Microneedle array containing semaglutide and manufacturing method therefor

Abstract

The present invention provides a microneedle array containing semaglutide and a manufacturing method therefor, the microneedle array increasing the stability of a drug in a solution and minimizing the influence of enzymes in the skin, thereby enabling excessive use of the drug during manufacture of the microneedle to be reduced and skin permeability to be improved.

Description

Semaglutide-containing microneedle array and method for manufacturing the same

[0001] Cross-citation with related application(s)

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2023-0165718, filed November 24, 2023, the entire contents of which are incorporated herein by reference.

[0003] The present invention relates to a microneedle array containing semaglutide and a method for manufacturing the same.

[0004] Semaglutide is a glucagon-like peptide 1 receptor agonist used to treat type 2 diabetes and obesity and is classified as a long-term agent.

[0005] Semaglutide is primarily administered subcutaneously or orally. Subcutaneous injections are painful, and self-injection requires patients to administer the medication themselves, which can lead to fear and reluctance, leading to poor compliance and reduced therapeutic efficacy. Furthermore, oral administration carries the risk of side effects and low absorption, leading to increased dosage.

[0006] A transdermal drug delivery system using microneedles utilizes microneedles, typically hundreds of micrometers long, to deliver drugs through the stratum corneum and into the epidermis and dermis. Typically, drugs are administered at a depth of approximately 1 mm. Compared to the 4-6 mm depth of subcutaneous injections, microneedles offer a shallower penetration depth, reducing pain during administration. Furthermore, their higher bioavailability compared to oral medications allows for a reduced drug dosage.

[0007] Accordingly, various studies are being conducted to commercialize semaglutide in a microneedle formulation.

[0008] Microneedles for transdermal administration allow drugs dissolved within the epidermis to diffuse into the dermal layer, where they are absorbed through capillaries and circulated systemically. This process is influenced by enzymes within the skin. Enzyme-sensitive peptides, such as semaglutide, are particularly susceptible to enzymatic denaturation and degradation, making skin penetration difficult.

[0009] Patent Documents 1 and 2 disclose that the skin permeation rate of semaglutide can be improved by using a penetration enhancer or surfactant together with semaglutide. Patent Document 1 uses N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC, sodium salcaprozate) as a penetration enhancer, and Patent Document 2 uses surfactants such as TWEEN20 and floxamer 188. Even when using SNAC or surfactants suggested in these documents, there is a limit to improving the skin permeation rate due to the low enzyme resistance of semaglutide.

[0010] Therefore, development of a formulation that can minimize the effects of enzymes within the skin is required.

[0011] [Prior Art Literature]

[0012] [Patent Document]

[0013] CN 112274633 A (January 29, 2021)

[0014] CN 114699510 A (July 5, 2022)

[0015] The present invention manufactures microneedles by controlling pH and selecting a penetration enhancer to increase drug stability in a solution of semaglutide and to improve skin permeability by minimizing the influence of enzymes in the skin.

[0016] Accordingly, the purpose of the present invention is to provide a composition for manufacturing microneedles, microneedles or microneedle arrays comprising the same, and a method for manufacturing the same.

[0017] The present invention provides a composition for manufacturing microneedles comprising semaglutide, a penetration enhancer, a biodegradable polymer, and a solvent.

[0018] At this time, the penetration enhancer includes at least one selected from sodium glycocholate and sodium deoxycholate, and preferably, at least one of sodium glycocholate and sodium deoxycholate.

[0019] In addition, the present invention provides a microneedle comprising a lower layer; and an upper layer including a tip; wherein the upper layer comprises the composition for manufacturing the microneedle described above.

[0020] In addition, the present invention provides a microneedle array comprising a support; and a plurality of microneedles positioned on the support.

[0021] In addition, the present invention provides a method for manufacturing a microneedle array, comprising the steps of: preparing a negative mold including an negative pattern; dropping a composition for manufacturing microneedles into the negative pattern; performing decompression and rotation to form an upper layer of microneedles into the negative pattern of the negative mold; dropping a composition for manufacturing a lower layer into the negative pattern above the upper layer; and performing decompression and drying to form a lower layer.

[0022] In addition, the present invention provides a microneedle transdermal patch comprising the microneedle array; and an adhesive sheet to which at least one microneedle array is attached.

[0023] The composition according to the present invention increases the drug stability of semaglutide and minimizes the influence of enzymes in the skin, so that when microneedles are manufactured using the composition, excessive drug use can be reduced and the skin penetration rate of semaglutide can be improved.

[0024] Figure 1 is a cross-sectional view of a microneedle according to the present invention.

[0025] Figure 2 is a schematic diagram illustrating a method for manufacturing a microneedle array of the present invention.

[0026] According to one embodiment of the present invention, a composition for manufacturing a microneedle upper layer is provided, comprising semaglutide; and at least one penetration enhancer selected from sodium glycocholate and sodium deoxycholate.

[0027] According to another embodiment of the present invention, a microneedle array is provided, comprising a plurality of microneedles and a support, wherein the microneedles include an upper layer and a lower layer, and the upper layer includes the composition for manufacturing the upper layer of the microneedle described above.

[0028] According to another embodiment of the present invention, a method for manufacturing a microneedle array is provided, comprising: preparing a negative mold including an negative pattern; dropping the composition for manufacturing the upper layer of microneedles described above into the negative pattern; performing decompression and rotation to form an upper layer of microneedles into the negative pattern of the negative mold; dropping the composition for manufacturing a lower layer into the negative pattern above the upper layer; and performing decompression and drying to form the lower layer.

[0029] According to another embodiment of the present invention, a microneedle transdermal patch is provided, comprising the above-described microneedle array; and an adhesive sheet to which at least one of the microneedle arrays is attached.

[0030] The term "microneedle" used in the present invention refers to a needle-like structure with a length measured in micrometers (μm). The microneedle has a tip at its end, which forms a hole in the stratum corneum, the outermost layer of the skin, enabling drug delivery to the skin. Furthermore, the microneedle is designed to be short enough not to reach the dermis, where nerve cells reside, thereby minimizing or eliminating pain during the drug delivery process.

[0031] Additionally, the term "microneedle array" as used in the present invention means a structure comprising a plurality of microneedles designed to penetrate the stratum corneum to facilitate transdermal delivery of a therapeutic agent through or into the skin or sampling of a fluid.

[0032] Unless otherwise specified herein, microneedles are soluble microneedles. These soluble microneedles are microstructures that completely dissolve into the skin to deliver the drug.

[0033] Composition for manufacturing microneedles

[0034] According to one embodiment of the present invention, the present invention relates to a composition for manufacturing microneedles.

[0035] The composition of the present invention comprises a composition for manufacturing an upper layer of a microneedle comprising semaglutide, a penetration enhancer, a biodegradable polymer, and a solvent.

[0036] In this specification, the above-mentioned "Semaglutide" is a glucagon-like peptide 1 receptor agonist, used as a treatment for type 2 diabetes and obesity, and is classified as a long-term agent.

[0037] In the present invention, semaglutide can be manufactured in a microneedle formulation to promote transdermal absorption. However, semaglutide can be affected by enzymes present in the skin during the transdermal absorption process, and enzyme-sensitive peptide drug degradation can hinder skin penetration. Furthermore, if the drug's stability is low, aggregates may form, resulting in excessive drug consumption and reduced storage stability. To address these issues, the present invention optimized the structural characteristics of the microneedle, along with defining the composition for microneedle manufacturing and controlling the pH.

[0038] In order to achieve sufficient efficacy, the above semaglutide may be included in an amount of 5 to 50 wt% or 10 to 30 wt% based on the total weight of the composition for preparing the upper layer.

[0039] To effectively deliver the peptide drug semaglutide into the skin, it is necessary to minimize drug degradation due to the action of skin enzymes. Therefore, the composition of the present invention is characterized by including at least one selected from sodium glycocholate and sodium deoxycholate as a semaglutide penetration enhancer. These ingredients exhibit resistance to skin enzymes, thereby enhancing the skin permeation rate of semaglutide. While SNAC and surfactants have been used as penetration enhancers for semaglutide, the use of sodium glycocholate and / or sodium deoxycholate together with semaglutide can significantly improve the drug's enzyme resistance.

[0040] In the present invention, in addition to using sodium glycocholate and / or sodium deoxycholate as a penetration enhancer for the drug semaglutide, the drug penetration enhancing effect can be further increased by adjusting the amount of these added compared to semaglutide.

[0041] The above penetration enhancer may be included in an amount of 3 to 15 wt%, 4 to 12 wt%, or 5 to 11 wt% based on the total weight of the composition for preparing the upper layer.

[0042] In addition, semaglutide and the penetration enhancer in the composition may be included in a weight ratio of 1:0.4 to 1:1.3, and preferably in a weight ratio of 1:0.5 to 1:1.2, 1:0.7 to 1:1, 1:0.8 to 1:1, or 1:0.9 to 1:1.

[0043] If the content of the penetration enhancer falls below the aforementioned range, semaglutide may not be sufficiently delivered to the dermal layer and subcutaneous tissue. Conversely, if the content of the penetration enhancer exceeds the aforementioned range, the physical properties of the microneedles may deteriorate due to a relative decrease in the content of other ingredients in the composition.

[0044] The composition may include a biodegradable polymer. The biodegradable polymer is included to provide the microneedles with suitable strength to effectively penetrate the skin and to maintain their shape. The type of the above biodegradable polymer is not particularly limited, but examples thereof include sodium hyaluronate, sucrose, polyvinylpyrrolidone, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide, polyvinyl alcohol, polylactide-glycolide copolymer, pullulan polyanhydride, polycaprolactone, poly(butyric acid), poly(valeric acid), carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cyclodextrin, dextrin, glucose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, It may be at least one selected from the group consisting of turanose, melitose, melezitose, dextran, sorbitol, mannitol, xylitol, polyether ester, polyester amide, polyurethane, polyacrylate, ethylene-vinylacetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonate polyolefin, polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, and polymethacrylate.

[0045] As an example, the biodegradable polymer may include, but is not limited to, one or more of sodium hyaluronate, sucrose, and polyvinylpyrrolidone.

[0046] As another example, the biodegradable polymer may include, but is not limited to, sodium hyaluronate and sucrose together.

[0047] The biodegradable polymer may be included in an amount of 40 to 90 wt% based on the total weight of the composition for preparing the upper layer. If the content of the biodegradable polymer is less than 40 wt%, it may be difficult to secure sufficient strength of the microneedles and the desired shape may not be maintained. If the content exceeds 90 wt%, the physical properties of the microneedles may deteriorate as the content of other components in the composition relatively decreases.

[0048] As an example, the biodegradable polymer may include sodium hyaluronate and sucrose, and the sodium hyaluronate may be included in an amount of 25 to 40 wt%, 26 to 37 wt%, or 27 to 35 wt% based on the total weight of the composition for preparing the top layer. Additionally, the sucrose may be included in an amount of 15 to 50 wt%, 25 to 45 wt%, or 30 to 40 wt% based on the total weight of the composition for preparing the top layer.

[0049] As another example, the biodegradable polymer may include sodium hyaluronate and sucrose, and the sodium hyaluronate and sucrose may be included in a weight ratio of 1:0.4 to 1:2.3.

[0050] The composition may further comprise a solvent. Purified water may be used as the solvent, but a buffer solution may also be used to adjust the pH.

[0051] At this time, the buffer solution that can be used may be at least one selected from phosphate buffered saline (PBS), tris buffered saline, veronal buffered saline, and borate buffered saline, but phosphate buffered saline (PBS) is preferably used.

[0052] In the present invention, when preparing the composition for the upper layer of the microneedle, a buffer solution is used as a solvent to adjust the pH of the composition, thereby further enhancing drug stability. Here, excellent drug stability means that semaglutide aggregates do not form or are minimally formed after solution preparation, resulting in minimal changes in semaglutide content. Excellent solution stability can prevent excessive drug use for pharmacological effects. Furthermore, since drug stability is directly related to storage stability, high drug stability is advantageous from a quality control perspective.

[0053] Specifically, a buffer solution with a pH of 6.8 to 8.0 may be used. Using a buffer solution with a pH lower than 6.8 may result in the formation of semaglutide aggregates, reducing the effective drug content. A buffer solution with a pH higher than 8.0 is unsuitable for human administration.

[0054] The composition of the present invention may exclude the use of acidifying agents, alkalizing agents, antioxidants, or phenols, including a buffer solution satisfying the aforementioned pH range. The use of these ingredients may lead to the formation of semaglutide aggregates, which may negatively impact drug stability, i.e., storage stability. Furthermore, given the formulation's nature of direct skin delivery via microneedles, these substances have the potential to cause skin irritation. Therefore, the present invention prevents the aforementioned problems by excluding these ingredients.

[0055] The above buffer may be used at a concentration of 1 mM to 25 mM, and preferably at a concentration of 1 mM to 10 mM.

[0056] The buffer may be included in an amount of 8 to 13 wt%, 9 to 12 wt%, or 9 to 11 wt% based on the total weight of the composition for preparing the upper layer, but is not limited thereto.

[0057] To further enhance the solution stability of the drug, the composition of the present invention may be used by additionally mixing ethanol into the buffer solution. When the buffer solution alone is used, the composition having a pH of 6.8 to 8.0 can retain at least 95% of the semaglutide content when stored for 2 days. However, when ethanol is additionally included, the semaglutide content can be retained at least 96% under the same storage conditions.

[0058] The ethanol may be included in an amount of 10 to 90% by volume, 20 to 80% by volume, or 25 to 75% by volume based on the total volume of the mixture of the buffer and ethanol, but is not limited thereto.

[0059] The mixing ratio of the above buffer and ethanol may be a volume ratio of 90:10 to 10:90, preferably a volume ratio of 75:25 to 25:75.

[0060] The composition of the present invention may further include a composition for manufacturing the lower layer or support of the microneedle.

[0061] The composition for manufacturing the lower layer or support may include a biodegradable polymer and a solvent.

[0062] The above biodegradable polymer may be one or more of the biodegradable polymers described above, and preferably may be a high-hardness polystyrene having excellent strength.

[0063] The biodegradable polymer may be included in the composition for preparing the lower layer or support in an amount of, but not limited to, 50 to 250 μg / μL, 100 to 250 μg / μL, or 150 to 225 μg / μL.

[0064] The solvent may be a volatile solvent, and may be one selected from the group consisting of ethanol, 1,4-dioxane, and mixed solvents thereof, but is not limited thereto.

[0065] The solvent may be included in the composition for preparing the lower layer or support in an amount of 100 to 500 μL, or 200 to 400 μL, but is not limited thereto.

[0066] The composition for manufacturing microneedles of the present invention preferably has a viscosity of 300 to 1,000 cPs. If the viscosity of the composition for manufacturing microneedles falls below the aforementioned range, it is difficult to maintain the microneedle shape. Conversely, if the viscosity exceeds the aforementioned range, it may be difficult to remove the microneedle from the mold after manufacturing, which may lower production efficiency.

[0067] If necessary, the composition may further include additives such as a solubilizer, plasticizer, preservative, or anti-inflammatory agent according to the intended use.

[0068] microneedle array

[0069] According to another embodiment of the present invention, there is provided a microneedle array comprising a plurality of microneedles and a support, wherein the microneedles comprise the composition for manufacturing the microneedles described above.

[0070] The microneedle may include an upper layer comprising a composition for preparing the upper layer; and a lower layer comprising a composition for preparing the lower layer. The microneedle of the present invention is loaded with semaglutide only in the upper layer, and not in the lower layer. This structural feature can reduce the loss of semaglutide during transdermal administration of the microneedle.

[0071] The upper layer may contain semaglutide in an amount of 5 to 50 wt% or 10 to 30 wt% relative to the total weight of the upper layer.

[0072] The above penetration enhancer may be at least one selected from sodium glycocholate and sodium deoxycholate, and may be included in an amount of 3 to 15 wt%, 4 to 12 wt%, or 5 to 11 wt% relative to the total weight of the upper layer.

[0073] In addition, semaglutide and the penetration enhancer in the upper layer may be included in a weight ratio of 1:0.4 to 1:1.3, and preferably in a weight ratio of 1:0.5 to 1:1.2, 1:0.7 to 1:1, 1:0.8 to 1:1, or 1:0.9 to 1:1.

[0074] If the content of the penetration enhancer falls below the aforementioned range, semaglutide may not be sufficiently delivered to the dermal layer and subcutaneous tissue. Conversely, if the content of the penetration enhancer exceeds the aforementioned range, the physical properties of the microneedle may deteriorate due to a relative decrease in the content of other components within the upper layer.

[0075] The top layer may comprise a biodegradable polymer. The type of the above biodegradable polymer is not particularly limited, but examples thereof include sodium hyaluronate, sucrose, polyvinylpyrrolidone, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide, polyvinyl alcohol, polylactide-glycolide copolymer, pullulan polyanhydride, polycaprolactone, poly(butyric acid), poly(valeric acid), carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cyclodextrin, dextrin, glucose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, It may be at least one selected from the group consisting of turanose, melitose, melezitose, dextran, sorbitol, mannitol, xylitol, polyether ester, polyester amide, polyurethane, polyacrylate, ethylene-vinylacetate polymer, acrylic substituted cellulose acetate, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonate polyolefin, polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, and polymethacrylate.

[0076] As an example, the biodegradable polymer may include, but is not limited to, one or more of sodium hyaluronate, sucrose, and polyvinylpyrrolidone.

[0077] As another example, the biodegradable polymer may include, but is not limited to, sodium hyaluronate and sucrose together.

[0078] The biodegradable polymer may be included in an amount of 40 to 90 wt% based on the total weight of the top layer. If the content of the biodegradable polymer is less than 40 wt%, it may be difficult to secure sufficient strength of the microneedle and the desired shape may not be maintained. If the content exceeds 90 wt%, the physical properties of the microneedle may deteriorate as the content of other components in the top layer relatively decreases.

[0079] As an example, the biodegradable polymer may include sodium hyaluronate and sucrose, and the sodium hyaluronate may be included in an amount of 25 to 40 wt%, 26 to 37 wt%, or 27 to 35 wt% based on the total weight of the top layer. Additionally, the sucrose may be included in an amount of 15 to 50 wt%, 25 to 45 wt%, or 30 to 40 wt% based on the total weight of the top layer.

[0080] As another example, the biodegradable polymer may include sodium hyaluronate and sucrose, and the sodium hyaluronate and sucrose may be included in a weight ratio of 1:0.4 to 1:2.3.

[0081] The upper layer may further comprise a solvent. Purified water may be used as the solvent, but a buffer solution may also be used to adjust the pH.

[0082] At this time, the buffer solution that can be used may be at least one selected from phosphate buffered saline (PBS), tris buffered saline, veronal buffered saline, and borate buffered saline, but phosphate buffered saline (PBS) is preferably used.

[0083] The above buffer may be used at a concentration of 1 mM to 25 mM, and preferably at a concentration of 1 mM to 10 mM.

[0084] The buffer may be included in an amount of 8 to 13 wt%, 9 to 12 wt%, or 9 to 11 wt% based on the total weight of the upper layer, but is not limited thereto.

[0085] Ethanol may be additionally mixed into the above buffer solution, and the ethanol may be included in an amount of 10 to 90% by volume, 20 to 80% by volume, or 25 to 75% by volume based on the total volume of the mixture of the buffer solution and ethanol, but is not limited thereto.

[0086] The mixing ratio of the above buffer and ethanol may be a volume ratio of 90:10 to 10:90, preferably a volume ratio of 75:25 to 25:75.

[0087] The lower layer and support may include a biodegradable polymer and a solvent.

[0088] The above biodegradable polymer may be one or more of the biodegradable polymers described above, and preferably may be a high-hardness polystyrene having excellent strength.

[0089] The biodegradable polymer may be included in the lower layer or support in an amount of, but not limited to, 50 to 250 μg / μL, 100 to 250 μg / μL, or 150 to 225 μg / μL.

[0090] The solvent may be a volatile solvent, and may be at least one selected from the group consisting of ethanol, 1,4-dioxane, and mixed solvents thereof, but is not limited thereto.

[0091] The solvent may be included in the lower layer or support in an amount of, but not limited to, 100 to 500 μL, or 200 to 400 μL.

[0092] The structure of the microneedle array of the present invention is described with reference to the drawings, but the drawings illustrate exemplary representative structures of the microneedle array of the present invention, and the scope of the present invention is not limited to the structures illustrated in the drawings.

[0093] Figure 1 illustrates a cross-sectional view of a microneedle array according to the present invention, which is a structure in which a plurality of microneedles (20) are protruded on one surface of a support (10) and arranged at regular intervals in the vertical and horizontal directions.

[0094] The above microneedle (20) may include two or more layers including an upper layer (tip, 21) and a lower layer (23).

[0095] The upper layer (21) is a region designed to perform a function of contacting the skin or target tissue. The upper layer (21) includes the tip of the microneedle, and refers to a region corresponding to a certain upper percentage of the total length from the tip of the microneedle, for example, 20% to 80%, 30% to 70%, or 40% to 60%.

[0096] The lower layer (23) is connected to the support of the microneedle, and is designed to structurally support the upper layer and provide the structural strength required during the process of inserting the microneedle into the skin or target tissue. The lower layer (23) refers to a region corresponding to a lower certain percentage of the total length from the lower end connected to the support based on the length of the microneedle, for example, a percentage of 20% to 80%, 30% to 70%, or 40% to 60%.

[0097] The upper layer (21) may be positioned on the lower layer (23), but it may also be within the scope of the present invention to include an additional layer between the upper layer (21) and the lower layer (23).

[0098] The upper layer (21) and lower layer (23) and other layers can be distinguished by having different compositions.

[0099] The length (height) of the above microneedle may be 10 to 1,000 μm, 100 to 1,000 μm, or 400 to 1,000 μm. Here, the length of the microneedle refers to the vertical height from the lower surface of the lower layer or the upper surface of the support to the tip of the microneedle.

[0100] The length (height) of the upper and lower layers of the above microneedles may be 5 to 800 μm or 50 to 500 μm, respectively.

[0101] The shape of the above microneedles may be a cone, a triangular pyramid, a square pyramid, a pentagonal pyramid, a hexagonal pyramid or a polygonal pyramid, and is preferably a cone or a square pyramid, but is not limited thereto.

[0102] Accordingly, the vertical cross-sectional shape of the microneedle in the longitudinal direction may be a circle, triangle, square, pentagon, hexagon or polygon, and may preferably be a circle or square, but is not limited thereto.

[0103] The major axis length on the lower surface of the upper layer may be 1 to 50 μm, or 5 to 30 μm. Here, the major axis means the longest axis on the lower surface of the upper layer, and when the shape of the lower surface is circular, it means the diameter.

[0104] The longitudinal length of the lower surface of the lower layer may be 100 to 900 μm, or 300 to 700 μm.

[0105] In the above microneedles, the support is a flat layer to which the microneedles can be attached, may have a sheet shape, and has a certain degree of elasticity and flexibility so that the microneedle array including it can adhere to the skin.

[0106] The thickness of the above support may be 0.3 mm to 10 mm. When the thickness is as above, mechanical strength is secured and deformation due to changes over time can be reduced.

[0107] The number of microneedles included in the above microneedle array may vary depending on the area to be applied and the size of the patch, and may be formed without limitation from several tens to tens of thousands. For example, the number of microneedles (20) per unit area (1 cm x 1 cm) of the support expressed in terms of integration may be 49 to 100.

[0108] By including the above-mentioned number of microneedles satisfying the above-mentioned composition in the present invention, semaglutide is formed into a 1 cm microneedle array. 2 It may be included in an amount of 0.1 to 3.0 mg per day.

[0109] The microneedle array of the present invention can be formed with a substrate and a plurality of microneedles (20), and has appropriate strength, elasticity and flexibility so that it adheres well to the skin and easily penetrates the skin, and also disappears after being applied to the skin, so that it causes little irritation to the skin and there is no need for removal.

[0110] Method for manufacturing microneedle arrays

[0111] According to one embodiment, a method for manufacturing a microneedle array using the composition for manufacturing microneedles of the present invention is provided.

[0112] Figure 2 is a schematic diagram illustrating a method for manufacturing a microneedle array of the present invention, and will be described in more detail with reference to this.

[0113] (S1) Step of dripping a composition for manufacturing a microneedle upper layer onto a mold

[0114] First, the composition for manufacturing the upper layer of the microneedle can be dropped onto the negative pattern of the negative mold.

[0115] The mold may be a negative mold having needle-shaped grooves.

[0116] The vertical length (height) of the above negative mold may be 10 to 1,000 ㎛, 100 to 1,000 ㎛, or 400 to 1,000 ㎛. Here, the vertical length of the negative mold means the vertical length from the mold surface to the bottom of the negative structure inside the mold.

[0117] The shape of the above negative mold may be a cone, a triangular pyramid, a square pyramid, a pentagonal pyramid, a hexagonal pyramid or a polygonal pyramid, and is preferably a cone or a square pyramid, but is not limited thereto.

[0118] Accordingly, the vertical cross-sectional shape of the longitudinal direction of the above-mentioned negative mold may be a circle, a triangle, a square, a pentagon, a hexagon or a polygon, and may preferably be a circle or a square, but is not limited thereto.

[0119] The above-mentioned negative mold may be made of one or more materials selected from the group consisting of silicone polymers, fluorine polymers, ultraviolet-curable polymers, thermosetting polymers, thermoplastic polymers, ceramic oxides, and metallic inorganic materials, but is not limited thereto.

[0120] For example, a mold can be manufactured using micromachining technology to form needles with a square pyramidal shape arranged at regular intervals. The micromold uses a PDMS material mold and has a thickness of 1 to 20 mm.

[0121] The composition for manufacturing the upper layer of the microneedle can be applied dropwise using methods commonly used in this field. If necessary, the drug and composition can be decompressed under vacuum by applying the dropwise method to minimize loss.

[0122] If necessary, in order to improve the release or wetting properties of the composition filled in the mold, the grooves may be treated with one or more surface treatment processes selected from the group consisting of plasma treatment, SAM (self-assembly monolayer) treatment, and surface deposition. Specifically, a hydrophilic surface treatment by plasma treatment, a hydrophobic release treatment by SAM treatment, etc. may be performed on a mold having needle-shaped grooves.

[0123] (S2) Upper layer formation stage

[0124] Next, the composition for manufacturing the upper layer of the microneedle can be injected into the negative mold through decompression to form the upper layer of the microneedle.

[0125] In the above step (S1), the composition simply dripped does not easily move into the negative mold due to the negative pattern at the micro-channel level. Since the drug must move to the inner end of the negative pattern to form the upper layer, the present invention can perform depressurization, rotation, and drying.

[0126] Specifically, the composition dripped into the negative mold can be injected into the negative mold through depressurization to form an upper layer.

[0127] The composition injected into the negative mold is injected from the tip to a certain upper percentage of the entire length based on the vertical length (height) of the negative mold, and may be injected to an area corresponding to a percentage of, for example, 20% to 80%, 30% to 70%, or 40% to 60%.

[0128] Next, the composition is injected into a rotating device capable of applying centrifugal force, thereby increasing the fluidity of the composition within the mold through the centrifugal force generated by the rotation, thereby moving the composition to the end of the negative pattern. Next, the upper layer of microneedles can be formed through drying.

[0129] The above depressurization can be performed using a known depressurization device and can be performed under pressure conditions of 0.6 to 0.8 bar.

[0130] Additionally, the rotation can be performed using a known rotation device, and can be performed at a speed of 3,000 to 4,000 rpm for 10 to 30 minutes.

[0131] Additionally, the drying can be performed at a pressure of 0.6 to 0.8 bar and a temperature of 35 to 50° C. for 10 to 30 minutes.

[0132] (S3) Lower layer formation stage

[0133] Next, a composition for forming a lower layer can be dripped onto the upper layer in the negative mold.

[0134] Next, the composition can be transferred into the negative pattern of the negative mold through decompression, and dried to form a lower layer.

[0135] At this time, the amount of the composition added can be adjusted to form a support.

[0136] The above depressurization can be performed using a known depressurization device and can be performed under pressure conditions of 0.6 to 0.8 bar.

[0137] Additionally, the drying can be performed at a pressure of 0.6 to 0.8 bar and a temperature of 35 to 50° C. for 12 to 18 hours.

[0138] The composition for manufacturing the lower layer may be used by mixing the aforementioned biodegradable polymer and a solvent. The solvent may be a volatile solvent, and may be one selected from the group consisting of ethanol, 1,4-dioxane, and mixed solvents thereof. The use of such a volatile solvent can shorten the drying time.

[0139] (S4) Support formation step

[0140] In the present invention, when the lower layer and the support are manufactured with different compositions, the composition for manufacturing the support can be dripped onto the lower layer formed in the negative mold as described above.

[0141] Next, the composition can be transferred to the upper portion of the negative pattern of the negative mold through decompression, and dried to form a support layer.

[0142] The above depressurization can be performed using a known depressurization device and can be performed under pressure conditions of 0.6 to 0.8 bar.

[0143] Additionally, the drying can be performed at a pressure of 0.6 to 0.8 bar and a temperature of 35 to 50° C. for 12 to 18 hours.

[0144] transdermal patches

[0145] According to another embodiment of the present invention, there is provided a transdermal patch comprising the above-described microneedle array.

[0146] In the present invention, the term "patch" means a formulation that is attached to the skin to deliver a drug into the body, and a transdermal patch means a patch that can deliver a drug transdermally.

[0147] The microneedle transdermal patch of the present invention may include a microneedle array; and an adhesive sheet to which at least one microneedle array is attached.

[0148] The adhesive sheet may comprise, for example, silicone, polyurethane, polyethylene, polyester, polypropylene, polyvinyl chloride, hydrocolloid or mixtures thereof.

[0149] The above microneedle transdermal patch comprises a microneedle array on one side, and can insert multiple microneedles into the skin by applying pressure. As the microneedles penetrate the skin and dissolve within the skin, the drug can be rapidly injected into the skin.

[0150] The microneedle transdermal patch containing semaglutide as a drug is a new drug delivery system that improves on the shortcomings of existing oral and injection semaglutide formulations. It can minimize pain by stably delivering the drug into the skin and increase the bioavailability of the drug due to its excellent skin permeability.

[0151] For example, the microneedle transdermal patch of the present invention can be used as a treatment for type 2 diabetes and obesity.

[0152] [Example]

[0153] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, these examples and experimental examples are merely illustrative of the present invention, and the scope of the present invention is not limited to these examples.

[0154] Test Example 1: Drug Solution Stability Evaluation

[0155] To determine the stability of semaglutide in solution during microneedle manufacturing, we evaluated its stability in distilled water, buffer, and a mixture of buffer and ethanol. Semaglutide was added to each solvent at a concentration of 100 ppm and stored at room temperature for 2 days. Stability was assessed by analyzing the semaglutide content at the initial, 1-day, and 2-day storage periods. Since solutions with a pH higher than 8.0 are generally not administered as injections, this experiment was conducted only with buffer solutions up to pH 8.0.

[0156] <Analysis Conditions - LC>

[0157] Column: SymmetryShield RP18 300A; 150 Х 4.6 mm, 5 μm particle size or equivalent column

[0158] Flow rate: 1.0 ml / min

[0159] Column temperature: 40 ℃

[0160] Sample temperature: 5 ℃

[0161] Injection volume: 50 μL

[0162] Mobile phase: 0.1% phosphoric acid: = 70:30 (v / v / v)

[0163] Semaglutide content (wt%)CompositionInitialDay 1Day 2Distilled water100.397.218.9pH 6.0 (4mM)100.898.293.1pH 6.8 (4mM)100.999.495.4pH 7.4 (4mM)100.999.795.7pH 8.0 (4mM)100.499.195.3pH 6.8 (4mM) + 25% EtOH100100.5102.1pH 6.8 (4mM) + 50% EtOH100100.6101.8pH 6.8 (4mM) + 75% EtOH100.297.396.1

[0164] *% of ethanol is volume %.

[0165] As shown in Table 1 above, when the pH ranges from 6.8 to 8.0 in a buffer solution of the same ionic strength, semaglutide maintained a content of over 95% after 2 days at room temperature, confirming its stability. Furthermore, when the buffer solution and ethanol were mixed, the content was maintained at over 96% after 2 days at room temperature, confirming a tendency for stability compared to using the buffer solution alone. These results imply that drug stability can be sufficiently increased through appropriate pH control of the buffer solution, and suggest that the use of separate acidifying or alkalizing agents, antioxidants, and preservatives such as phenol is unnecessary.

[0166] Test Example 2: Evaluation of enzyme resistance in the skin

[0167] To identify penetration enhancers that can improve the enzymatic resistance of drugs in the skin, enzyme resistance was evaluated using the substances presented in the table below.

[0168] To conduct an enzyme resistance test for each penetration enhancer, the test was conducted by extracting enzymes from the skin of rat skin. First, the rat skin of 1.5 x 1.5 (cm) was divided into 9 parts and stirred in 4 mL PBS buffer at 37℃ for 1 hour to extract enzymes from the skin. Then, 1 mL of a 100 ppm concentration semaglutide solution was added and the test was conducted at 37℃ and 200 rpm, and sampling was performed at regular intervals to inhibit the action of skin-derived enzymes in the solution through pretreatment, and the enzyme resistance was evaluated using the content analysis method presented above. At this time, the penetration enhancer was added so that the concentration in the extracted enzyme solution was 1%, and % means weight %.

[0169] Test Semaglutide Residue Content (Wt%) 0 0.5 min 15 min 30 min 60 min 120 min pH 6.8 PBS (negative control) 100 96.5 95.5 94.1 94.2 92.8 pH 6.8 PBS + rat skin (positive control) 100 92.7 7 13 8.9 15.8 6.5 pH 6.8 PBS + rat skin + sodium glycocholate 1% 100 100 97.3 97.4 94.1 94.1 pH 6.8 PBS + rat skin + sodium deoxycholate 1% 100 100 101.2 9.8 9.1 100.1 pH 6.8 PBS + rat skin + sodium caprate 1% 100 100 100.2 103.9 105.2 106 pH 6.8 PBS + rat skin + sodium Salcaprozate (SNAC) 1% 1001009 0.18 166.45 1.5 pH 6.8 PBS + rat skin + sodium taurocholate 1% 1001009 7.49 7.89 4.89 5.4 pH 6.8 PBS + rat skin + sodium caprylate 1% 1001007 1.24 7.72 7.84.3 pH 6.8 PBS + rat skin + oleyl polyoxyl-6-glyceride (Labrafil) 1% 1001008 3.76 0.94 4.12 0.9 pH 6.8 PBS + rat skin + polysorbate 80 1% 1001007 7.66 7.23 8.9 10.8

[0170] As shown in Table 2 above, in the negative control group that did not contain the enzyme extract, semaglutide tended to be stable, and in the positive control group that contained the enzyme extract, semaglutide tended to be unstable, confirming the instability of semaglutide due to enzymes in the skin.

[0171] When using a penetration enhancer, the retention rate of semaglutide varied depending on the type of enhancer. In particular, sodium glycocholate, sodium deoxycholate, sodium caprate, and sodium taurocholate showed high retention rates, indicating excellent resistance to enzymes in the skin.

[0172] In contrast, when sodium caprylate and sodium salcaproate were used, the content of semaglutide decreased rapidly over time, and the enzyme resistance tended to be lower than that of sodium glycocholate or sodium deoxycholate.

[0173] Additionally, when the surfactants Labrafil and polysorbate 80 were used, a similar trend was observed as with sodium caprylate.

[0174] Sodium caprate and sodium taurocholate, which were used as penetration enhancers, exhibited high enzyme resistance, but when applied to microneedles, they exhibited low actual skin penetration rates. This is explained in Test Example 3 below.

[0175] Test Example 3: Evaluation of Microneedle Permeability (Franz Diffusion Test)

[0176] (1) Manufacturing of microneedle arrays

[0177] The PDMS solution was mixed well to completely remove air bubbles, and then injected into a master mold made of resin. After drying and curing at 80°C for approximately 8 hours, it was removed from the master mold to manufacture a PDMS negative mold, which was then used. The structure of the mold used here was such that there were 7x7 (49) needles per unit area (1 cm x 1 cm), and it was manufactured in the shape of a square pyramid with a height of 1,000 ㎛ and a base of 500 ㎛.

[0178] Each component shown in Tables 3 and 4 below was mixed to prepare a composition for manufacturing the upper layer of microneedles, and a composition for manufacturing the lower layer and support was prepared.

[0179] About 50 μL of the composition for preparing the upper layer of the microneedle was precisely taken and dropped onto a microneedle structure mold. The mold onto which the composition was dropped was connected to a vacuum pump so that the composition for preparing the upper layer of the microneedle could be injected into the negative pattern, and then the pressure was reduced to 0.6 bar for about 3 hours so that the solution could be injected into the negative pattern of the mold. Next, the mold was placed in a rotating device, rotated at 4,000 rpm for 20 minutes, and then taken out. Next, the entire mold was dried at 40 °C under a pressure of 0.6 bar for 20 minutes, thereby forming the upper layer of the microneedle.

[0180] Here, about 100 μL of the composition for manufacturing the lower layer and support was precisely taken and dropped onto the mold. The mold on which the composition was dropped was connected to a vacuum pump so that the composition could be injected into the negative pattern, and then the pressure was reduced to 0.6 bar for about 3 hours so that a portion of the solution was injected into the negative pattern of the mold. Next, the entire mold was dried at 40 °C under a pressure of 0.6 bar and a temperature of 25 °C for 12 hours to form the lower layer and support of the microneedle. Then, the mold was separated to produce a microneedle array.

[0181] Ingredient (μg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Top layer Semaglutide 100 100 100 100 100 100 Sodium hyaluronate 300 300 325 325 275 275 Sucrose 375 375 375 375 375 375 Sodium glycocholate 75-50-100 Sodium deoxycholate-75-50-100 pH 6.8 4 mM phosphate buffer (ethanol 25%) 100 100 100 100 100 100 Bottom layer and support Polystyrene 40,000 40,000 40,000 40,000 40,000 40,000 1,4-dioxane 200 μL 200 μL200 μL200 μL200 μL200 μL

[0182] Ingredients (μg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Top layer Semaglutide 100 100 100 100 100 100 100 Sodium hyaluronic acid 375 300 300 300 300 300 Sucrose 375 375 375 375 375 375 375 Sodium caprate-75 ----- Sodium salcaproate--75 ----- Sodium taurocholate---75 ----- Sodium caprylate ----75 ----- Oleyl polyoxyl-6-glyceride (Labrafil) ----- 75 ----- Polysorbate 80 ----- 75 pH 6.8 4 mM phosphate buffer (ethanol) 25%)100100100100100100100Lower layer and support polystyrene40,00040,00040,00040,00040,00040,00040,0001,4-dioxane200 μL200 μL200 μL200 μL200 μL200 μL200 μL

[0183] (2) Evaluation

[0184] A skin permeation test (n=3) was conducted using a Franz-diffusion cell, a device for evaluating the permeation rate of a percutaneous absorption preparation, using a microneedle array.

[0185] Specifically, the microneedle array was attached to the pig skin by vertically transmitting a force of about 20 N to the pig skin for 1 minute, and then the permeation rate was evaluated using a Franz diffusion test device. At this time, the entire solution was sampled at a set time in a receptor device containing about 5.5 mL of a 1:1 mixture of PBS buffer (pH 6.8) and ethanol as a receptor medium, and 10 mL of the receptor medium was replenished again. The temperature of the receptor medium was maintained at 37°C using a water jacket. The sampled test solution was not subjected to additional pretreatment, and the hourly skin permeation rate was evaluated for 24 hours using the same analytical device and conditions as in Test Example 1.

[0186] (3) Results of the cumulative permeability of the microneedle array per hour

[0187] Table 5 below shows the cumulative permeability per hour of the microneedle arrays manufactured in the examples and comparative examples. Here, the cumulative permeability per hour refers to the content of semaglutide present in the dermal layer and subcutaneous tissue.

[0188] Cumulative hourly permeation rate of semaglutide (%) 0hr1hr3hr6hr12hr24hrExample 104.07.817.822.152.7Example 201.63.312.616.956.8Example 303.36.116.923.358.3Example 403.75.920.127.356.1Example 501.97.918.821.658.2Example 602.23.214.618.855.6Comparative Example 100.21.11.52.77.0Comparative Example 201.83.37.210.729.3Comparative Example 300.41.85.58.222.6Comparative Example 400.91.52.73.89.5Comparative example 500.10.40.70.91.7Comparative example 600.91.73.34.611.3Comparative example 700.20.40.60.81.1

[0189] As shown in Table 5 above, compared to the cumulative permeability of 7% after 24 hours for the microneedles manufactured without adding a permeation enhancer (Comparative Example 1), it was confirmed that the cumulative permeability of the microneedles manufactured by adding sodium deoxycholate and sodium glycocholate as permeation enhancers according to the present invention (Examples 1 to 6) was significantly improved to 52% or more after 24 hours.

[0190] On the other hand, the microneedles manufactured by adding sodium caprate (Comparative Example 2) and sodium taurocholate (Comparative Example 4), which showed high enzyme resistance, together with sodium deoxycholate and sodium glycocholate in the results of Table 2 above, showed a cumulative permeability of 29.3% and 9.5%, respectively, after 24 hours, which was a very low permeability compared to the microneedles manufactured according to the present invention.

[0191] In addition, microneedles manufactured by adding sodium salcaproate (Comparative Example 3) and sodium caprylate (Comparative Example 5), which are different types of penetration enhancers, and microneedles manufactured by adding Labrafil (Comparative Example 6) and polysorbate 80 (Comparative Example 7), which are surfactants instead of penetration enhancers, also exhibited very low penetration rates of less than 22%.

[0192] (4) Results of skin penetration rate of microneedle array

[0193] Table 6 below shows the permeability of the microneedle arrays manufactured in Examples and Comparative Examples, and indicates the in skin content, on skin content, and the content of recovered drug relative to the injected drug. Here, the on skin content refers to the content of semaglutide present on the surface of the stratum corneum, and the in skin refers to the content of semaglutide present in the stratum corneum and epidermal layers. In addition, the content of recovered drug relative to the injected drug refers to on skin + in skin + skin permeation amount, and the skin permeation amount refers to the content of semaglutide present in the dermis layer and subcutaneous tissue.

[0194] Semaglutide content (wt%) after 24 hours on skinin skinDrug permeationInjected drug vs. recovered drugExample 19.921.452.784.0Example 211.123.356.891.2Example 39.122.358.389.7Example 410.223.956.190.2Example 59.921.358.289.4Example 611.720.955.688.2Comparative Example 111.727.07.045.7Comparative Example 210.524.929.364.7Comparative Example 315.930.122.668.6Comparative Example 46.722.29.538.4Comparative Example 525.927.31.754.9Comparative example 620.435.511.367.2Comparative example 715.527.21.143.8

[0195] As shown in Table 6 above, compared to the microneedle manufactured without adding a penetration enhancer (Comparative Example 1), which had a recovered drug content of 45.7 wt% relative to the injected drug, the microneedles manufactured by adding sodium deoxycholate and sodium glycocholate as penetration enhancers according to the present invention (Examples 1 to 6) had a recovered drug content of 84 wt% or more relative to the injected drug, confirming that the loss of semaglutide was significantly reduced. In addition, it was found that about 52 wt% or more of semaglutide was permeated into the dermal layer and subcutaneous tissue. These results indicate that the sodium deoxycholate and sodium glycocholate added to the microneedle according to the present invention have high resistance to skin-derived enzymes present in the epidermal layer and dermal layer.

[0196] On the other hand, in the case of adding a different type of penetration enhancer than the one added in the present invention (Comparative Examples 2 to 5) and in the case of adding the surfactants Labrafil (Comparative Example 6) and polysorbate 80 (Comparative Example 7), the microneedles produced had an injected drug recovery rate of 68 wt% or less, indicating that a significant amount of semaglutide was lost, and it was found that semaglutide was mostly present on the skin and in the skin, so that it did not sufficiently penetrate to the dermal layer.

[0197] Test Example 4: Evaluation of Microneedle Permeability According to Penetration Enhancer Content (Franz Diffusion Test)

[0198] (1) Manufacturing of microneedle arrays

[0199] The composition for manufacturing the upper layer of microneedles and the composition for manufacturing the lower layer and support were manufactured by mixing the respective components shown in Table 7 below, and the composition was manufactured in the same manner as the microneedle array according to Test Example 3.

[0200] Ingredients (μg) Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Top layer Semaglutide 100 100 100 100 Sodium hyaluronate 350 350 225 225 Sucrose 375 375 375 375 Sodium glycocholate 25-150 Sodium deoxycholate-25-150 pH 6.8 4 mM phosphate buffer (ethanol 25%) 100 100 100 100 Bottom layer and support Polystyrene 40,000 40,000 40,000 40,000 1,4-dioxane 200 μL 200 μL 200 μL 200 μL

[0201] (2) Evaluation

[0202] The skin permeation rate per hour was evaluated for 24 hours using the same analytical equipment and conditions as in Test Example 3.

[0203] (3) Results of the cumulative permeability of the microneedle array per hour

[0204] Table 8 below shows the cumulative permeability per hour of the microneedle arrays manufactured in the examples and comparative examples. Here, the cumulative permeability per hour refers to the content of semaglutide present in the dermal layer and subcutaneous tissue.

[0205] Cumulative hourly permeation rate of semaglutide (%) 0hr1hr3hr6hr12hr24hrExample 104.07.817.822.152.7Example 201.63.312.616.956.8Example 303.36.116.923.358.3Example 403.75.920.127.356.1Example 501.97.918.821.658.2Example 602.23.214.618.855.6Comparative Example 801.11.77.311.130.9Comparative Example 900.92.38.915.641.1Comparative Example 1001.53.311.115.550.7Comparative example 1101.43.610.914.449.9

[0206] As shown in Table 8 above, in the case of microneedles (Examples 1 to 6) manufactured by adding 50 to 100 μg of sodium deoxycholate or sodium glycocholate as a penetration enhancer according to the present invention, it was confirmed that the cumulative penetration rate was 52% or more after 24 hours, showing a significant improvement in penetration rate.

[0207] On the other hand, in the case of microneedles manufactured by adding 25 μg of sodium deoxycholate or sodium glycocholate (Comparative Examples 8 and 9), the cumulative permeability after 24 hours was low at 41% or less, and in the case of microneedles manufactured by adding 150 μg, which is an amount exceeding the content range of the present invention (Comparative Examples 10 and 11), the cumulative permeability after 24 hours was similar to that of the present invention, but the content of semaglutide present on the surface of the stratum corneum was high. This is explained in Table 9 below.

[0208] (4) Results of skin penetration rate of microneedle array

[0209] Table 9 below shows the permeability of the microneedle arrays manufactured in Examples and Comparative Examples, and indicates the in skin content, on skin content, and the content of recovered drug relative to the injected drug. Here, the on skin content refers to the content of semaglutide present on the surface of the stratum corneum, and the in skin refers to the content of semaglutide present in the stratum corneum and epidermal layers. In addition, the content of recovered drug relative to the injected drug refers to on skin + in skin + skin permeation amount, and the skin permeation amount refers to the content of semaglutide present in the dermis layer and subcutaneous tissue.

[0210] Semaglutide content (wt%) after 24 hours on skinin skinDrug permeationInjected drug vs. recoveredDrug Example 19.921.452.784.0 Example 211.123.356.891.2 Example 39.122.358.389.7 Example 410.223.956.190.2 Example 59.921.358.289.4 Example 611.720.955.688.2 Comparative Example 811.325.130.967.3 Comparative Example 912.726.341.180.1 Comparative Example 1017.922.745.786.3 Comparative Example 1118.320.148.186.5

[0211] As shown in Table 9 above, in the case of microneedles (Examples 1 to 6) manufactured by adding 50 to 100 μg of sodium deoxycholate or sodium glycocholate as a penetration enhancer according to the present invention, it was confirmed that the recovered drug content was 84 wt% or more compared to the injected drug, indicating that the loss of semaglutide was significantly reduced. In addition, it was confirmed that about 52 wt% or more of semaglutide was penetrated into the dermal layer and subcutaneous tissue.

[0212] On the other hand, in the case of microneedles manufactured by adding 25 μg of sodium deoxycholate or sodium glycocholate (Comparative Examples 8 and 9), the content of semaglutide that penetrated into the dermal layer and subcutaneous tissue was less than about 41 wt%, and in the case of microneedles manufactured by adding 150 μg (Comparative Examples 10 and 11), the recovered drug content compared to the injected drug showed a similar level to that of the present invention, but the content present on the skin was about 18 wt% or more, and it was found that a significant amount of semaglutide existed on the skin due to high viscosity, and thus, it was found that penetration into the dermal layer was not sufficient.

[0213] Through the above test, it was found that in the case of the microneedle manufactured according to the present invention, the cumulative permeation rate per hour of semaglutide delivered to the dermal layer and subcutaneous tissue was excellent due to the high enzyme resistance of sodium deoxycholate and sodium glycocholate added in an appropriate amount as penetration enhancers, and the injected drug recovery rate was also excellent.

[0214] [Explanation of symbols]

[0215] 10: Support

[0216] 20: Microneedle

[0217] 21: Upper layer

[0218] 23: Lower layer

[0219] The present invention is applicable to microneedles containing semaglutide.

Claims

1. Semaglutide; and A composition for preparing a microneedle upper layer, comprising at least one penetration enhancer selected from sodium glycocholate and sodium deoxycholate.

2. In paragraph 1, A composition for manufacturing a microneedle upper layer, wherein the semaglutide is contained in an amount of 5 to 50 wt% based on the total weight of the composition.

3. In paragraph 1, A composition for manufacturing a microneedle upper layer, wherein the penetration enhancer is contained in an amount of 3 to 15 wt% based on the total weight of the composition.

4. In paragraph 1, A composition for manufacturing the upper layer of a microneedle, wherein the composition further comprises a biodegradable polymer.

5. In paragraph 4, The above biodegradable polymers are sodium hyaluronate, sucrose, polyvinylpyrrolidone, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide, polyvinyl alcohol, polylactide-glycolide copolymer, pullulan polyanhydride, polycaprolactone, poly(butyric acid), poly(valeric acid), carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cyclodextrin, dextrin, glucose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, A composition for manufacturing a microneedle upper layer, comprising at least one selected from the group consisting of melezitose, dextran, sorbitol, mannitol, xylitol and combinations thereof.

6. In paragraph 4, A composition for manufacturing a microneedle upper layer, wherein the biodegradable polymer is contained in an amount of 40 to 90 wt% based on the total weight of the composition.

7. In paragraph 1, A composition for manufacturing the upper layer of a microneedle, wherein the composition further comprises a solvent.

8. In paragraph 7, A composition for manufacturing an upper layer of microneedles, wherein the solvent is at least one buffer solution selected from a phosphate buffer solution, a Tris buffer solution, a veronal buffer solution, and a borate buffer solution.

9. In paragraph 8, A composition for manufacturing a microneedle upper layer, wherein the solvent further comprises ethanol.

10. In paragraph 9, A composition for manufacturing an upper layer of microneedles, wherein the ethanol is contained in an amount of 10 to 90% by volume based on the total volume of a mixture of a buffer solution and ethanol.

11. Containing a plurality of microneedles and a support, The above microneedles include an upper layer and a lower layer, A microneedle array, wherein the upper layer comprises a composition for manufacturing a microneedle upper layer according to any one of claims 1 to 10.

12. In paragraph 11, The above microneedle array is 1 cm 2 A microneedle array comprising 0.1 to 3.0 mg of semaglutide.

13. In paragraph 11, A microneedle array, wherein the microneedle has one type of tip selected from the group consisting of a cone, a triangular pyramid, a square pyramid, a pentagonal pyramid, a hexagonal pyramid, and a polyhedron.

14. In paragraph 11, A microneedle array, wherein the lower layer of the microneedles and the support contain a biodegradable polymer.

15. In paragraph 14, The above biodegradable polymers are sodium hyaluronate, sucrose, polyvinylpyrrolidone, alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan polylactide, polyglycolide, polyvinyl alcohol, polylactide-glycolide copolymer, pullulan polyanhydride, polycaprolactone, poly(butyric acid), poly(valeric acid), carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, cyclodextrin, dextrin, glucose, starch, trehalose, glucose, maltose, lactose, lactulose, fructose, turanose, melitose, A microneedle array comprising at least one selected from the group consisting of melezitose, dextran, sorbitol, mannitol, xylitol, polyetheresters, polyesteramides, polyurethanes, polyacrylates, ethylene-vinylacetate polymers, acrylic substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonate polyolefins, polyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol, polymethacrylate, and combinations thereof.

16. In paragraph 11, The above microneedle array is a soluble microneedle array.

17. A step of preparing a negative mold including an negative pattern; A step of depositing a composition for manufacturing a microneedle upper layer according to any one of claims 1 to 10 into the engraved pattern; A step of forming an upper layer of microneedles within the negative pattern of the negative mold by performing decompression and rotation; A step of depositing a composition for manufacturing a lower layer within an engraved pattern on the upper layer; and A method for manufacturing a microneedle array, comprising the steps of forming a lower layer by depressurizing and drying.

18. A microneedle transdermal patch comprising a microneedle array according to claim 11; and an adhesive sheet having at least one microneedle array attached thereto.

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