Drug delivery microneedle array and drug delivery microneedle patch comprising same

Abstract

The present invention relates to a drug delivery microneedle array and a microneedle patch comprising same, the array comprising a substrate, and a plurality of microneedles spaced apart from each other and positioned on the substrate, wherein the microneedles contain hyaluronic acid and hyaluronidase. The present invention enables a drug to be delivered quickly into the dermis without causing a user to feel pain during insertion into the skin, and thus can improve drug delivery efficiency.

Description

Microneedle array for drug delivery and microneedle patch for drug delivery comprising the same

[0001] The present invention relates to a microneedle array for drug delivery and a microneedle patch for drug delivery comprising the same.

[0002] A microneedle array containing multiple microneedles is a device that delivers drugs into the human body by inserting microneedles into the skin. It is promising in the field of drug delivery because the drug administration method is simple and the pain felt by the user is minimal.

[0003] However, in order to deliver the drug to the dermis layer where muscles and blood vessels exist, the microneedles must first pass through the epidermis layer, which is about 1 mm thick or more. However, the epidermis has a strong and rigid structure as it protects the skin from the external environment. Therefore, there is a problem that the drug released from the microneedle is absorbed into the dermis layer through the epidermis layer slowly, and the drug delivery efficiency is low. To solve this problem, as the length of the microneedle is increased beyond the thickness of the epidermis, the strength decreases, and there is a risk that the microneedle will break easily. If the diameter of the lower part of the microneedle is increased to maintain strength, the intensity of pain felt by the user increases, so there is a limit to extending the length of the microneedle.

[0004] Accordingly, there is a need for research on a drug delivery microneedle array that can rapidly administer drugs to a target area without the user feeling pain when inserting the microneedle into the skin.

[0005] The purpose of the present invention is to solve the problems of the above-mentioned prior art, and to provide a microneedle array and a microneedle patch including the same that can rapidly diffuse a drug into the dermal layer without the user feeling pain when inserted into the skin.

[0006] The drug delivery microneedle array of the present invention comprises a substrate; and a plurality of microneedles positioned on the substrate and spaced apart from each other; wherein the microneedles contain hyaluronic acid and hyaluronidase.

[0007] In one example, the hyaluronidase may be located on the surface of the microneedle.

[0008] In one example, the hyaluronidase can be uniformly dispersed in the microneedles.

[0009] In one example, the hyaluronidase may have a concentration gradient such that the concentration decreases from the tip of the microneedle toward the substrate.

[0010] In one example, the microneedles may contain 100 to 6000 units of hyaluronidase.

[0011] In one example, the ratio (U / W) of the content (unit, U) of the hyaluronidase and the weight % (W) of hyaluronic acid may be 50 to 3000 unit / wt%.

[0012] In one example, the length of the microneedle may be 100 to 1000 μm.

[0013] In one example, the microneedles may further comprise hyaluronic acid and other biodegradable polymers.

[0014] In one example, the microneedles may comprise hyaluronic acid:biodegradable polymer in a weight ratio of 1:1 to 8.

[0015] In one example, the biodegradable polymer may include at least one selected from the group consisting of polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polylactic acid (PLA), polyglycolic acid (PGA), polyacrylic acid (PAA), polyacrylamide, polyethylene oxide (PEO), polydioxanone, polyhydroxyalkanoates (PHA), polysaccharides, and proteins.

[0016] In one example, the microneedles may contain a drug inside.

[0017] In one example, the drug may include at least one selected from the group consisting of an anti-wrinkle agent, an anti-aging agent, a skin whitening agent, a hair growth agent, a photosensitizer (PS), a lipolytic agent, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-arthritic agent, an antispasmodic, an antidepressant, an antipsychotic drug, a tranquilizer, an anxiolytic, an narcotic antagonist, an anti-Parkinsonian drug, an anti-dementia agent, a cholinergic agent, an anti-cancer agent, an anti-angiogenesis inhibitor, an immunosuppressant, an antiviral agent, an antibiotic, an appetite suppressant, an analgesic, an antihistamine, an anti-migraine agent, a hormonal agent, an agent for improving lung function, an anticoagulant, a coronary vascular, cerebrovascular or peripheral vasodilator, a contraceptive, an antithrombotic agent, a diuretic, an antihypertensive agent, a cardiovascular disease treatment agent and a natural product.

[0018] The drug delivery microneedle patch of the present invention comprises the above-described microneedle array; and an adhesive sheet positioned on the other surface of the substrate included in the microneedle array.

[0019] The microneedle array of the present invention and the microneedle patch including the same can rapidly diffuse a drug into the dermal layer without the user feeling pain when inserted into the skin.

[0020] Figure 1 is a schematic diagram illustrating a microneedle array for drug delivery of the present invention.

[0021] Figure 2 is a schematic diagram showing an enlarged view of a microneedle of a microneedle array according to the first aspect of the present invention.

[0022] Figure 3 is a schematic diagram showing an enlarged view of a microneedle of a microneedle array according to a second aspect of the present invention.

[0023] Figure 4 is a schematic diagram showing an enlarged view of a microneedle of a microneedle array according to a third aspect of the present invention.

[0024] Figure 5 is a schematic diagram illustrating a microneedle patch of the present invention.

[0025] Figure 6 is a photograph of a microneedle array for drug delivery according to the first aspect of the present invention.

[0026] Figures 7 and 8 are photographs of a microneedle array for drug delivery according to the second aspect of the present invention, respectively.

[0027] Figure 9 is an image of a cross-section of skin observed using (a) an optical microscope and (b) a fluorescence microscope, respectively, after inserting a drug delivery microneedle array according to the second aspect of the present invention into the skin.

[0028] The present invention provides a detailed description of a drug delivery microneedle array and a drug delivery microneedle patch comprising the same. The terminology used herein has been selected from widely used, current terms, taking into account the functions of the present invention. However, this may vary depending on the intentions of engineers working in the relevant fields, precedents, the emergence of new technologies, etc. Unless otherwise defined, the technical and scientific terms used may have the meaning commonly understood by those of ordinary skill in the art to which this invention pertains.

[0029] 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.

[0030] In this specification and the appended claims, the terms first, second, etc. are not used in a limiting sense but are used for the purpose of distinguishing one component from another.

[0031] 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.

[0032] 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.

[0033] The term "about" or the like used in this specification and the appended claims is used to encompass the tolerance when an tolerance exists.

[0034] A microneedle array containing multiple microneedles is a device that delivers drugs into the human body by inserting fine needles into the skin. It has promising advantages in the field of drug delivery as the drug administration method is simple and the pain felt by the user is minimal.

[0035] However, in order to deliver the drug to the dermis layer where muscles and blood vessels exist, the microneedles must first pass through the epidermis layer, which is about 1 mm thick or more. However, the epidermis has a strong and rigid structure as it protects the skin from the external environment. Therefore, there is a problem that the drug released from the microneedles is absorbed into the dermis layer through the epidermis layer slowly, and the drug delivery efficiency is low. To solve this problem, as the length of the microneedle is increased beyond the thickness of the epidermis, the strength decreases, and there is a risk of easy breakage. If the diameter of the lower part of the microneedle is increased to maintain strength, the intensity of pain felt by the user increases, so there is a limit to extending the length of the microneedle.

[0036] Accordingly, the present applicant has developed a drug delivery microneedle array that can rapidly deliver drugs to the dermal layer containing muscles and blood vessels of the human body without extending the length of the microneedle, thereby enabling the user to effectively administer drugs to a target area without feeling pain when inserting the microneedle into the skin.

[0037] Hereinafter, the present invention will be described with reference to the attached drawings.

[0038] A microneedle array (100) according to the present invention, as illustrated in FIG. 1, includes a substrate (10); and a plurality of microneedles (20) positioned on the substrate (10) and spaced apart from each other; wherein the microneedles (20) contain hyaluronic acid and hyaluronidase.

[0039] When a microneedle array (100) containing a hyaluronidase is inserted into the skin through a microneedle (20), the hyaluronidase can catalyze the hydrolysis of hyaluronic acid in the epidermal layer of the skin. Accordingly, the viscosity of the hyaluronic acid located in the epidermal layer of the skin can be lowered, allowing the drug to rapidly diffuse into the dermal layer.

[0040] In one example, the hyaluronidase may include endo-β-N-acetylhexosaminidases that break down β-1,4 glycosidic bonds to form tetrasaccharides, endo-β-D-glucuronidases that break down β-1,3 glycosidic bonds to form pentasaccharides and hexasaccharides, or hyaluronate lyases that form unsaturated disaccharides through a β-elimination mechanism of β-1,4 glycosidic bonds.

[0041] The microneedle (20) contains hyaluronic acid together with hyaluronidase, so that it can exhibit excellent biocompatibility and biodegradability, as well as strength that allows the microneedle (20) to penetrate the firm and hard stratum corneum located at the outermost layer of the skin and be inserted into the skin. In addition, the microneedle (20) contains hyaluronic acid decomposition enzyme and hyaluronic acid, so that the speed at which the microneedle (20) inserted into the skin dissolves and the drug is released can be improved.

[0042] Although not necessarily limited to this interpretation, the hyaluronic acid within the skin is decomposed by hyaluronidase, thereby securing a path for drug diffusion, and the hyaluronic acid structure of the epidermal layer of the skin can be quickly restored by the hyaluronic acid contained in the microneedle (20). Therefore, there is an advantage of maximizing the drug delivery speed while minimizing damage to the epidermal layer of the skin.

[0043] In one example, the microneedle (20) may contain 100 to 6000 units, 500 to 5000 units, or 1000 to 4000 units of hyaluronidase. When hyaluronidase is contained in the above range, hyaluronic acid decomposition activity may be improved, thereby increasing the area through which the drug is diffused within the skin. In this specification, “unit” means the amount of hyaluronidase capable of converting 1 μmol of hyaluronic acid per unit time.

[0044] More specifically, the ratio (U / W) of the content (unit, U) of the hyaluronic acid decomposing enzyme (hyaluronidase) and the weight % (wt%, W) of hyaluronic acid may be 50 to 3000 unit / wt%, 100 to 2300 unit / wt%, or 500 to 1500 unit / wt%. When hyaluronic acid and hyaluronic acid decomposing enzyme are contained in the above range, drug delivery efficiency and strength can be improved at the same time.

[0045] In one example, the microneedle (20) may further include hyaluronic acid and other biodegradable polymers. By further including hyaluronic acid and other types of biodegradable polymers in the microneedle (20), the strength of the microneedle can be further enhanced. In addition, but not limited to, even if the hyaluronic acid contained in the microneedle (20) is decomposed by a hyaluronic acid decomposing enzyme, the strength of the microneedle (20) can be maintained at a high level through the biodegradable polymer of a type different from hyaluronic acid.

[0046] As a specific example, the microneedle (20) may contain hyaluronic acid:biodegradable polymer in a weight ratio of 1:1 to 8, 1:2 to 7, or 1:3 to 6. At the above weight ratio, the microneedle (20) exhibits strength that allows it to be inserted into the skin, maintains excellent strength for a long time, and prevents the drug contained in the microneedle (20) from being exposed to the external environment and becoming contaminated.

[0047] The biodegradable polymer may include at least one selected from the group consisting of polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polylactic acid (PLA), polyglycolic acid (PGA), polyacrylic acid (PAA), polyacrylamide, polyethylene oxide (PEO), polydioxanone, polyhydroxyalkanoates (PHA), polysaccharides, and proteins. For example, the polysaccharide may include alginic acid, chitosan, pectin, cellulose, and carboxymethyl cellulose.CMC), Carrageenan, Chondroitin Sulfate, Dextran Sulfate, Carboxymethyl Chitin, Agarose, Pullulan, Acrylic Substituted Cellulose Acetate, Hydroxypropylmethylcellulose (HPMC), Ethylcellulose (EC), Hydroxypropylcellulose (HPC), Cyclodextrin, Maltose, Lactose, Trehalose, Cellobiose, Isomaltose, Turanose and Lactulose, wherein the protein comprises at least one selected from the group consisting of collagen, fibrin, gelatin, gluten or these. The combination may include, and preferably, polyvinyl alcohol (PVA), but the present invention is not limited by the specific type of biodegradable polymer.;

[0048] In one example, the substrate (10) may include a biodegradable polymer to support the microneedles (20). The substrate (10) including the biodegradable polymer has excellent flexibility and can be inserted with high adhesion even into body parts with a lot of movement, and can effectively absorb exudates discharged from the human body by the insertion of the microneedles. More specifically, the substrate (10) may adopt a material of the same or different kind as the microneedles (20), and preferably may include a material of the same kind, but is not necessarily limited thereto.

[0049] In one specific example, the microneedle (20) contains a drug inside, so that when the microneedle (20) penetrates the skin and dissolves, the drug is released outside the microneedle (20), allowing the drug to be directly administered to a local area.

[0050] The above drug can be appropriately selected by a person skilled in the art as an effective ingredient having pharmacological or medical efficacy depending on the site into which the microneedle array (100) is inserted and the type of disease.Specifically, the drug may include at least one selected from the group consisting of an anti-wrinkle agent, a skin aging inhibitor, a skin whitening agent, a hair growth agent, a photosensitizer (PS), a fat-dissolving agent, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-arthritic agent, an antispasmodic, an antidepressant, an antipsychotic drug, a tranquilizer, an anxiolytic, an narcotic antagonist, an antiparkinsonian drug, an anti-dementia agent, a cholinergic agent, an anticancer agent, an antiangiogenesis inhibitor, an immunosuppressant, an antiviral agent, an antibiotic, an appetite suppressant, an analgesic, an antihistamine, an antimigraine agent, a hormone agent, an agent for improving lung function, an anticoagulant, a coronary vascular, cerebrovascular or peripheral vasodilator, a contraceptive, an antithrombotic agent, a diuretic, an antihypertensive agent, a cardiovascular disease treatment agent and a natural product, and for example, the drug may include retinol, retinyl palmitate, Adenosine, Hydroquinone, Arbutin, Vitamin C derivatives, Kojic acid, Niacin, Alpha-Hydroxy-Acid (AHA), Beta-Hydroxy-Acid (BHA), Insulin, Glucagon, Para-acetylaminophenol, Methyl aminolevulinate hydrochloride, Prolyl-tRNA Synthetase inhibitors, Deoxycholic acid, Heparin, Coumarin, Warfarin, Donepezil, Rasagiline, Exosome, Botulinum Toxin (BTX), It may include PN (polynucleotide), PDRN (polydeoxyribonucleotide), exosome, or a combination thereof, but the present invention is not limited by the specific type of drug.

[0051] In one example, the length of the microneedle (20) may be 100 to 1000 μm, 300 to 900 μm, or 500 to 800 μm. The microneedle array (100) of the present invention can effectively diffuse the drug to the blood vessels and muscles located in the dermal layer of the skin even within the above length range. Therefore, there is an advantage in that the drug delivery efficiency can be improved without the user feeling a foreign body sensation or pain when inserting the microneedle (20).

[0052] In one example, the speed at which the drug is released can be controlled depending on the location of the hyaluronic acid decomposition enzyme included in the microneedle (20).

[0053] In the first aspect of the present invention, as illustrated in FIG. 2, the hyaluronic acid decomposing enzyme (21) may be located on the surface of the microneedle (20). More specifically, the hyaluronic acid decomposing enzyme (21) is located on the surface of the tip (25) of the microneedle (20), so that when the microneedle (20) is inserted into the skin, the hyaluronic acid decomposing enzyme (21) located on the surface of the microneedle (20) is activated first to decompose hyaluronic acid in the epidermal layer, and then the hyaluronic acid (22) and biodegradable polymer (23) contained in the microneedle (20) are dissolved in the human body, thereby allowing the drug (24) to diffuse. After the microneedle (20) is inserted and the hyaluronic acid decomposition enzyme (21) is activated, the hyaluronic acid (22) and the biodegradable polymer (23) are dissolved and the drug (24) is diffused, so that the drug (24) can be stably administered for a long period of time. In addition, the strength of the microneedle (20) can be improved by minimizing the interaction between the hyaluronic acid decomposition enzyme (21) and the hyaluronic acid (22) contained in the microneedle (20).

[0054] In the second aspect of the present invention, as illustrated in FIG. 3, hyaluronidase (21) can be uniformly dispersed in the microneedles (20). Since the hyaluronidase (21) exists in a mixture with hyaluronic acid (22) and a biodegradable polymer (23), when the microneedles (20) are inserted into the skin, the hyaluronidase (21) is activated to decompose hyaluronic acid in the skin, and at the same time, the hyaluronic acid (22) and biodegradable polymer (23) contained in the microneedles (20) begin to dissolve and diffuse the drug (24), so that the microneedles (20) dissolve at a rapid rate, so that the drug (24) can be delivered to the affected area more quickly.

[0055] In the third aspect of the present invention, referring to FIG. 4, the hyaluronidase (21) may have a concentration gradient such that the concentration decreases from the tip (25) of the microneedle (20) toward the substrate (10). Since the tip (25) of the microneedle (20) contains a high concentration of the hyaluronidase (21), when the microneedle (20) is inserted into the skin, the activation of the hyaluronidase (21) and the dissolution of the hyaluronic acid (22) and the biodegradable polymer (23) occur simultaneously, but the hyaluronidase (21) is dominantly activated in the early stage, and the drug (24) diffusion due to the dissolution of the hyaluronic acid (22) and the biodegradable polymer (23) occurs dominantly in the later stage, so that the drug (24) can be efficiently delivered.

[0056] As described above, by controlling the dissolution rate of the microneedle (20) depending on the location of the hyaluronic acid decomposition enzyme (21), the drug diffusion rate and the drug dosage per hour can be easily controlled.

[0057] The present invention includes a drug delivery microneedle patch comprising the above-described microneedle array (100); and an adhesive sheet (30) positioned on the other surface of a substrate (10) included in the microneedle array (100). As illustrated in FIG. 5, a plurality of microneedles (20) may be positioned on one surface of the substrate (10), and an adhesive sheet (30) may be positioned on the other surface of the substrate. When attached to the skin, the adhesive sheet (30) seals the area where the microneedles (20) are inserted, thereby preventing external contaminants such as foreign substances, bacteria, and viruses from penetrating into the human body.

[0058] The adhesive sheet (30) may be made of a flexible material that can be easily attached to a curved area. For example, a rubber-based adhesive may be applied to a sheet of polyethylene (PE), polyurethane (PU), polyvinyl chloride (PVC), etc., and preferably, a hydrocolloid having flexibility and adhesiveness and excellent absorption rate of the extract may be included, but the present invention is not limited thereto.

[0059] Hereinafter, the present invention will be described in more detail through examples.

[0060] (Example 1)

[0061] A mold containing a plurality of negative grooves having a needle shape with a width that decreases in the depth direction was prepared. 2,000 units of hyaluronic acid degrading enzyme (Sigma Aldrich, H3506) at 400 units / mg was coated on the surface of the negative grooves and dried under pressure at 40°C. Subsequently, a solution containing 8 wt% polyvinyl alcohol, 2 wt% hyaluronic acid, and 1 wt% fluorescent material dissolved in distilled water was applied to the inside of the negative grooves and the surface of the mold and dried under pressure at 40°C. Subsequently, the mold was removed to manufacture a microneedle array having a microneedle length of 650 μm, as shown in Fig. 6.

[0062] (Example 2)

[0063] A mixed solution containing 8 wt% of polyvinyl alcohol, 2 wt% of hyaluronic acid, and 1 wt% of a fluorescent substance dissolved in distilled water and 2000 units of hyaluronic acid-decomposing enzyme (Sigma Aldrich, H3506) at 400 unit / mg was applied to a mold containing a plurality of negative grooves having a needle shape, and then dried under pressure at 40°C and the mold was removed to manufacture a microneedle array having a microneedle length of 650 μm as shown in Fig. 7.

[0064] (Example 3)

[0065] A first mixed solution was prepared by mixing 500 units of 400 unit / mg hyaluronic acid decomposition enzyme (Sigma Aldrich, H3506) with a first solution containing 8 wt% polyvinyl alcohol, 2 wt% hyaluronic acid, and 1 wt% fluorescent material dissolved in distilled water, a second mixed solution was prepared by mixing 1000 units of 400 unit / mg hyaluronic acid decomposition enzyme (Sigma Aldrich, H3506) with the first solution, and a third mixed solution was prepared by mixing 2000 units of 400 unit / mg hyaluronic acid decomposition enzyme (Sigma Aldrich, H3506) with the first solution. Afterwards, the third mixed solution, the second mixed solution, and the first mixed solution were sequentially injected into a mold including a plurality of negative grooves having a needle shape, and then dried under pressure at 40°C, and the mold was removed to manufacture a microneedle array having a microneedle length of 650 μm.

[0066] (Comparative Example 1)

[0067] A microneedle array was manufactured in the same manner as in Example 1, except that the hyaluronic acid decomposing enzyme was not coated on the negative groove of the mold.

[0068] (Comparative Example 2)

[0069] A microneedle array was manufactured in the same manner as in Example 2, except that the mixed solution did not contain hyaluronic acid.

[0070] (Experimental Example 1) Drug diffusion evaluation

[0071] After attaching the microneedle arrays of Examples 1 to 3 and Comparative Example 1 to pig skin for 30 minutes, the microneedle arrays were removed and the diffusion and penetration depth of the drug (fluorescent substance) that had penetrated the pig skin were observed using a fluorescence spectrophotometer, and the results are shown in Fig. 9. Thereafter, the diffusion area and diffusion depth of the fluorescent substance were quantitatively analyzed using the Image J program, and the results are shown in Table 1 below.

[0072] Comparative Example 1 Example 1 Example 2 Example 3 Diffusion Area 100 % 133 % 119 % 126 % Penetration Depth 0.20 mm 1.30 mm 0.50 mm 1.02 mm

[0073] Specifically, the diffusion area in Table 1 was calculated by setting the diffusion area of ​​Comparative Example 1 to 100%, and the diffusion areas of Examples 1 to 3 were calculated relative to the diffusion area of ​​Comparative Example 1. The diffusion depth was measured by measuring the distance from the tip of the microneedle to the skin at which the drug penetrated. In addition, the diffusion area and diffusion depth were calculated by averaging the values ​​of three measurements of the diffusion area and penetration depth for each microneedle array, and are shown in Table 1.

[0074] Compared to the microneedle array of Comparative Example 1 that does not contain hyaluronic acid degrading enzyme, the diffusion areas of the microneedle arrays of Examples 1 to 3 were measured to be 133%, 119%, and 126%, respectively. The drug penetration depth of the microneedle array of Comparative Example 1 was also only 0.20 mm, whereas the drug penetration depths of the microneedle arrays of Examples 1 to 3 containing hyaluronic acid degrading enzyme were measured to be 1.30 mm, 0.50 mm, and 1.02 mm, respectively. Therefore, when microneedles containing hyaluronic acid and hyaluronic acid degrading enzyme were inserted into the skin, the hyaluronic acid degrading enzyme decomposed hyaluronic acid in the epidermal layer of the skin, thereby increasing the drug diffusion area and diffusion depth, so that the drug could be effectively administered to the blood vessels and muscles of the dermal layer.

[0075] More specifically, in the case of Example 1, the hyaluronic acid decomposition enzyme is located on the tip surface of the microneedle, so that when the microneedle is inserted into the skin, the hyaluronic acid decomposition enzyme is activated first to decompose hyaluronic acid in the skin, and then the microneedle dissolves to release the drug, thereby exhibiting excellent diffusion area and diffusion depth.

[0076] In the case of Example 2, as illustrated in FIG. 8, it can be confirmed that hyaluronic acid, polyvinyl alcohol (PVA), and hyaluronic acid decomposing enzyme are uniformly dispersed in the microneedles. Referring to FIGS. 9(a) and 9(b), it can be seen that the microneedle array of Example 2 also effectively decomposes hyaluronic acid in the epidermal layer of the skin, thereby increasing the drug diffusion area and diffusion depth compared to Comparative Example 1.

[0077] Example 3 is a microneedle array having a concentration gradient such that the concentration of hyaluronic acid decomposing enzyme decreases from the tip of the microneedle toward the substrate, and since the hyaluronic acid decomposing enzyme is present at a high concentration at the tip, it decomposes hyaluronic acid in the skin, thereby improving the diffusion area and diffusion depth of the drug.

[0078] (Experimental Example 2) Solubility Evaluation

[0079] The microneedle arrays of Examples 1 to 3 and Comparative Example 1 were attached to pig skin for 30 minutes, and the time until the microneedles were completely dissolved was measured in 10-minute intervals. The measurement results are shown in Table 2 below. The dissolution time represents the average value of three measurements for each microneedle array.

[0080] Comparison of dissolution times: Example 13 hours 17 minutes, Example 12 hours 20 minutes, Example 21 hours 13 minutes, Example 31 hours 56 minutes

[0081] As shown in Table 2, in Comparative Example 1, which did not contain hyaluronic acid decomposition enzyme, it took 3 hours and 17 minutes for the microneedles to completely dissolve. However, in Examples 1 to 3, since the microneedles contained hyaluronic acid decomposition enzyme, hyaluronic acid within the skin was decomposed upon insertion of the microneedles, thereby lowering the viscosity, allowing the drug to diffuse more quickly, thus reducing the time required for the microneedles to completely dissolve.

[0082] Specifically, in Example 1, where the hyaluronic acid decomposition enzyme was positioned on the tip surface of the microneedle, the hyaluronic acid decomposition enzyme was first activated and then the hyaluronic acid and polyvinyl alcohol contained in the microneedle were dissolved to diffuse the drug, so it took 2 hours and 20 minutes for the microneedle to completely dissolve. However, in Example 2, the hyaluronic acid decomposition enzyme was uniformly dispersed within the microneedle, so that when the microneedle was inserted, the hyaluronic acid and polyvinyl alcohol were dissolved simultaneously with the activation of the hyaluronic acid decomposition enzyme, thereby releasing the drug. Therefore, it was confirmed that the drug was administered at a faster rate than in Example 1, as it took 1 hour and 13 minutes for the microneedle to dissolve.

[0083] In the case of Example 3, the hyaluronic acid decomposing enzyme has a concentration gradient, so that when the microneedle is inserted, the hyaluronic acid decomposing enzyme is activated and at the same time, the hyaluronic acid and polyvinyl alcohol are dissolved. However, when the microneedle is initially inserted, the hyaluronic acid decomposing enzyme present in high concentration at the tip is dominantly activated, and thereafter, the hyaluronic acid and polyvinyl alcohol are dissolved. Therefore, it takes 1 hour and 56 minutes for the microneedle to completely dissolve, which shows that the dissolution rate of the microneedle is faster than that of Example 1, but slower than that of Example 3.

[0084] (Experimental Example 3) Strength Evaluation

[0085] The compressive strength of the microneedle arrays of Examples 1 to 3 and Comparative Examples 1 and 2 was measured using a Universal Testing Machine (UTM). Specifically, a single microneedle of the microneedle array was fixed to a jig of the universal testing machine and compressed by 0.325 mm at a speed of 0.5 mm / s, and the force resisted by the microneedle was measured. The compressive strength for each microneedle array was measured three times, and the average value was calculated and shown in Table 3.

[0086] Compressive strength (kg / cm) 3) Comparative Example 12230 Comparative Example 21620 Exemplary Example 13230 Exemplary Example 22816 Exemplary Example 33045

[0087] As shown in Table 3, the compressive strengths of Examples 1 to 3 containing hyaluronic acid and hyaluronic acid decomposition enzyme were 3230 kg / cm each. 3 , 2816 kg / cm 3 and 3045 kg / cm 3 It was measured to be high enough that microneedles could be inserted through the hard stratum corneum, the outermost layer of the skin, and the inserted microneedles exhibited strength that prevented them from breaking.

[0088] On the other hand, the compressive strength of the microneedle array of Comparative Example 1 that does not contain hyaluronic acid decomposition enzyme is 2230 kg / cm 3 It was measured as low as 1620 kg / cm for the microneedle of comparative example 2 that does not contain hyaluronic acid. 3 It was measured very low. Accordingly, the microneedle arrays of Comparative Examples 1 and 2 were not able to penetrate the hard and strong stratum corneum of the skin and were not able to exhibit the strength to effectively insert the drug. Accordingly, not only was the drug delivery efficacy reduced, but the durability was also significantly low, as the microneedles broke and separated from the substrate.

[0089] As described above, the present invention has been described with specific details and limited examples and drawings, but these are provided only to help a more general understanding of the present invention, and the present invention is not limited to the above examples, and those skilled in the art to which the present invention pertains can make various modifications and variations based on this description.

[0090] Therefore, the idea of ​​the present invention should not be limited to the described embodiments, and all things that are equivalent or equivalent to the claims described below as well as the claims are considered to fall within the scope of the idea of ​​the present invention.

[0091] [Explanation of symbols]

[0092] 10: Base 20: Microneedle

[0093] 21: Hyaluronic acid decomposition enzyme 22: Hyaluronic acid

[0094] 23: Biodegradable polymer 24: Drug

[0095] 25: Microneedle cutting edge 30: Adhesive sheet

[0096] 100: Microneedle array 200: Microneedle patch

Claims

1. Description; and A plurality of microneedles positioned on the above-mentioned substrate and spaced apart from each other; The above microneedles are drug delivery microneedle arrays containing hyaluronic acid and hyaluronidase.

2. In paragraph 1, A drug delivery microneedle array, wherein the hyaluronidase is located on the surface of the microneedle.

3. In paragraph 1, The above hyaluronidase is a microneedle array for drug delivery, uniformly dispersed in the microneedles.

4. In paragraph 1, A drug delivery microneedle array in which the hyaluronidase has a concentration gradient such that the concentration decreases from the tip of the microneedle toward the substrate.

5. In paragraph 1, A microneedle array, wherein the microneedles contain 100 to 6,000 units of hyaluronidase.

6. In paragraph 1, A microneedle array for drug delivery, wherein the ratio (U / W) of the content (unit, U) of the hyaluronidase and the weight % (W) of hyaluronic acid is 50 to 3000 unit / wt%.

7. In paragraph 1, A microneedle array for drug delivery, wherein the length of the microneedles is 100 to 1000 μm.

8. In paragraph 1, A drug delivery microneedle array, wherein the microneedles further contain hyaluronic acid and other biodegradable polymers.

9. In paragraph 8, A drug delivery microneedle array, wherein the above microneedles contain hyaluronic acid and a biodegradable polymer in a weight ratio of 1:1 to 8.

10. In paragraph 8, A drug delivery microneedle array, wherein the biodegradable polymer comprises at least one selected from the group consisting of polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polylactic acid (PLA), polyglycolic acid (PGA), polyacrylic acid (PAA), polyacrylamide, polyethylene oxide (PEO), polydioxanone, polyhydroxyalkanoates (PHA), polysaccharides, and proteins.

11. In paragraph 1, A drug delivery microneedle array, wherein the microneedles contain a drug therein.

12. In paragraph 11, The above drug is a microneedle array including at least one selected from the group consisting of an anti-wrinkle agent, an anti-aging agent, a skin whitening agent, a hair growth agent, a photosensitizer (PS), a lipolytic agent, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-arthritic agent, an antispasmodic, an antidepressant, an antipsychotic, a tranquilizer, an anti-anxiety agent, an narcotic antagonist, an antiparkinsonian agent, an antidementia agent, a cholinergic agent, an anticancer agent, an antiangiogenesis inhibitor, an immunosuppressant, an antiviral agent, an antibiotic, an appetite suppressant, an analgesic, an antihistamine, an antimigraine agent, a hormone agent, an agent for improving lung function, an anticoagulant, a coronary vascular, cerebrovascular or peripheral vasodilator, a contraceptive, an antithrombotic agent, a diuretic, an antihypertensive agent, a cardiovascular disease treatment agent, and a natural product.

13. A microneedle array according to any one of claims 1 to 12; and A drug delivery microneedle patch comprising an adhesive sheet positioned on the other side of a substrate included in the above microneedle array.

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