Functional microstructure containing high conent of vitamins for whitening and wrinkle alleviation, manufacturing method therefor, and microstructure patch comprising same

Abstract

The present invention relates to a microstructure containing a high content of an active ingredient, and a manufacturing method therefor. When a composition for preparing the microstructure of the present invention is used, a high content of an active ingredient can be loaded into the microstructure, and a microstructure containing a high content of vitamins so as to have whitening and wrinkle alleviation functions can be provided.

Description

Functional microstructures for whitening and wrinkle improvement containing high-concentration vitamins, a method for manufacturing the same, and a microstructure patch containing the same

[0001] This patent application claims priority to Korean Patent Application No. 10-2025-0015173 filed with the Korean Intellectual Property Office on February 6, 2025, the disclosures of said patent application are incorporated herein by reference.

[0002] The present invention relates to a microstructure containing a high content of an active substance and a method for manufacturing the same.

[0003]

[0004] A Drug Delivery System (DDS) refers to a series of technologies that deliver drugs to target sites, such as cells and tissues, by controlling drug absorption and release to reduce side effects and maximize efficacy.

[0005] Drug delivery systems include transdermal delivery systems that allow for the local application of drugs in addition to general oral intake, and research has been continuously conducted to administer pharmaceutical substances, such as drugs, efficiently and safely.

[0006] Among these, injection therapy has the problem that the administration method is cumbersome, it may be accompanied by pain depending on the patient, and there are limitations in control other than the method of temporarily injecting the drug.

[0007] To improve upon the disadvantages of such injection therapy, research has been conducted on microstructures (microneedles) that are much smaller and less painful than syringe needles, and is being carried out in various fields such as drug delivery, blood collection, biosensors, and cosmetic dermatology.

[0008] Micro-needles are generally manufactured by injecting a biodegradable viscous material into a micro-mold made using a curable polymer, drying it, and then separating it from the mold (molding technique), or by coating a biodegradable viscous material to form biodegradable solid micro-needles, drying the coated biodegradable viscous material while drawing it into a frame patterned with pillars, and then cutting the drawn biodegradable viscous material (drawing technique).

[0009] Recently, micro-needle patches with micro-needles formed thereon are being used for skin care, such as mask packs, and their main material is often hyaluronic acid, a hydrophilic biomaterial. Hyaluronic acid is one of the polysaccharides present in the human body and is a biodegradable polymer compound composed of N-acetylglucosamine and glucuronic acid. It has high viscosity and excellent water retention properties, playing an important role in preventing bacterial invasion or the penetration of toxins, and also functions to supply moisture to the skin to maintain hydration and elasticity.

[0010] In conventional microneedle structures, stable film formation was only possible when hyaluronic acid accounted for more than 75% of the total composition. However, when hyaluronic acid accounts for more than 75% of the total composition, it is difficult to incorporate a high concentration of active ingredients. Although methods such as increasing the solid content ratio or increasing the plasticizer content have been proposed, these approaches have problems such as increased film thickness and hardness, and instability of film properties, respectively. Therefore, there is a need to develop an appropriate mixing ratio for compositions to produce microneedle structures containing a high concentration of active ingredients.

[0011] Throughout this specification, numerous papers and patent documents are referenced and cited. The disclosures of the cited papers and patent documents are incorporated by reference into this specification in their entirety to more clearly explain the state of the art to which the present invention pertains and the content of the present invention.

[0012]

[0013] The inventors made diligent research efforts to find an appropriate mixing ratio of a composition for producing a microstructure containing a high concentration of active ingredients. As a result, they discovered that a high concentration of active ingredients can be loaded into a microstructure by combining the biodegradable polymer pullulan and hyaluronic acid to form a stable film polymer. Furthermore, they developed a microneedle patch containing a high concentration of vitamins to provide whitening and wrinkle improvement functions, and completed the present invention by identifying a patch with optimal stability by mixing the antioxidant glutathione in different ratios to ensure the long-term stability of the vitamins.

[0014] Accordingly, the object of the present invention is to provide a composition for manufacturing microstructures comprising hyaluronic acid and pullulan.

[0015] Another objective of the present invention is to provide a method for manufacturing a microstructure using the composition for manufacturing the microstructure.

[0016] Another objective of the present invention is to provide a microstructure comprising hyaluronic acid and pullulan.

[0017] Another objective of the present invention is to provide a patch comprising the microstructure.

[0018] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims, and drawings.

[0019]

[0020] The present invention provides the inventions of 1 to 18 below.

[0021] 1. Composition for manufacturing microstructures comprising hyaluronic acid and pullulan:

[0022] Of the total solid content of 100 parts by weight included in the above composition, the hyaluronic acid is included in an amount of 50 to 75 parts by weight, or the pullulan is included in an amount of 1 to 10 parts by weight.

[0023] 2. A composition for manufacturing a microstructure, wherein the hyaluronic acid in 1 comprises cross-linked hyaluronic acid, non-cross-linked hyaluronic acid, or a combination thereof.

[0024] 3. A composition for manufacturing a microstructure, wherein, in 1 or 2, the composition comprises 1 to 5 parts by weight of cross-linked hyaluronic acid in 100 parts by weight of the total solid content included in the composition.

[0025] 4. A composition for manufacturing a microstructure, wherein, in any one of 1 to 3, the pullulan is included in an amount of 1 to 10 parts by weight.

[0026] 5. A composition for manufacturing a microstructure, wherein, in any one of 1 to 4, the composition additionally comprises an antioxidant, a vitamin, or a combination thereof.

[0027] 6. In any one of 1 to 5, the antioxidant is glutathione, ascorbic acid derivatives, tocopherol or its derivatives, catechins, lutein, beta-carotene, alpha-lipoic acid, coenzyme Q10, resveratrol, selenium, flavonoids, polyphenols, gallic acid, quercetin, eriocitrin, proanthocyanidins, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene A composition for manufacturing microstructures, comprising one or more selected from the group consisting of hydroxytoluene, ferulic acid, curcumin, ursolic acid, zeaxanthin, and gluconolactone.

[0028] 7. A composition for manufacturing a microstructure, wherein, in 5 or 6, the weight ratio of the vitamin to the antioxidant is 0.5 to 2.

[0029] 8. A method for manufacturing a microstructure comprising the step of dispensing any one of 1 to 7 compositions for manufacturing a microstructure into a mold and drying to obtain a microstructure.

[0030] 9. Microstructures containing hyaluronic acid and pullulan:

[0031] Of the total solid content of 100 parts by weight contained in the microstructure, the hyaluronic acid is included in an amount of 50 to 75 parts by weight, or the pullulan is included in an amount of 1 to 10 parts by weight.

[0032] 10. A microstructure in which the hyaluronic acid in 9 comprises cross-linked hyaluronic acid, non-cross-linked hyaluronic acid, or a combination thereof.

[0033] 11. A microstructure according to 9 or 10, wherein the microstructure comprises 1 to 5 parts by weight of cross-linked hyaluronic acid in 100 parts by weight of total solid content contained in the microstructure.

[0034] 12. A microstructure comprising, in either 9 or 11, 3 to 7 parts by weight of pulluran in 100 parts by weight of total solid content contained in the structure.

[0035] 13. A microstructure in any one of 9 to 12, wherein the microstructure additionally comprises an antioxidant, a vitamin, or a combination thereof.

[0036] 14. In 13, the antioxidant is glutathione, ascorbic acid derivatives, tocopherol or its derivatives, catechins, lutein, beta-carotene, alpha-lipoic acid, coenzyme Q10, resveratrol, selenium, flavonoids, polyphenols, gallic acid, quercetin, eriocitrin, proanthocyanidins, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene A microstructure that is one or more selected from the group consisting of hydroxytoluene), ferulic acid, curcumin, ursolic acid, zeaxanthin, and gluconolactone.

[0037] 15. A microstructure in which, in 13 or 14, the weight ratio of the vitamin to the antioxidant is 0.5 to 2.

[0038] 16. A patch for whitening, wrinkle improvement, or a combination thereof comprising any one of 8 to 15 microstructures.

[0039] 17. A non-therapeutic cosmetic method for whitening or improving wrinkles by attaching a microstructure of any one of 8 to 15 or a patch containing the same to the skin of a subject.

[0040] 18. A non-therapeutic cosmetic method according to 17, wherein the cosmetic method comprises: (a) attaching the microstructure or patch to the surface of the skin of a subject; and (b) maintaining the microstructure for a certain period of time so that it releases an active ingredient as it dissolves in the moisture inside the skin.

[0041]

[0042] In one aspect of the present invention, the present invention provides a composition for manufacturing a microstructure comprising hyaluronic acid and pullulan:

[0043] Of the total solid content of 100 parts by weight included in the above composition, the hyaluronic acid is included in an amount of 50 to 75 parts by weight, or the pullulan is included in an amount of 1 to 10 parts by weight.

[0044] The inventors have made diligent research efforts to find an appropriate mixing ratio of a composition for producing a microneedle structure containing a high concentration of active ingredients. As a result, they discovered that a high concentration of active ingredients can be loaded into a microstructure by combining the biodegradable polymer pullulan and hyaluronic acid to form a stable film polymer. Furthermore, they developed a microneedle patch containing a high concentration of vitamins to provide whitening and wrinkle improvement functions, and identified a patch with optimal stability by mixing the antioxidant glutathione in different ratios to ensure the long-term stability of the vitamins.

[0045] In this specification, the biodegradable polymer performs the following roles in the microstructure.

[0046] 1) Encapsulation: Polymers are used to form microneedles and encapsulate active ingredients. This protects the active ingredients from environmental factors and improves product stability.

[0047] 2) Controlled release: Polymers also play an important role in controlling the release of active components. Depending on the structure and properties of the polymer, active components can be released slowly at a constant rate or rapidly under specific conditions.

[0048] 3) Control of physical properties: Polymers also play an important role in determining physical properties such as the size, shape, and strength of microstructures.

[0049] In addition, the composition for manufacturing the microstructure may include medical drugs, pharmaceutical drugs, and dermatological drugs.

[0050] In this specification, the term "hyaluronic acid" includes hyaluronic acid or its salts. The hyaluronic acid salts may be, for example, sodium hyaluronate, potassium hyaluronate, lithium hyaluronate, magnesium hyaluronate, zinc hyaluronate, hyaluronic acid esters, cross-linked hyaluronic acid, or hyaluronic acid derivatives, but are not limited thereto.

[0051] Sodium hyaluronate is a representative substance with wrinkle-reducing and anti-aging functions. This sodium hyaluronate acts as a moisturizer that double-strengthens the skin barrier by forming a moisturizing film on both the inside and outside of the skin. To this end, it is more desirable to use sodium hyaluronate with a low molecular weight of 60 kDa or less.

[0052] In this specification, the term "Pullulan" refers to a natural polysaccharide in which maltotriose units are linked by α(1→4) and α(1→6) glycosidic bonds. Pullulan is a colorless, odorless, water-soluble polymer with the ability to form transparent, thin films. Due to its high biocompatibility and biodegradability, it is widely used in the food, pharmaceutical, and cosmetics industries. Pullulan is utilized as a packaging material due to its low oxidative stress and excellent oxygen barrier properties. Furthermore, due to its excellent hydrophilicity and viscosity, it is also attracting attention in various biotechnological applications, such as drug delivery systems and the manufacture of microstructures.

[0053] Furthermore, the term "pululan" in the present invention should be interpreted in a broad sense to include not only the naturally derived pullulan but also all of its pharmaceutically or cosmetically acceptable salts, derivatives, solvates, hydrates, and cross-linked forms.

[0054] Specifically, the "derivative" includes a form in which some or all of the hydroxyl groups (-OH) of pullulan are chemically modified, and may be, for example, pullulan acetate, carboxymethyl pullulan, sulfated pullulan, esterified pullulan, etherified pullulan, or hydrophobically modified pullulan with a hydrophobic group attached, but is not limited thereto.

[0055] The above "salt" may include inorganic salts such as sodium salts, potassium salts, calcium salts, magnesium salts, etc., or organic salts such as ammonium salts, triethylamine salts, etc.

[0056] In addition, the pullulan of the present invention may include a form (Cross-linked Pullulan) that is chemically or physically crosslinked by a crosslinking agent to control the mechanical strength and dissolution rate of the microstructure, and in terms of molecular weight (Mw), it covers all molecular weight ranges having viscosity and film-forming ability capable of achieving the purpose of the present invention, ranging from low molecular weight (e.g., 10,000 Da or less) to high molecular weight (e.g., 500,000 Da or more).

[0057] In one embodiment of the present invention, the composition may additionally include a conventional composition for manufacturing microstructures or a component that may be contained in a microstructure. For example, it may include, but is not limited to, water-soluble polymers such as hyaluronic acid or its salt, carboxymethyl cellulose or its salt, vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol and polyvinylpyrrolidone; sugars such as xylose, sucrose, maltose, lactose, and trehalose; or a mixture thereof.

[0058] More specifically, the material that may be included in the above composition or microstructure is a water-soluble material that can swell or dissolve well within the skin, and may include hyaluronic acid or its salt, sodium carboxymethyl cellulose, poly(vinyl alcohol), poly(vinyl pyrrolidone), polyacrylate, sugars, or mixtures thereof.

[0059] In addition, the above composition or microstructure may additionally include plasticizers, surfactants, preservatives, etc., by comprehensively considering the skin penetration strength of the microstructure, the dissolution rate within the skin, etc.

[0060] As the above plasticizer, polyols such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, and glycerin may be used alone or in combination.

[0061] In one embodiment of the present invention, the composition may include a biodegradable polymer other than pullulan. The above-mentioned biodegradable polymer is polyester, polyhydroxyalkanoate (PHAs), poly(α-hydroxy acid), poly(β-hydroxy acid), poly(3-hydroxybutyrate-co-valerate; PHBV), poly(3-hydroxypropionate; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxy acid), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), poly(4-hydroxyhexanoate), poly(esteramide), polycaprolactone, polylactide, polyglycolide, poly(lactide-co-glycolide; PLGA), polydioxanone, polyorthoester, polyetherester, polyanhydride, poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acid), Polycyanoacrylate, Poly(trimethylene carbonate), Poly(iminocarbonate), Poly(tyrosine carbonate), Polycarbonate, Poly(tyrosine arylate), Polyalkylene oxalate, Polyphosphazenes, Polyvinylpyrrolidone (PVP), Polyvinyl alcohol, Polylactic glycolic acid, PHA-PEG, Carboxymethylcellulose (CMC), Hydroxyethylcellulose (HEC), Cellulose acetate phthalate, Polyvinyl acetate phthalate, Methacryl acid gelatin, Hydroxymethylcellulose phthalate, Hydroxypropylmethylcellulose phthalate, Hydroxyalkylmethylcellulose phthalate, Hydroxypropylmethylcellulose acetate succinate, Polyvinylpyrrolidone, Polyvinyl alcohol, Polyethylene oxide, Polyvinylacrylic acid, Hydroxypropylcellulose, Hydroxypropylmethyl It is one or more selected from the group consisting of cellulose, gelatin, agar, carrageenan, algin, collagen, chitosan, dextran, cellulose, hyaluronic acid, pullulan and salts thereof.

[0062] In this specification, the term "solids" may refer to the remaining substances excluding water contained in the composition. In one embodiment of the present invention, the solids include, for example, hyaluronic acid, a biodegradable polymer, a vitamin, and an antioxidant.

[0063] Among the 100 parts by weight of total solids included in the above composition, hyaluronic acid may be included, for example, 50 to 75 parts by weight, 50 to 72 parts by weight, 50 to 69 parts by weight, 50 to 66 parts by weight, 50 to 63 parts by weight, 50 to 60 parts by weight, 50 to 57 parts by weight, 50 to 54 parts by weight, 50 to 51 parts by weight, 53 to 75 parts by weight, 56 to 75 parts by weight, 59 to 75 parts by weight, 62 to 75 parts by weight, 65 to 75 parts by weight, 68 to 75 parts by weight, 71 to 75 parts by weight, 74 to 75 parts by weight, 55 to 73 parts by weight, 60 to 73 parts by weight, 65 to 73 parts by weight, or 67 to 73 parts by weight.

[0064] Among 100 parts by weight of total solids included in the above composition, pullulan may be included, for example, 1 to 10 parts by weight, 1 to 9 parts by weight, 1 to 8 parts by weight, 1 to 7 parts by weight, 1 to 6 parts by weight, 1 to 5 parts by weight, 1 to 4 parts by weight, 1 to 3 parts by weight, 1 to 2 parts by weight, 2 to 10 parts by weight, 3 to 10 parts by weight, 4 to 10 parts by weight, 5 to 10 parts by weight, 6 to 10 parts by weight, 7 to 10 parts by weight, 8 to 10 parts by weight, 9 to 10 parts by weight, 2 to 9 parts by weight, 3 to 5 parts by weight, 3 to 7 parts by weight, 3 to 8 parts by weight, or 4 to 6 parts by weight.

[0065] In one embodiment of the present invention, the hyaluronic acid comprises cross-linked hyaluronic acid, non-cross-linked hyaluronic acid, or a combination thereof.

[0066] In one embodiment of the present invention, the composition comprises 1 to 5 parts by weight of cross-linked hyaluronic acid in 100 parts by weight of total solids included in the composition. For example, the cross-linked hyaluronic acid may be included in 1 to 5 parts by weight, 1 to 4.5 parts by weight, 1 to 4 parts by weight, 1 to 3.5 parts by weight, 1 to 3 parts by weight, 1 to 2.5 parts by weight, 1 to 2 parts by weight, 1 to 1.5 parts by weight, 1.5 to 5 parts by weight, 2 to 5 parts by weight, 2.5 to 5 parts by weight, 3 to 5 parts by weight, 3.5 to 5 parts by weight, 4 to 5 parts by weight, 4.5 to 5 parts by weight, or 2 to 4 parts by weight in 100 parts by weight of total solids, but is not limited thereto.

[0067] In this specification, the meaning that hyaluronic acid is cross-linked refers to a state in which chemical or physical bonds (cross-linking) are formed between hyaluronic acid molecules, thereby forming a three-dimensional network structure in which a plurality of hyaluronic acid molecules are connected to each other.

[0068] Specifically, the cross-linked structure may include a mesh-like structure constructed by the reaction of functional groups of a cross-linker with hydroxyl groups (-OH) or carboxyl groups (-COOH) present in the backbone of hyaluronic acid to form covalent bonds.

[0069] For example, when an epoxy-based crosslinking agent (e.g., BDDE) is used, the hydroxyl groups of hyaluronic acid react with the epoxide groups of the crosslinking agent to form "ether bonds (-COC-)" and result in a cross-link bridge structure connecting the hyaluronic acid chains. Additionally, when a carbadiimide-based crosslinking agent is used, the carboxyl groups of hyaluronic acid react with amine or hydroxyl groups to form "amide bonds" or "ester bonds," resulting in a structure.

[0070] During this process, the physical, chemical, and mechanical properties of hyaluronic acid change. Cross-linked hyaluronic acid possesses a more robust network structure than individual hyaluronic acid molecules, resulting in increased physical stability. This property is highly advantageous when forming structures such as films, gels, and microneedles.

[0071] At this time, the above three-dimensional network structure may include not only a "full cross-linking" form in which both legs of the cross-linking agent are bonded to hyaluronic acid, but also a "pendent" form in which only one end of the cross-linking agent is bonded to hyaluronic acid. The cross-linked hyaluronic acid in the present invention has hydrogel characteristics that swell in an aqueous solution but do not dissolve through such cross-linking, or structural characteristics in which tensile strength is enhanced through a dense lattice structure when forming a film.

[0072] Furthermore, cross-linked hyaluronic acid can capture more moisture thanks to its three-dimensional network structure, thereby enhancing the moisturizing effect. Additionally, the degradation rate of cross-linked hyaluronic acid caused by enzymes (hyaluronidase) or environmental factors is slowed. This increases the duration of the product's action and enables the gradual release of the drug's efficacy in drug delivery. Moreover, cross-linking increases viscosity and strengthens mechanical strength during film formation.

[0073] The crosslinking of the hyaluronic acid can be achieved through various chemical or physical methods. For example, it can be formed by chemical crosslinking using epoxy compounds such as BDDE (1,4-butanediol diglycidyl ether) and ethylene glycol diglycidyl ether (EGDGE), or crosslinking agents such as DVS (divinyl sulfone) and carbodiimide, or by physical crosslinking using ultraviolet (UV) crosslinking with a photoinitiator, radiation, or heat treatment, but is not limited thereto.

[0074] In one embodiment of the present invention, the composition comprises cross-linked hyaluronic acid and non-cross-linked hyaluronic acid. In one embodiment of the present invention, the weight ratio of non-cross-linked hyaluronic acid to cross-linked hyaluronic acid is 5 to 100. For example, the weight ratio of non-crosslinked hyaluronic acid to crosslinked hyaluronic acid may be 5 to 100, 5 to 90, 5 to 80, 5 to 70, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 20, 5 to 15, 5 to 10, 10 to 100, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, 90 to 100, 10 to 80, 10 to 50, 10 to 30, 6 to 15, or 6 to 10, but is not limited thereto.

[0075] In one embodiment of the present invention, the pullulan is included in an amount of 3 to 7 parts by weight of 100 parts by weight of total solids included in the composition.

[0076] In one embodiment of the present invention, a microstructure with excellent physical stability and shape retention was formed within the content range of the pullulan; however, when the range was exceeded, the possibility of cracking of the film containing the manufactured microstructure increased, and when the range was exceeded, the microstructure was significantly reduced during drying and failed to maintain a stable shape.

[0077] In one embodiment of the present invention, the composition additionally comprises an antioxidant, a vitamin, or a combination thereof.

[0078] In this specification, the term "vitamin" includes various vitamins and their derivatives, precursors, modifications, etc., and such vitamins may exhibit various physiological effects such as skin improvement, antioxidant activity, and cell activation. The vitamins may include water-soluble vitamins (e.g., vitamin C, B vitamins) and fat-soluble vitamins (e.g., vitamin A, vitamin D, vitamin E, vitamin K). Preferably, vitamins having antioxidant properties, such as vitamin C (ascorbic acid) and vitamin E (tocopherol), may be included as key ingredients suitable for the present invention as they may exhibit skin whitening and wrinkle improvement effects.

[0079] The vitamins used in the present invention may be used not only in their original forms but also as precursors (e.g., ascorbyl palmitate, retinyl palmitate) or modified forms (e.g., chloride, phosphate, and glucoside forms of vitamin C) to improve stability and bioavailability. These precursors and modified forms can enhance stability while maintaining the physiological activity of the vitamins, thereby contributing to maximizing the performance of vitamin-containing microstructures. In addition, vitamins provided in mixed or complex forms may also be included within the scope of the present invention.

[0080] In one embodiment of the present invention, the antioxidant is glutathione, ascorbic acid derivatives, tocopherol, catechins, lutein, beta-carotene, alpha-lipoic acid, coenzyme Q10, resveratrol, selenium, flavonoids, polyphenols, gallic acid, quercetin, eriocitrin, proanthocyanidins, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene, One or more selected from the group consisting of ferulic acid, curcumin, ursolic acid, zeaxanthin, and gluconolactone. However, they are not limited thereto, and any that have antioxidant properties and can improve the storage stability of the vitamin may be used without restriction.

[0081] In one embodiment of the present invention, the weight ratio of the vitamin to the antioxidant is 0.5 to 2. The ratio of the above antioxidant to vitamin is, for example, 0.5 to 2, 0.5 to 1.9, 0.5 to 1.8, 0.5 to 1.7, 0.5 to 1.6, 0.5 to 1.5, 0.5 to 1.4, 0.5 to 1.3, 0.5 to 1.2, 0.5 to 1.1, 0.5 to 1.0, 0.5 to 0.9, 0.5 to 0.8, 0.5 to 0.7, 0.5 to 0.6, 0.6 to 2, 0.7 to 2, 0.8 to 2, 0.9 to 2, 1.0 to 2, 1.1 to 2, 1.2 to 2, 1.3 to 2, 1.4 to 2, 1.5 to 2, 1.6 to 2, It may be 1.7 to 2, 1.8 to 2, 1.9 to 2, 0.7 to 1.9, 0.9 to 1.7, 1.0 to 1.9, 1.5 to 1.8, 1.0 to 1.7, 1.0 to 1.6, or 1.0 to 1.5, but is not limited thereto.

[0082] In one embodiment of the present invention, it was confirmed that the storage stability of the vitamin is improved within the weight ratio range of the vitamin to the antioxidant. In particular, it was confirmed that the long-term storage stability of the vitamin is relatively excellent when the weight ratio of the vitamin to the antioxidant is 1 or 1.5.

[0083]

[0084] In one aspect of the present invention, a method for manufacturing a microstructure is provided, comprising the step of dispensing a composition for manufacturing a microstructure into a mold and drying to obtain a microstructure.

[0085] The micro mold of the present invention can be fabricated using any micro mold fabrication technique in the art. For example, MEMS (Micro-Electro Mechanical System) fabrication techniques, photolithography (Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery, Journal of Controlled Release 104, 51-66, 2005) fabrication techniques and soft lithography fabrication techniques may be used to fabricate the micro mold of the present invention, but are not limited thereto. Among these, when using soft lithography fabrication techniques, an elastomer mold such as PDMS (polydimethylsiloxane) or PMMA (Poly(methyl methacrylate e)) can be fabricated and used to fabricate microstructures. The technology for fabricating PDMS molds is a type of plastic processing technology, and a desired molding structure can be obtained through various methods such as casting, injection, and hot embossing. For example, a master is created by coating a photosensitive material onto a substrate such as a silicon wafer or glass and patterning it using a photomask. By casting PDMS into this as a mold and sintering it, a PDMS mold that functions as a stamp can be completed.

[0086] According to one embodiment of the present invention, the dispensing step of the present invention additionally includes the step of supplying the composition for manufacturing a microstructure of the present invention to a mold to form a base of a constant thickness. In this case, a base identical to the material constituting the microstructure can be formed, and the thickness of the base to minimize distortion of the base is 10 μm-200 μm or 30 μm-100 μm.

[0087] According to one embodiment of the present invention, the drying step of the present invention is carried out at 15-90°C for 10 minutes to 60 hours, at 20-80°C for 1-60 hours, or at 20-80°C for 1-50 hours. According to any embodiment of the present invention, the drying carried out after step (a) of the present invention is carried out at 10°C to less than 30°C for 12-60, 18-52, 24-48, 18-30, 42-54 hours; at 40-60°C for 1-8 hours, 2-8, 2-6, 2.5-6, 2-3, 4-8, 4-6, 5-7, or 3-5 hours; Or, perform at 60-90℃ or 60-80℃ for 1-5, 1-3, 1.5-5, 1.5-3, 1.5-2.5, 2-4, 2-3, or 1-2 hours.

[0088] The above drying process increases the mechanical strength of the microstructure and helps improve the flatness of the base.

[0089]

[0090] In one aspect of the present invention, the present invention provides a microstructure comprising hyaluronic acid and pullulan:

[0091] Of the total solid content of 100 parts by weight contained in the microstructure, the hyaluronic acid is included in an amount of 50 to 75 parts by weight, or the pullulan is included in an amount of 1 to 10 parts by weight.

[0092] Since the microstructure of the present invention shares commonalities with the composition for manufacturing the microstructure in that it contains hyaluronic acid and pullulan, redundant details are omitted to prevent excessive complexity in the specification.

[0093] The present invention may provide various microstructures, such as microneedles, microblades, microknives, microfibers, microspikes, microprobes, microbarbs, microarrays, or microelectrodes. According to one embodiment of the present invention, the microstructure of the present invention is a microneedle.

[0094] The shape of the micro-needle may be conical, pyramidal, sphere-shaped, brachycephalic, wedge-shaped, or blade-shaped. The length of the micro-needle may be in the range of 50 µm to 1,500 µm.

[0095] In one embodiment of the present invention, the hyaluronic acid comprises cross-linked hyaluronic acid, non-cross-linked hyaluronic acid, or a combination thereof.

[0096] In one embodiment of the present invention, the microstructure comprises 1 to 5 parts by weight of cross-linked hyaluronic acid in 100 parts by weight of total solid content included in the microstructure. For example, the cross-linked hyaluronic acid may be included in 1 to 5 parts by weight, 1 to 4.5 parts by weight, 1 to 4 parts by weight, 1 to 3.5 parts by weight, 1 to 3 parts by weight, 1 to 2.5 parts by weight, 1 to 2 parts by weight, 1 to 1.5 parts by weight, 1.5 to 5 parts by weight, 2 to 5 parts by weight, 2.5 to 5 parts by weight, 3 to 5 parts by weight, 3.5 to 5 parts by weight, 4 to 5 parts by weight, 4.5 to 5 parts by weight, or 2 to 4 parts by weight in 100 parts by weight of total solid content, but is not limited thereto.

[0097] In one embodiment of the present invention, the microstructure comprises cross-linked hyaluronic acid and non-cross-linked hyaluronic acid. In one embodiment of the present invention, the weight ratio of non-cross-linked hyaluronic acid to cross-linked hyaluronic acid is 10 to 100. For example, the weight ratio of non-crosslinked hyaluronic acid to crosslinked hyaluronic acid may be 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20, 20 to 100, 30 to 100, 40 to 100, 50 to 100, 60 to 100, 70 to 100, 80 to 100, 90 to 100, 20 to 90, 20 to 80, or 20 to 70, but is not limited thereto.

[0098] In one embodiment of the present invention, the pullulan is included in an amount of 3 to 7 parts by weight.

[0099] In one embodiment of the present invention, the composition additionally comprises an antioxidant, a vitamin, or a combination thereof.

[0100] In one embodiment of the present invention, the antioxidant is glutathione, ascorbic acid derivatives, tocopherol or its derivatives, catechins, lutein, beta-carotene, alpha-lipoic acid, coenzyme Q10, resveratrol, selenium, flavonoids, polyphenols, gallic acid, quercetin, eriocitrin, proanthocyanidins, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene One or more selected from the group consisting of Hydroxytoluene), Ferulic acid, Curcumin, Ursolic acid, Zeaxanthin, and Gluconolactone.

[0101] In one embodiment of the present invention, the weight ratio of the vitamin to the antioxidant is 0.5 to 2.

[0102] In one embodiment of the present invention, the microstructure has sufficient mechanical strength to penetrate the stratum corneum of the skin due to the optimal mixing ratio of hyaluronic acid and pullulan and the network structure of the cross-linked hyaluronic acid. Specifically, the microstructure may have a compressive strength or failure force of 0.05 N or more, preferably 0.1 N or more per needle. This enables the structure to stably deliver active ingredients to the dermis layer without buckling or breaking upon skin insertion. In particular, when 3 to 7 parts by weight of pullulan are included, the tip of the needle remains sharp even after the drying process, thereby maximizing skin insertability.

[0103] In one embodiment of the present invention, the microstructure may exhibit controlled release characteristics in which it does not immediately collapse upon contact with moisture in the skin, but rather swells and dissolves at a constant rate. For example, the microstructure of the present invention may have a dissolution profile in which at least 50%, preferably at least 80%, of the structure dissolves within 10 to 60 minutes after application to the skin. These dissolution characteristics are achieved by the rapid solubility of pullulan, a water-soluble polymer, and the swelling delay effect of cross-linked hyaluronic acid working complementarily, thereby minimizing skin irritation that may occur due to the rapid release of high-concentration vitamins and increasing the absorption rate of active ingredients.

[0104] In one embodiment of the present invention, the microstructure has excellent shape retention, such that the needle length reduction rate is maintained at less than 10%, preferably less than 5%, even when exposed to a high temperature and high humidity environment (e.g., 40°C, 75% relative humidity). This is because the oxygen blocking ability and low hygroscopicity of pullulan inhibit the melting down of the structure caused by the absorption of hyaluronic acid. Accordingly, the sharpness of the microneedle can be maintained for a long period during distribution even if a separate moisture-proof packaging is damaged.

[0105]

[0106] In one aspect of the present invention, the present invention provides a patch or cosmetic composition for whitening, wrinkle improvement, or a combination thereof, comprising the microstructure.

[0107] The cosmetic composition of the present invention may be prepared in any formulation conventionally manufactured in the art, for example, as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, and spray, but is not limited thereto. More specifically, it may be prepared in the form of a softening lotion, a nourishing lotion, a lotion, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.

[0108] The cosmetic composition of the present invention may include a carrier acceptable in a cosmetic formulation in addition to the active ingredient. The term "carrier acceptable in a cosmetic formulation" refers to an additional ingredient that is known and used to be included in a cosmetic formulation and can improve the application of the active ingredient to the skin, user convenience, and preference without significantly attenuating the main efficacy of the active ingredient or causing adverse effects on the human body.

[0109] The above carrier may be included in an amount of about 1% to about 99.99% by weight, preferably about 50% to about 99% by weight, based on the total weight of the composition of the present invention. However, the content of the above carrier may be appropriately adjusted according to the formulation of the cosmetic, the specific application site, and the preferred amount of application, and is not particularly limited.

[0110] In the case where the formulation of the present invention is a paste, cream, lotion, or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component.

[0111] In the case where the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, it may additionally include a propellant such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether.

[0112] When the formulation of the present invention is a solution or an emulsion, a solvent, a solubilizing agent, or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, or fatty acid ester of sorbitan.

[0113] In the case where the formulation of the present invention is a suspension, liquid diluents such as water, ethanol, or propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used as carrier components.

[0114] In the case where the formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester, etc. may be used as a carrier component.

[0115] In addition to the active ingredient and the carrier ingredient, the ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions, and may include, for example, conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances.

[0116] In one embodiment of the present invention, the patch comprising the microstructure is characterized by being attached to the skin.

[0117] In one embodiment of the present invention, the patch (or film) comprising the microstructure has excellent flexibility and elasticity. Specifically, the patch has physical properties that prevent it from lifting or tearing when attached to a curved skin surface, because 1 to 5 parts by weight of cross-linked hyaluronic acid and / or 3 to 7 parts by weight of pullulan in the total solid content perform the role of dispersing stress within the film matrix. In addition, the film prepared with the composition of the present invention does not crack even after drying and has secured durability that prevents it from being easily damaged by external impact.

[0118] In one embodiment of the present invention, the patch is characterized by comprising a microstructure and a sheet to which the structure is attached or formed.

[0119] In one embodiment of the present invention, the sheet may be made of a stretchable fabric. The sheet may be made of a fabric containing a hydrocolloid. The hydrophilic polymer constituting the hydrocolloid may include natural hydrophilic polymers such as pectin, gelatin, cellulose, specifically carboxymethylcellulose (CMC), collagen, dextran, elastin, chitin, chitosan, and sodium alginate; or synthetic hydrophilic polymers such as polyacrylic acid (PAA), polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, polyurethane, polyhydroxyethyl methacrylate, and silicone; or a combination thereof.

[0120] The above fabric may additionally further comprise an adhesive and / or a plasticizer. The adhesive may comprise phenol-modified terpenes; rosin esters, e.g., glycerol esters of rosin and pentaerythritol esters of rosin; elastomeric adhesives such as polyisobutylene; non-elastomeric adhesives including synthetic polyterpene adhesives; or a combination of two or more of these. The plasticizer may be used to provide wetting action and / or viscosity control. These plasticizers are well known in the art and may comprise liquid or flexible adhesives, waxes, and oil mixtures, including hydrocarbon oils, liquid hydrocarbon resins, liquid polyterpenes, liquid poly(isobutylene), e.g., GLISSOPAL. As an example, the plasticizer may be a paraffin wax.

[0121] The fabric containing the above hydrocolloid may additionally contain aerogel particles. The aerogel particles are highly porous nanostructures having nanometer-sized pores obtained by replacing the liquid within the gel structure with air, and may be silica aerogel particles.

[0122] In one embodiment of the present invention, the microstructure patch is made of a biodegradable material and has sufficient ductility and strength. The microstructure patch contains the aforementioned cosmetic ingredients and has the advantage of being able to efficiently deliver the cosmetic ingredients directly into the skin through the microstructure.

[0123] The material forming the above microstructure patch may be one that swells or dissolves within the skin.

[0124] When looking from the base to the tip, the structure or shape of the microstructure of the present invention can be any shape, such as a square pyramid shape, a triangular pyramid shape, a combination of a triangular pyramid and a frustum of a triangle, a combination of a square pyramid and a frustum of a square, a cone shape, a combination of a cone and a frustum of a cone, a stepped pyramid shape, a microblade shape, a bullet shape, etc., with the width of the base narrowing from wide to tip.

[0125] The length of the microstructure of the present invention is preferably within the range of 20 μm to 1 mm. More specifically, the length is preferably 500 μm or less, 400 μm or less, 300 μm, 290 μm or less, 280 μm or less, 270 μm, 250 μm or less, and is characterized by having a length of 270 μm or less so as not to cause pain or uncomfortable irritation during outdoor activities.

[0126] The diameter of the above microstructure may be 150 μm or less, 140 μm or less, 130 μm or less, 120 μm or less, 110 μm or less, 100 μm or less, but must have a diameter of 120 μm or less to ensure that there is no pain or uncomfortable irritation during outdoor activities.

[0127] The spacing of the above microstructures is preferably 1 mm or less, but is not limited thereto.

[0128] The microstructure patch of the present invention can be manufactured to include 500 or more, 600 or more, 700 or more, or 800 or more microstructures inside the patch.

[0129]

[0130] In one aspect of the present invention, the present invention provides a non-therapeutic cosmetic method for whitening or improving wrinkles by attaching the microstructure or a patch containing the same to the skin of a subject.

[0131] In one embodiment of the present invention, the cosmetic method includes the step of dissolving the microstructure by maintaining the microstructure or patch on the skin for 10 to 60 minutes.

[0132] Specifically, the cosmetic method according to the present invention may include the steps of: (a) attaching the microstructure or patch to the surface of the skin of a subject; and (b) maintaining the microstructure for a certain period of time so that it releases an active ingredient as it dissolves due to moisture inside the skin.

[0133] The above method may be limited to a non-therapeutic method for achieving cosmetic effects such as skin whitening, wrinkle improvement, elasticity enhancement, and moisturization, rather than for therapeutic purposes. Additionally, step (b) may include maintaining the patch for 10 minutes to 12 hours, preferably 30 minutes to 2 hours, after application, and during this process, high concentrations of vitamins and antioxidants contained in the microstructure are delivered to the dermis layer to improve skin tone and exhibit an effect of inhibiting aging.

[0134] In addition, the cosmetic method of the present invention may further include a step of cleansing the skin or applying a pretreatment agent such as a toner or essence before and after attaching the patch. Such a pretreatment step can contribute to increasing the penetration efficiency of the microstructure or controlling the dissolution rate by adjusting the surface tension of the skin.

[0135]

[0136] The features and advantages of the present invention are summarized as follows:

[0137] (a) The present invention provides a composition for manufacturing a microstructure comprising hyaluronic acid and pullulan.

[0138] (b) The present invention provides a method for manufacturing a microstructure using the composition for manufacturing the microstructure.

[0139] (c) The present invention provides a microstructure comprising hyaluronic acid and pullulan.

[0140] (d) The present invention provides a patch comprising the microstructure.

[0141] (e) When using the composition for manufacturing microstructures according to the present invention, a high concentration of active ingredients can be loaded into the microstructure, and a microstructure having whitening and wrinkle improvement functions can be formed by including a high concentration of vitamins.

[0142]

[0143] Figures 1 and 2 show the results of analyzing the characteristics of microstructures according to the type of biodegradable polymer.

[0144] Figure 3 shows the results of analyzing the characteristics of the microstructure according to the pullulan content.

[0145]

[0146]

[0147] The present invention will be described in more detail below through examples. These examples are intended solely to explain the invention more specifically, and it will be obvious to those skilled in the art that the scope of the invention is not limited by these examples according to the gist of the invention.

[0148]

[0149] Examples

[0150] The present invention will be described in more detail below through examples. These examples are intended solely to explain the invention more specifically, and it will be obvious to those skilled in the art that the scope of the invention is not limited by these examples according to the gist of the invention.

[0151]

[0152] Examples

[0153] Example 1: Comparison of Productivity and Stability of Microstructures According to Type of Biodegradable Polymer

[0154] In existing compositions for forming microneedle structures, a high content of hyaluronic acid (over 75%) was essential to ensure film stability; however, this posed a limitation in incorporating high concentrations of active ingredients. Therefore, we aimed to develop a new composition capable of forming stable microstructures while containing high concentrations of active ingredients by optimizing the type and ratio of biodegradable polymers, including hyaluronic acid.

[0155] Microstructures were prepared using various biodegradable polymers and hyaluronic acid. The types and proportions of biodegradable polymers were determined based on the compositions presented in Table 1. Each composition was fabricated using a known molding technique, and the shape and stability of each microstructure were evaluated.

[0156]

[0157]

[0158] Microstructure Formulation Ratio According to Type of Biodegradable Polymer (Solid Content) No. Component Comparison Example 1-1 Comparison Example 1-2 Comparison Example 1-3 Comparison Example 1-4 Comparison Example 1-5 Preparation Example 1 1 Sodium hyaluronate 66667471717 12 Cellulose gum 10-----Trehalose-10----Xanthan gum--2---Glycerin---5--1,3-bg (Butylene glycol)----5-Pululan-----5 3 Ascorbic acid 121212121212 4 Gluthathione 121212121212 Total-100100100100100100

[0159]

[0160] The results are shown in Figures 1 and 2.

[0161] As shown in FIGS. 1 and 2, in the case of Comparative Examples 1-1 and 1-3 containing cellulose gum and xanthan gum, a large number of defective needles were produced, such as those with foreign matter on the needle tips, and the film containing the microstructure exhibited poor physical properties, such as flaring. In Comparative Example 1-2, trehalose showed severe needle shrinkage, and it was confirmed that the needle length was significantly reduced after high-temperature drying; when produced as a film, it showed a lack of flexibility and a tendency to break. In the case of the glycerin and butylene glycol-containing microstructures of Comparative Examples 1-4 and 1-5, they absorbed moisture well, resulting in severe film sagging and a high likelihood of tearing due to the thinness of the film; furthermore, the needle tips were thin and slender at 25°C. Additionally, after drying under accelerated conditions, the needles shrank significantly, causing the needle tips to become blunt. On the other hand, the pullulan-containing microstructure of Preparation Example 1 showed excellent results in terms of needle length and shape. In other words, it was confirmed that pullulan, among biodegradable polymers, can provide excellent physical properties of the manufactured microstructures.

[0162]

[0163] Example 2: Comparison of the stability of microstructures according to pullulan content

[0164] To determine the optimal content ratio of the selected pullulan, the effect of pullulan content on microstructure formation and stability was evaluated. Based on the compositions presented in Table 2, a total of five samples were prepared by adjusting the pullulan content to 0%, 3%, 5%, 7%, and 10%. The remaining compositions contained hyaluronic acid, ascorbic acid, and glutathione in specific proportions. Microneedles were formed from each composition using a molding technique, and the fabricated microstructures were evaluated based on shape, physical stability, and shape retention under storage conditions (25°C, 60% relative humidity).

[0165]

[0166] Microstructure Formulation Ratios with Different Pullulan Contents (Solid Content) No. Component Preparation Example 2-1 Preparation Example 2-2 Preparation Example 2-3 Preparation Example 2-4 Preparation Example 2-5 1 Sodium hyaluronate 7673 7169 66 2 Pullulan 357 10 3 Ascorbic acid 12 12 12 12 12 4 Gluthaline 12 12 12 12 Total 100 100 100 100 100

[0167]

[0168] The results are shown in Figure 3.

[0169] As shown in Figure 3, the composition with 0% pullulan content had a short length of microstructures, and the length of the needles was significantly reduced when dried at high temperature under accelerated conditions. This is believed to be because hyaluronic acid alone lacked the physical strength required for film formation.

[0170] Compositions with pullulan contents of 3% and 5% formed microstructures of excellent shape and showed the best results in physical stability and shape retention. The composition with a pullulan content of 7% also formed stable microstructures, but a slight increase in hardness and a decrease in flexibility were observed compared to the 3% and 5% compositions. The composition with a pullulan content of 10% resulted in an excessively thick film, and the fabricated microstructures had low flexibility, increasing the likelihood of film cracking.

[0171] As a result, it was confirmed that a composition with a pullulan content of 3% to 7% is suitable for forming microstructures, and in particular, a composition with 3% to 5% exhibits the best stability and physical properties. Pullulan plays an important role in interacting with hyaluronic acid to improve the mechanical strength of the film and enabling the formulation of high concentrations of active ingredients.

[0172]

[0173] Example 3: Comparison of Stability of Microstructures Loaded with High-Content Vitamins According to Antioxidant Ratio

[0174] The effect of the ratio of the antioxidants glutathione (GSH) and ascorbic acid on the stability of microstructures containing high-dose vitamins was analyzed. Through this, the aim was to identify the optimal antioxidant formulation ratio capable of ensuring the long-term stability of high-dose vitamins.

[0175] As shown in Table 3, five compositions containing various ratios of glutathione and ascorbic acid were designed, and the ratios of antioxidant to vitamin C in each composition were 1:12, 3:12, 6:12, 12:12, and 18:12, respectively. Microstructures were formed using a molding technique with compositions containing pullulan (5%) and hyaluronic acid.

[0176]

[0177] Microstructure formulation ratios with varying ratios of ascorbic acid and glutathione (solid content) No. Component Comparison Example 3 Preparation Example 3-1 Preparation Example 3-2 Preparation Example 3-3 Preparation Example 3-4 Preparation Example 3-5 1 Sodium hyaluronate 8 2.00 8 1.00 7 9.00 7 6.00 7 0.00 6 4.00 2 sodium hyaluronate crosspolymer 2 1.00 1.00 1.00 1.00 1.00 1.00 3 pullulan 5.00 5.00 5.00 5.00 5.00 4 ascorbic acid12.0012.0012.0012.0012.0012.005Glutathione0.001.003.006.0012.0018.00Total-100100100100100100

[0178]

[0179] The manufactured microstructures were stored under accelerated conditions (40°C, 75% relative humidity) and the vitamin content was analyzed over a certain period. The vitamin retention rate (%) over time was compared based on the initial vitamin content (week 0).

[0180] The results are shown in Table 4.

[0181] As shown in Table 4, the vitamin retention rate decreased sharply to 20.2% after 8 weeks in the composition without antioxidants. Vitamin stability improved in the composition containing glutathione, and the vitamin retention rate tended to increase with higher glutathione ratios. A vitamin retention rate of 62.1% was observed after 8 weeks at a GSH:VC ratio of 6:12, demonstrating relatively high stability. The best stability was observed when the GSH:VC ratios were 12:12 and 18:12, with vitamin retention rates of 84.7% and 89.9%, respectively, after 8 weeks.

[0182] After 12 weeks, the vitamin retention rate was very low at 6.3% in the composition without antioxidants, which indicates that vitamin oxidation had progressed significantly. On the other hand, the composition with a GSH:VC ratio of 6:12 showed relatively good stability with a vitamin retention rate of 59% after 12 weeks, while the compositions with GSH:VC ratios of 12:12 and 18:12 showed even higher stability at 76.5% and 92.4%, respectively. In particular, the GSH:VC ratio of 18:12 was found to have the best long-term stability of vitamins.

[0183] After 16 weeks, the vitamin retention rate in the composition without antioxidants was 4.1%, indicating almost complete loss, whereas the composition with a GSH:VC ratio of 6:12 showed a vitamin retention rate of 34.9%. The compositions with GSH:VC ratios of 12:12 and 18:12 showed 73.6% and 80.4%, respectively, demonstrating a distinct difference in long-term vitamin stability. This confirmed that the higher the glutathione ratio, the more effectively the stability of the vitamin can be maintained.

[0184]

[0185] Vitamin Residue Rate According to Ratio of Glutathione and Ascorbic Acid Vitamin Content Analysis Comparative Example 3 Preparation Example 3-1 Preparation Example 3-2 Preparation Example 3-3 Preparation Example 3-4 Preparation Example 3-5 0 100 100 100 100 100 100 1W 75.9 98.4 96.3 105.6 94.8 99.82W 70.4 878 4.9 98.3 93.8 99.84W 50.5 60.3 70.4 74.5 90 92.58W 20.2 27.6 55.1 62.1 84.7 89.9 12W 6.3 20.7 36.8 59 76.5 92.4 16W 4.1 6.6 4.9 34.9 73.6 80.4

[0186]

[0187] In conclusion, the ratio of the antioxidant glutathione had a significant impact on the stability of microstructures containing high-dose vitamins. In particular, compositions with GSH:VC ratios of 12:12 and 18:12 were determined to be optimal formulations capable of effectively maintaining the long-term stability of vitamins. Through this example, it was confirmed that controlling the ratio of antioxidants is an important design factor in ensuring vitamin stability.

[0188]

[0189] Example 4: Comparison of Stability of Microstructures Loaded with High-Content Vitamins According to Hyaluronic Acid Crosslinking Ratio

[0190] To ensure excellent physical properties of the fabricated microstructures, cross-linked hyaluronic acid hydrogel and non-cross-linked hyaluronic acid were combined to determine an appropriate formulation ratio. The advantages of incorporating cross-linked hyaluronic acid hydrogel in appropriate proportions are as follows: First, the cross-linked structure significantly improves the physical stability of hyaluronic acid, thereby enhancing the structural durability of the microstructures, which are uniform during film formation with minimized distortion. Second, the cross-linked hyaluronic acid hydrogel provides high moisture retention, maximizing hydration and moisturizing effects when applied to the skin. Third, due to the excellent swelling properties of the cross-linked structure, the degradation rate of hyaluronic acid can be controlled, resulting in a longer in vivo duration and enabling more stable delivery of the active ingredients in the microneedle patch. These characteristics contribute to simultaneously securing the stability and functionality of microstructures containing high concentrations of active ingredients. The formulation ratios are shown in Table 5.

[0191]

[0192] Formulation ratios with different ratios of non-crosslinked hyaluronic acid and crosslinked hyaluronic acid (Solid content) No. Component Comparison Example 4 Preparation Example 4-1 Preparation Example 4-2 Preparation Example 4-3 Preparation Example 4-4 Preparation Example 4-5 1 Sodium hyaluronate 7 1.00 7 0.00 6 6.00 6 1.00 5 1.00 4 1.00 2 sodium hyaluronate crosspolymer 2 0.00 1.00 5.00 10.00 20.00 30.00 3 pullulan 5.00 5.00 5.00 5.00 5.00 5.00 4 ascorbic acid12.0012.0012.0012.0012.0012.005Glutathione12.0012.0012.0012.0012.0012.00Total-100100100100100100

[0193]

[0194] As a result of analyzing the structural stability of the manufactured microstructures and films containing them, it was confirmed that Preparation Examples 4-1 and 4-2 exhibited excellent physical properties due to the flexibility of the thin film itself. On the other hand, Preparation Examples 4-3, 4-4, and 4-5, which had a high proportion of cross-linked hyaluronic acid, were found to be unsuitable for manufacturing microstructure films because the thin film became opaque.

[0195] As a result, it was confirmed that the physical properties of the microstructure can be improved when cross-linked hyaluronic acid is included in an amount of 1 to 5% of the total solid content in the composition for manufacturing the microstructure, or when the weight ratio of non-cross-linked hyaluronic acid to cross-linked hyaluronic acid is 5 to 100.

Claims

1. Composition for manufacturing microstructures comprising hyaluronic acid and pullulan: Of the total solid content of 100 parts by weight included in the above composition, the hyaluronic acid is included in an amount of 50 to 75 parts by weight, or the pullulan is included in an amount of 1 to 10 parts by weight.

2. A composition for manufacturing a microstructure according to claim 1, wherein the hyaluronic acid comprises cross-linked hyaluronic acid, non-cross-linked hyaluronic acid, or a combination thereof.

3. A composition for manufacturing a microstructure according to claim 1, wherein the composition comprises 1 to 5 parts by weight of cross-linked hyaluronic acid in 100 parts by weight of total solid content included in the composition.

4. A composition for manufacturing a microstructure according to claim 1, wherein the pullulan is included in an amount of 1 to 10 parts by weight.

5. A composition for manufacturing a microstructure according to claim 1, wherein the composition additionally comprises an antioxidant, a vitamin, or a combination thereof.

6. In claim 5, the antioxidant is glutathione, ascorbic acid derivatives, tocopherol or its derivatives, catechins, lutein, beta-carotene, alpha-lipoic acid, coenzyme Q10, resveratrol, selenium, flavonoids, polyphenols, gallic acid, quercetin, eriocitrin, proanthocyanidins, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene A composition for manufacturing microstructures, comprising one or more selected from the group consisting of hydroxytoluene, ferulic acid, curcumin, ursolic acid, zeaxanthin, and gluconolactone.

7. A composition for manufacturing a microstructure, wherein, in claim 5, the weight ratio of the vitamin to the antioxidant is 0.5 to 2.

8. A method for manufacturing a microstructure comprising the step of dispensing a composition for manufacturing a microstructure according to any one of claims 1 to 7 into a mold and drying to obtain a microstructure.

9. Microstructures containing hyaluronic acid and pullulan: Of the total solid content of 100 parts by weight contained in the microstructure, the hyaluronic acid is included in an amount of 50 to 75 parts by weight, or the pullulan is included in an amount of 1 to 10 parts by weight.

10. A microstructure according to claim 9, wherein the hyaluronic acid comprises cross-linked hyaluronic acid, non-cross-linked hyaluronic acid, or a combination thereof.

11. In claim 9, the microstructure comprises 1 to 5 parts by weight of cross-linked hyaluronic acid in 100 parts by weight of total solid content contained in the microstructure.

12. In claim 9, the microstructure is a microstructure that additionally comprises an antioxidant, a vitamin, or a combination thereof.

13. In claim 9, the antioxidant is glutathione, ascorbic acid derivatives, tocopherol or its derivatives, catechins, lutein, beta-carotene, alpha-lipoic acid, coenzyme Q10, resveratrol, selenium, flavonoids, polyphenols, gallic acid, quercetin, eriocitrin, proanthocyanidins, sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene A microstructure that is one or more selected from the group consisting of hydroxytoluene), ferulic acid, curcumin, ursolic acid, zeaxanthin, and gluconolactone.

14. A microstructure according to claim 12, wherein the weight ratio of the vitamin to the antioxidant is 0.5 to 2.

15. A patch for whitening, wrinkle improvement, or a combination thereof comprising the microstructure of claim 12.

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