WO2022071748A1 - Microstructure comprising microneedle and drug for wound healing - Google Patents

Microstructure comprising microneedle and drug for wound healing Download PDF

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Publication number
WO2022071748A1
WO2022071748A1 PCT/KR2021/013333 KR2021013333W WO2022071748A1 WO 2022071748 A1 WO2022071748 A1 WO 2022071748A1 KR 2021013333 W KR2021013333 W KR 2021013333W WO 2022071748 A1 WO2022071748 A1 WO 2022071748A1
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microstructure
polyethylene oxide
tranilast
skin
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PCT/KR2021/013333
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French (fr)
Korean (ko)
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허찬영
남선영
정재헌
정지훈
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서울대학교병원
성균관대학교산학협력단
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Publication of WO2022071748A1 publication Critical patent/WO2022071748A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles

Definitions

  • Microneedle herein; and a drug for wound healing contained therein; a microstructure comprising is disclosed.
  • the skin is composed of three major layers: the epidermis, the dermis, and the subcutaneous fat.
  • the damaged area is invaded by bacteria and external toxins, and the skin's defense function against it causes inflammation.
  • Wound healing is a complex biological process that includes chemotaxis, cell differentiation and replication, lipoprotein synthesis, angiogenesis, and the like as a tissue recovery process as a response of tissue to damaged skin, and various factors intervene.
  • tranilast is used to repair wounds by inhibiting collagen synthesis in fibroblasts and inhibits the production of TGF and the like in inflammatory cells. Based on this, tranilast is currently prescribed under the trade name Rizaben for the treatment of keloids and hypertrophic scars.
  • Patent Document 1 KR 10-2018-7028095 A
  • Patent Document 2 KR 10-2015-7028929 A
  • Non-Patent Document 1 Imran Majid, Microneedling Therapy in Atrophic Facial Scars: An Objective Assessment, J Cutan Aesthet Surg. 2009 Jan-Jun; 2(1): 26-30.
  • an object of the present invention is to provide a microstructure including a microneedle containing a wound healing drug, particularly tranilast.
  • an object of the present invention is, when tranilast is provided to the skin using a microneedle, Scar Elevation Index (SEI), dermal layer thickness, fibrous layer thickness, blood vessel formation, type 1 collagen expression level , collagen density, smooth muscle action (SMA) expression level, and tumor growth factor-beta (tumor growth factor-beta, TGF-beta) values were evaluated to provide effective concentrations.
  • SEI Scar Elevation Index
  • SMA smooth muscle action
  • tumor growth factor-beta tumor growth factor-beta
  • a microneedle comprising a biocompatible amphiphilic block copolymer; and tranilast included in the microneedle; provides a microstructure comprising.
  • the present invention provides a composition for wound healing for use as a microneedle, comprising tranilast at a concentration of 2.5 to 150 ⁇ g/ml as an active ingredient.
  • the microstructure according to an aspect of the present invention or the composition for wound healing used therein contains tranilast, particularly at a specific concentration, inside the microneedle, so that the microneedle is not processed or tranil Compared to microneedles that do not contain the last (tranilast), the thickness of the dermal layer and the fibrous layer is reduced when treated on the wound skin, the blood vessel formation is significantly increased, the collagen density is reduced, and fibrosis factors such as type 1 collagen and SMA, and TGF It has a better wound healing effect, such as a decrease in the expression of inflammatory factors such as -beta.
  • 1A is a photograph of a camera measuring the wound healing effect according to whether the microstructure is treated or not according to an aspect of the present invention.
  • 1B is a graph showing the results of measuring the scar increase index (SEI) by the wound area calculation method by observing the wound healing effect according to the microstructure treatment of one aspect of the present invention with a camera.
  • SEI scar increase index
  • Figures 2a and 2b is a microscopic image of the dermal layer thickness according to whether microstructure treatment of one aspect of the present invention is observed (FIG. 2a), and a graph showing the dermal layer thickness measured therefrom (FIG. 2b).
  • FIG. 3A and 3B are graphs showing an image ( FIG. 3A ) of an aspect of the present invention observing the thickness of the fiber layer according to whether the microstructure is processed or not, and a graph showing the thickness of the fiber layer measured therefrom ( FIG. 3B ).
  • Figures 5a and 5b is a microscopic image of the wound healing effect according to whether microstructure treatment of one aspect of the present invention is observed (FIG. 5a), and a graph showing the collagen density measured therefrom (FIG. 5b).
  • FIG. 6 is a result of confirming the expression levels of fibrosis factor (collagen I, COL 1 and SMA) and inflammatory factor (TGF-beta) according to whether or not the microstructure of one aspect of the present invention is treated by Western blot. .
  • skin refers to an organ covering the outside of an organism, and is composed of the epidermis, dermis, and subcutaneous fat layer, and includes not only the tissues covering the outside of the face or the entire body, but also the scalp and hair. It's the ultimate concept.
  • the present invention provides a microneedle comprising a biocompatible amphiphilic block copolymer; and tranilast included in the microneedle; provides a microstructure comprising.
  • microstructure according to an aspect of the present invention may include microneedles including a biocompatible amphiphilic block copolymer.
  • the biocompatible amphiphilic block copolymer is a di-block, tri-block or multi-block copolymer of a polymer of a hydrophilic region and a polymer of a hydrophobic region.
  • the polymer of the hydrophilic region is polyacrylic acid (Polyacrylic acid, PAA), polyethylene glycol (polyethyleneglycol, PEG), polyacrylonitrile (polyacrylonitrile, PAN), polyethylene oxide (Polyethyleneoxide, PEO), It may be at least one selected from the group consisting of polyvinylacetate (PVAc), polyvinylalcohol (PVA), and polymethyl methacrylate (PMMA)).
  • PVAc polyvinylacetate
  • PVA polyvinylalcohol
  • PMMA polymethyl methacrylate
  • the polymer of the hydrophobic region is polypropyleneoxide (PPO), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA) , poly(lactic-co-glycolic acid) (Poly(lactic-co-glycolic acid), PLGA), polyanhydride, polyorthoester, polyester, polyesteramide ( Polyesteramide), polystyrene, polydiene, polyisobutylene, polyisopropylacrylamide, polysiloxane, poly(2-vinyl naphthalene) (Poly(2-vinyl naphthalene) )), poly(vinyl pyridine and N-methyl vinyl pyridinium iodide), and poly(vinyl pyrrolidone)) It may be one or more selected.
  • PPO polypropyleneoxide
  • PCL polycaprolactone
  • PCL polylactic acid
  • PGA polyglycolic acid
  • the biocompatible amphiphilic block copolymer is specifically, poloxamer (polyethylene oxide-polypropylene oxide-polyethylene oxide) (PEO-PPO-PEO) triblock copolymer, poloxamer ( Polypropylene oxide-polyethylene oxide-polypropylene oxide) (PPO-PEO-PPO) triblock copolymer, polyethylene oxide-polylactic acid-polyethylene oxide (PEO-PLA-PEO) triblock copolymer, polylactic acid -Polyethylene oxide-polylactic acid (PLA-PEO-PLA) triblock copolymer, polyethylene oxide-polyglycolic acid-polyethylene oxide (PEO-PGA-PEO) triblock copolymer, polyglycolic acid-polyethylene oxide- Polyglycolic acid (PGA-PEO-PGA) triblock copolymer, polyethylene oxide-poly(lactic-co-glycolic acid)-polyethylene oxide (PEO-PL
  • the microstructure according to an aspect of the present invention may include a drug or composition for wound healing contained inside the microneedle.
  • the microstructure may further include a substrate portion on which the microneedles are arranged, and the substrate portion may include a drug input portion into which the drug is injected.
  • the microneedle may include a drug therein.
  • a drug therein.
  • drugs water-soluble drugs or fat-soluble drugs may be included.
  • chemical drugs, immune enhancers, vaccines, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, cosmetic efficacy substances, and medical use One or a mixture of two or more from the group consisting of antibodies may be included, and more specifically, a drug for wound healing may be included, and more specifically, the drug may be tranilast.
  • the concentration of tranilast included in the wound healing drug or composition may be 2.5 to 150 ⁇ g/ml, specifically, the concentration of tranilast is 2.5 ⁇ g/ml or more, 2.6 ⁇ g /ml or more, 2.7 ⁇ g/ml or more, 2.8 ⁇ g/ml or more, 2.9 ⁇ g/ml or more, 3 ⁇ g/ml or more, 4 ⁇ g/ml or more, 6 ⁇ g/ml or more, 8 ⁇ g/ml or more, 10 ⁇ g/ml or more or more, 12 ⁇ g/ml or more, 14 ⁇ g/ml or more, 16 ⁇ g/ml or more, 18 ⁇ g/ml or more, 20 ⁇ g/ml or more, 21 ⁇ g/ml or more, 22 ⁇ g/ml or more, 23 ⁇ g/ml or more, 24 ⁇ g/ml or more, 25 ⁇ g/ml or more, 26 ⁇
  • the microstructure containing tranilast at a concentration of 25 to 150 ⁇ g/ml reduces the Scar Elevation Index (SEI), reduces the thickness of the dermal layer, increases the formation of blood vessels, or type 1 collagen It shows an excellent effect in reducing the expression level (Experimental Examples 2, 3, 4 and 6).
  • SEI Scar Elevation Index
  • the microstructures containing tranilast at a concentration of 25 to 30 ⁇ g/ml have reduced collagen density and smooth muscle actin (smooth muscle) compared to microstructures containing tranilast at a higher concentration than this.
  • action, SMA) expression level reduction or tumor growth factor-beta shows an excellent effect in reducing the expression level (Experimental Examples 5 and 6).
  • the microstructure containing tranilast at a concentration of 100 to 150 ⁇ g/ml shows an excellent effect in reducing the thickness of the fiber layer compared to the microstructure containing tranilast at a lower concentration than this.
  • tranilast may be one in which the microneedle is inserted into the skin and injected into the body, and the skin may be skin in need of wound healing, specifically, the skin may be acne, Psoriasis, skin infections, blemishes, hyperpigmentation, hypopigmentation, alopecia, excessive hair growth, unwanted hair growth, rough skin, dry skin, loose skin, wrinkles, hypervascularized skin, sebum production disorders, excessive pores, excessive sweating, one or more skin selected from the group consisting of hyperhidrosis, tattoos, rashes, scars, pain, itching, burns, sores, warts, corns, calluses, edema, poison ivy, and bites from insects, spiders, snakes, and other animals It may be a diseased skin, but is not limited thereto.
  • the microstructure may include 0.0001 to 50% by weight of the tranilast after drying based on the total weight of the microneedles, and specifically, the content of the tranilast after drying the microneedles It may be 0.01 to 20% by weight based on the total weight of , but is not limited thereto, and may include all cases in which even a small amount of drug is contained.
  • the microstructure may further include an additive for enhancing the stability of tranilast and the strength of the needle in the microstructure.
  • the additives include hyaluronic acid, chitosan, polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, dextran, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene-vinyl acetate polymer, cellulose acetate, Acrylic-substituted cellulose acetate, polyurethane, polycaprolactone, polylactic-co-glycolic acid, polylactic acid, polyglycolic acid, polyanhydride, polystyrene, polyvinyl acetate, polyvinyl chloride, polyvinylfluoride, polyvinyl fluoride from the group consisting of midazole, chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol,
  • composition ratio of the biocompatible amphiphilic block copolymer, tranilast, and the additive may be variously changed depending on the characteristics of the tranilast to be delivered or the form to be delivered.
  • the microstructure when the microstructure is inserted into the living epithelium, it can be dissolved to form spherical self-assembled nanoparticles carrying tranilast, and the self-assembled nanoparticles are micelles with a diameter of 10 to 2000 nm. , specifically, may be spherical self-assembled nanoparticles of 50 to 1000 nm.
  • the microstructure can maintain a stable structure in an aqueous solution by forming self-assembled nanoparticles when dissolved in an aqueous solution, and at the same time increase the solubility of the drug in the aqueous solution when delivering a hydrophobic drug, and inject the loaded drug into the cell Because it can be delivered smoothly, it is possible to facilitate the simultaneous transdermal delivery of a hydrophobic drug delivery or a vaccine antigen and a hydrophobic adjuvant.
  • the wound refers to a state in which the living body is damaged as a meaning encompassing all the damaged living bodies, and is also referred to as a wound.
  • the wounds are wounds, non-healing traumatic wounds, destruction of tissue by irradiation, abrasions, lacerations, bursae, penetrating wounds, gunshot wounds, cuts, burns, frostbite, skin ulcers, dry skin, keratosis, cracks, ruptures, dermatitis , surgical or vascular disease wounds, bruises, corneal wounds, bedsores, pits, chronic ulcers, post-operative suture sites, spinal injuries, gynecological wounds, chemical wounds and acne may be at least one selected from the group consisting of , but not limited thereto.
  • wound and wound may be used interchangeably.
  • the microstructure may be a microstructure for wound healing.
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment
  • the Scar Elevation Index (SEI) may be reduced by 10% or more, specifically 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, It may be reduced by 45% or more or 50% or more, and in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 ⁇ g/ml, specifically 25 ⁇ g/ml or more, 26 ⁇ g/ml or more , 27 ⁇ g/ml or more, 28 ⁇ g/ml or more, 29 ⁇ g/ml or more, 30 ⁇ g/ml or more, 40 ⁇ g/ml or more, 50 ⁇ g/ml or more, 60 ⁇ g/ml or more, 70 ⁇ g/ml or more, 80 More
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment
  • the thickness of the dermal layer may be reduced by 10% or more, specifically 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more , 55% or more, 60% or more, 65% or more, or 70% or more may be reduced, in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 ⁇ g / ml, specifically 25 ⁇ g /ml or more, 26 ⁇ g/ml or more, 27 ⁇ g/ml or more, 28 ⁇ g/ml or more, 29 ⁇ g/ml or more, 30 ⁇ g/ml or more, 40 ⁇ g/ml or more, 50 ⁇ g/ml or more, 60 ⁇ g/m
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment
  • the thickness of the fibrous layer may be reduced by 10% or more, and specifically 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more , 55% or more, 60% or more, 65% or more, or 70% or more may be reduced, in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 ⁇ g / ml, specifically 25 ⁇ g /ml or more, 26 ⁇ g/ml or more, 27 ⁇ g/ml or more, 28 ⁇ g/ml or more, 29 ⁇ g/ml or more, 30 ⁇ g/ml or more, 40 ⁇ g/ml or more, 50 ⁇ g/ml or more, 60 ⁇ g/
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment Post-vascularization may be increased, and in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 ⁇ g/ml, specifically 25 ⁇ g/ml or more, 26 ⁇ g/ml or more, 27 ⁇ g /ml or more, 28 ⁇ g/ml or more, 29 ⁇ g/ml or more, 30 ⁇ g/ml or more, 40 ⁇ g/ml or more, 50 ⁇ g/ml or more, 60 ⁇ g/ml or more, 70 ⁇ g/ml or more, 80 ⁇ g/ml or more or more, 90 ⁇ g/ml or more, 92 ⁇ g/ml or more, 94 ⁇ g/ml or more, 96 ⁇ g/ml or more,
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment
  • the collagen density may be reduced by 5% or more, specifically 5% or more, 5.5% or more, 6% or more, 6.5% or more, 7% or more, 7.5% or more, 8% or more, 8.5% or more, 9% or more
  • the concentration of tranilast contained in the treated microstructure may be 2.5 to 150 ⁇ g/ml, more specifically 2.5 ⁇ g/ml or more, 2.6 ⁇ g/ml or more, 2.7 ⁇ g/ml or more, 2.8 ⁇ g/ml or more, 2.9 ⁇ g/ml or more, 3 ⁇ g/ml or more, 4 ⁇ g/ml or more, 6 ⁇ g/ml or more, 8 ⁇ g/m
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment Later, the expression level of the fibrosis factor may be reduced by 10% or more.
  • the fibrosis factor may be one or more selected from the group consisting of smooth muscle action (SMA) and type 1 collagen (collagen I), but is not limited thereto.
  • wound healing is an object or wound that has not been treated with the microstructure according to an aspect of the present invention, or an object or wound treated with the microstructure compared to before the microstructure is treated, or smooth muscle actin (SMA) after microstructure treatment ) of 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, in which case the treated microstructure
  • concentration of tranilast contained in the may be 2.5 to 150 ⁇ g / ml, more specifically 2.5 ⁇ g / ml or more, 2.6 ⁇ g / ml or more, 2.7 ⁇ g / ml or more, 2.8 ⁇ g / ml or more, 2.9 ⁇ g / ml or more, 3 ⁇ g/ml or more, 4 ⁇ g/ml or more, 6 ⁇ g/ml or more, 8 ⁇ g/ml or more, 10 ⁇ g/ml or more, 12 ⁇ g/m
  • wound healing is an individual or wound that has not been treated with the microstructure according to an aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or the first after treatment of the microstructure
  • the expression level of collagen I may be decreased by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more
  • the concentration of tranilast contained in the treated microstructure may be 25 to 150 ⁇ g/ml, and more specifically, 25 ⁇ g/ml or more, 26 ⁇ g/ml or more, 27 ⁇ g/ml or more, 28 ⁇ g/ml or more.
  • wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment Later, the expression level of the inflammatory factor may be reduced by 10% or more.
  • the inflammatory factor may be tumor growth factor-beta (tumor growth factor-beta, TGF-beta), but is not limited thereto.
  • wound healing is an object or wound that has not been treated with the microstructure according to an aspect of the present invention, or an object or wound treated with the microstructure compared to before processing the microstructure, or tumor growth factor after microstructure treatment-
  • the expression level of beta (TGF-beta) may be decreased by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more,
  • the concentration of tranilast contained in the treated microstructure may be 2.5 to 150 ⁇ g/ml, and more specifically, 2.5 ⁇ g/ml or more, 2.6 ⁇ g/ml or more, 2.7 ⁇ g/ml or more, 2.8 ⁇ g/ml or more , 2.9 ⁇ g/ml or more, 3 ⁇ g/ml or more, 4 ⁇ g/ml or more, 6 ⁇ g/ml or more, 8 ⁇ g/ml or more, 10 ⁇ g/ml or more, 12 ⁇ g/m
  • the microstructure according to an aspect of the present invention comprises the steps of dissolving a biocompatible amphiphilic block copolymer and a drug in a solvent to prepare a mixed solution; And it may be prepared by a manufacturing method comprising the step of manufacturing a microstructure using the mixed solution.
  • Descriptions of the biocompatible amphiphilic block copolymer, drug, tranilast, and microstructure are the same as described above.
  • the solvent may be water, an organic solvent, or a mixture thereof, and the organic solvent may include a volatile organic solvent, specifically, the volatile organic solvent is dichloromethane (CH 2 Cl 2 ) , tetrahydrofuran (THF), acetonitrile, ethyl acetate, acetone, ethanol, may be at least one selected from the group consisting of methanol and trifluoroalcohol (TFA), but is not limited thereto.
  • the volatile organic solvent is dichloromethane (CH 2 Cl 2 ) , tetrahydrofuran (THF), acetonitrile, ethyl acetate, acetone, ethanol
  • THF tetrahydrofuran
  • acetonitrile ethyl acetate
  • acetone acetone
  • ethanol may be at least one selected from the group consisting of methanol and trifluoroalcohol (TFA), but is not limited thereto.
  • the concentration of the biocompatible amphiphilic block copolymer in the mixed solution may be 5 to 50% (volume per volume; v/v), but is not limited thereto.
  • microstructure of one aspect of the present invention can be manufactured using the mixed solution, and conventionally known methods can be used without limitation as a manufacturing method thereof.
  • the microstructure manufacturing step comprises: administering a mixed solution of a drug and a biocompatible amphiphilic block copolymer to a mold and centrifuging under vacuum to inject it into a cavity of the mold; forming microneedles by drying the mold in which the mixed solution of the drug and the biocompatible amphiphilic block copolymer is injected; and separating the microstructure from the mold.
  • the mold may include an elastomer mold such as polydimethylsiloxane (PDMS) manufactured by a known soft lithography technique.
  • PDMS mold manufacturing technology is a kind of plastic processing technology, and a desired molding structure can be obtained by various methods such as casting, injection, and hot-embossing.
  • a photosensitive material is coated on a substrate such as a silicon wafer or glass and patterned using a photomask to prepare a master mold, then cast PDMS as a mold and sintered, A PDMS mold with a stamp function can be completed.
  • the mixed solution may further include an additive for enhancing the stability of the drug and the strength of the needle in the structure, and the additive is specifically hyaluronic acid, chitosan, poly Vinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, dextran, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene-vinyl acetate polymer, cellulose acetate, acrylic substituted cellulose acetate, polyurethane, polycaprolactone , poly(lactic-co-glycolic acid) (poly(lactic-co-glycolic acid, PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyanhydride, polystyrene, polyvinyl acetate, Polyvinyl chloride (PVC), polyvinyl fluoride (PVF), polyvinylimidazole, chlorosulphonate polyolefins, polyethylene oxide, polyvinyl
  • the drying process may include heating to a temperature of 4 °C to 500 °C under vacuum depending on the properties of the drug and block copolymer and solvent, and the drying temperature is the drug, block copolymer and It may be adjusted according to the characteristics of the solvent.
  • aqueous solution containing polyethylene glycol (PEG MW 6000) and ovalbumin (OVA), a hydrophilic molecule is prepared and added to the formed film, followed by an ultrasonic disperser
  • PEG MW 6000 polyethylene glycol
  • OVA ovalbumin
  • the film was uniformly dispersed in the aqueous solution using a sonicator, and the aqueous solution was filtered through a filter to remove undissolved substances.
  • aqueous solution was administered to a 1 cm x 1 cm reusable polydimethylsiloxane (PDMS) microneedle engraved mold, and centrifuged at 4 ° C. 2,000 rpm for 10 minutes using a swing bucket rotor, A soluble microneedle was prepared by drying under vacuum in a vacuum oven equipped with a vacuum trap.
  • PDMS polydimethylsiloxane
  • a finished microneedle was obtained by attaching and detaching a 2cm x 2cm adhesive tape to the base plate of the dried microneedle.
  • NZW New Zealand White
  • Animal experiments were conducted according to the rules of IACUC, and New Zealand white rabbits (NZW conventional Rabbit) were female and were purchased from Orient Bio (Seongnam, Gyeonggi-do, Korea) at 30 weeks of age.
  • rabbits were anesthetized by injecting ketamine (60 mg/kg) and xylazine (5 mg/kg). When the anesthesia is complete, the surgical site is sufficiently disinfected with betadine and the surrounding area is also disinfected to prevent infection. Then, using a Biopsy Punch, 5 wounds with a diameter of 6 mm on one ear of the rabbit in each group made Injury was supervised to become a hypertrophic scar model for 2 weeks. After surgery, rabbits were supervised according to standard post-operative animal care protocols. In order to protect the predicate, the animals were closely observed, and while Ketoprofen was administered 3SC (3 mg/kg, subcutaneous (SC)) daily, rabbits were bred in one cage.
  • the standard post-operative animal care protocol involves bandaging the ears well and putting on a neck collar to prevent the rabbit from scratching the ears after surgery, and faithfully implementing care supervision to protect the artificial wounds.
  • a patch was prepared by matching the microstructure including the microneedle prepared according to the above preparation example for each group except for the negative control group on a 6 mm wound, respectively. At this time, after the scar was formed, microneedles were treated a total of 3 times for 2 weeks.
  • the group was a negative control group that was not treated with microneedles, a positive control group treated with microneedles that did not contain any drug (bare microneedle), and tranilast (Rizaben) had a concentration of 2.5 to 3 ug/ml, respectively (Example 1) , 25 to 30 ug/ml (Example 2), 100 to 150 ug/ml (Example 3)
  • Example 1 A total of 5 types of microstructures containing microneedles were treated It was randomly divided into groups, and the experiment was performed with a total of 5 animals, 1 in each group. While replacing the microneedle, scar images were taken and SEI (Scar Elevation Index) was measured. In addition, 4 weeks after the wound, it was euthanized using potassium chloride (KCl), and a tissue sample for wound treatment was collected.
  • KCl potassium chloride
  • the obtained tissue was fixed in 10% neutral buffered formalin (NBF) at 4° C. for 24 hours. Then, ethanol was dehydrated through treatment by concentration and embedded in paraffin to prepare a paraffin block. The prepared paraffin block was cut to a thickness of 5 ⁇ m using a microtome (Leica, Wetzlar, Germany) to obtain a tissue section.
  • NAF neutral buffered formalin
  • the scar increase index represents the ratio of the total wound area tissue height to the normal tissue area under the hypertrophic scar, and it followed the general SEI calculation method, and was evaluated by an inspector using a camera. Wounds of each group of species were measured twice and counted, and the results are shown in FIGS. 1A and 1B .
  • FIGS. 1A and 1B are results obtained by measuring the wound healing effect of the microstructure including microneedles containing tranilast with a camera and observed by the wound area calculation method. As shown in FIGS. 1A and 1B , a statistically significant difference was observed in the overall wound healing effect, and the negative control (microneedle untreated group) and positive control (microneedle treated group without tranilast) were In comparison, it was confirmed that there was a wound healing effect in Examples 1 to 3.
  • the SEI value rather increases compared to when microneedles not containing tranilast are treated (positive control), but at a certain concentration (25 and 30 ug/ml) or more of tranilast, the SEI value begins to decrease significantly, and when microstructures containing microneedles containing high concentration (100 to 150 ug/ml) of tranilast are treated ( Example 3), the SEI value was reduced by about 50% compared to the treatment of microneedles without tranilast (positive control). It was found that there was a better scar increase index reduction effect when microstructures including microneedles included in a specific concentration range were processed.
  • the wound healing effect was compared by measuring the thickness of the dermal layer using the tissue sections obtained from each of the five groups of Experimental Example 1.
  • tissue sections obtained from each of the five groups of Experimental Example 1 were subjected to a general tissue staining method with Mayer's hematoxylin (BBC Biochemical, Washington, USA) and floxin and eosin Y (eosin Y). with phloxine) (Cancer Diagnostics, North Carolina, USA).
  • a confocal image X20 was obtained using an LSM 700 laser scanning confocal microscope (Carl Zeiss, Jena, Germany), and the thickness of the dermal layer and the fibrous layer was measured from this.
  • FIG. 2A and 2B are a microscopic image ( FIG. 2A ) of the wound healing effect (dermal layer) of the microstructure treatment containing tranilast-containing microneedles, and a graph showing the dermal layer thickness measured therefrom. (Fig. 2b).
  • FIG. 2A When microstructures containing microneedles containing a low concentration of 2.5 to 3 ug/ml of tranilast were treated (Example 1), no significant difference was observed, but the change in the thickness of the overall fiber layer was statistically significant. A difference was observed.
  • FIG. 3A and 3B are a microscopic image (FIG. 3A) of the wound healing effect (fibrous layer) of the microstructure treatment containing microneedles containing tranilast, and a graph showing the thickness of the fiber layer measured therefrom.
  • FIG. 3b When microstructures containing microneedles containing 2.5 to 3 ug/ml and 25 and 30 ug/ml of tranilast, respectively, were treated compared to the positive control containing no drug (Examples 1 and 2), Although no significant difference was observed in the thickness of the fiber layer, in Examples 1 and 2, it was confirmed that the thickness of the fiber layer was reduced by about 20% or more compared to the negative control group.
  • Example 3 when microstructures containing microneedles containing a high concentration of 100 to 150 ug/ml of tranilast were treated (Example 3), a clear difference was observed in the change in the thickness of the fiber layer, and about 70 compared to the negative control. % or more of the thickness of the fiber layer was reduced.
  • microneedles that do not process microneedles or do not contain drugs when microstructures containing microneedles containing tranilast in a specific concentration range are treated, there is a better dermal layer or fiber layer thickness reduction effect. And it was found.
  • the wound healing effect was compared by observing blood vessel formation from the confocal images of the tissues of each of the five groups of Experimental Example 1 obtained in Experimental Example 3 above.
  • FIG. 4 is a microscopic image of the wound healing effect of microstructure treatment including microneedles containing tranilast. As shown in FIG. 4 , a statistically significant difference was observed in the overall angiogenesis effect, and compared to the negative control (microneedle untreated group) and positive control (microneedle treated group not containing tranilast), tranil Examples 1 to 3 in which microstructures including microneedles containing last were treated were confirmed to have angiogenic effects.
  • the wound healing effect was compared by measuring the collagen density using the tissue sections obtained from each of the five groups of Experimental Example 1.
  • tissue sections obtained from each of the five groups of Experimental Example 1 were stained using a Mason's Trichrome Stain Kit (Polyscience, Inc, Philadelphia, USA) according to a general tissue staining method.
  • a confocal image X20 was obtained using an LSM 700 laser scanning confocal microscope (Carl Zeiss, Jena, Germany), and collagen density was measured therefrom.
  • FIG. 5A and 5B are microscopic images of the wound healing effect of microstructure treatment containing tranilast-containing microneedles (FIG. 5A), and graphs showing the collagen density measured therefrom (FIG. 5B) ).
  • a statistically significant difference was observed in the overall collagen density change, and the microneedle containing tranilast was compared to the negative control (microneedle untreated group) and positive control (microneedle treated group not containing tranilast).
  • Examples 1 to 3 in which the microstructure containing In one case (Example 2), it was confirmed that the collagen density was lower (Example 3) than when a high concentration (100 to 150 ug/ml) of tranilast was included.
  • a lysis buffer was added and homogenized, followed by vortexing every 15 minutes at 4° C. for 1 hour. After reacting for a while, centrifugation was performed at 15,000 x g. Then, the supernatant was quantified by BCA protein assay (Thermo Fisher Scientific Inc, Massachusetts, USA). After electrophoresis of 20 ⁇ g of protein on a 10% gel, it was transferred to nitrocellulose paper and blocked with 10% skim milk (BD difco, New Jersey, USA) for 1 hour.
  • BCA protein assay Thermo Fisher Scientific Inc, Massachusetts, USA
  • a-SMA anti-smooth muscle antibody, anti-smooth muscle antibody
  • Collagen I Collagen type 1
  • TGF-beta tumor growth factor-beta
  • GAPDH GAPDH
  • Example 2 Collagen I 2.23 0.28 0.54 0.12 0.07 SMA 1.54 0.54 0.34 0.13 0.21 TGF-beta 2.27 1.10 0.60 0.50 0.60
  • Table 1 and FIG. 6 show the results of observation of the wound healing effect of the microstructure including microneedles containing tranilast by protein analysis.
  • Table 1 and FIG. 6 show the results of observation of the wound healing effect of the microstructure including microneedles containing tranilast by protein analysis.
  • fibrosis factors Collagen I and SMA and the inflammatory factor TGF-beta
  • TGF-beta a statistically significant difference was observed in the overall fibrosis/inflammatory response, and compared to the negative control group (microneedle untreated group), the microneedle treated group ( It was confirmed that the fibrosis/inflammatory response was reduced in the positive control group and Examples 1 to 3).
  • Examples 1 to 3 in which microstructures containing microneedles containing tranilast were treated compared to negative control (microneedle untreated group) and positive control (microneedle treatment group not containing tranilast) The expression of SMA, a fibrosis factor, and TGF-beta, an inflammatory factor, was decreased.
  • SMA a fibrosis factor
  • TGF-beta an inflammatory factor
  • type 1 collagen which is superior to microstructures containing microneedles containing tranilast, in particular in a specific concentration range, is better than microneedles, It was found that there is an effect of reducing the expression level of SMA or TGF-beta.
  • microstructure including the microneedle containing tranilast will be able to exhibit the same superior effect compared to the wound treatment used in the existing market.
  • microstructure including the microneedle and the drug for wound healing may be usefully used for wound healing.

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Abstract

The present invention relates to a microstructure comprising: a microneedle; and a drug for wound healing, contained therein. The microstructure according to an aspect of the present invention comprises a wound-healing drug containing tranilast inside a microneedle, and thus, as compared to a microneedle that is not treated or a microneedle that does not contain a drug, has better wound-healing effects when used to treat wounded skin, such as reduced thicknesses of a dermal layer and a fibrous layer, significantly increased blood vessel formation, reduced collagen density, and reduced expression of fibrotic factors such as type 1 collagen and SMA, and inflammatory factors such as TGF-beta.

Description

마이크로 니들 및 상처 치유용 약물을 포함하는 마이크로 구조체Microstructure comprising microneedles and a drug for wound healing
본 명세서에는 마이크로 니들; 및 이의 내부에 포함되는 상처 치유용 약물;을 포함하는 마이크로 구조체가 개시된다.Microneedle herein; and a drug for wound healing contained therein; a microstructure comprising is disclosed.
[이 발명을 지원한 국가연구개발사업] [National R&D project supporting this invention]
[과제고유번호] 1711117017 [Project unique number] 1711117017
[과제번호] 2020-0-00990-001 [task number] 2020-0-00990-001
[부처명] 과학기술정보통신부 [Name of Ministry] Ministry of Science and Technology Information and Communication
[과제관리(전문)기관명] 정보통신기획평가원 [Name of project management (specialized) institution] Information and Communication Planning and Evaluation Institute
[연구사업명] 5G기반IoT핵심기술개발(R＆D) [Research project name] 5G-based IoT core technology development (R&D)
[연구과제명] 5G-IoT 환경에서 이기종ㆍ비정형ㆍ대용량 데이터의 고신뢰 [Research project name] High reliability of heterogeneous, unstructured, and large-capacity data in 5G-IoT environment
ㆍ저지연 처리를 위한 플랫폼 개발 및 실증 ㆍPlatform development and demonstration for low-latency processing
[기여율] 1/1 [Contribution rate] 1/1
[과제수행기관명] 성균관대학교 산학협력단 [Name of project execution institution] Sungkyunkwan University Industry-Academic Cooperation Foundation
[연구기간] 2020.04.01 ~ 2023.12.31 [Research period] 2020.04.01 ~ 2023.12.31
피부는 표피, 진피, 피하지방 등 크게 3개의 층으로 구성되어 있으며, 각층의 피부 조직은 피부의 여러 기능을 담당하는 다양한 세포들과 이를 둘러싼 물질들로 구성되어 있다. 피부가 손상을 입었을 경우 손상부위가 세균과 외부의 독소에 의해 침입을 받게 되고, 이에 대한 피부의 방어기능으로 염증이 유발되기도 한다.The skin is composed of three major layers: the epidermis, the dermis, and the subcutaneous fat. When the skin is damaged, the damaged area is invaded by bacteria and external toxins, and the skin's defense function against it causes inflammation.
상처 치유(wound healing)는 손상된 피부에 대한 조직의 반응으로 조직회복 과정으로 화학주성, 세포의 분화 및 복제, 지질 단백질의 합성, 혈관생성 등을 포함하는 복잡한 생물학적 과정이며, 다양한 인자가 개입한다.Wound healing is a complex biological process that includes chemotaxis, cell differentiation and replication, lipoprotein synthesis, angiogenesis, and the like as a tissue recovery process as a response of tissue to damaged skin, and various factors intervene.
손상된 피부에 대한 조직 회복과정은 세포의 증식과 함께 손상된 피부부위를 회복시키기 위한 세포 이동과정이 복합적으로 작용한다. 즉 손상된 피부조직을 복구하기 위해 피부 세포 생성이 활발해지고 새롭게 생성된 세포를 손상된 부위로 이동시켜 새로운 피부조직을 형성하게 하는 과정을 거친다. 따라서 상처 치유를 위해서는 피부 세포의 증식을 촉진하고, 생성된 피부 세포가 손상된 피부 부위로 이동되는 것을 조절하는 작용을 담당하는 약물의 사용이 필수적이다.In the tissue recovery process for damaged skin, cell proliferation and cell migration to restore the damaged skin area act in a complex way. In other words, in order to repair damaged skin tissue, skin cell production is activated and the newly created cells are moved to the damaged area to form new skin tissue. Therefore, for wound healing, it is essential to use a drug that promotes the proliferation of skin cells and controls the movement of the generated skin cells to the damaged skin area.
한편, 트라닐라스트는 섬유 아세포의 콜라겐 합성을 억제하여 상처를 회복시키는데 사용되고 염증세포에서 TGF 등의 생성을 억제한다. 이에 기초하여 트라닐라스트는 현재 켈로이드 및 비후성 반흔의 치료에 리자벤(Rizaben)이라는 상표명으로 처방되고 있다.On the other hand, tranilast is used to repair wounds by inhibiting collagen synthesis in fibroblasts and inhibits the production of TGF and the like in inflammatory cells. Based on this, tranilast is currently prescribed under the trade name Rizaben for the treatment of keloids and hypertrophic scars.
그러나, 기존에 경구 투여로만 사용되어 왔기 때문에 다른 투여 방식에 대한연구가 여전히 필요하다.However, since it has been used only for oral administration, studies on other administration methods are still needed.
[선행기술문헌][Prior art literature]
[특허문헌][Patent Literature]
(특허문헌 1) KR 10-2018-7028095 A(Patent Document 1) KR 10-2018-7028095 A
(특허문헌 2) KR 10-2015-7028929 A(Patent Document 2) KR 10-2015-7028929 A
[비특허문헌][Non-patent literature]
(비특허문헌 1) Imran Majid, Microneedling Therapy in Atrophic Facial Scars: An Objective Assessment, J Cutan Aesthet Surg. 2009 Jan-Jun; 2(1): 26-30.(Non-Patent Document 1) Imran Majid, Microneedling Therapy in Atrophic Facial Scars: An Objective Assessment, J Cutan Aesthet Surg. 2009 Jan-Jun; 2(1): 26-30.
일 측면에서, 본 발명의 목적은, 상처 치유용 약물 특히 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 제공하는 것이다.In one aspect, an object of the present invention is to provide a microstructure including a microneedle containing a wound healing drug, particularly tranilast.
다른 측면에서, 본 발명의 목적은, 피부 상처 치유를 위하여 트라닐라스트를 피부에 제공하기 위한 효과적인 방법을 제공하는 것이다.In another aspect, it is an object of the present invention to provide an effective method for providing tranilast to the skin for skin wound healing.
또 다른 측면에서, 본 발명의 목적은, 마이크로니들을 이용하여 트라닐라스트를 피부에 제공시 흉터 증가 지수(Scar Elevation Index, SEI), 진피층 두께, 섬유층 두께, 혈관 형성, 제1형 콜라겐 발현량, 콜라겐 밀도, 평활근 액틴(smooth muscle action, SMA) 발현량, 종양성장인자-베타(tumor growth factor-beta, TGF-beta) 값에서의 효능을 평가하여 유효한 농도를 제공 하고자 하는 것이다.In another aspect, an object of the present invention is, when tranilast is provided to the skin using a microneedle, Scar Elevation Index (SEI), dermal layer thickness, fibrous layer thickness, blood vessel formation, type 1 collagen expression level , collagen density, smooth muscle action (SMA) expression level, and tumor growth factor-beta (tumor growth factor-beta, TGF-beta) values were evaluated to provide effective concentrations.
일 측면에서, 본 발명은, 생체 적합성 양친성 블록 공중합체를 포함하는 마이크로 니들; 및 상기 마이크로 니들의 내부에 포함되는 트라닐라스트(tranilast);를 포함하는 마이크로 구조체를 제공한다.In one aspect, the present invention, a microneedle comprising a biocompatible amphiphilic block copolymer; and tranilast included in the microneedle; provides a microstructure comprising.
다른 측면에서, 본 발명은 마이크로니들로 제공하기 위한 상처 치유용 조성물로서, 2.5 내지 150 μg/ml 농도의 트라닐라스트를 유효 성분으로 포함하는, 상처 치유용 조성물을 제공한다.In another aspect, the present invention provides a composition for wound healing for use as a microneedle, comprising tranilast at a concentration of 2.5 to 150 μg/ml as an active ingredient.
본 발명의 일 측면에 따른 마이크로 구조체 또는 이에 사용되는 상처 치유용 조성물은 마이크로 니들의 내부에 트라닐라스트(tranilast)를 포함, 특히 특정 농도로 포함하고 있어, 마이크로 니들을 처리하지 않거나, 또는 트라닐라스트(tranilast)를 포함하지 않은 마이크로 니들에 비하여, 상처 피부에 처리 시 진피층 및 섬유층의 두께가 감소하고 혈관 형성이 현저히 증가하며 콜라겐 밀도가 감소하고 제1형 콜라겐 및 SMA와 같은 섬유화 인자, 및 TGF-beta와 같은 염증성 인자의 발현이 감소하는 등 보다 우수한 상처 치유 효과가 있다.The microstructure according to an aspect of the present invention or the composition for wound healing used therein contains tranilast, particularly at a specific concentration, inside the microneedle, so that the microneedle is not processed or tranil Compared to microneedles that do not contain the last (tranilast), the thickness of the dermal layer and the fibrous layer is reduced when treated on the wound skin, the blood vessel formation is significantly increased, the collagen density is reduced, and fibrosis factors such as type 1 collagen and SMA, and TGF It has a better wound healing effect, such as a decrease in the expression of inflammatory factors such as -beta.
도 1a은 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 상처 치유 효과를 카메라로 측정한 사진이다.1A is a photograph of a camera measuring the wound healing effect according to whether the microstructure is treated or not according to an aspect of the present invention.
도 1b는 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 상처 치유 효과를 카메라로 관찰하여 상처 면적 계산법에 의해 흉터 증가 지수(SEI)를 측정한 결과를 나타낸 그래프이다. 1B is a graph showing the results of measuring the scar increase index (SEI) by the wound area calculation method by observing the wound healing effect according to the microstructure treatment of one aspect of the present invention with a camera.
도 2a 및 도 2b는 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 진피층 두께를 현미경으로 관찰한 이미지(도 2a), 및 이로부터 측정된 진피층 두께를 나타낸 그래프이다(도 2b).Figures 2a and 2b is a microscopic image of the dermal layer thickness according to whether microstructure treatment of one aspect of the present invention is observed (FIG. 2a), and a graph showing the dermal layer thickness measured therefrom (FIG. 2b).
도 3a 및 도 3b는 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 섬유층 두께를 현미경으로 관찰한 이미지(도 3a), 및 이로부터 측정된 섬유층 두께를 나타낸 그래프이다(도 3b).3A and 3B are graphs showing an image ( FIG. 3A ) of an aspect of the present invention observing the thickness of the fiber layer according to whether the microstructure is processed or not, and a graph showing the thickness of the fiber layer measured therefrom ( FIG. 3B ).
도 4는 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 혈관 형성 정도를 현미경으로 관찰한 이미지이다.4 is a microscopic image of the degree of blood vessel formation according to whether or not the microstructure is processed according to an aspect of the present invention.
도 5a 및 도 5b는 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 상처 치유 효과를 현미경으로 관찰한 이미지(도 5a), 및 이로부터 측정된 콜라겐 밀도를 나타낸 그래프이다(도 5b).Figures 5a and 5b is a microscopic image of the wound healing effect according to whether microstructure treatment of one aspect of the present invention is observed (FIG. 5a), and a graph showing the collagen density measured therefrom (FIG. 5b).
도 6은 본 발명의 일 측면의 마이크로 구조체 처리 여부에 따른 섬유화 인자(제1형 콜라겐(Collagen I, COL 1) 및 SMA)와 염증성 인자(TGF-beta)의 발현량을 웨스턴 블롯으로 확인한 결과이다.6 is a result of confirming the expression levels of fibrosis factor (collagen I, COL 1 and SMA) and inflammatory factor (TGF-beta) according to whether or not the microstructure of one aspect of the present invention is treated by Western blot. .
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면에서, "피부"는 생물의 외부를 덮고 있는 기관을 의미하는 것으로서 표피, 진피 및 피하지방층으로 구성되어 있으며 얼굴 또는 몸 전체의 외부를 덮는 조직뿐만 아니라, 두피와 모발을 포함하는 최광의의 개념이다.In one aspect of the present invention, "skin" refers to an organ covering the outside of an organism, and is composed of the epidermis, dermis, and subcutaneous fat layer, and includes not only the tissues covering the outside of the face or the entire body, but also the scalp and hair. It's the ultimate concept.
일 측면에서, 본 발명은 생체 적합성 양친성 블록 공중합체를 포함하는 마이크로 니들; 및 상기 마이크로 니들의 내부에 포함되는 트라닐라스트(tranilast);를 포함하는 마이크로 구조체를 제공한다.In one aspect, the present invention provides a microneedle comprising a biocompatible amphiphilic block copolymer; and tranilast included in the microneedle; provides a microstructure comprising.
본 발명의 일 측면에 따른 마이크로 구조체는 생체 적합성 양친성 블록 공중합체를 포함하는 마이크로 니들을 포함할 수 있다.The microstructure according to an aspect of the present invention may include microneedles including a biocompatible amphiphilic block copolymer.
본 발명의 일 측면에서, 상기 생체적합성 양친성 블록 공중합체는 친수성 영역의 고분자와 소수성 영역의 고분자의 이중(di-block), 삼중(tri-block) 또는 다중(multi-block) 블록공중합체일 수 있다.In one aspect of the present invention, the biocompatible amphiphilic block copolymer is a di-block, tri-block or multi-block copolymer of a polymer of a hydrophilic region and a polymer of a hydrophobic region. can
본 발명의 일 측면에서, 상기 친수성 영역의 고분자는 폴리아크릴릭산(Polyacrylic acid, PAA), 폴리에틸렌글리콜(polyethyleneglycol, PEG), 폴리아크릴로니트릴(polyacrylonitrile, PAN), 폴리에틸렌옥시드(Polyethyleneoxide, PEO), 폴리비닐아세테이트(Polyvinylacetate, PVAc), 폴리비닐알콜(Polyvinylalcohol, PVA), 및 폴리메틸메타아크릴레이트(Polymehtylmethacrylate, PMMA))로 이루어진 군으로부터 선택된 하나 이상일 수 있다. In one aspect of the invention, the polymer of the hydrophilic region is polyacrylic acid (Polyacrylic acid, PAA), polyethylene glycol (polyethyleneglycol, PEG), polyacrylonitrile (polyacrylonitrile, PAN), polyethylene oxide (Polyethyleneoxide, PEO), It may be at least one selected from the group consisting of polyvinylacetate (PVAc), polyvinylalcohol (PVA), and polymethyl methacrylate (PMMA)).
본 발명의 일 측면에서, 상기 소수성 영역의 고분자는 폴리프로필렌옥시드(Polypropyleneoxide, PPO), 폴리카프로락톤(Polycaprolactone, PCL), 폴리락트산(Polylactic acid, PLA), 폴리글리콜릭산(Polyglycolic acid, PGA), 폴리(락틱-코-글리콜릭산)(Poly(lactic-co-glycolic acid), PLGA), 폴리안하이드라이드(Polyanhydride), 폴리오르쏘에스테르(Polyorthoester), 폴리에스테르(Polyester), 폴리에스테르아마이드(Polyesteramide), 폴리스티렌(Polystyrene), 폴리디엔(Polydiene), 폴리이소부틸렌(Polyisobutylene), 폴리이소프로필아크릴아마이드(Polyisopropylacrylamide), 폴리실록산(Polysiloxane), 폴리(2-비닐 나프탈렌)(Poly(2-vinyl naphthalene)), 폴리(비닐 피리딘 및 N-메틸 비닐 피리디늄 요오드)(Poly(vinyl pyridine and N-methyl vinyl pyridinium iodide)), 및 폴리(비닐 피롤리딘)(Poly(vinyl pyrrolidone))으로 이루어진 군으로부터 선택된 하나 이상일 수 있다.In one aspect of the present invention, the polymer of the hydrophobic region is polypropyleneoxide (PPO), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA) , poly(lactic-co-glycolic acid) (Poly(lactic-co-glycolic acid), PLGA), polyanhydride, polyorthoester, polyester, polyesteramide ( Polyesteramide), polystyrene, polydiene, polyisobutylene, polyisopropylacrylamide, polysiloxane, poly(2-vinyl naphthalene) (Poly(2-vinyl naphthalene) )), poly(vinyl pyridine and N-methyl vinyl pyridinium iodide), and poly(vinyl pyrrolidone)) It may be one or more selected.
본 발명의 일 측면에서, 상기 생체적합성 양친성 블록 공중합체는 구체적으로, 폴록사머 (폴리에틸렌옥시드-폴리프로필렌옥시드-폴리에틸렌옥시드)(PEO-PPO-PEO) 삼중블록 공중합체, 폴록사머 (폴리프로필렌옥시드-폴리에틸렌옥시드-폴리프로필렌옥시드) (PPO-PEO-PPO) 삼중블록 공중합체, 폴리에틸렌옥시드-폴리락트산-폴리에틸렌옥시드(PEO-PLA-PEO) 삼중블록 공중합체, 폴리락트산-폴리에틸렌옥시드-폴리락트산(PLA-PEO-PLA) 삼중블록 공중합체, 폴리에틸렌옥시드-폴리글리콜릭산-폴리에틸렌옥시드(PEO-PGA-PEO) 삼중블록 공중합체, 폴리글리콜릭산-폴리에틸렌옥시드-폴리글리콜릭산(PGA-PEO-PGA) 삼중블록 공중합체, 폴리에틸렌옥시드-폴리(락틱-코-글리콜릭산)-폴리에틸렌옥시드(PEO-PLGA-PEO) 삼중블록 공중합체, 폴리(락틱-코-글리콜릭산)-폴리에틸렌옥시드-폴리(락틱-코-글리콜릭산)(PLGA-PEO-PLGA) 삼중블록 공중합체, 폴리에틸렌옥시드-폴리카프로락톤-폴리에틸렌옥시드(PEO-PCL-PEO) 삼중블록 공중합체, 폴리카프로락톤-폴리에틸렌옥시드-폴리카프로락톤(PCL-PEO-PCL) 삼중블록 공중합체, 폴리에틸렌옥시드-폴리락트산(PEO-PLA) 이중블록 공중합체, 폴리에틸렌옥시드-폴리글리콜릭산(PEO-PGA) 이중블록 공중합체, 폴리에틸렌옥시드-폴리(락틱-코-글리콜릭산)(PEO-PLGA) 이중블록 공중합체, 및 폴리에틸렌옥시드-폴리카프로락톤(PEO-PCL) 이중블록 공중합체로 이루어진 군으로부터 선택된 하나 이상일 수 있고, 보다 구체적으로 상기 생체적합성 양친성 블록 공중합체는 폴록사머 (폴리에틸렌옥시드-폴리프로필렌옥시드-폴리에틸렌옥시드)(PEO-PPO-PEO) 삼중블록 공중합체일 수 있으나, 이에 제한되지 않는다.In one aspect of the present invention, the biocompatible amphiphilic block copolymer is specifically, poloxamer (polyethylene oxide-polypropylene oxide-polyethylene oxide) (PEO-PPO-PEO) triblock copolymer, poloxamer ( Polypropylene oxide-polyethylene oxide-polypropylene oxide) (PPO-PEO-PPO) triblock copolymer, polyethylene oxide-polylactic acid-polyethylene oxide (PEO-PLA-PEO) triblock copolymer, polylactic acid -Polyethylene oxide-polylactic acid (PLA-PEO-PLA) triblock copolymer, polyethylene oxide-polyglycolic acid-polyethylene oxide (PEO-PGA-PEO) triblock copolymer, polyglycolic acid-polyethylene oxide- Polyglycolic acid (PGA-PEO-PGA) triblock copolymer, polyethylene oxide-poly(lactic-co-glycolic acid)-polyethylene oxide (PEO-PLGA-PEO) triblock copolymer, poly(lactic-co-glycolic acid) Glycolic acid)-polyethylene oxide-poly(lactic-co-glycolic acid) (PLGA-PEO-PLGA) triblock copolymer, polyethylene oxide-polycaprolactone-polyethylene oxide (PEO-PCL-PEO) triblock copolymer Copolymer, polycaprolactone-polyethylene oxide-polycaprolactone (PCL-PEO-PCL) triblock copolymer, polyethylene oxide-polylactic acid (PEO-PLA) diblock copolymer, polyethylene oxide-polyglycolic acid (PEO) -PGA) diblock copolymer, polyethylene oxide-poly(lactic-co-glycolic acid) (PEO-PLGA) diblock copolymer, and polyethylene oxide-polycaprolactone (PEO-PCL) diblock copolymer consisting of It may be at least one selected from the group, and more specifically, the biocompatible amphiphilic block copolymer may be a poloxamer (polyethylene oxide-polypropylene oxide-polyethylene oxide) (PEO-PPO-PEO) triblock copolymer. , but not limited thereto.
본 발명의 일 측면에 따른 마이크로 구조체는 상기 마이크로 니들의 내부에 포함되는 상처 치유용 약물 또는 조성물을 포함할 수 있다. 또한, 본 발명의 일 측면에 따른 마이크로 구조체는 상기 마이크로 구조체는 상기 마이크로 니들이 나열된 기판부를 추가로 포함하고, 상기 기판부는 상기 약물이 투입되는 약물 투입부를 포함할 수 있다.The microstructure according to an aspect of the present invention may include a drug or composition for wound healing contained inside the microneedle. In addition, in the microstructure according to an aspect of the present invention, the microstructure may further include a substrate portion on which the microneedles are arranged, and the substrate portion may include a drug input portion into which the drug is injected.
본 발명의 일 측면에서, 상기 마이크로 니들은 내부에 약물을 포함할 수 있다. 상기 포함되는 약물에 특별한 제한은 없고, 수용성 약물 또는 지용성 약물이 모두 포함될 수 있으며, 구체적으로 화학 약물, 면역 증강제, 백신, 단백질 약물, 펩타이드 약물, 유전자 치료용 핵산 분자, 화장품용 효능물질, 및 의료용 항체로 이루어진 군으로부터 하나 또는 둘 이상의 혼합물이 포함될 수 있으며, 보다 구체적으로 상처 치유용 약물이 포함될 수 있고, 보다 더 구체적으로 상기 약물은 트라닐라스트(tranilast)일 수 있다.In one aspect of the present invention, the microneedle may include a drug therein. There is no particular limitation on the included drugs, and water-soluble drugs or fat-soluble drugs may be included. Specifically, chemical drugs, immune enhancers, vaccines, protein drugs, peptide drugs, nucleic acid molecules for gene therapy, cosmetic efficacy substances, and medical use One or a mixture of two or more from the group consisting of antibodies may be included, and more specifically, a drug for wound healing may be included, and more specifically, the drug may be tranilast.
본 발명의 일 측면에서, 상기 상처 치유용 약물 또는 조성물에 포함되는 트라닐라스트의 농도는 2.5 내지 150 μg/ml일 수 있고, 구체적으로 상기 트라닐라스트의 농도는 2.5 μg/ml 이상, 2.6 μg/ml 이상, 2.7 μg/ml 이상, 2.8 μg/ml 이상, 2.9 μg/ml 이상, 3 μg/ml 이상, 4 μg/ml 이상, 6 μg/ml 이상, 8 μg/ml 이상, 10 μg/ml 이상, 12 μg/ml 이상, 14 μg/ml 이상, 16 μg/ml 이상, 18 μg/ml 이상, 20 μg/ml 이상, 21 μg/ml 이상, 22 μg/ml 이상, 23 μg/ml 이상, 24 μg/ml 이상, 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하, 26 μg/ml 이하, 25 μg/ml 이하, 20 μg/ml 이하, 10 μg/ml 이하, 8 μg/ml 이하, 6 μg/ml 이하, 4 μg/ml 이하, 3.9 μg/ml 이하, 3.8 μg/ml 이하, 3.7 μg/ml 이하, 3.6 μg/ml 이하, 3.5 μg/ml 이하, 3.4 μg/ml 이하, 3.3 μg/ml 이하, 3.2 μg/ml 이하, 3.1 μg/ml 이하, 3 μg/ml 이하, 2.9 μg/ml 이하, 2.8 μg/ml 이하, 2.7 μg/ml 이하 또는 2.6 μg/ml 이하일 수 있다. In one aspect of the present invention, the concentration of tranilast included in the wound healing drug or composition may be 2.5 to 150 μg/ml, specifically, the concentration of tranilast is 2.5 μg/ml or more, 2.6 μg /ml or more, 2.7 μg/ml or more, 2.8 μg/ml or more, 2.9 μg/ml or more, 3 μg/ml or more, 4 μg/ml or more, 6 μg/ml or more, 8 μg/ml or more, 10 μg/ml or more or more, 12 μg/ml or more, 14 μg/ml or more, 16 μg/ml or more, 18 μg/ml or more, 20 μg/ml or more, 21 μg/ml or more, 22 μg/ml or more, 23 μg/ml or more, 24 μg/ml or more, 25 μg/ml or more, 26 μg/ml or more, 27 μg/ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg /ml or more, 60 μg/ml or more, 70 μg/ml or more, 80 μg/ml or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more, or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 μg/ml or less, 34 μg/ml or less, 33 μg/ml or less, 32 μg/ml or less, 31 μg/ml or less, 30 μg/ml or less, 29 μg/ml or less, 28 μg /ml or less, 27 µg/ml or less, 26 µg/ml or less, 25 µg/ml or less, 20 µg/ml or less, 10 µg/ml or less, 8 µg/ml or less, 6 µg/ml or less, 4 µg/ml or less Hereinafter, 3. 9 μg/ml or less, 3.8 μg/ml or less, 3.7 μg/ml or less, 3.6 μg/ml or less, 3.5 μg/ml or less, 3.4 μg/ml or less, 3.3 μg/ml or less, 3.2 μg/ml or less, 3.1 μg /ml or less, 3 μg/ml or less, 2.9 μg/ml or less, 2.8 μg/ml or less, 2.7 μg/ml or less, or 2.6 μg/ml or less.
본 발명의 일 실시예에 따르면, 25 내지 150 μg/ml 농도의 트라닐라스트를 포함하는 마이크로 구조체는 흉터 증가 지수(Scar Elevation Index, SEI) 감소, 진피층 두께 감소, 혈관 형성 증가 또는 제1형 콜라겐 발현량 감소에 있어 우수한 효과를 보인다(실험예 2, 3, 4 및 6). According to an embodiment of the present invention, the microstructure containing tranilast at a concentration of 25 to 150 μg/ml reduces the Scar Elevation Index (SEI), reduces the thickness of the dermal layer, increases the formation of blood vessels, or type 1 collagen It shows an excellent effect in reducing the expression level (Experimental Examples 2, 3, 4 and 6).
또한, 본 발명의 일 실시예에 따르면, 25 내지 30 μg/ml 농도의 트라닐라스트를 포함하는 마이크로 구조체는 이보다 고농도의 트라닐라스트를 포함하는 마이크로 구조체에 비하여 콜라겐 밀도 감소, 평활근 액틴(smooth muscle action, SMA) 발현량 감소 또는 종양성장인자-베타(tumor growth factor-beta, TGF-beta) 발현량 감소에 있어 우수한 효과를 보인다(실험예 5 및 6). In addition, according to an embodiment of the present invention, the microstructures containing tranilast at a concentration of 25 to 30 μg/ml have reduced collagen density and smooth muscle actin (smooth muscle) compared to microstructures containing tranilast at a higher concentration than this. action, SMA) expression level reduction or tumor growth factor-beta (tumor growth factor-beta, TGF-beta) shows an excellent effect in reducing the expression level (Experimental Examples 5 and 6).
또한, 본 발명의 일 실시예에 따르면, 100 내지 150 μg/ml 농도의 트라닐라스트를 포함하는 마이크로 구조체는 이보다 저농도의 트라닐라스트를 포함하는 마이크로 구조체에 비하여 섬유층 두께 감소에 있어 우수한 효과를 보인다(실험예 3).In addition, according to an embodiment of the present invention, the microstructure containing tranilast at a concentration of 100 to 150 μg/ml shows an excellent effect in reducing the thickness of the fiber layer compared to the microstructure containing tranilast at a lower concentration than this. (Experimental Example 3).
구체적으로, 본 발명의 일 측면에 따른 트라닐라스트는 상기 마이크로 니들이 피부에 삽입되어 체내로 주입되는 것일 수 있고, 상기 피부는 상처 치유를 필요로 하는 피부일 수 있으며, 구체적으로 상기 피부는 여드름, 건선, 피부 감염, 잡티, 과색소침착, 저색소침착, 탈모증, 과도한 발모, 원치 않는 발모, 거친 피부, 건조한 피부, 느슨한 피부, 주름, 혈관과다성 피부, 피지 생산 장애, 과도한 모공, 과도한 발한, 다한증, 문신, 발진, 흉터, 통증, 가려움, 화상, 염증, 무사마귀, 티눈, 굳은살, 부종, 옻 중독, 및 곤충, 거미, 뱀, 및 다른 동물로부터 물린 상처로 이루어진 군에서 선택되는 하나 이상의 피부 질환을 앓고 있는 피부일 수 있으나, 이에 제한되지 않는다.Specifically, tranilast according to an aspect of the present invention may be one in which the microneedle is inserted into the skin and injected into the body, and the skin may be skin in need of wound healing, specifically, the skin may be acne, Psoriasis, skin infections, blemishes, hyperpigmentation, hypopigmentation, alopecia, excessive hair growth, unwanted hair growth, rough skin, dry skin, loose skin, wrinkles, hypervascularized skin, sebum production disorders, excessive pores, excessive sweating, one or more skin selected from the group consisting of hyperhidrosis, tattoos, rashes, scars, pain, itching, burns, sores, warts, corns, calluses, edema, poison ivy, and bites from insects, spiders, snakes, and other animals It may be a diseased skin, but is not limited thereto.
본 발명의 일 측면에서, 상기 마이크로 구조체는 상기 트라닐라스트를 건조 후 마이크로 니들의 총 중량을 기준으로 0.0001 내지 50 중량%로 포함할 수 있고, 구체적으로 상기 트라닐라스트의 함량은 건조 후 마이크로 니들의 총 중량을 기준으로 0.01 내지 20 중량%일 수 있으나, 상기 트라닐라스트의 함량은 트라닐라스트의 최소효과농도(minimal effective concentration)와 마이크로 니들 및 마이크로 구조체 각각의 형태에 따라 다양하게 설정할 수 있으며, 이에 제한되지 않고, 미량의 약물이라도 함유되는 모든 경우를 포함할 수 있다.In one aspect of the present invention, the microstructure may include 0.0001 to 50% by weight of the tranilast after drying based on the total weight of the microneedles, and specifically, the content of the tranilast after drying the microneedles It may be 0.01 to 20% by weight based on the total weight of , but is not limited thereto, and may include all cases in which even a small amount of drug is contained.
본 발명의 일 측면에서, 상기 마이크로 구조체는 마이크로 구조체 내 트라닐라스트의 안정성 및 니들의 강도를 강화하는 첨가제를 추가로 포함할 수 있다. 구체적으로 상기 첨가제는 히알루론산, 키토산, 폴리비닐알코올, 카르복시비닐폴리머, 아크릴비닐폴리머, 덱스트란, 카르복시메틸셀룰로오스, 하이드록시에틸셀룰로오스, 산탄검, 로카스트빈검, 에틸렌-비닐아세테이트 중합체, 셀룰로스아세테이트, 아크릴 치환 셀룰로오스 아세테이트, 폴리우레탄, 폴리카프로락톤, 폴리락틱-코-글리콜릭산, 폴리락트산, 폴리글리콜산, 폴리안하이드라이드, 폴리스티렌, 폴리비닐 아세테이트, 폴리비닐 클로라이드, 폴리비닐플루오라이드, 폴리비닐이미다졸, 클로로설포네이트 폴리올레핀, 폴리에틸렌옥사이드, 폴리비닐피롤리돈, 폴리에틸렌글리콜, 폴리메타크릴레이트, 하이드록시프로필메틸셀룰로오스, 에틸셀룰로오스, 하이드록시프로필셀룰로오스, 카복시메틸셀룰로오스, 및 싸이클로덱스트린으로 이루어진 군으로부터 선택된 하나 또는 둘 이상의 혼합물일 수 있다.In one aspect of the present invention, the microstructure may further include an additive for enhancing the stability of tranilast and the strength of the needle in the microstructure. Specifically, the additives include hyaluronic acid, chitosan, polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, dextran, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene-vinyl acetate polymer, cellulose acetate, Acrylic-substituted cellulose acetate, polyurethane, polycaprolactone, polylactic-co-glycolic acid, polylactic acid, polyglycolic acid, polyanhydride, polystyrene, polyvinyl acetate, polyvinyl chloride, polyvinylfluoride, polyvinyl fluoride from the group consisting of midazole, chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, and cyclodextrin. It may be one or a mixture of two or more selected.
본 발명의 일 측면에서, 상기 생체적합성 양친성 블록 공중합체, 트라닐라스트 및 첨가제의 조성비는 전달하고자 하는 트라닐라스트의 특성 또는 전달하고자 하는 형태에 따라 다양하게 변화할 수 있다.In one aspect of the present invention, the composition ratio of the biocompatible amphiphilic block copolymer, tranilast, and the additive may be variously changed depending on the characteristics of the tranilast to be delivered or the form to be delivered.
본 발명의 일 측면에서, 상기 마이크로 구조체는 생체 상피에 삽입되면 용해되어 트라닐라스트를 담지한 구형의 자가 조립 나노입자를 형성할 수 있고, 상기 자가 조립 나노입자는 미셀 형태의 직경 10 내지 2000 nm, 구체적으로 50 내지 1000 nm인 구형의 자가 조립 나노입자일 수 있다.In one aspect of the present invention, when the microstructure is inserted into the living epithelium, it can be dissolved to form spherical self-assembled nanoparticles carrying tranilast, and the self-assembled nanoparticles are micelles with a diameter of 10 to 2000 nm. , specifically, may be spherical self-assembled nanoparticles of 50 to 1000 nm.
본 발명의 일 측면에서, 상기 마이크로 구조체는 수용액에 용해 시 자가 조립 나노입자를 형성함으로써 수용액상에서 안정한 구조를 유지할 수 있으며, 소수성 약물을 전달시 수용액 내 약물의 용해도를 높이는 동시에 담지 된 약물을 세포 내로 원활히 전달할 수 있어 소수성 약물 전달 또는 백신용 항원과 소수성 면역증강제(adjuvant)의 동시 경피 전달을 용이하게 할 수 있다.In one aspect of the present invention, the microstructure can maintain a stable structure in an aqueous solution by forming self-assembled nanoparticles when dissolved in an aqueous solution, and at the same time increase the solubility of the drug in the aqueous solution when delivering a hydrophobic drug, and inject the loaded drug into the cell Because it can be delivered smoothly, it is possible to facilitate the simultaneous transdermal delivery of a hydrophobic drug delivery or a vaccine antigen and a hydrophobic adjuvant.
본 발명의 일 측면에서, 상처는 생체가 손상된 것을 모두 아우르는 의미로서, 생체가 손상된 상태를 말하는 것이며, 창상이라고도 한다. 상기 상처는 창상, 비-치유 외상성 상처, 방사선조사에 의한 조직의 파괴, 찰과상, 열상, 결출상, 관통상, 총상, 절상, 화상, 동상, 피부궤양, 피부건조, 피부각화증, 갈라짐, 터짐, 피부염, 수술상 또는 혈관질환 상처, 타박상, 각막창상, 욕창, 와창, 만성궤양, 수술 후 봉합부위, 척추상해성 상처, 부인과적 상처, 화학적 상처 및 여드름으로 구성되는 군에서 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않는다. 또한, 본 발명의 일 측면에 있어서 상처와 창상은 상호 교환적으로 사용될 수 있다.In one aspect of the present invention, the wound refers to a state in which the living body is damaged as a meaning encompassing all the damaged living bodies, and is also referred to as a wound. The wounds are wounds, non-healing traumatic wounds, destruction of tissue by irradiation, abrasions, lacerations, bursae, penetrating wounds, gunshot wounds, cuts, burns, frostbite, skin ulcers, dry skin, keratosis, cracks, ruptures, dermatitis , surgical or vascular disease wounds, bruises, corneal wounds, bedsores, pits, chronic ulcers, post-operative suture sites, spinal injuries, gynecological wounds, chemical wounds and acne may be at least one selected from the group consisting of , but not limited thereto. In addition, in one aspect of the present invention wound and wound may be used interchangeably.
본 발명의 일 측면에서, 상기 마이크로 구조체는 상처 치유용 마이크로 구조체일 수 있다.In one aspect of the present invention, the microstructure may be a microstructure for wound healing.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 흉터 증가 지수(Scar Elevation Index, SEI)가 10% 이상 감소한 것일 수 있고, 구체적으로 10% 이상, 15% 이상, 20% 이상, 25% 이상, 30% 이상, 35% 이상, 40% 이상, 45% 이상 또는 50% 이상 감소한 것일 수 있으며, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 25 내지 150 μg/ml일 수 있고, 구체적으로 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하 또는 26 μg/ml 이하일 수 있으나, 이에 제한되지 않는다. 상기 흉터 증가 지수(SEI)는 비대성 흉터 아래의 정상 조직 영역 대비 총 상처 영역 조직 높이의 비율을 의미할 수 있고, 일반적인 SEI 계산 방법에 따라 계산된 값일 수 있다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment The Scar Elevation Index (SEI) may be reduced by 10% or more, specifically 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, It may be reduced by 45% or more or 50% or more, and in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 μg/ml, specifically 25 μg/ml or more, 26 μg/ml or more , 27 μg/ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more, 70 μg/ml or more, 80 More than μg/ml, more than 90 μg/ml, more than 92 μg/ml, more than 94 μg/ml, more than 96 μg/ml, more than 98 μg/ml, more than 100 μg/ml, more than 110 μg/ml, more than 120 μg/ ml or more, 130 μg/ml or more, or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 μg/ml or less, 34 μg/ml or less , 33 μg/ml or less, 32 μg/ml or less, 31 μg/ml or less, 30 μg/ml or less, 29 μg/ml or less, 28 μg/ml or less, 27 μg/ml or less, or 26 μg/ml or less , but not limited thereto. The scar increase index (SEI) may mean a ratio of the total wound area tissue height to the normal tissue area under the hypertrophic scar, and may be a value calculated according to a general SEI calculation method.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 진피층의 두께가 10% 이상 감소한 것일 수 있고, 구체적으로 10% 이상, 15% 이상, 20% 이상, 25% 이상, 30% 이상, 35% 이상, 40% 이상, 45% 이상, 50% 이상, 55% 이상, 60% 이상, 65% 이상 또는 70% 이상 감소한 것일 수 있으며, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 25 내지 150 μg/ml일 수 있고, 구체적으로 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하 또는 26 μg/ml 이하일 수 있으나, 이에 제한되지 않는다. 상기 진피층의 두께는 본 기술분야에서 공지된 방법에 의해 측정된 것일 수 있으며, 측정 방법이 제한되지 않는다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment The thickness of the dermal layer may be reduced by 10% or more, specifically 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more , 55% or more, 60% or more, 65% or more, or 70% or more may be reduced, in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 μg / ml, specifically 25 μg /ml or more, 26 μg/ml or more, 27 μg/ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more or more, 70 μg/ml or more, 80 μg/ml or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more, or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 μg /ml or less, 34 µg/ml or less, 33 µg/ml or less, 32 µg/ml or less, 31 µg/ml or less, 30 µg/ml or less, 29 µg/ml or less, 28 µg/ml or less, 27 µg/ml or less or less or 26 μg/ml or less, but is not limited thereto. The thickness of the dermal layer may be measured by a method known in the art, and the measurement method is not limited.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 섬유층의 두께가 10% 이상 감소한 것일 수 있고, 구체적으로 10% 이상, 15% 이상, 20% 이상, 25% 이상, 30% 이상, 35% 이상, 40% 이상, 45% 이상, 50% 이상, 55% 이상, 60% 이상, 65% 이상 또는 70% 이상 감소한 것일 수 있으며, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 25 내지 150 μg/ml일 수 있고, 구체적으로 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하 또는 26 μg/ml 이하일 수 있으며, 보다 구체적으로 100 내지 150 μg/ml일 수 있으나, 이에 제한되지 않는다. 상기 섬유층의 두께는 본 기술분야에서 공지된 방법에 의해 측정된 것일 수 있으며, 측정 방법이 제한되지 않는다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment The thickness of the fibrous layer may be reduced by 10% or more, and specifically 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more , 55% or more, 60% or more, 65% or more, or 70% or more may be reduced, in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 μg / ml, specifically 25 μg /ml or more, 26 μg/ml or more, 27 μg/ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more or more, 70 μg/ml or more, 80 μg/ml or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more, or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 μg /ml or less, 34 µg/ml or less, 33 µg/ml or less, 32 µg/ml or less, 31 µg/ml or less, 30 µg/ml or less, 29 µg/ml or less, 28 µg/ml or less, 27 µg/ml or less It may be less than or equal to 26 μg/ml, and more specifically, 100 to 150 μg/ml, but is not limited thereto. The thickness of the fiber layer may be measured by a method known in the art, and the measurement method is not limited.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 혈관 형성이 증가한 것일 수 있으며, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 25 내지 150 μg/ml일 수 있고, 구체적으로 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하 또는 26 μg/ml 이하일 수 있으며, 보다 구체적으로 100 내지 150 μg/ml일 수 있으나, 이에 제한되지 않는다. 상기 혈관 형성 정도는 본 기술분야에서 공지된 방법에 의해 측정된 것일 수 있으며, 측정 방법이 제한되지 않는다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment Post-vascularization may be increased, and in this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 μg/ml, specifically 25 μg/ml or more, 26 μg/ml or more, 27 μg /ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more, 70 μg/ml or more, 80 μg/ml or more or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 μg/ml or less, 34 μg/ml or less, 33 μg /ml or less, 32 μg/ml or less, 31 μg/ml or less, 30 μg/ml or less, 29 μg/ml or less, 28 μg/ml or less, 27 μg/ml or less, or 26 μg/ml or less, more specifically As may be 100 to 150 μg / ml, but is not limited thereto. The degree of blood vessel formation may be measured by a method known in the art, and the measurement method is not limited.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 콜라겐 밀도가 5% 이상 감소한 것일 수 있고, 구체적으로 5% 이상, 5.5% 이상, 6% 이상, 6.5% 이상, 7% 이상, 7.5% 이상, 8% 이상, 8.5% 이상, 9% 이상, 9.5% 이상 또는 10% 이상 감소한 것일 수 있으며, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 2.5 내지 150 μg/ml일 수 있고, 보다 구체적으로 2.5 μg/ml 이상, 2.6 μg/ml 이상, 2.7 μg/ml 이상, 2.8 μg/ml 이상, 2.9 μg/ml 이상, 3 μg/ml 이상, 4 μg/ml 이상, 6 μg/ml 이상, 8 μg/ml 이상, 10 μg/ml 이상, 12 μg/ml 이상, 14 μg/ml 이상, 16 μg/ml 이상, 18 μg/ml 이상, 20 μg/ml 이상, 21 μg/ml 이상, 22 μg/ml 이상, 23 μg/ml 이상, 24 μg/ml 이상, 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하, 26 μg/ml 이하, 25 μg/ml 이하, 20 μg/ml 이하, 10 μg/ml 이하, 8 μg/ml 이하, 6 μg/ml 이하, 4 μg/ml 이하, 3.9 μg/ml 이하, 3.8 μg/ml 이하, 3.7 μg/ml 이하, 3.6 μg/ml 이하, 3.5 μg/ml 이하, 3.4 μg/ml 이하, 3.3 μg/ml 이하, 3.2 μg/ml 이하, 3.1 μg/ml 이하, 3 μg/ml 이하, 2.9 μg/ml 이하, 2.8 μg/ml 이하, 2.7 μg/ml 이하 또는 2.6 μg/ml 이하일 수 있으며, 보다 더 구체적으로 25 내지 150 μg/ml일 수 있으나, 이에 제한되지 않는다. 상기 콜라겐 밀도는 본 기술분야에서 공지된 방법에 의해 측정된 것일 수 있으며, 측정 방법이 제한되지 않는다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment After the collagen density may be reduced by 5% or more, specifically 5% or more, 5.5% or more, 6% or more, 6.5% or more, 7% or more, 7.5% or more, 8% or more, 8.5% or more, 9% or more, It may be a decrease of 9.5% or more or 10% or more, in this case, the concentration of tranilast contained in the treated microstructure may be 2.5 to 150 μg/ml, more specifically 2.5 μg/ml or more, 2.6 μg/ml or more, 2.7 μg/ml or more, 2.8 μg/ml or more, 2.9 μg/ml or more, 3 μg/ml or more, 4 μg/ml or more, 6 μg/ml or more, 8 μg/ml or more, 10 μg/ml or more, 12 μg/ml or more, 14 μg/ml or more, 16 μg/ml or more, 18 μg/ml or more, 20 μg/ml or more, 21 μg/ml or more, 22 μg/ml or more, 23 μg/ml or more, 24 μg /ml or more, 25 μg/ml or more, 26 μg/ml or more, 27 μg/ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more, 70 μg/ml or more, 80 μg/ml or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more, or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 μg/ml or less, 34 μg/ml or less, 33 μg/ml or less, 32 μg/ml or less, 31 μg/ml or less, 30 μg/ml or less ml or less, 29 µg/ml or less, 28 µg/ml or less, 27 µg/ml or less, 26 µg/ml or less, 25 µg/ml or less, 20 µg/ml or less, 10 µg/ml or less, 8 µg/ml or less , 6 μg/ml or less, 4 μg/ml or less, 3.9 μg/ml or less, 3.8 μg/ml or less, 3.7 μg/ml or less, 3.6 μg/ml or less, 3.5 μg/ml or less, 3.4 μg/ml or less, 3.3 μg/ml or less, 3.2 μg/ml or less, 3.1 μg/ml or less, 3 μg/ml or less, 2.9 μg/ml or less, 2.8 μg/ml or less, 2.7 μg/ml or less, or 2.6 μg/ml or less, and more More specifically, it may be 25 to 150 μg/ml, but is not limited thereto. The collagen density may be measured by a method known in the art, and the measurement method is not limited.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 섬유화 인자의 발현량이 10% 이상 감소한 것일 수 있다. 상기 섬유화 인자는 평활근 액틴(smooth muscle action, SMA) 및 제1형 콜라겐(collagen I)으로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되지 않는다. 구체적으로 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 평활근 액틴(SMA)의 발현량이 10% 이상, 20% 이상, 30% 이상, 40% 이상, 50% 이상, 60% 이상, 70% 이상, 80% 이상 또는 90% 이상 감소한 것일 수 있고, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 2.5 내지 150 μg/ml일 수 있고, 보다 구체적으로 2.5 μg/ml 이상, 2.6 μg/ml 이상, 2.7 μg/ml 이상, 2.8 μg/ml 이상, 2.9 μg/ml 이상, 3 μg/ml 이상, 4 μg/ml 이상, 6 μg/ml 이상, 8 μg/ml 이상, 10 μg/ml 이상, 12 μg/ml 이상, 14 μg/ml 이상, 16 μg/ml 이상, 18 μg/ml 이상, 20 μg/ml 이상, 21 μg/ml 이상, 22 μg/ml 이상, 23 μg/ml 이상, 24 μg/ml 이상, 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하, 26 μg/ml 이하, 25 μg/ml 이하, 20 μg/ml 이하, 10 μg/ml 이하, 8 μg/ml 이하, 6 μg/ml 이하, 4 μg/ml 이하, 3.9 μg/ml 이하, 3.8 μg/ml 이하, 3.7 μg/ml 이하, 3.6 μg/ml 이하, 3.5 μg/ml 이하, 3.4 μg/ml 이하, 3.3 μg/ml 이하, 3.2 μg/ml 이하, 3.1 μg/ml 이하, 3 μg/ml 이하, 2.9 μg/ml 이하, 2.8 μg/ml 이하, 2.7 μg/ml 이하 또는 2.6 μg/ml 이하일 수 있으며, 보다 더 구체적으로 25 내지 30 μg/ml일 수 있으나, 이에 제한되지 않는다. 또한, 구체적으로 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 제1형 콜라겐(collagen I)의 발현량이 10% 이상, 20% 이상, 30% 이상, 40% 이상, 50% 이상, 60% 이상, 70% 이상, 80% 이상 또는 90% 이상 감소한 것일 수 있고, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 25 내지 150 μg/ml일 수 있고, 보다 구체적으로 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하 또는 26 μg/ml 이하일 수 있으나, 이에 제한되지 않는다. 상기 섬유화 인자의 발현량은 본 기술분야에서 공지된 방법에 의해 측정된 것일 수 있으며, 측정 방법이 제한되지 않는다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment Later, the expression level of the fibrosis factor may be reduced by 10% or more. The fibrosis factor may be one or more selected from the group consisting of smooth muscle action (SMA) and type 1 collagen (collagen I), but is not limited thereto. Specifically, wound healing is an object or wound that has not been treated with the microstructure according to an aspect of the present invention, or an object or wound treated with the microstructure compared to before the microstructure is treated, or smooth muscle actin (SMA) after microstructure treatment ) of 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, in which case the treated microstructure The concentration of tranilast contained in the may be 2.5 to 150 μg / ml, more specifically 2.5 μg / ml or more, 2.6 μg / ml or more, 2.7 μg / ml or more, 2.8 μg / ml or more, 2.9 μg / ml or more, 3 μg/ml or more, 4 μg/ml or more, 6 μg/ml or more, 8 μg/ml or more, 10 μg/ml or more, 12 μg/ml or more, 14 μg/ml or more, 16 μg/ml or more, 18 μg/ml or more, 20 μg/ml or more, 21 μg/ml or more, 22 μg/ml or more, 23 μg/ml or more, 24 μg/ml or more, 25 μg/ml or more, 26 μg/ml or more, 27 μg /ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more, 70 μg/ml or more, 80 μg/ml or more or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more or 140 μg/ml or more, and 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 Less than or equal to μg/ml, less than or equal to 34 μg/ml, less than or equal to 33 μg/ml, or less than 32 μg/ml, or less than or equal to 31 μg/ml, or less than or equal to 30 μg/ml, or less than or equal to 29 μg/ml, or less than or equal to 28 μg/ml or less than or equal to 27 μg/ml ml or less, 26 µg/ml or less, 25 µg/ml or less, 20 µg/ml or less, 10 µg/ml or less, 8 µg/ml or less, 6 µg/ml or less, 4 µg/ml or less, 3.9 µg/ml or less , 3.8 μg/ml or less, 3.7 μg/ml or less, 3.6 μg/ml or less, 3.5 μg/ml or less, 3.4 μg/ml or less, 3.3 μg/ml or less, 3.2 μg/ml or less, 3.1 μg/ml or less, 3 It may be less than μg/ml, less than 2.9 μg/ml, less than 2.8 μg/ml, less than 2.7 μg/ml, or less than 2.6 μg/ml, and more specifically 25 to 30 μg/ml, but is not limited thereto. In addition, specifically, wound healing is an individual or wound that has not been treated with the microstructure according to an aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or the first after treatment of the microstructure The expression level of collagen I may be decreased by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, In this case, the concentration of tranilast contained in the treated microstructure may be 25 to 150 μg/ml, and more specifically, 25 μg/ml or more, 26 μg/ml or more, 27 μg/ml or more, 28 μg/ml or more. , 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more, 70 μg/ml or more, 80 μg/ml or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 μg/ml or more, 130 μg/ml or more, or 140 μg/ml or more ml or less, 150 μg/ml or less, 140 μg/ml or less, 130 μg/ml or less, 120 μg/ml or less, 110 μg/ml or less, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less ml or less, 70 µg/ml or less, 60 µg/ml or less, 50 µg/ml or less, 40 µg/ml or less, 35 µg/ml or less, 34 µg/ml or less, 33 µg/ml or less, 32 µg/ml or less , 31 μg/ml or less, 30 μg/ml or less, 29 μg/ml or less, 28 μg/ml or less, 27 μg/ml or less, or 26 μg/ml or less, but is not limited thereto. The expression level of the fibrosis factor may be measured by a method known in the art, and the measurement method is not limited.
본 발명의 일 측면에서, 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 염증성 인자의 발현량이 10% 이상 감소한 것일 수 있다. 상기 염증성 인자는 종양성장인자-베타(tumor growth factor-beta, TGF-beta)일 수 있으나, 이에 제한되지 않는다. 구체적으로 상처 치유는 본 발명의 일 측면에 따른 마이크로 구조체를 처리하지 않은 개체 또는 상처, 또는 상기 마이크로 구조체를 처리하기 전에 비하여 상기 마이크로 구조체를 처리한 개체 또는 상처, 또는 마이크로 구조체 처리 후의 종양성장인자-베타(TGF-beta)의 발현량이 10% 이상, 20% 이상, 30% 이상, 40% 이상, 50% 이상, 60% 이상, 70% 이상, 80% 이상 또는 90% 이상 감소한 것일 수 있고, 이 경우 처리된 마이크로 구조체에 포함된 트라닐라스트의 농도는 2.5 내지 150 μg/ml일 수 있고, 보다 구체적으로 2.5 μg/ml 이상, 2.6 μg/ml 이상, 2.7 μg/ml 이상, 2.8 μg/ml 이상, 2.9 μg/ml 이상, 3 μg/ml 이상, 4 μg/ml 이상, 6 μg/ml 이상, 8 μg/ml 이상, 10 μg/ml 이상, 12 μg/ml 이상, 14 μg/ml 이상, 16 μg/ml 이상, 18 μg/ml 이상, 20 μg/ml 이상, 21 μg/ml 이상, 22 μg/ml 이상, 23 μg/ml 이상, 24 μg/ml 이상, 25 μg/ml 이상, 26 μg/ml 이상, 27 μg/ml 이상, 28 μg/ml 이상, 29 μg/ml 이상, 30 μg/ml 이상, 40 μg/ml 이상, 50 μg/ml 이상, 60 μg/ml 이상, 70 μg/ml 이상, 80 μg/ml 이상, 90 μg/ml 이상, 92 μg/ml 이상, 94 μg/ml 이상, 96 μg/ml 이상, 98 μg/ml 이상, 100 μg/ml 이상, 110 μg/ml 이상, 120 μg/ml 이상, 130 μg/ml 이상 또는 140 μg/ml 이상일 수 있고, 150 μg/ml 이하, 140 μg/ml 이하, 130 μg/ml 이하, 120 μg/ml 이하, 110 μg/ml 이하, 100 μg/ml 이하, 90 μg/ml 이하, 80 μg/ml 이하, 70 μg/ml 이하, 60 μg/ml 이하, 50 μg/ml 이하, 40 μg/ml 이하, 35 μg/ml 이하, 34 μg/ml 이하, 33 μg/ml 이하, 32 μg/ml 이하, 31 μg/ml 이하, 30 μg/ml 이하, 29 μg/ml 이하, 28 μg/ml 이하, 27 μg/ml 이하, 26 μg/ml 이하, 25 μg/ml 이하, 20 μg/ml 이하, 10 μg/ml 이하, 8 μg/ml 이하, 6 μg/ml 이하, 4 μg/ml 이하, 3.9 μg/ml 이하, 3.8 μg/ml 이하, 3.7 μg/ml 이하, 3.6 μg/ml 이하, 3.5 μg/ml 이하, 3.4 μg/ml 이하, 3.3 μg/ml 이하, 3.2 μg/ml 이하, 3.1 μg/ml 이하, 3 μg/ml 이하, 2.9 μg/ml 이하, 2.8 μg/ml 이하, 2.7 μg/ml 이하 또는 2.6 μg/ml 이하일 수 있으며, 보다 구체적으로 25 내지 30 μg/ml일 수 있으나, 이에 제한되지 않는다. 상기 염증성 인자의 발현량은 본 기술분야에서 공지된 방법에 의해 측정된 것일 수 있으며, 측정 방법이 제한되지 않는다.In one aspect of the present invention, wound healing is an individual or wound that has not been treated with the microstructure according to one aspect of the present invention, or an object or wound that has been treated with the microstructure compared to before processing the microstructure, or microstructure treatment Later, the expression level of the inflammatory factor may be reduced by 10% or more. The inflammatory factor may be tumor growth factor-beta (tumor growth factor-beta, TGF-beta), but is not limited thereto. Specifically, wound healing is an object or wound that has not been treated with the microstructure according to an aspect of the present invention, or an object or wound treated with the microstructure compared to before processing the microstructure, or tumor growth factor after microstructure treatment- The expression level of beta (TGF-beta) may be decreased by 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, In this case, the concentration of tranilast contained in the treated microstructure may be 2.5 to 150 μg/ml, and more specifically, 2.5 μg/ml or more, 2.6 μg/ml or more, 2.7 μg/ml or more, 2.8 μg/ml or more , 2.9 μg/ml or more, 3 μg/ml or more, 4 μg/ml or more, 6 μg/ml or more, 8 μg/ml or more, 10 μg/ml or more, 12 μg/ml or more, 14 μg/ml or more, 16 More than μg/ml, more than 18 μg/ml, more than 20 μg/ml, more than 21 μg/ml, more than 22 μg/ml, more than 23 μg/ml, more than 24 μg/ml, more than 25 μg/ml, more than 26 μg/ ml or more, 27 μg/ml or more, 28 μg/ml or more, 29 μg/ml or more, 30 μg/ml or more, 40 μg/ml or more, 50 μg/ml or more, 60 μg/ml or more, 70 μg/ml or more , 80 μg/ml or more, 90 μg/ml or more, 92 μg/ml or more, 94 μg/ml or more, 96 μg/ml or more, 98 μg/ml or more, 100 μg/ml or more, 110 μg/ml or more, 120 may be greater than or equal to μg/ml, greater than or equal to 130 μg/ml, or greater than 140 μg/ml, and less than or equal to 150 μg/ml, less than or equal to 140 μg/ml, less than or equal to 130 μg/ml, less than or equal to 120 μg/ml, less than or equal to 110 μg/ml, 100 μg/ml or less, 90 μg/ml or less, 80 μg/ml or less, 70 μg/ml or less, 60 μg/ml or less, 50 μg/ml or less, 40 μg/ml or less, 35 µg/ml or less, 34 µg/ml or less, 33 µg/ml or less, 32 µg/ml or less, 31 µg/ml or less, 30 µg/ml or less, 29 µg/ml or less, 28 µg/ml or less, 27 μg/ml or less, 26 μg/ml or less, 25 μg/ml or less, 20 μg/ml or less, 10 μg/ml or less, 8 μg/ml or less, 6 μg/ml or less, 4 μg/ml or less, 3.9 μg /ml or less, 3.8 µg/ml or less, 3.7 µg/ml or less, 3.6 µg/ml or less, 3.5 µg/ml or less, 3.4 µg/ml or less, 3.3 µg/ml or less, 3.2 µg/ml or less, 3.1 µg/ml It may be 3 μg/ml or less, 2.9 μg/ml or less, 2.8 μg/ml or less, 2.7 μg/ml or less, or 2.6 μg/ml or less, and more specifically 25 to 30 μg/ml, but is not limited thereto. does not The expression level of the inflammatory factor may be measured by a method known in the art, and the measurement method is not limited.
본 발명의 일 측면에 따른 마이크로 구조체는 생체적합성 양친성 블록 공중합체과 약물을 용매에 용해시켜 혼합용액을 제조하는 단계; 및 상기 혼합용액을 이용해 마이크로 구조체를 제조하는 단계를 포함하는 제조방법에 의해 제조된 것일 수 있다. 상기 생체적합성 양친성 블록 공중합체, 약물, 트라닐라스트, 마이크로 구조체에 대한 설명은 상술한 바와 같다.The microstructure according to an aspect of the present invention comprises the steps of dissolving a biocompatible amphiphilic block copolymer and a drug in a solvent to prepare a mixed solution; And it may be prepared by a manufacturing method comprising the step of manufacturing a microstructure using the mixed solution. Descriptions of the biocompatible amphiphilic block copolymer, drug, tranilast, and microstructure are the same as described above.
본 발명의 일 측면에서, 상기 용매는 물, 유기용매, 또는 그 혼합물일 수 있고, 상기 유기용매는 휘발성 유기용매를 포함할 수 있고, 구체적으로 상기 휘발성 유기용매는 디클로로메탄(CH2Cl2), 테트라하이드로퓨란(THF), 아세토니트릴, 에틸아세테이트, 아세톤, 에탄올, 메탄올 및 트리플루오로알코올(TFA)로 이루어진 군으로부터 선택된 하나 이상일 수 있으나, 이에 제한되지는 않는다.In one aspect of the present invention, the solvent may be water, an organic solvent, or a mixture thereof, and the organic solvent may include a volatile organic solvent, specifically, the volatile organic solvent is dichloromethane (CH 2 Cl 2 ) , tetrahydrofuran (THF), acetonitrile, ethyl acetate, acetone, ethanol, may be at least one selected from the group consisting of methanol and trifluoroalcohol (TFA), but is not limited thereto.
본 발명의 일 측면에서, 상기 혼합용액 내 생체적합성 양친성 블록 공중합체의 농도는 5 내지 50%(volume per volume; v/v)일 수 있으나, 이에 제한되지 않는다.In one aspect of the present invention, the concentration of the biocompatible amphiphilic block copolymer in the mixed solution may be 5 to 50% (volume per volume; v/v), but is not limited thereto.
본 발명의 일 측면의 마이크로 구조체는 상기 혼합용액을 이용하여 제조할 수 있으며, 그 제조방법으로 종래 공지된 방법들을 제한 없이 사용할 수 있다.The microstructure of one aspect of the present invention can be manufactured using the mixed solution, and conventionally known methods can be used without limitation as a manufacturing method thereof.
본 발명의 일 측면에서, 구체적으로 상기 마이크로 구조체 제조 단계는 약물 및 생체적합성 양친성 블록 공중합체의 혼합용액을 주형에 투여하고 진공 하에서 원심 분리하여 주형의 구멍(cavity)에 주입하는 단계; 상기 약물 및 생체적합성 양친성 블록 공중합체의 혼합용액이 주입된 주형을 건조하여 마이크로 니들을 형성하는 단계; 및 상기 주형으로부터 마이크로 구조체를 분리하는 단계를 포함할 수 있다.In one aspect of the present invention, specifically, the microstructure manufacturing step comprises: administering a mixed solution of a drug and a biocompatible amphiphilic block copolymer to a mold and centrifuging under vacuum to inject it into a cavity of the mold; forming microneedles by drying the mold in which the mixed solution of the drug and the biocompatible amphiphilic block copolymer is injected; and separating the microstructure from the mold.
본 발명의 일 측면에서, 상기 주형은 공지된 소프트 리소그래피(soft lithography) 기술로 제조된 PDMS(polydimethylsiloxane)와 같은 탄성체 몰드를 포함할 수 있다. PDMS 몰드를 제조하는 기술은 일종의 플라스틱 가공기술로서 캐스팅(casting), 인젝션(injection), 핫-엠보싱(hot-embossing) 등의 다양한 방법으로 원하는 몰딩구조를 얻을 수 있다. 또한, 본 발명의 일 측면에서, 실리콘웨이퍼, 글래스 등의 기판상에 감광물질을 코팅하고 포토마스크를 이용하여 패터닝하여 마스터(master) 몰드를 제조한 후, 이를 주형으로 PDMS를 캐스팅하고 소결시켜, 스탬프 기능을 하는 PDMS 몰드를 완성할 수 있다.In one aspect of the present invention, the mold may include an elastomer mold such as polydimethylsiloxane (PDMS) manufactured by a known soft lithography technique. The PDMS mold manufacturing technology is a kind of plastic processing technology, and a desired molding structure can be obtained by various methods such as casting, injection, and hot-embossing. In addition, in one aspect of the present invention, a photosensitive material is coated on a substrate such as a silicon wafer or glass and patterned using a photomask to prepare a master mold, then cast PDMS as a mold and sintered, A PDMS mold with a stamp function can be completed.
본 발명의 일 측면에서, 상기 혼합용액은 구조체 내에 약물의 안정성 및 니들의 강도를 강화하는 첨가제를 추가로 포함할 수 있고, 상기 첨가제는 구체적으로 히알루론산(hyaluronic acid), 키토산(chitosan), 폴리비닐알코올, 카르복시비닐폴리머, 아크릴비닐폴리머, 덱스트란, 카르복시메틸셀룰로오스, 하이드록시에틸셀룰로오스, 산탄검, 로카스트빈검, 에틸렌-비닐아세테이트 중합체, 셀룰로스 아세테이트, 아크릴 치환 셀룰로오스 아세테이트, 폴리우레탄, 폴리카프로락톤, 폴리(락틱-코-글리콜릭산)(poly(lactic-co-glycolic acid, PLGA), 폴리락트산(PLA), 폴리글리콜산(PGA), 폴리안하이드라이드(polyanhydride), 폴리스티렌, 폴리비닐 아세테이트, 폴리비닐 클로라이드(PVC), 폴리비닐 플루오라이드(PVF), 폴리비닐이미다졸, 클로로설포네이트 폴리올레핀(chlorosulphonate polyolefins), 폴리에틸렌옥사이드, 폴리비닐피롤리돈(PVP), 폴리에틸렌글리콜(PEG), 폴리메타크릴레이트, 하이드록시프로필메틸셀룰로오스(HPMC), 에틸셀룰로오스(EC), 하이드록시프로필셀룰로오스(HPC), 카복시메틸셀룰로오스, 및 싸이클로덱스트린으로 이루어진 군으로부터 선택된 하나 또는 둘 이상의 혼합물일 수 있으나, 이에 제한되지 않는다.In one aspect of the present invention, the mixed solution may further include an additive for enhancing the stability of the drug and the strength of the needle in the structure, and the additive is specifically hyaluronic acid, chitosan, poly Vinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, dextran, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene-vinyl acetate polymer, cellulose acetate, acrylic substituted cellulose acetate, polyurethane, polycaprolactone , poly(lactic-co-glycolic acid) (poly(lactic-co-glycolic acid, PLGA), polylactic acid (PLA), polyglycolic acid (PGA), polyanhydride, polystyrene, polyvinyl acetate, Polyvinyl chloride (PVC), polyvinyl fluoride (PVF), polyvinylimidazole, chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymetha It may be one or a mixture of two or more selected from the group consisting of acrylate, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), carboxymethylcellulose, and cyclodextrin, but is not limited thereto. does not
본 발명의 일 측면에서, 상기 건조과정은 약물 및 블록공중합체 및 용매의 특성에 따라 진공 하에서 4℃내지 500℃의 온도로 가열하는 단계를 포함할 수 있으며, 건조 온도는 약물, 블록 공중합체 및 용매의 특성에 따라 조절될 수 있다.In one aspect of the present invention, the drying process may include heating to a temperature of 4 ℃ to 500 ℃ under vacuum depending on the properties of the drug and block copolymer and solvent, and the drying temperature is the drug, block copolymer and It may be adjusted according to the characteristics of the solvent.
이하, 실시예 및 실험예를 들어 본 발명의 구성 및 효과를 보다 구체적으로 설명한다. 그러나 아래 실시예 및 실험예는 본 발명에 대한 이해를 돕기 위해 예시의 목적으로만 제공된 것일 뿐 본 발명의 범주 및 범위가 그에 의해 제한되는 것은 아니다.Hereinafter, the configuration and effect of the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples and experimental examples are provided only for the purpose of illustration to help the understanding of the present invention, and the scope and scope of the present invention are not limited thereto.
[제조예] 마이크로 니들 제조[Production Example] Microneedle production
삼중블록공중합체(tri-block copolymer)인 Pluronic F127을 최종농도 15%로 에탄올에 녹인 후, 에탄올에 녹인 소수성 분자 (1,1'-디옥타데실-3,3,3',3'-테트라메틸인도디카르보시아닌, 4-클로로벤젠술폰산 염 (1,1' -Dioctadecyl - 3,3,3',3'-tetramethylindodicarbocyanine iodide; DiD) 또는 Resiquimod(R848)) 용액을 균일하게 혼합시킨 다음, 회전증발농축기(Rotary evaporator)를 이용하여 용액 내에 존재하는 에탄올 용매를 제거하였다.After dissolving Pluronic F127, a tri-block copolymer, in ethanol to a final concentration of 15%, hydrophobic molecules (1,1'-dioctadecyl-3,3,3',3'-tetra Methylindodicarbocyanine, 4-chlorobenzenesulfonic acid salt (1,1'-Dioctadecyl - 3,3,3',3'-tetramethylindodicarbocyanine iodide; DiD) or Resiquimod (R848)) solution was uniformly mixed, The ethanol solvent present in the solution was removed using a rotary evaporator.
필름을 얻은 후, 질소로 남아있는 용매를 완전히 증발시켜 제거하고, 상기 형성된 필름에 폴리에틸렌 글리콜(PEG MW 6000) 및 친수성 분자인 오브알부민(OVA)을 함유하는 수용액을 제조하여 첨가한 다음, 초음파분산기(Sonicator)를 이용해 필름을 수용액 속으로 균일하게 분산시켰으며, 용해되지 않은 물질을 제거하기 위해 수용액을 필터에 여과시켰다.After obtaining a film, the solvent remaining with nitrogen is completely evaporated to remove it, and an aqueous solution containing polyethylene glycol (PEG MW 6000) and ovalbumin (OVA), a hydrophilic molecule, is prepared and added to the formed film, followed by an ultrasonic disperser The film was uniformly dispersed in the aqueous solution using a sonicator, and the aqueous solution was filtered through a filter to remove undissolved substances.
실온에서 0.15ml의 수용액을 1cm x 1cm 크기의 재사용이 가능한 폴리디메틸실록산(polydimethylsiloxane;PDMS) 마이크로니들 음각 주형에 투여한 후, swing bucket 로터를 사용하여 4℃ 2,000 rpm에서 10분 간 원심분리하였고, 진공 트랩이 설치된 vacuum oven에서 진공 하에 건조해 용해성 마이크로니들을 제작하였다.At room temperature, 0.15 ml of an aqueous solution was administered to a 1 cm x 1 cm reusable polydimethylsiloxane (PDMS) microneedle engraved mold, and centrifuged at 4 ° C. 2,000 rpm for 10 minutes using a swing bucket rotor, A soluble microneedle was prepared by drying under vacuum in a vacuum oven equipped with a vacuum trap.
건조한 마이크로니들의 base plate에 2cm x 2cm의 접착테이프를 부착하였다 떼어냄으로써, 완성된 마이크로 니들을 얻을 수 있었다.A finished microneedle was obtained by attaching and detaching a 2cm x 2cm adhesive tape to the base plate of the dried microneedle.
[실험예 1] 마이크로 구조체를 이용한 동물 실험[Experimental Example 1] Animal experiments using microstructures
동물 실험을 위한 뉴질랜드 흰 토끼(New Zealand White (NZW) conventional Rabbit)의 사육을 분당서울대병원 전임상실험센터(대한민국 경기도 성남시)에서 진행하였다. 동물 실험은 IACUC의 규율을 따라 진행하였고, 뉴질랜드 흰 토끼(NZW conventional Rabbit)은 암컷이고, 30주령으로 오리엔트바이오 (대한민국 경기도 성남시)에서 구입하였다. Breeding of New Zealand White (NZW) conventional Rabbit for animal experiments was conducted at Seoul National University Bundang Hospital Preclinical Experiment Center (Seongnam, Gyeonggi-do, Korea). Animal experiments were conducted according to the rules of IACUC, and New Zealand white rabbits (NZW conventional Rabbit) were female and were purchased from Orient Bio (Seongnam, Gyeonggi-do, Korea) at 30 weeks of age.
마이크로 구조체를 이용한 동물 실험을 위해, 토끼에 케타민(ketamine)(60 mg/kg)과 자일라진(xylazine)(5 mg/kg)을 주사하여 마취를 하였다. 마취가 완료되면 수술부위를 베타딘(betadine)을 이용하여 충분히 소독하고 주위 부위도 소독하여 감염을 예방한 후, 생검 펀치(Biopsy Punch)를 이용하여 그룹별로 토끼의 한 쪽 귀에 지름 6mm 창상 5개를 만들어주었다. 창상을 내고 2주 동안 비대성 흉터 모델(hypertrophic scar model)이 되도록 관리 감독하였다. 수술이 완료된 토끼들은 표준 수술 후 동물 관리 프로토콜(Standard post-operative animal care protocols)에 따라 관리 감독하였다. 술부를 보호하기 위해 동물을 세밀히 관찰하고 케토프로펜(Ketoprofen)을 매일 3SC (3 mg/kg, 피하조직(subcutaneous(SC))에 투여)을 넣어주면서 한 케이지에 토끼를 한 마리씩 사육하였다. 여기서, 표준 수술 후 동물 관리 프로토콜은 수술 후 토끼가 귀를 긁을 수 없도록 귀를 붕대로 잘 감싸고 넥카라를 씌우며, 인위적인 상처를 보호하기 위한 관리 감독을 성실히 이행하는 것을 포함한다.For animal experiments using microstructures, rabbits were anesthetized by injecting ketamine (60 mg/kg) and xylazine (5 mg/kg). When the anesthesia is complete, the surgical site is sufficiently disinfected with betadine and the surrounding area is also disinfected to prevent infection. Then, using a Biopsy Punch, 5 wounds with a diameter of 6 mm on one ear of the rabbit in each group made Injury was supervised to become a hypertrophic scar model for 2 weeks. After surgery, rabbits were supervised according to standard post-operative animal care protocols. In order to protect the predicate, the animals were closely observed, and while Ketoprofen was administered 3SC (3 mg/kg, subcutaneous (SC)) daily, rabbits were bred in one cage. Here, the standard post-operative animal care protocol involves bandaging the ears well and putting on a neck collar to prevent the rabbit from scratching the ears after surgery, and faithfully implementing care supervision to protect the artificial wounds.
그런 다음, 음성 대조군 그룹을 제외한 각 그룹에 맞는 상기 제조예에 따라 제조된 마이크로 니들을 포함하는 마이크로 구조체를 각각 6mm 창상에 맞춰서 패치를 준비하였다. 이 때, 흉터가 생기고 난 뒤 마이크로 니들을 2주 동안 총 3번 처리하였다. 그룹은 마이크로 니들을 처리하지 않은 음성 대조군, 어떠한 약물도 포함되지 않은 마이크로 니들을 처리한 양성 대조군(bare microneedle), 트라닐라스트(Rizaben)가 각각 2.5 내지 3 ug/ml의 농도(실시예 1), 25 내지 30 ug/ml의 농도(실시예 2), 100 내지 150 ug/ml의 농도(실시예 3)로 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 3 종의 실험군의 총 5 종의 그룹으로 무작위로 나누고, 각 그룹 당 1 마리씩 총 5 마리로 실험을 수행하였다. 마이크로 니들을 교체해주면서 흉터 이미지를 찍어 SEI(Scar Elevation Index, 흉터 증가 지수)를 측정하였다. 또한, 창상 4주 후에 KCl(Potassium chloride)을 이용하여 안락사시키고, 창상 치료 조직 샘플을 채취했다. Then, a patch was prepared by matching the microstructure including the microneedle prepared according to the above preparation example for each group except for the negative control group on a 6 mm wound, respectively. At this time, after the scar was formed, microneedles were treated a total of 3 times for 2 weeks. The group was a negative control group that was not treated with microneedles, a positive control group treated with microneedles that did not contain any drug (bare microneedle), and tranilast (Rizaben) had a concentration of 2.5 to 3 ug/ml, respectively (Example 1) , 25 to 30 ug/ml (Example 2), 100 to 150 ug/ml (Example 3) A total of 5 types of microstructures containing microneedles were treated It was randomly divided into groups, and the experiment was performed with a total of 5 animals, 1 in each group. While replacing the microneedle, scar images were taken and SEI (Scar Elevation Index) was measured. In addition, 4 weeks after the wound, it was euthanized using potassium chloride (KCl), and a tissue sample for wound treatment was collected.
상기 수득된 조직을 10% 중성 완충 포르말린(neutral buffered formalin, NBF)에 4℃에서 24시간 동안 고정시켰다. 그 다음, 에탄올을 농도별 처리를 통해 탈수시키고 파라핀에 포매(embedding)하여 파라핀 블록(block)을 제작하였다. 상기 제작된 파라핀 블록을 마이크롬(microtome)(Leica, Wetzlar, Germany)을 이용해 5 μm 두께로 잘라, 조직 섹션(tissue section)을 얻었다.The obtained tissue was fixed in 10% neutral buffered formalin (NBF) at 4° C. for 24 hours. Then, ethanol was dehydrated through treatment by concentration and embedded in paraffin to prepare a paraffin block. The prepared paraffin block was cut to a thickness of 5 μm using a microtome (Leica, Wetzlar, Germany) to obtain a tissue section.
[실험예 2] 흉터 증가 지수(Scar Elevation Index, SEI) 측정을 통한 상처 치유 효과 확인[Experimental Example 2] Confirmation of wound healing effect through measurement of Scar Elevation Index (SEI)
상기 실험예 1의 5종의 그룹 각각에서, 흉터 증가 지수(SEI) 측정을 통해 상처 치유 효과를 비교하였다.In each of the five groups of Experimental Example 1, the wound healing effect was compared by measuring the scar increase index (SEI).
구체적으로, 흉터 증가 지수(SEI)는 비대성 흉터 아래의 정상 조직 영역 대비 총 상처 영역 조직 높이의 비율을 나타내는 것으로, 일반적인 SEI 계산 방법에 따랐으며, 카메라를 사용하여 검사관에 의해 상기 실험예 1의 5종의 그룹 각각의 상처를 2회 측정하여 계산하고, 그 결과를 도 1a 및 도 1b에 나타내었다.Specifically, the scar increase index (SEI) represents the ratio of the total wound area tissue height to the normal tissue area under the hypertrophic scar, and it followed the general SEI calculation method, and was evaluated by an inspector using a camera. Wounds of each group of species were measured twice and counted, and the results are shown in FIGS. 1A and 1B .
도 1a 및 도 1b은 트라닐라스트가 함유된 마이크로 니들을 포함하는 마이크로 구조체 처리에 따른 상처 치유 효과를 카메라로 측정하여 상처 면적 계산법에 의해 관찰한 결과이다. 도 1a 및 도 1b에 나타난 바와 같이, 전체적인 창상 치유 효과는 통계적으로 유의한 차이가 관찰되었으며, 음성 대조군(마이크로 니들 무처리군)과 양성 대조군(트라닐라스트가 포함되지 않은 마이크로 니들 처리군)에 비하여 실시예 1 내지 3에서 상처 치유 효과가 있음을 를 확인할 수 있었다. 1A and 1B are results obtained by measuring the wound healing effect of the microstructure including microneedles containing tranilast with a camera and observed by the wound area calculation method. As shown in FIGS. 1A and 1B , a statistically significant difference was observed in the overall wound healing effect, and the negative control (microneedle untreated group) and positive control (microneedle treated group without tranilast) were In comparison, it was confirmed that there was a wound healing effect in Examples 1 to 3.
특히, 저농도(2.5 내지 3 ug/ml)의 트라닐라스트가 포함되는 경우에는 트라닐라스트가 포함되지 않은 마이크로 니들을 처리할 때(양성 대조군)에 비하여 SEI 값이 오히려 증가하다가, 일정 농도(25 및 30 ug/ml) 이상의 트라닐라스트가 포함되면서 SEI 값이 크게 감소하기 시작하며, 고농도(100 내지 150 ug/ml)의 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 3), 트라닐라스트가 포함되지 않은 마이크로 니들을 처리할 때(양성 대조군)에 비하여 SEI 값이 약 50% 정도로 감소하였는바, 이를 통해 약물을 포함하지 않은 마이크로 니들에 비하여 트라닐라스트 특히 특정 농도 범위에서 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리 시 보다 우수한 흉터 증가 지수 감소 효과가 있음을 알 수 있었다.In particular, when a low concentration (2.5 to 3 ug/ml) of tranilast is included, the SEI value rather increases compared to when microneedles not containing tranilast are treated (positive control), but at a certain concentration (25 and 30 ug/ml) or more of tranilast, the SEI value begins to decrease significantly, and when microstructures containing microneedles containing high concentration (100 to 150 ug/ml) of tranilast are treated ( Example 3), the SEI value was reduced by about 50% compared to the treatment of microneedles without tranilast (positive control). It was found that there was a better scar increase index reduction effect when microstructures including microneedles included in a specific concentration range were processed.
[실험예 3] 진피층 및 섬유층 두께 측정을 통한 상처 치유 효과 확인[Experimental Example 3] Confirmation of wound healing effect by measuring the thickness of the dermal layer and the fibrous layer
상기 실험예 1의 5종의 그룹 각각에서 수득한 조직 섹션을 이용하여 진피층의 두께를 측정하여 상처 치유 효과를 비교하였다.The wound healing effect was compared by measuring the thickness of the dermal layer using the tissue sections obtained from each of the five groups of Experimental Example 1.
구체적으로, 상기 실험예 1의 5종의 그룹 각각에서 수득한 조직 섹션을 일반적인 조직 염색 방법에 따라 메이어 헤마톡실린 (Mayer's hematoxylin)(BBC Biochemical, Washington, USA)과 플록신 및 에오신 Y (eosin Y with phloxine) (Cancer Diagnostics, North Carolina, USA)을 이용해 염색하였다. 염색한 슬라이드는 LSM 700 공초점레이저주사현미경 (laser scanning confocal microscope)(Carl Zeiss, Jena, Germany)을 이용해 공초점 이미지(X20)를 얻었으며, 이로부터 진피층 및 섬유층의 두께를 측정하였다. Specifically, the tissue sections obtained from each of the five groups of Experimental Example 1 were subjected to a general tissue staining method with Mayer's hematoxylin (BBC Biochemical, Washington, USA) and floxin and eosin Y (eosin Y). with phloxine) (Cancer Diagnostics, North Carolina, USA). For the stained slides, a confocal image (X20) was obtained using an LSM 700 laser scanning confocal microscope (Carl Zeiss, Jena, Germany), and the thickness of the dermal layer and the fibrous layer was measured from this.
도 2a 및 도 2b는 트라닐라스트가 함유된 마이크로 니들을 포함하는 마이크로 구조체 처리에 따른 상처 치유 효과(진피층)를 현미경으로 관찰한 이미지(도 2a), 및 이로부터 측정된 진피층 두께를 나타낸 그래프이다(도 2b). 저농도인 2.5 내지 3 ug/ml의 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 1)에는 유의한 차이가 관찰되지 않았으나, 전체적인 섬유층의 두께 변화는 통계적으로 유의한 차이가 관찰되었다. 또한, 상처가 없는 일반적인 진피층의 두께에 비하여(무상처 진피), 25 내지 30 ug/ml, 및 100 및 150 ug/ml의 트라닐라스트가 각각 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 2 및 3) 진피층의 두께가 크게 감소한 것을 확인할 수 있었다. 특히 중간 농도인 25 내지 30 ug/ml 및 고농도인 100 내지 150 ug/ml 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 3), 음성 대조군에 비하여 진피층의 두께가 약 50% 정도로 감소하였다(도 2b).2A and 2B are a microscopic image ( FIG. 2A ) of the wound healing effect (dermal layer) of the microstructure treatment containing tranilast-containing microneedles, and a graph showing the dermal layer thickness measured therefrom. (Fig. 2b). When microstructures containing microneedles containing a low concentration of 2.5 to 3 ug/ml of tranilast were treated (Example 1), no significant difference was observed, but the change in the thickness of the overall fiber layer was statistically significant. A difference was observed. In addition, when the microstructure containing microneedles containing tranilast of 25 to 30 ug/ml, and 100 and 150 ug/ml, respectively, compared to the thickness of the normal dermal layer without a wound (unwounded dermis) was treated (Examples 2 and 3) It was confirmed that the thickness of the dermal layer was greatly reduced. In particular, when microstructures containing microneedles containing tranilast at a medium concentration of 25 to 30 ug/ml and a high concentration of 100 to 150 ug/ml tranilast were treated (Example 3), the thickness of the dermal layer was higher than that of the negative control. It was reduced to about 50% (Fig. 2b).
도 3a 및 도 3b는 트라닐라스트가 함유된 마이크로 니들을 포함하는 마이크로 구조체 처리에 따른 상처 치유 효과(섬유층)를 현미경으로 관찰한 이미지(도 3a), 및 이로부터 측정된 섬유층 두께를 나타낸 그래프이다(도 3b). 약물을 포함하지 않은 양성 대조군에 비하여 2.5 내지 3 ug/ml, 및 25 및 30 ug/ml의 트라닐라스트가 각각 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 1 및 2), 섬유층 두께에 있어 유의한 차이가 관찰되지 않았으나, 실시예 1 및 2는 음성 대조군에 비하여 약 20% 이상 섬유층의 두께가 감소된 것을 확인할 수 있었다. 나아가, 고농도인 100 내지 150 ug/ml의 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 3) 섬유층의 두께 변화에서 뚜렷한 차이가 관찰되었으며, 음성 대조군에 비하여 약 70% 이상 섬유층의 두께가 감소된 것을 하였다.3A and 3B are a microscopic image (FIG. 3A) of the wound healing effect (fibrous layer) of the microstructure treatment containing microneedles containing tranilast, and a graph showing the thickness of the fiber layer measured therefrom. (Fig. 3b). When microstructures containing microneedles containing 2.5 to 3 ug/ml and 25 and 30 ug/ml of tranilast, respectively, were treated compared to the positive control containing no drug (Examples 1 and 2), Although no significant difference was observed in the thickness of the fiber layer, in Examples 1 and 2, it was confirmed that the thickness of the fiber layer was reduced by about 20% or more compared to the negative control group. Furthermore, when microstructures containing microneedles containing a high concentration of 100 to 150 ug/ml of tranilast were treated (Example 3), a clear difference was observed in the change in the thickness of the fiber layer, and about 70 compared to the negative control. % or more of the thickness of the fiber layer was reduced.
이를 통해 마이크로 니들을 처리하지 않거나, 또는 약물을 포함하지 않은 마이크로 니들에 비하여, 트라닐라스트가 특정 농도 범위로 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리 시 보다 우수한 진피층 또는 섬유층 두께 감소 효과가 있음을 알 수 있었다.Through this, compared to microneedles that do not process microneedles or do not contain drugs, when microstructures containing microneedles containing tranilast in a specific concentration range are treated, there is a better dermal layer or fiber layer thickness reduction effect. And it was found.
[실험예 4] 혈관 형성 관찰을 통한 상처 치유 효과 확인[Experimental Example 4] Confirmation of wound healing effect through observation of blood vessel formation
상기 실험예 3에서 수득한 상기 실험예 1의 5종의 그룹 각각의 조직의 공초점 이미지로부터 혈관 형성을 관찰하여 상처 치유 효과를 비교하였다.The wound healing effect was compared by observing blood vessel formation from the confocal images of the tissues of each of the five groups of Experimental Example 1 obtained in Experimental Example 3 above.
도 4는 트라닐라스트가 함유된 마이크로 니들을 포함하는 마이크로 구조체 처리에 따른 상처 치유 효과를 현미경으로 관찰한 이미지이다. 도 4에 나타난 바와 같이, 전체적인 혈관 형성 효과는 통계적으로 유의한 차이가 관찰되었으며, 음성 대조군(마이크로 니들 무처리군)과 양성 대조군(트라닐라스트가 포함되지 않은 마이크로 니들 처리군)에 비하여 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 실시예 1 내지 3는 혈관 형성 효과를 확인할 수 있었다. 특히 중간 농도인 25 내지 30 ug/ml 및 고농도인 100 내지 150 ug/ml 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 2, 3), 양성 대조군에 비하여 혈관 형성이 현저히 증가하였는바, 이를 통해 마이크로 니들에 비하여 트라닐라스트가 특정 농도 범위로 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리 시 보다 우수한 혈관 형성 효과가 있음을 알 수 있었다.4 is a microscopic image of the wound healing effect of microstructure treatment including microneedles containing tranilast. As shown in FIG. 4 , a statistically significant difference was observed in the overall angiogenesis effect, and compared to the negative control (microneedle untreated group) and positive control (microneedle treated group not containing tranilast), tranil Examples 1 to 3 in which microstructures including microneedles containing last were treated were confirmed to have angiogenic effects. In particular, when microstructures containing microneedles containing a medium concentration of 25 to 30 ug/ml and a high concentration of 100 to 150 ug/ml tranilast were treated (Examples 2 and 3), angiogenesis compared to the positive control group was significantly increased, and it was found that, compared to microneedles, when microstructures containing microneedles containing tranilast in a specific concentration range were treated, there was a better angiogenesis effect.
[실험예 5] 콜라겐 밀도 측정을 통한 상처 치유 효과 비교[Experimental Example 5] Comparison of wound healing effect by measuring collagen density
상기 실험예 1의 5종의 그룹 각각에서 수득한 조직 섹션을 이용하여 콜라겐밀도를 측정하여 상처 치유 효과를 비교하였다.The wound healing effect was compared by measuring the collagen density using the tissue sections obtained from each of the five groups of Experimental Example 1.
구체적으로, 상기 실험예 1의 5종의 그룹 각각에서 수득한 조직 섹션을 일반적인 조직 염색 방법에 따라 메이슨 삼색염색 키트 (Masson's Trichrome Stain Kit)(Polyscience, Inc, Philadelphia, USA)를 이용해 염색하였다. 염색한 슬라이드는 LSM 700 공초점레이저주사현미경 (laser scanning confocal microscope)(Carl Zeiss, Jena, Germany)을 이용해 공초점 이미지(X20)를 얻었으며, 이로부터 콜라겐 밀도를 측정하였다. Specifically, the tissue sections obtained from each of the five groups of Experimental Example 1 were stained using a Mason's Trichrome Stain Kit (Polyscience, Inc, Philadelphia, USA) according to a general tissue staining method. For the stained slides, a confocal image (X20) was obtained using an LSM 700 laser scanning confocal microscope (Carl Zeiss, Jena, Germany), and collagen density was measured therefrom.
도 5a 및 도 5b는 트라닐라스트가 함유된 마이크로 니들을 포함하는 마이크로 구조체 처리에 따른 상처 치유 효과를 현미경으로 관찰한 이미지(도 5a), 및 이로부터 측정된 콜라겐 밀도를 나타낸 그래프이다(도 5b). 전체적인 콜라겐의 밀도 변화는 통계적으로 유의한 차이가 관찰되었으며, 음성 대조군(마이크로 니들 무처리군) 및 양성 대조군(트라닐라스트가 포함되지 않은 마이크로 니들 처리군)에 비하여 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 실시예 1 내지 3은 콜라겐의 밀도가 약 5% 또는 10% 이상 감소하였으며, 특히 25 내지 30 ug/ml 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 2), 고농도(100 내지 150 ug/ml)의 트라닐라스트가 포함된 경우에 비하여(실시예 3) 콜라겐 밀도가 보다 낮음을 확인하였다. 이를 통해, 마이크로 니들을 처리하지 않거나, 또는 약물을 포함하지 않은 마이크로 니들에 비하여, 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리 시 특정 농도 범위에서 보다 우수한 콜라겐 밀도 감소 효과가 있음을 알 수 있었다.5A and 5B are microscopic images of the wound healing effect of microstructure treatment containing tranilast-containing microneedles (FIG. 5A), and graphs showing the collagen density measured therefrom (FIG. 5B) ). A statistically significant difference was observed in the overall collagen density change, and the microneedle containing tranilast was compared to the negative control (microneedle untreated group) and positive control (microneedle treated group not containing tranilast). Examples 1 to 3, in which the microstructure containing In one case (Example 2), it was confirmed that the collagen density was lower (Example 3) than when a high concentration (100 to 150 ug/ml) of tranilast was included. Through this, compared to microneedles that are not treated with microneedles or do not contain drugs, when microstructures containing microneedles containing tranilast are treated, there is a better collagen density reduction effect in a specific concentration range. Could know.
[실험예 6] 섬유화 인자 및 염증성 인자 발현 정도 측정을 통한 상처 치유 효과 비교[Experimental Example 6] Comparison of wound healing effects by measuring the expression level of fibrotic factors and inflammatory factors
상기 실험예 1의 5종의 그룹 각각에서 생검을 채취하여 섬유화 인자(Collagen I, SMA(smooth muscle action, 평활근 액틴))와 염증성 인자(TGF-beta)의 발현 정도를 측정하여 상처 치유 효과를 비교하였다.By collecting biopsies from each of the five groups of Experimental Example 1, the expression levels of fibrosis factor (Collagen I, SMA (smooth muscle action, smooth muscle actin)) and inflammatory factor (TGF-beta) were measured to compare the wound healing effect. did
구체적으로, 상기 실험예 1의 5종의 그룹 각각에서 생검을 채취하여 잘게 절개한 후, 용해 버퍼(lysis buffer)를 넣고 균질화(homogenization)시킨 다음 4℃에서 15분마다 섞어(vortexing)하여 1시간 동안 반응시킨 후 15,000 x g로 원심 분리하였다. 그런 다음, 상층액을 BCA 단백질 분석(BCA protein assay)(Thermo Fisher Scientific Inc, Massachusetts, USA)로 정량하였다. 20 ㎍의 단백질을 10% 겔에서 전기 영동한 후, 니트로셀룰로오스 페이퍼(nitrocellulose paper)에 옮기고 10% 탈지유(skim milk)(BD difco, New Jersey, USA)로 1시간 동안 블로킹(blocking)하였다. a-SMA(anti-smooth muscle antibody, 항평활근항체)(abcam, Oregon, USA) 및 Collagen I(제1형 콜라겐), TGF-beta(tumor growth factor-beta, 종양성장인자-베타) 및 GAPDH에 대한 1차 항체(abcam, Oregon, USA)를 24시간 동안 처리하고 PBS-트윈으로 세정한 후, 각각에 대한 2차 항체 (Santa Cruz Biotechnology, Inc, Texas, USA)를 1시간 동안 처리하고 세척하고, ECL 용액 키트(ECL solution kit)(WestGlow, North Carolina, USA)를 처리하여 ChemiDoc Imaging System (Bio-Rad, California, USA)를 이용해 상기 각 인자를 검출하였으며, 그 결과는 하기 표 1 및 도 6과 같다.Specifically, after taking a biopsy from each of the five groups of Experimental Example 1 and making a fine incision, a lysis buffer was added and homogenized, followed by vortexing every 15 minutes at 4° C. for 1 hour. After reacting for a while, centrifugation was performed at 15,000 x g. Then, the supernatant was quantified by BCA protein assay (Thermo Fisher Scientific Inc, Massachusetts, USA). After electrophoresis of 20 μg of protein on a 10% gel, it was transferred to nitrocellulose paper and blocked with 10% skim milk (BD difco, New Jersey, USA) for 1 hour. a-SMA (anti-smooth muscle antibody, anti-smooth muscle antibody) (abcam, Oregon, USA) and Collagen I (collagen type 1), TGF-beta (tumor growth factor-beta) and GAPDH After treatment with the primary antibody (abcam, Oregon, USA) for 24 hours and washing with PBS-Twin, the secondary antibody for each (Santa Cruz Biotechnology, Inc, Texas, USA) was treated for 1 hour and washed , ECL solution kit (ECL solution kit) (WestGlow, North Carolina, USA) was treated to detect each factor using the ChemiDoc Imaging System (Bio-Rad, California, USA), and the results are shown in Table 1 and FIG. 6 same as
(단위: A.U. )(Unit: A.U. )
구분division 음성 대조군negative control 양성 대조군positive control 실시예 1Example 1 실시예 2Example 2 실시예 3Example 3
Collagen ICollagen I 2.232.23 0.280.28 0.540.54 0.120.12 0.070.07
SMASMA 1.541.54 0.540.54 0.340.34 0.130.13 0.210.21
TGF-betaTGF-beta 2.272.27 1.101.10 0.600.60 0.500.50 0.600.60
표 1 및 도 6은 트라닐라스트가 함유된 마이크로 니들을 포함하는 마이크로 구조체 처리에 따른 상처 치유 효과를 단백질 분석법으로 관찰한 결과이다. 섬유화 인자인 Collagen I 및 SMA와 염증성 인자인 TGF-beta를 확인한 결과 전체적인 섬유화/염증 반응의 변화가 통계적으로 유의한 차이가 관찰되었으며, 음성 대조군(마이크로 니들 무처리군)에 비하여 마이크로 니들 처리군(양성 대조군 및 실시예 1 내지 3)에서 섬유화/염증 반응이 감소한 것을 확인할 수 있었다. 특히, 음성 대조군(마이크로 니들 무처리군) 및 양성 대조군(트라닐라스트가 포함되지 않은 마이크로 니들 처리군)에 비하여 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 실시예 1 내지 3은 섬유화 인자인 SMA와 염증성 인자인 TGF-beta의 발현이 감소하였다. 특히, 25 내지 30 ug/ml 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리한 경우(실시예 2), 고농도(100 내지 150 ug/ml)의 트라닐라스트가 포함된 경우에 비하여(실시예 3) SMA 및 TGF-beta의 발현량이 감소함을 확인하였다. 따라서, 마이크로 니들을 처리하지 않거나, 또는 약물을 포함하지 않은 마이크로 니들에 비하여, 트라닐라스트가 포함, 특히 특정 농도 범위로 포함된 마이크로 니들을 포함하는 마이크로 구조체를 처리 시 보다 우수한 제1형 콜라겐, SMA 또는 TGF-beta 발현량 감소 효과가 있음을 알 수 있었다.Table 1 and FIG. 6 show the results of observation of the wound healing effect of the microstructure including microneedles containing tranilast by protein analysis. As a result of confirming the fibrosis factors Collagen I and SMA and the inflammatory factor TGF-beta, a statistically significant difference was observed in the overall fibrosis/inflammatory response, and compared to the negative control group (microneedle untreated group), the microneedle treated group ( It was confirmed that the fibrosis/inflammatory response was reduced in the positive control group and Examples 1 to 3). In particular, Examples 1 to 3 in which microstructures containing microneedles containing tranilast were treated compared to negative control (microneedle untreated group) and positive control (microneedle treatment group not containing tranilast) The expression of SMA, a fibrosis factor, and TGF-beta, an inflammatory factor, was decreased. In particular, when microstructures containing microneedles containing 25 to 30 ug/ml tranilast were treated (Example 2), compared to the case where high concentrations (100 to 150 ug/ml) of tranilast were included. (Example 3) It was confirmed that the expression levels of SMA and TGF-beta decreased. Therefore, compared to microneedles that are not treated with microneedles or do not contain drugs, type 1 collagen, which is superior to microstructures containing microneedles containing tranilast, in particular in a specific concentration range, is better than microneedles, It was found that there is an effect of reducing the expression level of SMA or TGF-beta.
종합적으로, 트라닐라스트가 포함된 마이크로 니들을 포함하는 마이크로 구조체가 기존 시장에서 사용되던 상처 치료제와 비교할 때 동일 우위의 효과를 나타낼 수 있을 것이라고 기대할 수 있다.Overall, it can be expected that the microstructure including the microneedle containing tranilast will be able to exhibit the same superior effect compared to the wound treatment used in the existing market.
본 발명의 일 측면에 따른 마이크로 니들 및 상처 치유용 약물을 포함하는 마이크로 구조체는 상처 치유를 위하여 유용하게 사용될 수 있다.The microstructure including the microneedle and the drug for wound healing according to an aspect of the present invention may be usefully used for wound healing.

Claims (14)

  1. 생체 적합성 양친성 블록 공중합체를 포함하는 마이크로 니들; 및microneedles comprising a biocompatible amphiphilic block copolymer; and
    상기 마이크로 니들의 내부에 포함되는 트라닐라스트(tranilast);을 포함하는 마이크로 구조체.A microstructure comprising a; tranilast included in the microneedle.
  2. 제1항에 있어서,According to claim 1,
    상기 트라닐라스트의 농도는 2.5 내지 150 μg/ml인, 마이크로 구조체.The concentration of the tranilast is 2.5 to 150 μg / ml, microstructure.
  3. 제1항에 있어서,According to claim 1,
    상기 마이크로 구조체는 상기 마이크로 니들이 나열된 기판부를 추가로 포함하고,The microstructure further comprises a substrate portion on which the microneedles are listed,
    상기 기판부는 상기 트라닐라스트가 투입되는 약물 투입부를 포함하는, 마이크로 구조체.The substrate part includes a drug injection part into which the tranilast is injected, microstructure.
  4. 제1항에 있어서,According to claim 1,
    상기 트라닐라스트는 상기 마이크로 니들이 피부에 삽입되어 체내로 주입되는 것이고,The tranilast is that the microneedle is inserted into the skin and injected into the body,
    상기 피부는 여드름, 건선, 피부 감염, 잡티, 과색소침착, 저색소침착, 탈모증, 과도한 발모, 원치 않는 발모, 거친 피부, 건조한 피부, 느슨한 피부, 주름, 혈관과다성 피부, 피지 생산 장애, 과도한 모공, 과도한 발한, 다한증, 문신, 발진, 흉터, 통증, 가려움, 화상, 염증, 무사마귀, 티눈, 굳은살, 부종, 옻 중독, 및 곤충, 거미, 뱀, 및 다른 동물로부터 물린 상처로 이루어진 군에서 선택되는 하나 이상의 피부 질환을 앓고 있는 피부인, 마이크로 구조체.The skin is acne, psoriasis, skin infection, blemishes, hyperpigmentation, hypopigmentation, alopecia, excessive hair growth, unwanted hair growth, rough skin, dry skin, loose skin, wrinkles, hypervascular skin, impaired sebum production, excessive Pores, excessive sweating, hyperhidrosis, tattoos, rashes, scars, pain, itching, burns, sores, warts, corns, calluses, edema, poison ivy, and wounds from insect, spider, snake, and other animal bites A microstructure, wherein the skin is suffering from one or more selected skin conditions.
  5. 제1항에 있어서, According to claim 1,
    상기 마이크로 구조체는 상처 치유용 마이크로 구조체이고,The microstructure is a microstructure for wound healing,
    상기 상처 치유는 상기 마이크로 구조체를 처리한 개체가 상기 마이크로 구조체를 처리하지 않은 개체에 비하여 하기 특성들 중 하나를 갖는 것인, 마이크로 구조체:In the wound healing, microstructures, wherein the subject treated with the microstructure has one of the following characteristics compared to the subject not treated with the microstructure:
    (i) 흉터 증가 지수(Scar Elevation Index, SEI)가 10% 이상 감소;(i) a reduction of at least 10% in the Scar Elevation Index (SEI);
    (ii) 진피층 또는 섬유층의 두께가 10% 이상 감소;(ii) a reduction in the thickness of the dermal layer or fibrous layer by at least 10%;
    (iii) 콜라겐 밀도가 5% 이상 감소; 또는(iii) a decrease in collagen density of at least 5%; or
    (iv) 평활근 액틴(smooth muscle action, SMA) 및 제1형 콜라겐(collagen I)으로 이루어진 군으로부터 선택된 하나 이상의 섬유화 인자, 또는 종양성장인자-베타(tumor growth factor-beta, TGF-beta)인 염증성 인자의 발현량이 10% 이상 감소.(iv) one or more fibrosis factors selected from the group consisting of smooth muscle action (SMA) and collagen type 1 (collagen I), or tumor growth factor-beta (tumor growth factor-beta, TGF-beta), an inflammatory The expression level of the factor decreased by more than 10%.
  6. 제1항에 있어서, According to claim 1,
    상기 생체적합성 양친성 블록 공중합체는 폴리에틸렌옥시드-폴리프로필렌옥시드-폴리에틸렌옥시드 삼중블록 공중합체, 폴리프로필렌옥시드-폴리에틸렌옥시드-폴리프로필렌옥시드 삼중블록 공중합체, 폴리에틸렌옥시드-폴리락트산-폴리에틸렌옥시드 삼중블록 공중합체, 폴리락트산-폴리에틸렌옥시드-폴리락트산 삼중블록 공중합체, 폴리에틸렌옥시드-폴리글리콜릭산-폴리에틸렌옥시드 삼중블록 공중합체, 폴리글리콜릭산-폴리에틸렌옥시드-폴리글리콜릭산 삼중블록 공중합체, 폴리에틸렌옥시드-폴리(락틱-코-글리콜릭산)-폴리에틸렌옥시드 삼중블록 공중합체, 폴리(락틱-코-글리콜릭산)-폴리에틸렌옥시드-폴리(락틱-코-글리콜릭산) 삼중블록 공중합체, 폴리에틸렌옥시드-폴리카프로락톤-폴리에틸렌옥시드 삼중블록 공중합체, 폴리카프로락톤-폴리에틸렌옥시드-폴리카프로락톤 삼중블록 공중합체, 폴리에틸렌옥시드-폴리락트산 이중블록 공중합체, 폴리에틸렌옥시드-폴리글리콜릭산 이중블록 공중합체, 폴리에틸렌옥시드-폴리(락틱-코-글리콜릭산) 이중블록 공중합체, 및 폴리에틸렌옥시드-폴리카프로락톤 이중블록 공중합체로 이루어진 군으로부터 선택된 하나 이상인, 마이크로 구조체.The biocompatible amphiphilic block copolymer is polyethylene oxide-polypropylene oxide-polyethylene oxide triblock copolymer, polypropylene oxide-polyethylene oxide-polypropylene oxide triblock copolymer, polyethylene oxide-polylactic acid -Polyethylene oxide triblock copolymer, polylactic acid-polyethyleneoxide-polylactic acid triblock copolymer, polyethyleneoxide-polyglycolic acid-polyethylene oxide triblock copolymer, polyglycolic acid-polyethyleneoxide-polyglycolic acid Triblock copolymer, polyethylene oxide-poly(lactic-co-glycolic acid)-polyethylene oxide triblock copolymer, poly(lactic-co-glycolic acid)-polyethyleneoxide-poly(lactic-co-glycolic acid) Triblock copolymer, polyethylene oxide-polycaprolactone-polyethylene oxide triblock copolymer, polycaprolactone-polyethylene oxide-polycaprolactone triblock copolymer, polyethylene oxide-polylactic acid diblock copolymer, polyethylene oxide At least one selected from the group consisting of seed-polyglycolic acid diblock copolymer, polyethylene oxide-poly(lactic-co-glycolic acid) diblock copolymer, and polyethylene oxide-polycaprolactone diblock copolymer, microstructure .
  7. 제1항에 있어서, According to claim 1,
    상기 트라닐라스트는 건조 후 마이크로 니들의 총 중량을 기준으로 0.0001 내지 50 중량%로 포함되는, 마이크로 구조체.The microstructure, wherein the tranilast is included in an amount of 0.0001 to 50% by weight based on the total weight of the microneedles after drying.
  8. 제1항에 있어서, According to claim 1,
    상기 마이크로 구조체는 마이크로 구조체 내 트라닐라스트의 안정성 및 니들의 강도를 강화하는 첨가제를 추가로 포함하고,The microstructure further comprises an additive for strengthening the stability of tranilast and the strength of the needle in the microstructure,
    상기 첨가제는 히알루론산, 키토산, 폴리비닐알코올, 카르복시비닐폴리머, 아크릴비닐폴리머, 덱스트란, 카르복시메틸셀룰로오스, 하이드록시에틸셀룰로오스, 산탄검, 로카스트빈검, 에틸렌-비닐아세테이트 중합체, 셀룰로스아세테이트, 아크릴 치환 셀룰로오스 아세테이트, 폴리우레탄, 폴리카프로락톤, 폴리락틱-코-글리콜릭산, 폴리락트산, 폴리글리콜산, 폴리안하이드라이드, 폴리스티렌, 폴리비닐 아세테이트, 폴리비닐 클로라이드, 폴리비닐플루오라이드, 폴리비닐이미다졸, 클로로설포네이트 폴리올레핀, 폴리에틸렌옥사이드, 폴리비닐피롤리돈, 폴리에틸렌글리콜, 폴리메타크릴레이트, 하이드록시프로필메틸셀룰로오스, 에틸셀룰로오스, 하이드록시프로필셀룰로오스, 카복시메틸셀룰로오스, 및 싸이클로덱스트린으로 이루어진 군으로부터 선택된 하나 또는 둘 이상의 혼합물인, 마이크로 구조체.The additives include hyaluronic acid, chitosan, polyvinyl alcohol, carboxyvinyl polymer, acrylic vinyl polymer, dextran, carboxymethyl cellulose, hydroxyethyl cellulose, xanthan gum, locast bean gum, ethylene-vinyl acetate polymer, cellulose acetate, acrylic substitution Cellulose acetate, polyurethane, polycaprolactone, polylactic-co-glycolic acid, polylactic acid, polyglycolic acid, polyanhydride, polystyrene, polyvinyl acetate, polyvinyl chloride, polyvinylfluoride, polyvinylimidazole One selected from the group consisting of chlorosulfonate polyolefin, polyethylene oxide, polyvinylpyrrolidone, polyethylene glycol, polymethacrylate, hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, and cyclodextrin or a mixture of two or more, microstructures.
  9. 제1항에 있어서,According to claim 1,
    상기 마이크로 구조체는 생체 상피에 삽입되면 용해되어 트라닐라스트를 담지한 구형의 자가 조립 나노입자를 형성하는 것인, 마이크로 구조체.When the microstructure is inserted into the living epithelium, it is dissolved to form spherical self-assembled nanoparticles carrying tranilast.
  10. 제9항에 있어서,10. The method of claim 9,
    상기 자가 조립 나노입자는 직경이 10 내지 2000 nm인, 마이크로 구조체.The self-assembled nanoparticles have a diameter of 10 to 2000 nm, a microstructure.
  11. 마이크로니들로 제공하기 위한 상처 치유용 조성물로서,A composition for wound healing for use with microneedles, comprising:
    트라닐라스트를 유효 성분으로 포함하는, 상처 치유용 조성물.A composition for wound healing comprising tranilast as an active ingredient.
  12. 제11항에 있어서,12. The method of claim 11,
    하기 특성들 중 하나를 갖는 것인, 상처 치유용 조성물.A composition for healing a wound, having one of the following properties.
    (i) 흉터 증가 지수(Scar Elevation Index, SEI)가 10% 이상 감소;(i) a reduction of at least 10% in the Scar Elevation Index (SEI);
    (ii) 진피층 또는 섬유층의 두께가 10% 이상 감소;(ii) a reduction in the thickness of the dermal layer or fibrous layer by at least 10%;
    (iii) 콜라겐 밀도가 5% 이상 감소; 또는(iii) a decrease in collagen density of at least 5%; or
    (iv) 평활근 액틴(smooth muscle action, SMA) 및 제1형 콜라겐(collagen I)으로 이루어진 군으로부터 선택된 하나 이상의 섬유화 인자, 또는 종양성장인자-베타(tumor growth factor-beta, TGF-beta)인 염증성 인자의 발현량이 10% 이상 감소.(iv) one or more fibrosis factors selected from the group consisting of smooth muscle action (SMA) and collagen type 1 (collagen I), or tumor growth factor-beta (tumor growth factor-beta, TGF-beta), an inflammatory The expression level of the factor decreased by more than 10%.
  13. 제11항에 있어서,12. The method of claim 11,
    상기 농도는 25 내지 150 μg/ml인, 상처 치유용 조성물.The concentration is 25 to 150 μg / ml, wound healing composition.
  14. 제13항에 있어서,14. The method of claim 13,
    상기 농도는 25 내지 30 μg/ml 또는 100 내지 150 μg/ml인, 상처 치유용 조성물.The concentration is 25 to 30 μg / ml or 100 to 150 μg / ml, wound healing composition.
PCT/KR2021/013333 2020-09-29 2021-09-29 Microstructure comprising microneedle and drug for wound healing WO2022071748A1 (en)

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