure formability, and ii) each microneedle patch was attached to the skin of the human wrist for skin permeability. It was measured by a photograph and compared. In addition, iii) the biodegradability (dissolution) of the microneedle, each patch was attached to the skin of the human eye, detached after 2 hours, and the surface of the microneedle patch was measured by optical microscopy, and iv) distortion occurred in appearance. Whether or not was compared. A comparison result is shown in FIG.

As can be seen from the comparison result of FIG. 5, it was found that the multilayer microneedle patch of the example had excellent moldability at the same level as the comparative example made of a single material in needle structure formability. In addition, both the Examples and Comparative Examples were made of a polymer having a high hardness and a compressive strength, so both showed excellent skin permeability. However, it was confirmed that the microneedle patch of the example using the high hardness and soft biocompatible biodegradable polymer is more biodegradable than the comparative example made of the single polymer.

In addition, it can be seen that the multilayer microneedle patch of the embodiment having the soft lower hardness lower layer is not hard, flexible, easy to handle, and no appearance deformation, but the microneedle patch of the comparative example made of a single polymer is performed. Compared with the example, it was confirmed that there was no flexibility and hardness, and thus the handling was poor, and the appearance distortion was also very severe.

Claims (13)

A microneedle comprising two or more layers comprising a top layer and a bottom layer,
Each layer is made of a mixture comprising biocompatible biodegradable polymers, each exhibiting different hardness and compressive strength,
Multilayer microneedle. The method of claim 1,
Multilayer microneedle, the compressive strength of the top layer is more than 10 20,000 MPa or less. The method of claim 1,
Compression strength of the bottom layer is 0.1 to 10MPa, multi-layered microneedle. The method of claim 1,
A multilayer microneedle exhibiting different hardness and compressive strengths only in adjacent layers. The method of claim 1,
The height of the top layer is a multi-layer microneedle occupies 10% to 90% of the total height of the multi-layer microneedle based on the depth from the tip of the microneedle. The method of claim 1,
The biocompatible biodegradable polymer is hyaluronic acid and its salt form polymer, polyvinylpyrrolidone (PVP) polymer, polyvinyl alcohol (PVA) polymer, polyvinylacetate (PVAc) polymer, polyethylene glycol (PEG) Polymer, polypropylene glycol (PPG) polymer, polyethylene oxide (PEO) polymer, polypropylene oxide (PPO) polymer, polyacrylamide (PAAm) polymer, polymethacrylic acid polymer, cellulose polymer, polypeptide Polymer, polylactic acid (PLA) polymer, polylactide (PL) polymer, polyglycolic acid (PGA) polymer, polycaprolactone (PCL) polymer, glucan (starch) polymer, gelatin, collagen peptide, Glycerin, dextran, povidone, carbomer, locust bean gum, xanthan gum, catty gum, guar gum, glucosamine, damma gum, alginic acid, chitosan, alginic acid, chitin, pectin, fibrin, agarose, pullul , Polylysine, chondroitin sulfate, carrageenan and one or more, a multi-layer micro-needle selected from the group consisting of copolymers of the monomers forming the polymer. The method of claim 1,
The mixture comprising the biocompatible biodegradable polymer further comprises one or more drugs or bioactive substances, multilayer microneedle. The method of claim 1,
Multilayer microneedle having an aspect ratio of 0.5 to 5, a height of 20 to 1,000 μm, and a base of 5 to 500 μm in diameter. A multilayer microneedle according to any one of claims 1 to 8; And
An adhesive film attached to the lower end of the multilayer microneedle;
Multilayer microneedle patch comprising a. The method of claim 9,
The adhesive film is a hydrocolloid gel or polyurethane material, multilayer microneedle patch. A first step of injecting a solution containing a biocompatible biodegradable polymer into a recessed mold having a needle-shaped groove in accordance with a desired layer height;
Defoaming and drying the injected solution in a vacuum atmosphere;
A third step of repeating the first and second steps according to the desired number of layers; And
And a fourth step of releasing the microneedles from the intaglio mold by attaching the adhesive film to the lower end of the formed microneedles.
Solutions containing biocompatible biodegradable polymers injected into the respective layers, respectively, will exhibit different hardness and compressive strength,
Method for producing a multilayer microneedle patch. The method of claim 11,
The intaglio mold having a needle-shaped groove is made of at least one material selected from the group consisting of silicon-based polymers, fluorine-based polymers, UV-curable polymers, thermosetting polymers, thermoplastic polymers, ceramic oxides, and metallic inorganic materials, and multilayer microneedle Manufacturing method. The method of claim 11,
The intaglio mold having the needle-shaped groove is treated by one or more surface treatment processes selected from the group consisting of plasma treatment, self-assembly monolayer (SAM) treatment and surface deposition. .

Images