Microstructure containing oil-soluble component and manufacturing method therefor

Abstract

The present invention relates to a microneedle containing an oil-soluble component and a manufacturing method therefor. The use of an emulsion composition and a composition for manufacturing a microstructure of the present invention enables the effective production of microstructures containing an oil-soluble component.

Description

Microstructure containing useful components and method for manufacturing the same

[0001] This patent application claims priority to Republic of Korea Patent Application No. 10-2023-0168655, filed with the Korean Intellectual Property Office on November 28, 2023, the disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a microstructure containing a useful component and a method for manufacturing the same.

[0003]

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

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

[0006] Among these, injection therapy has the problem that the administration method is cumbersome, may be painful for some patients, and there are limitations to control other than the method of temporarily injecting the drug.

[0007] To improve the shortcomings of these injection therapies, research has been conducted on micro-structures (microneedles) that are much smaller and less painful than syringe needles, and research is being conducted in various fields such as drug delivery, blood collection, biosensors, and skin beauty.

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

[0009] Recently, microneedle patches with microneedles have been used for skin care applications, such as mask packs. Their primary ingredient is often hyaluronic acid, a hydrophilic biomaterial. Hyaluronic acid, a polysaccharide found in the human body, is a biodegradable polymer compound composed of N-acetylglucosamine and glucuronic acid. Its high viscosity and excellent water-holding properties play a crucial role in preventing bacterial invasion and the infiltration of toxins, while also supplying moisture to the skin, helping maintain its moisture and elasticity.

[0010] In the case of microneedles containing such hydrophilic polymers, there is a risk that the oil components will not be evenly mixed and will separate when mixing the oil components, and even if the hydrophilic component and the oil particles are mixed, the oil particles exist in a form with a relatively large particle size compared to the hydrophilic component, so when forcibly mixing and solidifying them to manufacture microneedles, the mixed liquid oil particles may be very large, which may cause a decrease in the strength and quality of the microneedles.

[0011] Therefore, research is needed on an emulsification process to effectively load oil components while maintaining the stability of microneedles.

[0012]

[0013] The inventors of the present invention have diligently researched and developed appropriate emulsifying conditions for loading oil components into microstructures. As a result, they discovered that using a specific combination of emulsifiers could produce stable, oil-loaded microstructures, thereby completing the present invention.

[0014] Accordingly, an object of the present invention is to provide an emulsion composition comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

[0015] Another object of the present invention is to provide a composition for producing a microstructure comprising an emulsion containing a water-soluble component and a biodegradable polymer.

[0016] Another object of the present invention is to provide a method for manufacturing a microstructure comprising a useful component.

[0017] Another object of the present invention is to provide a microstructure comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

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

[0019]

[0020] In one aspect of the present invention, the present invention provides an emulsion composition comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

[0021] The inventors of the present invention have conducted extensive research to identify appropriate emulsifying conditions for loading oil components into microstructures. As a result, they have discovered that using a specific emulsifier combination can produce microstructures loaded with stable oil.

[0022] In the present invention, the term "emulsion" refers to a mixture of two or more insoluble liquids. While these liquids typically do not mix, an emulsion allows tiny droplets of one liquid to be evenly dispersed within the other. This phenomenon occurs with the help of an emulsifier, which helps ensure the stable mixing of the two liquids.

[0023] In the present invention, the term "emulsifier" refers to a substance that helps water and oil mix to form a stable mixture. This substance may be a surfactant, an emulsifying agent, or a combination thereof. Surfactants play a crucial role in creating a stable mixture by mixing water and oil components. Emulsifying agents play a supporting role in this emulsifying process and can affect the texture and stability of the product.

[0024] In this specification, the term polysorbate 80 means a surfactant that is highly soluble in water, sorbitan stearate means a nonionic surfactant that mainly works in an oil phase, glyceryl monostearate means an emulsifying agent that mainly works in an oil phase, glyceryl stearate and PEG-100 stearate are a complex of glyceryl stearate and PEG-100 stearate and are emulsifying agents that mainly work in an oil phase, cetyl alcohol means an emulsifying agent that mainly works in an oil phase, and stearic acid means an emulsifying agent that mainly works in an oil phase.

[0025] In one specific embodiment of the present invention, the oil is, for example, Arnica (Arnica Montana), Basil (Ocimum Basilicum), Bergamot (Citrus Bergamia), Cedarwood (Cedrus Atlantica), Chamomile Roman (Chamaemelum Nobile), Cinnamon (Cinnamomum Cassia), Cinnamon Bark (Cinnamomum Verum), Cistus Ladanifer, Clary Sage (Salvia Sclarea), Clover (Syzygium Aromaticum), Eugenol, Coriander (Coriandrum Sativum), Cypress (Cupressus Sempervirens), Dill (Anethum Graveolens), Elemi (Canarium Luzonicum), Eucalyptus Dives, Eucalyptus Globulus, Eucalyptus Polybractia (Eucalyptus Polybractea), Eucalyptus Radiata (Eucalyptus Radiata), Fennel (Foeniculum Vulgare), Douglas Fir (Pseudotsuga Menziesii), White Fir (Abies Grandis), Frankincense (Boswellia Carteri), Galbanum (Ferula Gummosa), Geranium (Pelargonium Graveolens), Ginger (Zingiber Officinale), Goldenrod (Solidago Canadensis), Gotu Kola (Centella Asiatica), Grapefruit (Citrus Paradisi), Helichrysum (Helichrysum Italicum), Hyssop (Hyssopus Officinalis), Idaho Balsam Fir (Abies Balsamea), Jasmine (Jasminum Officinale), Juniper (Juniperus Osteosperma, Juniperus Scopulorum), Laurus Nobilis (Laurus Nobilis), Lavender (Lavandula Angustifolia), Ledum (Ledum Groenlandicum),Lemon (Citrus Limon), Lemongrass (Cymbopogon Flexuosus), Marjoram (Origanum Majorana), Melaleuca Alternifolia or Tea Tree Oil (Melaleuca Alternifolia), Melaleuca Ericifolia, Melissa (Melissa Officinalis), Mountain or Winter Savory (Satureja Montana), Myrrh (Commiphora Myrrha), Myrtle (Myrtus Communis), Nutmeg (Myristica Fragrans), Orange (Citrus Aurantium), Oregano (Origanum Compactum), Palmarosa (Cinopogon Martini), Patchouli (Pogostemon Cablin), Black Pepper (Piper Nigrum), Peppermint (Mentha piperita), Petitgrain (Citrus Aurantium), Pine (Pinus Sylvestris), Ravensara (Ravensara Aromatica), Rose (Rosa Damascena), Rosemary (Rosmarinus Officinalis), Rosewood (Aniba Rosaeodora), Sage (Salvia Officinalis), Sandalwood (Santalum Album), Spearmint (Mentha Spicata), Spikenard (Nardostachys Jatamansi), Spruce (Picea Mariana), St. John's Wort (Hypericum Perforatum), Tangerine (Citrus Reticulata), Tansy Idaho (Tanacetum Vulgare), Tarragon (Artemisia Dracunculus), Thyme (Thymus Vulgaris), Tsuga (Tsuga Canadensis), Valerian (Valariana Officinalis), Vetiver (Vetiveria Zizanioides), Western Red Cedar (Thuja Plicata), Wintergreen (Gaultheria Procumbens), Ylang Ylang (Cananga Odorata), Jojoba Seed, or their oils.But it is not limited to this.

[0026] In one embodiment of the present invention, the emulsion composition comprises water, and comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80, based on 100 parts by weight of water.

[0027] For example, sorbitan stearate is present in an amount of 0.2 to 1.0 parts by weight, 0.2 to 0.95 parts by weight, 0.2 to 0.9 parts by weight, 0.2 to 0.85 parts by weight, 0.2 to 0.8 parts by weight, 0.2 to 0.75 parts by weight, 0.2 to 0.7 parts by weight, 0.2 to 0.65 parts by weight, 0.2 to 0.6 parts by weight, 0.2 to 0.55 parts by weight, 0.2 to 0.5 parts by weight, 0.2 to 0.45 parts by weight, 0.2 to 0.4 parts by weight, 0.2 to 0.35 parts by weight, 0.2 to 0.3 parts by weight, 0.2 to 0.25 parts by weight, 0.25 to 1.0 parts by weight, 0.3 to 1.0 parts by weight, 0.35 to 1.0 part by weight, 0.4 to 1.0 part by weight, 0.45 to 1.0 part by weight, 0.5 to 1.0 part by weight, 0.55 to 1.0 part by weight, 0.6 to 1.0 part by weight, 0.65 to 1.0 part by weight, 0.7 to 1.0 part by weight, 0.75 to 1.0 part by weight, 0.8 to 1.0 part by weight, 0.85 to 1.0 part by weight, 0.9 to 1.0 part by weight, 0.95 to 1.0 part by weight, 0.3 to 0.9 part by weight, 0.3 to 0.8 part by weight, 0.3 to 0.75 part by weight, 0.3 to 0.7 part by weight, 0.3 to 0.65 part by weight, 0.3 to 0.6 part by weight, 0.3 to 0.55 part by weight, It may include, but is not limited to, 0.3 to 0.5 parts by weight, 0.3 to 0.45 parts by weight, 0.3 to 0.4 parts by weight, or 0.3 to 0.35 parts by weight.

[0028] For example, glyceryl monostearate is present in an amount of 0.2 to 1.8 parts by weight, 0.2 to 1.6 parts by weight, 0.2 to 1.4 parts by weight, 0.2 to 1.2 parts by weight, 0.2 to 1.0 parts by weight, 0.2 to 0.8 parts by weight, 0.2 to 0.6 parts by weight, 0.2 to 0.4 parts by weight, 0.4 to 2.0 parts by weight, 0.6 to 2.0 parts by weight, 0.8 to 2.0 parts by weight, 1.0 to 2.0 parts by weight, 1.2 to 2.0 parts by weight, 1.4 to 2.0 parts by weight, 1.6 to 2.0 parts by weight, 1.8 to 2.0 parts by weight, 0.3 to 1.7 parts by weight, 0.3 to 1.4 parts by weight, 0.3 to 1.1 parts by weight, It may include, but is not limited to, 0.3 to 0.8 parts by weight, 0.3 to 0.7 parts by weight, 0.4 to 0.6 parts by weight, or 0.5 to 0.6 parts by weight.

[0029] For example, glyceryl stearate and PEG-100 stearate may be present in amounts of 1.0 to 5.0 parts by weight, 1.0 to 4.5 parts by weight, 1.0 to 4.0 parts by weight, 1.0 to 3.5 parts by weight, 1.0 to 3.0 parts by weight, 1.0 to 2.5 parts by weight, 1.0 to 2.0 parts by weight, 1.0 to 1.5 parts by weight, 1.5 to 5.0 parts by weight, 2.0 to 5.0 parts by weight, 2.5 to 5.0 parts by weight, 3.0 to 5.0 parts by weight, 3.5 to 5.0 parts by weight, 4.0 to 5.0 parts by weight, 4.5 to 5.0 parts by weight, 1.5 to 4.5 parts by weight, 2.0 to 4.0 parts by weight, 2.0 to 3.0 parts by weight, 2.0 to 2.5 parts by weight may be included, but is not limited thereto.

[0030] For example, polysorbate 80 may be present in an amount of 0.2 to 1.8 parts by weight, 0.2 to 1.6 parts by weight, 0.2 to 1.4 parts by weight, 0.2 to 1.2 parts by weight, 0.2 to 1.0 parts by weight, 0.2 to 0.8 parts by weight, 0.2 to 0.6 parts by weight, 0.2 to 0.4 parts by weight, 0.4 to 2.0 parts by weight, 0.6 to 2.0 parts by weight, 0.8 to 2.0 parts by weight, 1.0 to 2.0 parts by weight, 1.2 to 2.0 parts by weight, 1.4 to 2.0 parts by weight, 1.6 to 2.0 parts by weight, 1.8 to 2.0 parts by weight, 0.3 to 1.5 parts by weight, 0.3 to 1.0 parts by weight, 0.3 to 0.7 parts by weight or It may contain, but is not limited to, 0.4 to 0.6 parts by weight.

[0031] In one embodiment of the present invention, the emulsion composition additionally contains 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof, per 100 parts by weight of water.

[0032] For example, cetyl alcohol may be present in an amount of 1.0 to 5.0 parts by weight, 1.0 to 4.5 parts by weight, 1.0 to 4.0 parts by weight, 1.0 to 3.5 parts by weight, 1.0 to 3.0 parts by weight, 1.0 to 2.5 parts by weight, 1.0 to 2.0 parts by weight, 1.0 to 1.5 parts by weight, 1.5 to 5.0 parts by weight, 2.0 to 5.0 parts by weight, 2.5 to 5.0 parts by weight, 3.0 to 5.0 parts by weight, 3.5 to 5.0 parts by weight, 4.0 to 5.0 parts by weight, 4.0 to 5.0 parts by weight, 1.5 to 4.0 parts by weight, 1.0 to 3.5 parts by weight, 1.0 to 3.0 parts by weight, 1.0 to 2.5 parts by weight, or 1.5 to 2.5 parts by weight may be included, but is not limited thereto.

[0033] For example, stearic acid may be present in an amount of 0.1 to 1.0 parts by weight, 0.1 to 0.9 parts by weight, 0.1 to 0.8 parts by weight, 0.1 to 0.7 parts by weight, 0.1 to 0.6 parts by weight, 0.1 to 0.5 parts by weight, 0.1 to 0.4 parts by weight, 0.1 to 0.3 parts by weight, 0.1 to 0.2 parts by weight, 0.2 to 1.0 parts by weight, 0.3 to 1.0 parts by weight, 0.4 to 1.0 parts by weight, 0.5 to 1.0 parts by weight, 0.6 to 1.0 parts by weight, 0.7 to 1.0 parts by weight, 0.8 to 1.0 parts by weight, 0.9 to 1.0 parts by weight, 0.2 to 0.8 parts by weight, 0.3 to 0.7 parts by weight, or 0.4 to May contain, but is not limited to, 0.6 parts by weight.

[0034] In one embodiment of the present invention, the emulsion composition contains 1.0 to 10.0 parts by weight of oil per 100 parts by weight of water. For example, the oil may be present in an amount of 1.0 to 10.0 parts by weight, 1.0 to 9.5 parts by weight, 1.0 to 9.0 parts by weight, 1.0 to 8.5 parts by weight, 1.0 to 8.0 parts by weight, 1.0 to 7.5 parts by weight, 1.0 to 7.0 parts by weight, 1.0 to 6.5 parts by weight, 1.0 to 6.0 parts by weight, 1.0 to 5.5 parts by weight, 1.0 to 5.0 parts by weight, 1.0 to 4.5 parts by weight, 1.0 to 4.0 parts by weight, 1.0 to 3.5 parts by weight, 1.0 to 3.0 parts by weight, 1.0 to 2.5 parts by weight, 1.0 to 2.0 parts by weight, 1.0 to 1.5 parts by weight, 1.5 to 10.0 parts by weight, 2.0 to 10.0 parts by weight, 2.5 to 10.0 parts by weight, 3.0 to 10.0 parts by weight, 3.5 to 10.0 parts by weight, 4.0 to 10.0 parts by weight, 4.5 to 10.0 parts by weight, 5.0 to 10.0 parts by weight, 5.5 to 10.0 parts by weight, 6.0 to 10.0 parts by weight, 6.5 to 10.0 parts by weight, 7.0 to 10.0 parts by weight, 7.5 to 10.0 parts by weight, 8.0 to 10.0 parts by weight, 8.5 to 10.0 parts by weight, 9.0 to 10.0 parts by weight, 9.5 to 10.0 parts by weight, 1.5 to 9.5 parts by weight, 2.0 to 9.0 parts by weight, 2.5 to 8.5 parts by weight, 3.0 to 8.0 parts by weight, 3.5 to 8.5 parts by weight, 4.0 to 8.0 parts by weight, 4.0 to 7.5 parts by weight, 4.0 to 7.0 parts by weight, 4.0 to 6.5 parts by weight, 4.0 to 6.0 parts by weight, 4.0 to 5.5 parts by weight, 4.0 to 5.0 parts by weight may be included, but is not limited thereto.

[0035] In one embodiment of the present invention, the emulsion is an O / W (oil-in-water) formulation.

[0036] The type of emulsion, i.e., oil in water (O / W), water in oil (W / O), or oil in oil (O / O), can be determined primarily by the choice of emulsifier and the manufacturing process. For example, nonionic surfactants are primarily used to form O / W emulsions, and ionic surfactants are primarily used to form W / O emulsions. The type of emulsion can also be determined by how the water and oil phases are combined during the manufacturing process. For example, slowly adding the oil component to the water phase can form an O / W emulsion, while slowly adding the water component to the oil phase can form a W / O emulsion. In addition, other factors, such as the specific ratio of the components or the temperature during the manufacturing process, can also affect the type of emulsion.

[0037]

[0038] In one aspect of the present invention, the present invention provides a composition for producing a microstructure comprising an emulsion comprising a water-soluble component and an oil-soluble component and a biodegradable polymer:

[0039] The above emulsion comprises an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

[0040] In one embodiment of the present invention, the emulsion comprises water, and comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80, based on 100 parts by weight of water.

[0041] In one specific example of the present invention, the emulsion additionally contains 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof, per 100 parts by weight of water.

[0042] In one specific example of the present invention, the emulsion contains 1.0 to 10.0 parts by weight of oil per 100 parts by weight of water.

[0043] In one embodiment of the present invention, the emulsion is an O / W (oil-in-water) emulsion.

[0044] In one embodiment of the present invention, the biodegradable polymer is polyester, polyhydroxyalkanoates (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydroxybutyrate-co-valerate; PHBV), poly(3-hydroxyproprionate; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), 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, polyvinylacetate phthalate, methacrylic acid gelatin, hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxyalkylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, polyvinylacrylic acid, At least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, agar, carrageenan, algin, collagen, chitosan, dextran, cellulose, hyaluronic acid and salts thereof.

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

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

[0047] 2) Controlled Release: Polymers also play a key role in controlling the release of active ingredients. Depending on the structure and properties of the polymer, the active ingredient 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 the physical properties of microneedles, such as size, shape, and strength.

[0049] Additionally, the composition for producing the microstructure may include a medical drug, a pharmaceutical drug, or a dermatological drug. The drug may be a fat-soluble ingredient. Examples thereof include, but are not limited to, retinol 10S, kappa resin, camphor, methyl salicylate, retinol, paraffin, ceramide, menthol, vanillyl butyl ether, capsaicin, or a combination thereof.

[0050] Sodium hyaluronate is a representative substance with wrinkle-improving and anti-aging properties. It acts as a moisturizer by forming a moisture barrier on both the inner and outer layers of the skin, doubly strengthening the skin barrier. For this purpose, it is preferable to use sodium hyaluronate with a low molecular weight of 60 kDa or less.

[0051]

[0052] In one embodiment of the present invention, the dry weight ratio of the emulsion and the biodegradable polymer is 1:9 to 1:99. For example, the ratio of dry weight of the emulsion and the biodegradable polymer is 1:9 to 1:99, 1:9 to 1:99, 1:9 to 1:95, 1:9 to 1:90, 1:9 to 1:85, 1:9 to 1:80, 1:9 to 1:75, 1:9 to 1:70, 1:9 to 1:65, 1:9 to 1:60, 1:9 to 1:55, 1:9 to 1:50, 1:9 to 1:45, 1:9 to 1:40, 1:9 to 1:35, 1:9 to 1:30, 1:9 to 1:25, 1:9 to 1:20, 1:9 to 1:15, 1:9 to 1:10, 1:10 to 1:99, 1:15 to 1:99, 1:20 to 1:99, 1:25 to 1:99, 1:30 to 1:99, 1:35 to 1:99, 1:40 to 1:99, 1:45 to 1:99, 1:50 to 1:99, 1:55 to 1:99, 1:60 to 1:99, 1:65 to 1:99, 1:70 to 1:99, 1:75 to 1:99, 1:80 to 1:99, 1:85 to 1:99, 1:90 to 1:99, 1:95 to 1:99, 1:10 to 1:90, 1:10 to 1:70, 1:10 to It can be, but is not limited to, 1:50, 1:10 to 1:30, or 1:15 to 1:25.

[0053] In one embodiment of the present invention, the dry weight ratio of the emulsion and the biodegradable polymer is 1:19 to 1:99.

[0054]

[0055] In one aspect of the present invention, the present invention provides a method for producing a microstructure comprising a useful component, the method comprising the following steps:

[0056] (a) A step of heating and dissolving the water and oil raw materials, mixing them, and cooling them to prepare an emulsion;

[0057] (b) mixing the emulsion into a solvent containing a biodegradable polymer; and

[0058] (c) A step of dispensing and drying into a mold to obtain a microstructure.

[0059] According to one embodiment of the present invention, the step of heating the water and oil raw materials may be performed at 50°C to 90°C. The cooling step may be cooling to 30°C or lower.

[0060] The step of mixing the solvent containing the polymer and the emulsion can be performed using a high-pressure emulsifier or a high-pressure homogenizer.

[0061] The micro mold of the present invention can be manufactured using any micro mold manufacturing technique known in the art. For example, a MEMS (Micro-Electro Mechanical System) manufacturing technique, a photolithography (Biodegradable polymer microneedles: Fabrication, mechanics and transdermal drug delivery, Journal of Controlled Release 104, 51-66, 2005) manufacturing technique, and a soft lithography manufacturing technique can be used to manufacture the micro mold of the present invention, but are not limited thereto. When a soft lithography manufacturing technique is used, an elastic mold such as PDMS (polydimethylsiloxane) or PMMA (poly(methyl methacrylate e)) can be manufactured and used to manufacture a microstructure. The technique for manufacturing a PDMS mold is a type of plastic processing technique, and a desired molding structure can be obtained through various methods such as casting, injection, and hot embossing. For example, a photosensitive material is coated on a substrate such as a silicon wafer or glass and patterned using a photomask, resulting in the creation of a master. This master can then be used as a mold to cast PDMS and sinter it, creating a PDMS mold that functions as a stamp.

[0062] According to one embodiment of the present invention, the dispensing step of step (c) of the present invention additionally includes a step of supplying the composition for producing a microstructure of the present invention to a mold to form a base having a constant thickness. In this case, the base may be formed using the same material as the microstructure constituent, and the thickness of the base to minimize distortion of the base is 10 μm-200 μm or 30 μm-100 μm.

[0063] According to one embodiment of the present invention, the drying step (c) of the present invention is performed 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 performed after step (a) of the present invention is performed 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.

[0064] The above drying process helps to increase the mechanical strength of the microstructure and increase the flatness of the base.

[0065] In one embodiment of the present invention, the emulsifier comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80, per 100 parts by weight of water.

[0066] In one embodiment of the present invention, a method for producing a microstructure, wherein the emulsifier additionally includes 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof, per 100 parts by weight of water.

[0067] In one embodiment of the present invention, the aqueous raw material comprises a polysorbate 80 emulsifier; the oily raw material comprises one or more emulsifiers composed of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate and PEG-100 stearate, polysorbate 80, cetyl alcohol and stearic acid; or a combination thereof.

[0068]

[0069] In one aspect of the present invention, the present invention provides a microstructure comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof; and a biodegradable polymer.

[0070] The present invention can 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.

[0071] The shape of the microneedle may be conical, pyramidal, spherical, short-headed, wedge-shaped, or blade-shaped. The length of the microneedle may range from 50 μm to 1,500 μm.

[0072] In one embodiment of the present invention, the emulsifier comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80.

[0073] In one embodiment of the present invention, the emulsifier additionally includes 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof.

[0074] In one embodiment of the present invention, the dry weight ratio of the emulsion and the biodegradable polymer is 1:9 to 1:99.

[0075] In one embodiment of the present invention, the biodegradable polymer is polyester, polyhydroxyalkanoates (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydroxybutyrate-co-valerate; PHBV), poly(3-hydroxyproprionate; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), 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, At least one selected from the group consisting of 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), gelatin, collagen, chitosan, dextran, cellulose, hyaluronic acid, and salts thereof.

[0076]

[0077] The features and advantages of the present invention are summarized as follows:

[0078] (a) The present invention provides an emulsion composition comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

[0079] (b) The present invention provides a composition for producing a microstructure comprising an emulsion containing a water-soluble component and a biodegradable polymer.

[0080] (c) The present invention provides a method for manufacturing a microstructure including a useful component.

[0081] (d) The present invention provides a microstructure comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

[0082] (e) When using the emulsion composition and composition for producing microstructures of the present invention, microstructures containing useful components can be effectively produced.

[0083]

[0084] Figure 1 is a photograph of the emulsion state of the mixed emulsifier group I of Table 1.

[0085] Figure 2 is a photograph of a state in which the mixed emulsifier group I of Table 1 and the polymer aqueous solution are mixed.

[0086] Figure 3 is a photograph of the emulsion state of the mixed emulsifier group II of Table 1.

[0087] Figure 4 shows a photograph of a microneedle when 95 wt% of Na-HA was used as a biodegradable polymer based on dry content.

[0088]

[0089] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0090]

[0091] Example

[0092] Example 1: Preparation of microstructures containing useful components

[0093] A method for producing a microstructure including a useful component comprises the steps of producing an emulsion, adding the emulsion to a biodegradable polymer aqueous solution to produce a base liquid, dispensing the liquid into a mold, and drying the same to obtain a microstructure thin film.

[0094]

[0095] 1-1. Preparation of emulsion containing useful ingredients

[0096] Microneedle patches are manufactured by evaporating water from a water-based liquid phase to obtain only a solid component, making it difficult to incorporate oil-soluble ingredients. However, this study aimed to create microneedles that stably contain oil-soluble ingredients by emulsifying the components in an oil-in-water formulation, forming micelles with oily components within the inner phase, and evenly dispersing them in a stable state in the aqueous phase.

[0097] The HLB value (Hydrophile-Lipophile Balance) is a measure of the degree of hydrophilicity and lipophilicity of a surfactant (emulsifier). To produce an O / W emulsion, the surfactant was formulated with an HLB value of at least 8. Higher alcohols and fatty acids were used as emulsifying agents to enhance stability.

[0098] The aqueous and oily raw materials were placed in separate beakers and dissolved at a temperature of 50 to 90°C. The oily raw materials and emulsifier were added to the beaker containing the aqueous raw materials, mixed using a homomixer at 3,000 rpm for more than 5 minutes, and then cooled to 30°C or lower and defoamed to produce an emulsion.

[0099]

[0100] 1-2. Prepare a base liquid by adding a polymer aqueous solution to the emulsion.

[0101] Emulsion was added to a base liquid containing sodium hyaluronate mixed with purified water and stirred at room temperature at 2,000 rpm using a homogenizer until evenly dispersed, and then defoamed. Other active ingredients that are well dissolved in water can be added and stirred in the same manner as above.

[0102]

[0103] 1-3. Fabrication of microstructures containing useful components

[0104] To fabricate microstructures, a certain amount of liquid was dispensed into a mold and degassed. After drying at 10–70°C, the thin film was removed from the mold to obtain a microneedle thin film.

[0105]

[0106]

[0107] Example 2: Microstructures according to emulsifier composition

[0108] To determine the optimal emulsifier composition for fabricating microstructures containing functional ingredients, emulsions were prepared with varying emulsifier compositions, and base liquids were prepared to compare their stability. The emulsifier compositions for each group are shown in Table 1.

[0109] Emulsifier Composition Composition (wt%) Ingredient Mixed Emulsifier I Mixed Emulsifier II Mixed Emulsifier III Mixed Emulsifier IV Di Water 90.29 2.79 0.29 0.2 Arlacel 60 (sorbitan stearate) 0.30 0.30 1.00 0.20 GMS 105 (glyceryl monostearate) 0.50 0.50 2.00 0.10 Arlacel 165 (Glyceryl stearate & PEG-100 stearate) 2.00 2.00 0.10 1.00 Tween 80 (polysorbate 80) 0.50 0.50 0.20 2.00 Kalcol 6850 (cetyl alcohol) 2.00 2.00 2.00 Stearic Acid 0.500.500.50 Jojoba Seed Oil 4.004.004.004.00 Total 100.00

[0110] The results are shown in Figures 1, 2 and 3.

[0111] As shown in FIGS. 1, 2 and 3, in the case of mixed emulsifier I, the particle size was relatively constant and did not clump in both the emulsion state and the state in which the polymer aqueous solution was added, whereas in the case of mixed emulsifier groups II, III and IV, the particle size was not constant and clumping was observed already in the emulsion state.

[0112]

[0113] Example 3: Verification of the stability of microstructures

[0114] The stability of the microneedles produced was verified by varying the type of biodegradable polymer and the dry weight ratio of the polymer to the emulsion. The emulsion was produced using the mixed emulsifier I of Example 2. Jojoba seed oil was used as the oil component, and retinol 10S was used as the oil-soluble active ingredient.

[0115] The results are shown in Tables 2 to 7.

[0116] As shown in Tables 3, 5, and 7, it was confirmed that the stability of the manufactured microneedles varied depending on the type of biodegradable polymer. When the content of Na-HA and PVP in the emulsion was 1 or 5 wt% based on the weight after drying, the formulation of the composition before drying did not separate, and the microneedle patch maintained a stable shape even after drying. However, when the content of the emulsion was 10 wt% based on the weight after drying, the formulation of the composition before drying separated, and crystallization of the component was observed in the microneedle patch after drying. A photograph of the microneedle when 95 wt% based on the dry content of Na-HA as the biodegradable polymer was used is shown in Fig. 4.

[0117] On the other hand, in all cases where the content of PEC emulsion was 1, 5, and 10 wt% based on the weight after drying, the formulation of the composition before drying was not separated, and the microneedle patch maintained a stable shape even after drying.

[0118]

[0119] Stability verification of microstructure Experimental group composition (Na-HA) No. Raw material dry content (%) #1 #2 #3 1 Na-HA (Sodium hyaluronate) 99.00 95.00 90.00 2 Water 1.00 5.00 10.00 Arlacel 60 (sorbitan stearate) GMS 105 (glyceryl monostearate) Arlacel 165 (Glyceryl stearate & PEG-100 stearate) Tween 80 (polysorbate 80) Kalcol 68 50 (cetyl alcohol) Stearic Acid Retinol 10S Jojoba seed oil Total 100.00 100.00 100.00

[0120] Stability verification results of microstructure (Na-HA) Stability Dry content #1 #2 #3 Before drying (high molecular polymer + emulsion) Stability (O: Formulation stability, X: Formulation separation) Day 1 OOX Day 2 OOX After drying (patch formulation) Stability (O: Stable in patch, X: Insoluble / crystallized in patch) Week 1 OOX Week 2 OOX Week 4 OOX

[0121] Stability verification of microstructure Experimental group composition (PVP) No. Raw material dry content (%) #1 #2 #3 1 PVP (Polyvinyl Pyrrolidone) 99.00 95.00 90.00 2 Water 1.00 5.00 10.00 Arlacel 60 (sorbitan stearate) GMS 105 (glyceryl monostearate) Arlacel 165 (Glyceryl stearate & PEG-100 stearate) Tween 80 (polysorbate 80) Kalcol 68 50 (cetyl alcohol) Stearic Acid Retinol 10S Jojoba seed oil Total 100.00 100.00 100.00

[0122] Stability verification results of microstructure (PVP) Stability Dry content #1 #2 #3 Before drying (high molecular polymer + emulsion) Stability (O: Formulation stability, X: Formulation separation) Day 1 OOX Day 2 OOX After drying (patch formulation) Stability (O: Stable in patch, X: Insoluble / crystallized in patch) Week 1 OOX Week 2 OOX Week 4 OOX

[0123] Stability verification of microstructure Experimental group composition (HEC) No. Raw material Dry content (%) #1 #2 #3 1 HEC (hydroxyethylcellulose) 99.00 95.00 90.00 2 Water 1.00 5.00 10.00 Arlacel 60 (sorbitan stearate) GMS 105 (glyceryl monostearate) Arlacel 165 (Glyceryl stearate & PEG-100 stearate) Tween 80 (polysorbate 80) Kalcol 68 50 (cetyl alcohol) Stearic Acid Retinol 10S Jojoba seed oil Total 100.00 100.00 100.00

[0124] Stability verification results of microstructure (HEC) Stability Dry content #1 #2 #3 Before drying (high molecular polymer + emulsion) Stability (O: Formulation stability, X: Formulation separation) Day 1 OOO Day 2 OOO After drying (patch formulation) Stability (O: Stable in patch, X: Insoluble / crystallized in patch) Week 1 OOO Week 2 OOO Week 4 OOO

Claims

1. An emulsion composition comprising an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

2. In the first paragraph, the emulsion composition comprises water, and comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80, per 100 parts by weight of water.

3. An emulsion composition in claim 2, wherein the emulsion composition additionally contains 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof, per 100 parts by weight of water.

4. An emulsion composition according to claim 1, wherein the emulsion is an O / W (oil-in-water) formulation.

5. Composition for producing microstructures comprising an emulsion containing a water-soluble component and a biodegradable polymer: The above emulsion contains an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

6. A composition for producing a microstructure, wherein in paragraph 5, the emulsion contains water, and comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80, per 100 parts by weight of water.

7. A composition for producing a microstructure, wherein in paragraph 6, the emulsion additionally contains 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof, per 100 parts by weight of water.

8. A composition for producing a microstructure, wherein the emulsion in paragraph 5 is an O / W (oil-in-water) emulsion.

9. In paragraph 5, the biodegradable polymer is selected from the group consisting of polyester, polyhydroxyalkanoates (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydroxybutyrate-co-valerate; PHBV), poly(3-hydroxyproprionate; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), 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, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), cellulose acetate phthalate, polyvinylacetate phthalate, methacrylic acid gelatin, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxyalkyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, polyvinylacrylic acid, A composition for producing a microstructure, comprising at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, agar, carrageenan, algin, collagen, chitosan, dextran, cellulose, hyaluronic acid and salts thereof.

10. A composition for producing a microstructure, wherein the dry weight ratio of the emulsion and the biodegradable polymer in paragraph 5 is 1:9 to 1:

99.

11. A composition for producing a microstructure, wherein the dry weight ratio of the emulsion and the biodegradable polymer in paragraph 5 is 1:19 to 1:

99.

12. A method for manufacturing a microstructure comprising a useful component comprising the following steps: (a) a step of preparing an emulsion by heating and dissolving the water and oil raw materials respectively, mixing them, and then cooling them; (b) mixing the emulsion into a solvent containing a biodegradable polymer; and (c) A step of dispensing and drying into a mold to obtain a microstructure.

13. A method for producing a microstructure in claim 12, wherein the emulsion preparation step of (a) comprises a step of adding an emulsifier selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

14. A method for producing a microstructure in claim 13, wherein the emulsifier comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80, per 100 parts by weight of water.

15. A method for producing a microstructure in claim 14, wherein the emulsifier additionally contains 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof, per 100 parts by weight of water.

16. Microstructures comprising emulsifiers and biodegradable polymers: The above emulsifier is selected from the group consisting of sorbitan stearate, glyceryl monostearate (GMS), glyceryl stearate & PEG-100 stearate, polysorbate 80, cetyl alcohol, stearic acid, and combinations thereof.

17. A microstructure according to claim 16, wherein the emulsifier comprises 0.2 to 1.0 parts by weight of sorbitan stearate, 0.2 to 2.0 parts by weight of glyceryl monostearate, 1.0 to 5.0 parts by weight of glyceryl stearate and PEG-100 stearate, and 0.2 to 2.0 parts by weight of polysorbate 80.

18. A microstructure according to claim 17, wherein the emulsifier additionally comprises 1.0 to 5.0 parts by weight of cetyl alcohol, 0.1 to 1.0 parts by weight of stearic acid, or a combination thereof.

19. A microstructure according to claim 16, wherein the dry weight ratio of the emulsion and the biodegradable polymer is 1:9 to 1:

99.

20. In the 16th paragraph, the biodegradable polymer is selected from the group consisting of polyester, polyhydroxyalkanoates (PHAs), poly(α-hydroxyacid), poly(β-hydroxyacid), poly(3-hydroxybutyrate-co-valerate; PHBV), poly(3-hydroxyproprionate; PHP), poly(3-hydroxyhexanoate; PHH), poly(4-hydroxyacid), 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, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), cellulose acetate phthalate, polyvinylacetate phthalate, methacrylic acid gelatin, hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxyalkyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, polyvinylacrylic acid, A microstructure comprising at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethyl cellulose, gelatin, agar, carrageenan, algin, collagen, chitosan, dextran, cellulose, hyaluronic acid and salts thereof.

Images