Microneedle array structure having lipophilic tips and method for producing same

Abstract

The present invention relates to a microneedle array structure having lipophilic tips not easily deformed even in environments exposed to moisture, and a method for producing same. The microneedle array structure of the present invention can minimize deformation of the tip portion of the microneedles due to exposure to moisture during post-production distribution of the microneedle arrays, and when used on the skin, the deformation of the microneedle tips due to contact with the moisture in the skin can be prevented, thus allowing the microneedles to be inserted to desired depths for effective delivery of active substances.

Description

Microneedle array structure with lipophilic tip and method for manufacturing same

[0001] This patent application claims priority to Republic of Korea Patent Application No. 10-2023-0197937, filed with the Korean Intellectual Property Office on December 29, 2023, the disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a microneedle array structure having a lipophilic tip that is not easily deformed even in an environment exposed to moisture, and a method for manufacturing the same.

[0003] As efforts continue to improve the convenience of applying cosmetics and pharmaceuticals to subjects in the beauty and medical fields, "microneedles," a next-generation active ingredient delivery technology, have been gaining attention. Microneedles, a replacement for injectable or oral medications, can be simply applied to the skin to produce the same effects as existing cosmetics or pharmaceuticals. In particular, the utility of microneedles is increasing as attempts are being made to integrate them into everyday applications aimed at improving quality of life, such as obesity medications and hair loss treatments.

[0004] Microneedles are typically microscopic needles measuring several hundred nanometers in size. A microneedle array is a transdermal delivery system that consists of a patch containing a collection of multiple microneedles. This patch is applied to the skin to deliver functional cosmetics and / or drugs. Because numerous microneedles are applied to the skin to allow the body to absorb the functional active ingredients, it is often referred to as a "patch injection," and has been primarily used in the cosmetic and plastic surgery fields.

[0005] There are several types of microneedles, and they vary in form, primarily depending on their intended use and manufacturing method. Solid microneedles are microneedles made from a single material and are primarily used to create microscopic holes in the target area, followed by the additional application of functional cosmetic compositions or drugs. They are typically manufactured using materials such as silicone, metal, and polymers. Coated microneedles are microneedles whose surfaces are coated with a specific substance and are used to deliver or detect specific substances into the skin. They are typically manufactured by manufacturing solid microneedles and then coating them with a specific substance. This coating is typically made of a biocompatible material. Dissolving microneedles are microneedles that melt for a specific period of time or under specific conditions. They are primarily used for the delivery of functional cosmetic compositions or drugs. The microneedle body is inserted into the skin and melts, effectively delivering the functional active substance into the skin. Hollow microneedles are microneedles with a hollow space in the center. They are mainly used to inject or extract liquids into the skin while the microneedles are inserted into the skin, and have a shape most similar to a typical syringe.

[0006] Microneedles can be used in a variety of functional cosmetics and pharmaceuticals, depending on their size, strength, and material. In particular, they offer significantly less pain than conventional injections, leading to improved medication compliance and reduced risk of infection. Furthermore, the use of microscopic needles allows for superior delivery of functional active substances even with minimal dosage, and the delivery speed of these active substances can be controlled.

[0007] Among these various advantages, dissolving microneedles are generally selected based on a component that is easily dissolved by contact with moisture after insertion into the body. Therefore, in the case of dissolving microneedles, the tip of the microneedle is easily deformed due to humid environmental factors during the storage and distribution process, and it may be difficult to maintain a sharp tip angle that is easy to apply to the skin. In addition, during the skin application step, the tip of the microneedle is easily deformed further due to moisture during the insertion process into the skin, which may cause a problem that makes it difficult to insert the microneedle to the desired depth.

[0008] The present invention was derived to solve the above-described problem, and relates to a microneedle array that solves the problem of deformation of the tip due to moisture.

[0009] The present inventors have diligently researched and developed a soluble microneedle array structure with minimal deformation of the microneedle tip due to moisture. As a result, they have completed the present invention by discovering that when manufacturing a microneedle array structure comprising microneedles having a tip (oil tip) made of a lipophilic component and a hydrophilic, soluble body, deformation of the microneedle tip due to moisture can be minimized.

[0010] Accordingly, an object of the present invention is to provide a microneedle array structure having a liquid tip.

[0011] Another object of the present invention is to provide a method for manufacturing a microneedle array structure having a liquid tip.

[0012] According to one aspect of the present invention, the present invention provides a microneedle array structure comprising microneedles having a lipophilic tip layer and a biocompatible biodegradable polymer shaft layer.

[0013]

[0014] The present inventors have conducted extensive research efforts to develop a soluble microneedle array structure with minimal deformation of the microneedle tip due to moisture. As a result, we have discovered that when a microneedle array structure is manufactured, comprising microneedles comprising a tip (oil tip) composed of a lipophilic component and a hydrophilic, soluble body, deformation of the microneedle tip due to moisture can be minimized.

[0015] In one embodiment of the present invention, the lipophilic tip layer comprises a mixture of a biocompatible biodegradable polymer material and oil.

[0016] In one embodiment of the present invention, the oil included in the lipophilic tip layer is one or a combination of two or more selected from the group consisting of camellia seed oil, jojoba seed oil, safflower seed oil, Brazil nut seed oil, broccoli seed oil, black cumin seed oil, apricot kernel oil, rapeseed oil, coix seed oil, quinoa seed oil, grape seed oil, camellia seed oil, castor seed oil, sunflower seed oil, pine seed oil, jojoba seed oil, pecan seed oil, cranberry seed oil, baobab seed oil, lemon seed oil, cypress seed oil, vitamin tree seed oil, western rapeseed oil, lime seed oil, amaranth seed oil, rosehip flower oil, evening primrose seed oil, tansy flower oil, and magnolia berry oil.

[0017] In one embodiment of the present invention, the ratio of the height of the tip layer to the height of the biocompatible polymer shaft layer is 1:1 to 1:100.

[0018] In one embodiment of the present invention, the height of the microneedle including both the tip layer and the shaft layer is 50 μm to 1000 μm.

[0019] In one embodiment of the present invention, the height of the microneedle and the maximum diameter of the bottom of the microneedle have a length ratio of 1:5 to 3:1.

[0020] In one embodiment of the present invention, the microneedle has a tip shaped like a cone, a polyhedron, or a bell tower.

[0021] In one embodiment of the present invention, the biocompatible biodegradable polymer shaft layer is selected from the group consisting of hyaluronic acid (HA), poly(lactic acid; PLA), poly(ε-caprolactone; PCL), polyhydroxyalkanoate (PHA), polyesteramide (PEA), polyethylene glycol (PEG), poly(p-dioxanone; PPDO), poly(lactic-co-glycolic acid; PLGA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), chitosan, collagen, gelatin, alginic acid, pectin, carrageenan, Chondroitin sulfate, dextran sulfate, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP);Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, gum arabic, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polyglycolic acid, polyethylene oxide, Comprising at least one biocompatible biodegradable polymer material selected from the group consisting of polyacrylic acid, polyacrylamide, polymethacrylic acid, and polymaleic acid;

[0022] In one embodiment of the present invention, the biocompatible biodegradable polymer material included in the lipophilic tip layer is hyaluronic acid (HA), poly(lactic acid; PLA), poly(ε-caprolactone; PCL), polyhydroxyalkanoate (PHA), polyesteramide (PEA), polyethylene glycol (PEG), poly(p-dioxanone; PPDO), poly(lactic-co-glycolic acid; PLGA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), chitosan, collagen, gelatin, alginic acid, pectin, carrageenan, Chondroitin sulfate, dextran sulfate, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP);Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, gum arabic, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polyglycolic acid, polyethylene oxide, At least one selected from the group consisting of polyacrylic acid, polyacrylamide, polymethacrylic acid, and polymaleic acid;

[0023] In one embodiment of the present invention, the biocompatible biodegradable polymer shaft layer additionally comprises a predetermined cargo material to be delivered into the skin of a subject.

[0024] In one embodiment of the present invention, the cargo material is at least one selected from the group consisting of low molecular weight compounds, peptides, proteins, nucleic acids, polysaccharides, viruses, and liposomes.

[0025] According to another aspect of the present invention, the present invention provides a method for manufacturing a microneedle array structure, comprising the following steps:

[0026] (a) a step of filling a mixture of a biocompatible biodegradable polymer material and oil into the tip of a microneedle-shaped filling portion in a negative mold including a plurality of microneedle-shaped filling portions, and drying the mixture;

[0027] (b) After the drying step of step (a), a step of filling a mixture of a biocompatible biodegradable polymer material and a specific cargo material to be delivered into the skin of a subject into the unfilled remaining space of the microneedle-shaped filling portion, and drying the mixture; and

[0028] (c) A step of separating the formed microneedle array structure from the negative mold.

[0029] The features and advantages of the present invention are summarized as follows:

[0030] (a) The present invention provides a microneedle array structure having a liquid tip.

[0031] (b) The present invention provides a method for manufacturing a microneedle array structure having a liquid tip.

[0032] (c) When using the microneedle array structure of the present invention, deformation of the tip portion of the microneedle due to exposure to moisture during the distribution process after manufacturing the microneedle array can be minimized, and deformation of the microneedle tip due to contact with moisture in the skin when applied to the skin can be prevented, thereby stably inserting the microneedle to a desired depth and effectively delivering an effective substance.

[0033] Figure 1 shows a schematic diagram of a microneedle (1) constituting a microneedle array structure (2).

[0034] Figure 2 shows examples of the shapes of various microneedles (1).

[0035] Figure 3 shows a schematic diagram of a microneedle array structure (2).

[0036] Fig. 4 shows a photograph of a test product of the microneedle array structure (2).

[0037]

[0038] Hereinafter, with reference to the attached drawings, embodiments of the microneedle array structure of the present invention will be described in detail so that those skilled in the art can easily practice the present invention. The terms used in this specification have been selected from currently widely used general terms as much as possible while considering the functions of the present invention, but these may vary depending on the intention of engineers working in the related field, precedents, the emergence of new technologies, etc. Unless otherwise defined, the technical and scientific terms used may have the meaning commonly understood by those skilled in the art to which this invention pertains.

[0039] As used herein and in the appended claims, the singular expression "singular" includes the plural expression unless the context clearly dictates otherwise. Furthermore, the plural expression "singular" includes the singular expression unless the context clearly dictates otherwise.

[0040] In this specification and the appended claims, the terms “include” or “have” mean that a feature or component described in the specification is present, and unless specifically limited, does not preclude the possibility that one or more other features or components may be added.

[0041] Additionally, the numerical ranges used herein include lower and upper limits and all values ​​within that range, increments logically derived from the shape and width of the defined range, all doubly defined values, and all possible combinations of upper and lower limits of numerical ranges defined in different shapes. Unless otherwise specifically defined in the specification of the present invention, values ​​outside the numerical range that may arise due to experimental error or rounding of values ​​are also included in the defined numerical range.

[0042] The term “about” or the like used in this specification and the appended claims is used to encompass the tolerance when an tolerance exists.

[0043] The term “biocompatibility” as used herein means the property of being substantially non-toxic, chemically inert and non-immunogenic to the human body.

[0044] The term “biodegradability” in this specification refers to the property of being self-decomposed in response to environmental factors within the human body, such as temperature, moisture, and microorganisms.

[0045] “Microneedle” according to one embodiment of the present invention refers to a dissolving microneedle, which is a microneedle that has the property of dissolving when inserted into the skin.

[0046] “Microneedle array structure” according to one embodiment of the present invention means a microneedle assembly in which a plurality of microneedles are arranged in a predetermined manner.

[0047] Conventional microneedles manufactured using biocompatible, biodegradable polymers have been plagued by issues such as moisture-induced deformation at the tips during distribution, leading to blunted tip shape and difficulty penetrating the skin when applied. Furthermore, contact with moisture within the skin during application can easily deform the shape of the microneedles, preventing them from being inserted to the desired depth.

[0048] In order to solve the above-described problem, the present inventors applied a biocompatible biodegradable component mixed with a lipophilic component only to the tip portion of the microneedle, thereby appropriately maintaining the solubility of the microneedle in the body, thereby facilitating the release of an effective substance while maintaining the shape of the tip portion capable of penetrating the skin, thereby enhancing the storage stability and the convenience and effectiveness of skin application of the microneedle array structure.

[0049] Meanwhile, when a lipophilic component is mixed throughout the microneedle to impart lipophilicity, there was a problem that it took longer to dissolve within the skin and the desired effective ingredient could not be effectively delivered into the skin.

[0050] The term “lipophilic” in this specification means a substance that has the property of dissolving well in oil or fat, and conversely, the property of not dissolving well in water.

[0051] According to one embodiment of the present invention, a lipophilic tip layer (10) can be manufactured by mixing a biocompatible biodegradable polymer material and a lipophilic material. The lipophilic material included in the tip layer (10) is sufficient as long as it can impart lipophilicity to the microneedle tip and prevent the microneedle tip from being easily deformed by moisture. Therefore, the use of a specific lipophilic component is not required. However, considering the characteristics of the microneedle (1) to be injected into the body, it is preferable to use a material having biocompatible properties. Meanwhile, by adding a lipophilic material that has a positive effect upon introduction into the body, secondary effects can also be obtained. Specifically, lipophilic components such as astaxanthin, lutein, zeaxanthin, and quercetin can be used. Since the effects of the above-mentioned components are well known in the art, they can be appropriately utilized according to the intended use of the microneedle array structure (2).

[0052] According to one embodiment of the present invention, the lipophilic tip layer (10) of the microneedle (1) includes a mixture of a biocompatible biodegradable polymer material and an oil. The biocompatible biodegradable polymer material and the oil may be mixed in a weight ratio (w / w) of 100:1 to 1:10, and as another specific example, the biocompatible biodegradable polymer material and the oil may be mixed in a ratio of 50:1 to 1:10, 40:1 to 1:10, 30:1 to 1:10, 20:1 to 1:10, 20:1 to 1:5, 15:1 to 1:5, or 10:1 to 1:5, but is not necessarily limited thereto, and may be appropriately adjusted according to the storage environment of the manufactured microneedle array structure, the application site on the human body, etc.

[0053] The term “oil” in this specification may be referred to as “oil” or “oil,” and means a flammable substance that can be obtained from plants, animals, minerals, etc., and does not necessarily mean a substance in a liquid state, and is used as a term that comprehensively refers to a component known to have a property of imparting lipophilicity to a composition containing the component, and specifically, it is used to encompass lipophilic components such as astaxanthin, lutein, zeaxanthin, quercetin, etc. described above. Since the microneedle array structure (2) of the present invention has a property of being applied to the skin of the human body, it is preferable that the oil of the present invention use a component that has biocompatibility.

[0054] In one embodiment of the present invention, the oil that can be included in the lipophilic tip layer (10) is selected from the group consisting of astaxanthin, lutein, zeaxanthin, quercetin, camellia japonica seed oil, jojoba seed oil, safflower seed oil, Brazil nut seed oil, broccoli seed oil, black cumin seed oil, apricot kernel oil, rapeseed oil, coix seed oil, quinoa seed oil, grape seed oil, camellia japonica seed oil, castor seed oil, sunflower seed oil, pine seed oil, jojoba seed oil, pecan seed oil, cranberry seed oil, baobab seed oil, lemon seed oil, zelkova seed oil, vitamin tree seed oil, western rapeseed oil, lime seed oil, amaranth seed oil, rose musk flower oil, evening primrose seed oil, tansy flower oil and magnolia berry oil. Any one or a combination of two or more may be used as appropriate, but is not necessarily limited thereto, and various oil components known to have biocompatibility may be used.

[0055] The term “Astaxanthin” in this specification refers to a substance with CAS No. 472-61-7, and astaxanthin exists in most red marine organisms. “Lutein is a xanthophylls with CAS No. 127-40-2, one of the 600 naturally occurring carotenoids known to date. Lutein is synthesized only by plants and other xanthophylls and is found in large quantities in leafy vegetables such as spinach, kale, and yellow carrots. The term “zeaxanthin” in this specification refers to a substance with CAS No. 144-68-3, also called zeaxanthin. It is a carotenoid pigment that constitutes the macula along with lutein. The term “quercetin” in this specification refers to a substance with CAS No. 117-39-5, 6151-25-3, a plant flavonol extracted from the flavonoid group of polyphenols. It is found in various fruits, vegetables, leaves, seeds, and grains. “Camellia Japonica Seed Oil” refers to a substance with CAS No. As a substance having CAS No. 223748-13-8, it means a fixed oil (non-volatile oil) obtained from the seeds of Camellia Japonica. The term “Jojoba Seed Oil (Simmondsia Chinensis (Jojoba) Seed Oil)” as used herein means a substance obtained from the non-volatile oil extracted or pressed from the seeds of the desert shrub jojoba (Simmondsia Chinensis) as a substance having CAS No. 61789-91-1, 90045-98-0. The term “Carthamus Tinctorius (Safflower) Seed Oil” as used herein means an oil component obtained from the seeds of safflower (Carthamus Tinctorius) as a substance having CAS No. 8001-23-8. The term “Rosa Moschata Flower Oil” as used herein means a volatile oil obtained from the flowers of the Rosa Moschata.The term “tangja flower oil” in this specification means oil obtained from the flower of the tangerine tree (Poncirus trifoliata), and “omija oil” means volatile oil obtained from the fruit of the omija (Schisandra chinensis). The terms “Brazil nut seed oil”, “broccoli seed oil”, “black cumin seed oil”, “apricot kernel oil”, “rapeseed oil”, “jobi seed oil”, “quinoa seed oil”, “grape seed oil”, “camellia seed oil”, “castor seed oil”, “sunflower seed oil”, “pine seed oil”, “jojoba seed oil”, “pecan seed oil”, “cranberry seed oil”, “baobab seed oil”, “lemon seed oil”, “biscuit seed oil”, “vitamin tree seed oil”, “western rapeseed oil”, “lime seed oil”, “amaranth seed oil” and “evening primrose oil” in this specification refer to oil components extracted from the seeds of each plant.

[0056] As illustrated in FIG. 1, the microneedles (1) constituting the microneedle array structure (2) according to one embodiment of the present invention form a layered structure in which a lipophilic tip layer (10) and a biocompatible polymer shaft layer (20) are laminated. The bonding surface of the tip layer (10) and the shaft layer (20) does not necessarily need to be flat, and a convex or concave cross-section may be formed depending on the characteristics of the negative mold and the filling material due to the characteristics of the manufacturing process.

[0057] In one embodiment of the present invention, the ratio of the height of the tip layer (10) to the height of the biocompatible polymer shaft layer (20) is 1:1 to 1:100. The height of the tip layer can be appropriately adjusted depending on the product's usage environment, distribution environment, application site on the skin, etc. In another specific example, the ratio of the height of the tip layer (10) to the height of the biocompatible polymer shaft layer (20) may be 1:1 to 1:90, 1:1 to 1:80, 1:1 to 1:70, 1:1 to 1:60, 1:1 to 1:50, 1:1 to 1:40, 1:1 to 1:30, 1:1 to 1:20, 1:2 to 1:20, 1:2 to 1:15, 1:2 to 1:12, 1:2 to 1:10, 1:2 to 1:8, or 1:2 to 1:5, but is not necessarily limited thereto, and may be appropriately adjusted by a person skilled in the art as described above.

[0058] In one embodiment of the present invention, the height (h) of the microneedle (1) may be 50 μm to 1000 μm. The height (h) of the microneedle (1) may be variously adjusted by various factors such as the application site on the skin, the depth to which the effective substance is to be delivered, or the change in the strength of the microneedle (1) due to a change in the raw material, and specifically, for example, the length (h) of the microneedle (1) may be 50 μm to 800 μm, 50 μm to 700 μm, 50 μm to 600 μm, 50 μm to 500 μm, or 100 μm to 500 μm, and may be variously adjusted.

[0059] In one embodiment of the present invention, the height (h) of the microneedle (10) and the maximum diameter (dm) of the bottom have a length ratio of 1:5 to 3:1. In other specific examples, the length (h) and the diameter (dm) have a length ratio of 1:4 to 3:1, 1:3 to 3:1, 1:2 to 3:1, 1:1 to 3:1, 1:1 to 2.5:1, or 1:1 to 2:1. The maximum diameter of the bottom surface of the microneedle (10) described above is, for example, if the shape of the bottom surface of the microneedle (1) is an equilateral triangle, the length of one side becomes the maximum diameter, if it is a circle, the length of the diameter becomes the maximum diameter, if it is a regular polygon with an even number of vertices, the length from one vertex to the opposite vertex becomes the maximum diameter, and if it is a regular polygon with an odd number of vertices, the length from one vertex to either of the two vertices of the opposite side becomes the maximum diameter.

[0060] The maximum diameter (dm) of the bottom surface of the microneedle (1) according to one embodiment of the present invention can be appropriately selected by a person skilled in the art so as to form a minimum tip angle of the microneedle (1) that can penetrate the skin, in relation to the length (h) of the microneedle (1). Specifically, for example, the maximum diameter (dm) of the bottom surface of the microneedle (1) can be 50 μm to 5000 μm. In other specific embodiments, the maximum diameter (dm) is 50 μm to 4500 μm, 50 μm to 4000 μm, 50 μm to 3500 μm, 50 μm to 3000 μm, 50 μm to 2500 μm, 50 μm to 2000 μm, 50 μm to 1500 μm, 50 μm to 1400 μm, 50 μm to 1300 μm, 50 μm to 1200 μm, 50 μm to 1100 μm, 50 μm to 1000 μm, 50 μm to 950 μm, 50 μm to 900 μm, 50 μm to 850 μm, 50 μm to 800 μm, 50 μm to 750 μm, 50 μm to 700 μm, 50 μm to 650 μm, 50 μm to 600 μm, 50 μm to 550 μm, or 50 μm to 500 μm, and can be variously adjusted.

[0061] In one embodiment of the present invention, the microneedle (1) may have a tip shape of a cone, a polygonal pyramid, or a bell tower shape as shown in FIG. 2, and any shape of the tip that can penetrate the skin is sufficient, but is not necessarily limited thereto. The polygonal pyramid shape includes a triangular pyramid, a square pyramid, and various polygonal pyramid shapes including a hexagonal pyramid, an octagonal pyramid, a dodecagonal pyramid, etc., and is not particularly limited. The bell tower shape refers to the shape shown on the far right of FIG. 2, and the shape of the microneedle (1) is not particularly limited as long as it has a tip shape suitable for penetrating the skin.

[0062] The plurality of microneedles (1) included in one microneedle array structure (1) do not need to all have the same shape, and may be a collection of various shapes. However, in order to uniformly apply the microneedle array structure (2) to the entire area of ​​the application site, it is preferable that the microneedles (1) included in one microneedle array structure (2) be designed to have the same shape.

[0063] In one specific example of the present invention, the biocompatible polymer shaft layer (20) is selected from the group consisting of hyaluronic acid (HA), poly(lactic acid; PLA), poly(ε-caprolactone; PCL), polyhydroxyalkanoate (PHA), polyesteramide (PEA), polyethylene glycol (PEG), poly(p-dioxanone; PPDO), poly(lactic-co-glycolic acid; PLGA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), chitosan, collagen, gelatin, alginic acid, pectin, carrageenan, Chondroitin sulfate, dextran sulfate, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP);Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, gum arabic, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polyglycolic acid, polyethylene oxide, It may include any one or a combination thereof selected from the group consisting of polyacrylic acid, polyacrylamide, polymethacrylic acid, and polymaleic acid.;

[0064] In addition, a polymer material that can be used for manufacturing a biocompatible polymer shaft layer (20) as a biocompatible biodegradable polymer material included in the lipophilic tip layer (10) of the microneedle (1) according to one specific example of the present invention can be selectively used, and specifically, for example, hyaluronic acid (HA), poly(lactic acid; PLA), poly(ε-caprolactone; PCL), polyhydroxyalkanoate (PHA), polyesteramide (PEA), polyethylene glycol (PEG), poly(p-dioxanone; PPDO), poly(lactic-co-glycolic acid; PLGA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), Chitosan, collagen, gelatin, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP);Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, gum arabic, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polyglycolic acid, polyethylene oxide, Any one or a combination thereof selected from the group consisting of polyacrylic acid, polyacrylamide, polymethacrylic acid, and polymaleic acid may be used.;

[0065] In one embodiment of the present invention, the biocompatible biodegradable polymer shaft layer (20) may additionally include a predetermined cargo material to be delivered into the skin of a subject.

[0066] The term "cargo" in the present embodiment refers to a biocompatible material suitable for injection into a living body, and is an effective material expected to exhibit a desired effect by the user, and is not particularly limited. Specifically, for example, the cargo material may be at least one selected from the group consisting of low-molecular-weight compounds, peptides, proteins, nucleic acids, polysaccharides, viruses, and liposomes. The nucleic acids described above may include oligonucleotides, plasmid DNA, siRNA, PNAs (peptide nucleic acids), and the like. Specifically, for example, the cargo material of the present invention may be selected without limitation from conventionally known pharmaceutical compositions or functional cosmetic compositions.

[0067] More specifically, for example, considering that the microneedle (1) of the present invention is mainly applied to the skin of a subject, it is possible to effectively mix and use effective substances known to have antioxidant, anti-inflammatory, and anti-allergic effects, and to effectively load effective substances known to have effects such as skin whitening, wrinkle improvement, UV protection, and acne relief. In addition, it is possible to load and use drugs that can be used to treat various diseases, including anticancer drugs, and to inject them into the body through the skin, and preferably, drugs that can be effectively administered in a subcutaneous injection form, specifically, for example, preventive vaccines for certain diseases, insulin, heparin, opioids, epinephrine, anti-allergic drugs, etc., can be effectively loaded and used.

[0068]

[0069] A microneedle array structure (2) according to one embodiment of the present invention can be manufactured by a method for manufacturing a microneedle array structure (2) comprising the following steps:

[0070] (a) a step of filling a mixture of a biocompatible biodegradable polymer material and oil into the tip of a microneedle-shaped filling portion in a negative mold including a plurality of microneedle-shaped filling portions, and drying the mixture;

[0071] (b) After the drying step of step (a), a step of filling a mixture of a biocompatible biodegradable polymer material and a specific cargo material to be delivered into the skin of a subject into the unfilled remaining space of the microneedle-shaped filling portion, and drying the mixture; and

[0072] (c) A step of separating the formed microneedle array structure from the negative mold.

[0073] In one embodiment of the present invention, the negative mold may be manufactured through a step of filling a curable resin or a biocompatible biodegradable polymer into a positive mold including the base layer and the microneedle shape and curing the curable resin.

[0074] In one embodiment of the present invention, as the curable resin, a thermosetting resin, such as phenol resin (PF), melamine resin (MF), epoxy resin (EP), urea resin, alkyd resin, polyisoprene, which is a natural rubber, styrene butadiene rubber (SBR), nitrile butadiene rubber (NBR), polychloroprene, and silicone rubber, which are synthetic rubbers, may be used. However, any material that has the property of being able to fill a positive mold mold to form a negative array mold may be used without limitation.

[0075] In one embodiment of the present invention, any one or more of the biocompatible polymers listed as being usable for manufacturing the microneedle (1) described above as a biocompatible biodegradable polymer for manufacturing the negative array mold can be appropriately selected and used.

[0076] The manufacturing method according to an aspect of the present invention relates to a method for manufacturing a microneedle array structure (2) according to another aspect of the present invention described above, and redundant contents are cited, and redundant descriptions are omitted to avoid excessive complexity of the description in this specification.

[0077]

[0078] Example 1: Fabrication of stacked microneedles

[0079] A microneedle array structure was manufactured in which microneedles having an average height of approximately 320 μm and a base diameter of approximately 240 μm were arranged. Hyaluronic acid (sodium hyaluronate) gel (water:hyaluronic acid = 91:7 in a weight ratio) and astaxanthin as an oil were mixed, and the mixture was poured into the microneedle-shaped mold part of the negative array mold to fill about 1 / 3 of the height, and the tip layer was manufactured by hot air drying. Then, hyaluronic acid (sodium hyaluronate) gel was sufficiently injected so that the microneedle array structure could be formed. Thereafter, the microneedle array structure was separated from the negative mold, and a microneedle array structure comprising a lipophilic tip layer and a shaft layer formed in layers was obtained. A small amount of fluorescent sample (Fluorescein Sodium Salt (Mw: 376.3 g / mol)) was used for future skin absorption tests.

[0080]

[0081] Comparative Example 1: Preparation of microneedles without lipophilic tips

[0082] Using the same negative mold, microneedles were manufactured using only hyaluronic acid. Hyaluronic acid was injected into the negative mold, and after hot air drying, the resulting microneedle array structure was separated.

[0083]

[0084] Comparative Example 2: Preparation of microneedles containing a lipophilic component throughout the microneedle.

[0085] The hyaluronic acid (sodium hyaluronate) gel and astaxanthin mixture used to manufacture the tip of the stacked microneedle were filled sufficiently into the same negative mold to a height sufficient to produce a microneedle array structure. After hot air drying, the product was separated from the negative mold to produce a microneedle array structure.

[0086]

[0087] Experimental Example 1: Skin Absorption Test

[0088] Each microneedle was left in a 24℃, 80% humidity environment for 30 minutes, then applied to Porcin skin (3 kgf / cm2 for 10 s) to check penetration and determine the penetration rate.

[0089] The results are shown in Table 1 below.

[0090] Example 1 Comparative Example 1 Comparative Example 2 Number of skin penetrating needles / total number of needles 92.66% (101 / 109) 75.23% (82 / 109) 86.24% (94 / 109)

[0091] Example 1 showed the highest permeability, and in the case of Comparative Example 1, the frequency of microneedles not significantly penetrating the skin was high. In the case of Comparative Example 2, the frequency of microneedles not penetrating the skin was very low, but the frequency of microneedles not significantly melting within the skin was high.

[0092]

[0093] Experimental Example 2: High-humidity storage test

[0094] After leaving each microneedle in a 24℃, 80% humidity environment for 12 hours, the presence or absence of deformation in the shape of the tip was observed.

[0095] As a result, a significant deformation (the tip became blunted) of the tip shape of Comparative Example 1 was observed compared to Example 1 and Comparative Example 2.

[0096]

[0097] Although some embodiments of the present invention have been described in detail based on some embodiments of the present invention as described above, the spirit of the present invention is not limited to the embodiments and examples presented in this specification, and a person having ordinary knowledge in the technical field to which the present invention pertains can easily propose other embodiments and examples by adding, changing, deleting, or adding components within the scope of the same spirit, and this is also included within the scope of the present invention.

[0098] [Explanation of symbols]

[0099] 1: Microneedle

[0100] 2: Microneedle array structure

[0101] 10: Lipophilic tip layer

[0102] 20: Shaft layer

[0103] h: microneedle length

[0104] ht: lipophilic tip layer height

[0105] hs: shaft layer height

[0106] dm: maximum diameter of the bottom of the microneedle

Claims

1. A microneedle array structure comprising microneedles having a lipophilic tip layer and a biocompatible, biodegradable polymer shaft layer.

2. In paragraph 1, A microneedle array structure, wherein the lipophilic tip layer comprises a mixture of a biocompatible biodegradable polymer material and oil.

3. In paragraph 2, The above oil is a microneedle array structure, wherein the oil is one or a combination of two or more selected from the group consisting of astaxanthin, lutein, zeaxanthin, quercetin, camellia seed oil, jojoba seed oil, safflower seed oil, Brazil nut seed oil, broccoli seed oil, black cumin seed oil, apricot kernel oil, rapeseed oil, coix seed oil, quinoa seed oil, grape seed oil, camellia seed oil, castor seed oil, sunflower seed oil, pine seed oil, jojoba seed oil, pecan seed oil, cranberry seed oil, baobab seed oil, lemon seed oil, zelkova seed oil, vitamin tree seed oil, western rapeseed oil, lime seed oil, amaranth seed oil, rosehip flower oil, evening primrose seed oil, tansy flower oil, and magnolia berry oil.

4. In paragraph 1, A microneedle array structure, wherein the ratio of the height of the tip layer to the height of the biocompatible polymer shaft layer is 1:1 to 1:

100.

5. In paragraph 4, A microneedle array structure, wherein the height of the microneedles is 50 ㎛ to 1000 ㎛.

6. In paragraph 1, A microneedle array structure, wherein the height of the microneedle and the maximum diameter of the bottom have a length ratio of 1:5 to 3:

1.

7. In paragraph 1, A microneedle array structure, wherein the microneedles have a tip shaped like a cone, a polyhedron, or a bell tower.

8. In paragraph 1, The biocompatible biodegradable polymer shaft layer is selected from the group consisting of hyaluronic acid (HA), poly(lactic acid; PLA), poly(ε-caprolactone; PCL), polyhydroxyalkanoate (PHA), polyesteramide (PEA), polyethylene glycol (PEG), poly(p-dioxanone; PPDO), poly(lactic-co-glycolic acid; PLGA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), chitosan, collagen, gelatin, alginic acid, pectin, carrageenan, and chondroitin sulfate. sulfate), dextran sulfate, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP);Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, gum arabic, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polyglycolic acid, polyethylene oxide, A microneedle array structure comprising at least one biocompatible, biodegradable polymer material selected from the group consisting of polyacrylic acid, polyacrylamide, polymethacrylic acid, and polymaleic acid.

9. In paragraph 2, Biocompatible biodegradable polymeric materials included in the lipophilic tip layer include hyaluronic acid (HA), poly(lactic acid; PLA), poly(ε-caprolactone; PCL), polyhydroxyalkanoate (PHA), polyesteramide (PEA), polyethylene glycol (PEG), poly(p-dioxanone; PPDO), poly(lactic-co-glycolic acid; PLGA), polyglycolic acid (PGA), polyvinyl alcohol (PVA), chitosan, collagen, gelatin, alginic acid, pectin, carrageenan, Chondroitin sulfate, dextran sulfate, polylysine, carboxymethyl chitin, fibrin, agarose, pullulan, cellulose, polyvinylpyrrolidone (PVP);Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose, gum arabic, cyclodextrin, dextrin, glucose, fructose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, melezitose, dextran, sorbitol, xylitol, palatinit, polyglycolic acid, polyethylene oxide, A microneedle array structure, wherein at least one material is selected from the group consisting of polyacrylic acid, polyacrylamide, polymethacrylic acid, and polymaleic acid.

10. In paragraph 1, A microneedle array structure characterized in that the biocompatible biodegradable polymer shaft layer additionally includes a specific cargo material to be delivered into the skin of a subject.

11. In paragraph 10, A microneedle array structure, wherein the cargo material is at least one selected from the group consisting of low molecular weight compounds, peptides, proteins, nucleic acids, polysaccharides, viruses, and liposomes.

12. A method for manufacturing a microneedle array structure comprising the following steps: (a) a step of filling a mixture of a biocompatible biodegradable polymer material and oil into the tip of a microneedle-shaped filling portion in a negative mold including a plurality of microneedle-shaped filling portions, and drying the mixture; (b) a step of filling a mixture of a biocompatible biodegradable polymer material and a specific cargo material to be delivered into the skin of a subject into the unfilled remaining space of the microneedle-shaped filling portion after the drying step of step (a), and drying the mixture; and (c) A step of separating the formed microneedle array structure from the negative mold.

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