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WO2025147178A1 - Composition comprising tubulin inhibitor for preventing or treating skin diseases - Google Patents

Composition comprising tubulin inhibitor for preventing or treating skin diseases Download PDF

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Publication number
WO2025147178A1
WO2025147178A1 PCT/KR2025/000257 KR2025000257W WO2025147178A1 WO 2025147178 A1 WO2025147178 A1 WO 2025147178A1 KR 2025000257 W KR2025000257 W KR 2025000257W WO 2025147178 A1 WO2025147178 A1 WO 2025147178A1
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Prior art keywords
skin
tubulin inhibitor
group
preventing
active ingredient
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Pending
Application number
PCT/KR2025/000257
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French (fr)
Korean (ko)
Inventor
황준성
김지은
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Cuepeak Bio Co ltd
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Cuepeak Bio Co ltd
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Publication of WO2025147178A1 publication Critical patent/WO2025147178A1/en
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    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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Definitions

  • Filaggrin is continuously processed by various proteases. This proteolytic process releases hygroscopic amino acids and their derivatives, which form the natural moisturizing factor (NMF) that acts to retain moisture in the stratum corneum.
  • NMF moisturizing factor
  • the inventors of the present invention confirmed that a tubulin inhibitor increases the expression of filaggrin in epidermal cells and promotes the differentiation of epidermal cells.
  • a tubulin inhibitor suppresses inflammatory signals, suppresses photoaging, suppresses collagen decomposition mechanisms, and even has a whitening effect, thereby completing the present invention.
  • the present invention provides a pharmaceutical composition for preventing or treating skin diseases, which contains a tubulin inhibitor as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or improving skin diseases, and a cosmetic composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient.
  • the present invention provides a cosmetic composition for skin moisturizing, whitening, wrinkle improvement, acne relief, skin barrier strengthening, or skin keratinocyte differentiation, which contains a tubulin inhibitor as an active ingredient.
  • Figure 3 shows the results of an experiment to confirm the inhibitory effect of a tubulin inhibitor on NF-kB signal transduction. It shows the results of inhibiting NF-kB signal transduction after treatment with a tubulin inhibitor.
  • Figure 4 shows the effect of tubulin inhibitors on reducing the expression levels of MMP-1, MMP-3, and MMP-9 induced by photoaging.
  • Tubulin inhibitors show results of suppressing the expression levels of MMPs induced by UV rays.
  • Figure 5 is about the inhibition of tyrosinase activity and whitening effect of a tubulin inhibitor. It shows that a tubulin inhibitor inhibits tyrosinase activity and reduces melanin production.
  • the present invention provides a pharmaceutical composition for preventing or treating skin diseases, comprising a tubulin inhibitor as an active ingredient.
  • the present invention also provides a method for preventing or treating a skin disease, comprising the step of administering a therapeutically effective amount of a tubulin inhibitor to a subject in need thereof.
  • Tubulin inhibitors refer to a group of drugs that regulate or inhibit the function of tubulin, a major component of microtubules. Microtubules are part of the cytoskeleton that plays an important role in cells and are essential structures for processes such as cell division, cell movement, and intracellular transport.
  • the tubulin inhibitor exhibits activity in increasing the expression of filaggrin in epidermal cells and in skin proliferation according to epidermal cell differentiation, inhibits the NF-kB signaling process induced by TNF- ⁇ , exhibits photoaging inhibition and wrinkle improvement effects, and exhibits a whitening effect.
  • the vinca alkaloid of the present invention may preferably be Vinblastine, Vincristine, Vinorelbine, or Vinflunine.
  • taxane may be paclitaxel or docetaxel.
  • the tubulin inhibitor of the present invention is a concept that includes all pharmaceutically acceptable salts, isomers, derivatives, and analogs exhibiting the same or similar effects.
  • the above tubulin inhibitor may be derived from an extract, produced biologically, or synthesized chemically, and is not limited in its origin and production method.
  • skin disease is a group of diseases caused by structural and functional abnormalities of the skin, and is a concept encompassing abnormal conditions occurring in the skin that can be caused by various causes such as inflammation, infection, allergy, and immune abnormality.
  • the skin disease may be at least one selected from the group consisting of, for example, atopic dermatitis, skin thermal damage, pruritus, acne, psoriasis, allergic dermatitis, contact dermatitis, exfoliative dermatitis, seborrheic dermatitis, seborrheic dermatitis, lichen planus, rosacea, pigmentation disorders, hypermelanosis, erythema, wounds, ulcers, bedsores, lupus, skin wrinkle-related diseases, and skin diseases caused by photodamage, without limitation in type.
  • atopic dermatitis skin thermal damage, pruritus, acne, psoriasis, allergic dermatitis, contact dermatitis, exfoliative dermatitis, seborrheic dermatitis, seborrheic dermatitis, lichen planus, rosacea, pigmentation disorders, hypermelanosis, erythema, wounds, ulcers, bedsores, lupus,
  • the above skin wrinkle-related diseases may be elasticity fibrosis, thinning of the skin, skin atrophy, decrease in collagen fibers and elastic fibers, loss of skin elasticity, dryness, wrinkle formation, or premature skin aging.
  • the skin diseases caused by the photodamage may be lentigines, freckles, hypopigmentation, hyperpigmentation, photodamage due to acute or chronic UV radiation, or photosensitivity.
  • the skin disease of the present invention may be squamous cell carcinoma, basal cell carcinoma, benign epithelial tumor, and radiation dermatitis.
  • the skin disease of the present invention may be panniculitis, calluses, vitiligo, urticaria, folliculitis, sebaceous keratosis pilaris, eczema, styes, freckles, blemishes, rashes, athlete's foot, spots, stretch marks, freckles, prickly heat, dry skin, chilblains, suppuration, keratosis pilaris, dermatitis, or psoriatic arthritis.
  • the present invention may further comprise, in addition to the tubulin inhibitor, a compound selected from the group consisting of calcium, colchicine, tapinarof, fingolimod, and tofacitinib.
  • a compound selected from the group consisting of calcium, colchicine, tapinarof, fingolimod, and tofacitinib may be used in combination or complex with a tubulin inhibitor, and administration may be simultaneous or sequential.
  • the tubulin inhibitor can be provided as an active ingredient in a pharmaceutical composition for preventing or treating skin diseases.
  • prevention may include inhibiting the occurrence of a disease.
  • treatment includes inhibition, alleviation, or elimination of the development of a disease.
  • tubulin inhibitor of this specification is added to an extent that it can exhibit the effect mentioned in this specification, and includes formulation in various forms by adding various components as auxiliary components for drug delivery and stabilization, etc.
  • the pharmaceutical composition may contain the tubulin inhibitor in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to achieve the efficacy or activity of an active ingredient.
  • the pharmaceutical composition may additionally comprise a pharmaceutically acceptable diluent or carrier.
  • the diluent may be lactose, corn starch, soybean oil, microcrystalline cellulose, mannitol, or a combination thereof.
  • the carrier may be an excipient, a disintegrant, a binder, a glidant, or a combination thereof.
  • the excipient may be microcrystalline cellulose, lactose, low-substituted hydroxycellulose, or a combination thereof.
  • the disintegrant may be calcium carboxymethylcellulose, sodium starch glycolate, calcium dihydrogen phosphate, or a combination thereof.
  • the above pharmaceutical composition may be formulated as an oral or parenteral dosage form.
  • the oral dosage form may be a granule, powder, solution, tablet, capsule, dry syrup, or a combination thereof.
  • the parenteral dosage form may be an injection, ointment, aerosol, spray, patch, etc., and the dosage form is not limited.
  • the dosage of the pharmaceutical composition according to one example is, for example, about 0.0001 to 10,000 mg/kg, 0.0001 to 5,000 mg/kg, 0.0001 to 1,000 mg/kg, 0.0001 to 900 mg/kg, 0.0001 to 800 mg/kg, 0.0001 to 700 mg/kg, 0.0001 to 600 mg/kg, 0.0001 to 500 mg/kg, 0.0001 to 400 mg/kg, 0.0001 to 300 mg/kg, 0.0001 to 200 mg/kg, 1 to 1,000 mg/kg, 1 to 900 mg/kg, 1 to 800 mg/kg, 1 to 700 mg/kg, 1 to 600 mg/kg, 1 to 500 mg/kg, 1 to 450 mg/kg, 1 to 400 mg/kg, 1 to 350 mg/kg, 1 to 300 mg/kg, 1 to 250 mg/kg, 10 to 1000 mg/kg, 10 to 900 mg/kg, 10 to 800 mg/kg, 10 to 700 mg/kg, 10 to 600 mg/kg, 10 to 500 mg/kg, 10 to 450 mg/kg, 10 to 400 mg/kg,
  • the subject of administration of the pharmaceutical composition provided in the present specification may be a mammal including a human, a dog, a cat, a horse, a cow, a pig, a goat, a rabbit, a mouse, a rat, etc., or a cell, tissue, or culture thereof isolated therefrom.
  • the subject may be a subject (a mammal such as a human) in need of prevention, improvement, and/or treatment of a skin disease as described above, or a cell, tissue, or culture thereof isolated therefrom.
  • quasi-drugs refer to all products other than drugs related to the treatment or prevention of diseases.
  • the quasi-drugs above refer to products that are used for the purpose of diagnosing, treating, improving, alleviating, managing or preventing diseases of humans or animals, and have a milder effect than drugs.
  • quasi-drugs are products other than those used for the purpose of drugs, and may include, but are not limited to, fiber and rubber products used for the treatment or prevention of diseases of humans or animals, non-applied or non-direct effects on the human body, non-applied instruments or machines and similar thereto, sterilizers and insecticides for preventing infectious diseases, etc.
  • the type or formulation of the pharmaceutical composition of the present invention is not particularly limited, but may preferably be a disinfectant, a shower foam, a garglin, a wet tissue, a detergent soap, a hand wash, a humidifier filler, a mask, an ointment, or a filter filler.
  • the composition of the present invention When the composition of the present invention is included in an over-the-counter drug for skin moisturizing purposes, the composition may be used as is or together with other over-the-counter drug ingredients, and may be used appropriately according to a conventional method.
  • the mixing amount of the effective ingredients may be appropriately determined depending on the intended use, and the over-the-counter drug composition according to the present invention may contain the tubulin inhibitor in an amount of 0.01 to 20 wt% based on the total weight of the composition.
  • the present invention provides a cosmetic composition for preventing or improving skin diseases, which contains a tubulin inhibitor as an active ingredient.
  • improvement herein may mean any action that at least reduces the severity of a symptom, for example, a parameter associated with alleviating or curing a condition.
  • the tubulin inhibitor is present in an amount of 0.0001 to 80 wt%, 0.01 to 70 wt%, 0.01 to 60 wt%, 0.01 to 50 wt%, 0.01 to 40 wt%, 0.01 to 30 wt%, 0.1 to 70 wt%, 0.1 to 60 wt%, 0.1 to 50 wt%, 0.1 to 40 wt%, 0.1 to 30 wt%, 0.5 to 70 wt%, 0.5 to 60 wt%, 0.5 to 50 wt%, 0.5 to 40 wt%, 0.5 to 30 wt%, 1 to 70 wt%, 1 to 60 wt%, 1 to 50 wt%, 1 to 40 wt%, or 1 to 30%, based on the total weight of the cosmetic composition. For example, it may be included at 30 wt%, but is not limited thereto.
  • the above cosmetic composition is not particularly limited to a specific formulation, and the formulation can be appropriately selected depending on the purpose.
  • the above cosmetic composition may have, for example, a solubilized formulation, an emulsified formulation, or a dispersed formulation.
  • the above cosmetic composition may have a cosmetic formulation of a flexible toner, a nourishing toner, a massage cream, a nourishing cream, an essence, a pack, a gel, an ampoule, or a skin adhesive type, but is not limited thereto.
  • the above cosmetic composition may additionally contain ingredients commonly used in cosmetic compositions in addition to the effective ingredients disclosed herein, and may include, for example, conventional auxiliary agents and carriers such as antioxidants, stabilizers, solubilizers, surfactants, dispersants, emulsifiers, preservatives, vitamins, pigments, and fragrances.
  • conventional auxiliary agents and carriers such as antioxidants, stabilizers, solubilizers, surfactants, dispersants, emulsifiers, preservatives, vitamins, pigments, and fragrances.
  • the present invention provides a cosmetic composition for skin moisturizing, whitening, wrinkle improvement, acne relief, skin barrier strengthening, or skin keratinocyte differentiation, containing a tubulin inhibitor as an active ingredient.
  • whitening may mean improving the brightness of skin tone or alleviating pigmentation by inhibiting melanin production.
  • wrinkle improvement may mean improving skin elasticity, reducing the depth of wrinkles, or increasing the smoothness of the skin surface.
  • acne relief may mean suppressing inflammation, redness, or excessive sebum production of acne, or promoting healing of acne lesions.
  • the term “strengthening the skin barrier” may mean any action that enhances the function of the skin barrier, which is located at the outermost part of the skin and prevents moisture and nutrient loss.
  • skin keratinocyte differentiation may mean promoting the process in which keratinocytes mature to form the stratum corneum, or thereby strengthening the function of the skin barrier.
  • Another aspect of the present invention provides a method for preventing, improving, or treating a skin disease, comprising administering an effective amount of the tubulin inhibitor to a subject in need thereof.
  • the subject may be a mammal, for example, a human, a cow, a horse, a pig, a dog, a sheep, a goat, or a cat.
  • the subject may be an object in need of a preventive, ameliorating, or therapeutic effect for a skin disease.
  • administering is used interchangeably with “introducing” and “implanting” and may mean placement of a composition according to one embodiment into a subject by a method or route that results in at least partial localization of the composition to a desired site according to one embodiment.
  • Administration may be by a method known in the art.
  • the administration method such as the route of administration and the number of administrations, may be appropriately selected by a person skilled in the art.
  • Administration may be directly administered to a subject by any means, for example, intravenous, intramuscular, oral, transdermal, mucosal, intranasal, intrabuccal, intratracheal or subcutaneous administration.
  • the administration may be systemic or local.
  • the administration may include application to the skin.
  • administration is 0.1 mg to 1,000 mg per day per individual of the composition according to one specific example, for example, 0.1 mg to 500 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 5 mg to 1,000 mg, 5 mg to 500 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 10 mg to 1,000 mg, 10 mg to 500 mg, 10 mg
  • the dosage may be administered in an amount of 100 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 25 mg.
  • NF- ⁇ B a DNA transcription factor, exists in the cytosol and exists in a bound form with I ⁇ B, which inhibits NF- ⁇ B.
  • NF- ⁇ B is related to innate and acquired immune responses and is a representative pro-inflammatory cytokine that appears in many inflammatory diseases.
  • the NF- ⁇ B mechanism is a protein family involved in regulating inflammatory responses, immune modulation, apoptosis, cell proliferation, and epithelial differentiation. It regulates the expression of various genes and forms the central axis of the intracellular signaling system.
  • the NfkB signaling pathway inhibition effect according to each tubulin inhibitor treatment was measured using a kit (Promega) that measures the degree of luciferase luminescence.
  • a kit Promega
  • 2 mM CaCl 2 , 1 ⁇ M colchicine, 1 ⁇ M tapinarof, 1 ⁇ M fingolimod, and 1 ⁇ M tofacitinib were co-treated with tubulin inhibitors, it was confirmed whether the NfkB signaling pathway inhibition effect was increased compared to the experimental group treated with the tubulin inhibitor alone.
  • the sun emits two types of ultraviolet rays, UV-A and UV-B, with wavelengths of 320–400 nm for UV-A and 290–320 nm for UV-B.
  • collagen is a representative example.
  • Collagen is the main component of connective tissue and is mainly found in bones and skin, and is broadly classified into five types.
  • Type 1 is the most abundant collagen found in skin connective tissue, followed by Type 3.
  • Matrix Metalloproteinases are protein-decomposing enzymes that break down collagen, a major component of human connective tissue, and their expression level increases due to UV rays. Therefore, when the skin is exposed to UV rays, the expression of these Matrix Metalloproteinases (MMPs) increases, destroying collagen in the dermal layer of the skin and causing photoaging such as wrinkles and pigmentation.
  • Tyrosinase activity was measured to confirm whether the tubulin inhibitor of the present invention has a whitening function.
  • Tyrosine is an enzyme that oxidizes in the presence of oxygen to produce melanin, and when the activity of tyrosinase is inhibited, melanin production is inhibited. Tyrosine is oxidized through tyrosinase and turns orange, but tyrosinase When activity is inhibited, the oxidation reaction of tyrosine through tyrosinase decreases, so the color gradually becomes lighter and transparent depending on the degree of tyrosinase activity inhibition. The degree of tyrosinase inhibition was evaluated by measuring the decreasing absorbance value at 490 nm.
  • filaggrin was measured using cell-based reporter assay and RT-PCR by treating cultured human epidermal keratinocyte (NHEK) cell lines with tubulin inhibitors.
  • Each tubulin inhibitor was treated with NHEK at a concentration of 1.0 ⁇ M, and as a control, DMSO was treated with the same dose of the treatment drug to compare filaggrin expression and cell differentiation, and after 24 hours of treatment, the amount of filaggrin expression and the degree of cell differentiation were observed.
  • NF-kB activation was induced by treating human epidermal cell lines (NHEK) with TNF- ⁇ , and then the NF-kB signaling process was inhibited by treating with a tubulin inhibitor at a concentration of 1.0 ⁇ M.
  • NHEK human epidermal cell lines
  • a tubulin inhibitor was applied to human NHEK cells and irradiated with UV light 30 minutes later to induce photoaging (especially, improvement of wrinkles).
  • a negative control group that was not treated and a positive control group that was irradiated with UV-A only were included in the experiment.
  • each tubulin inhibitor was treated at a concentration of 1.0 ⁇ M with 2 mM of L-tyrosine as a substrate, and the absorbance was measured at 490 nm. Then, tyrosinase enzyme was added again and the reaction was performed at 37oC. After measuring the absorbance at 490 nm again, the absorbance value was calculated to confirm the degree to which each tubulin inhibitor inhibits tyrosinase activity. Kojic acid, known to inhibit tyrosinase activity, was used as a comparison group. Through this, the degree to which each tubulin inhibitor inhibits melanin production can be known. The results are shown in Figs. 5a and 5b.

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Abstract

The present invention relates to a pharmaceutical composition comprising a tubulin inhibitor as an active ingredient for preventing or treating skin diseases. In addition, the present invention relates to a quasi-drug composition or cosmetic composition comprising a tubulin inhibitor as an active ingredient for preventing or alleviating skin diseases. In addition, the present invention relates to a cosmetic composition comprising a tubulin inhibitor as an active ingredient for skin moisturization, whitening, wrinkle alleviation, acne relief, skin barrier strengthening, or skin keratinocyte differentiation. The tubulin inhibitor of the present invention increases the expression level of filaggrin in epidermal cells, promotes skin differentiation, inhibits NF S-kB signaling induced by TNF-α, and exhibits photo-aging inhibition and wrinkle alleviation effects as well as whitening effects. Accordingly, the tubulin inhibitor of the present invention can be utilized as an active ingredient that exhibits activities, such as skin moisturization, whitening, wrinkle alleviation, acne relief, skin barrier strengthening, or skin keratinocyte differentiation, along with the prevention, treatment, or alleviation of skin diseases.

Description

튜불린 저해제를 포함하는 피부 질환 예방 또는 치료용 조성물Composition for preventing or treating skin diseases comprising tubulin inhibitor

본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for preventing or treating skin diseases, comprising a tubulin inhibitor as an active ingredient.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 의약외품 조성물에 관한 것이다.In addition, the present invention relates to a pharmaceutical composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 화장료 조성물에 관한 것이다. In addition, the present invention relates to a cosmetic composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 보습, 미백, 주름개선, 여드름 완화, 피부 장벽 강화, 또는 피부 케라티노사이트 (keratinocyte) 분화용 화장료 조성물에 관한 것이다. In addition, the present invention relates to a cosmetic composition for skin moisturizing, whitening, wrinkle improvement, acne relief, skin barrier strengthening, or skin keratinocyte differentiation, which contains a tubulin inhibitor as an active ingredient.

피부의 주요 기능은 내부 환경을 외부 환경과 분리하는 장벽 역할을 하며, 외부 물질의 공격으로부터 보호하고 수분 및 기타 필수 신체 성분의 외부 공간으로의 손실을 최소화하는 것이다. 필라그린은 피부 장벽 형성에서 특히 중요한데, 이는 표피의 최종 분화 과정에서의 근본적인 역할과 피부 질환들과의 연관성 때문이다. 필라그린은 1977년에 처음으로 중요한 구조 단백질로 확인된 이후, 필라그린이 케라틴 중간 필라멘트를 응집 및 압축시키는 역할을 한다는 것이 밝혀지면서 필라그린(filament-aggregating protein)의 약어로 이름이 붙여진 것이다. 이 단백질은 거대한 전구체 단백질인 프로필라그린(profilaggrin)으로 합성되며, 이는 표피의 과립층에 있는 각화유리질 과립의 주요 구성 요소이다. The primary function of the skin is to act as a barrier separating the internal environment from the external environment, protecting against aggression by foreign substances and minimizing the loss of water and other essential body components to the external space. Filaggrin is particularly important in the formation of the skin barrier because of its fundamental role in the final differentiation of the epidermis and its association with skin diseases. Filaggrin was first identified as an important structural protein in 1977 and was named filaggrin (filament-aggregating protein) when it was discovered that filaggrin acts to aggregate and compact keratin intermediate filaments. This protein is synthesized from the large precursor protein profilaggrin, which is the main component of keratin granules in the granular layer of the epidermis.

피부 장벽의 주요 요소는 각질층(stratum corneum)인 것이다. 이 각질층은 케라티노사이트 (keratinocytes)가 기저층(basal layer)에서 과립층(granulosum layer)으로 이동하며 분화된 결과물이다. 이 세포들은 성숙하면서 다양한 구조 단백질을 발현한다. The main component of the skin barrier is the stratum corneum. This stratum corneum is the result of differentiation of keratinocytes as they migrate from the basal layer to the granulosum layer. As these cells mature, they express various structural proteins.

필라그린은 다양한 프로테아제에 의해 계속해서 가공된다. 이러한 단백질 분해 과정은 흡습성 아미노산과 그 유도체를 방출하며, 이는 자연 보습 인자(NMF)를 형성하여 각질층에서 수분을 유지하는 역할을 하는 것이다. Filaggrin is continuously processed by various proteases. This proteolytic process releases hygroscopic amino acids and their derivatives, which form the natural moisturizing factor (NMF) that acts to retain moisture in the stratum corneum.

즉, 필라그린은 전구체 단백질인 프로필라그린에서 활성 필라그린 단량체로 전환되며, 케라틴 필라멘트를 응집·압축시켜 각질세포를 평평하게 만들어 각질층(stratum corneum)을 형성하며, 필라그린의 가공 과정에서 생성되는 천연보습인자(NMF)는 피부의 수분 유지와 산성 pH 조절에 기여한다.That is, filaggrin is converted from the precursor protein profilaggrin to active filaggrin monomer, and forms the stratum corneum by coagulating and compressing keratin filaments to flatten keratinocytes, and the natural moisturizing factor (NMF) generated during the filaggrin processing contributes to maintaining moisture in the skin and controlling acidic pH.

또한, 필라그린은 중간 케라틴 필라멘트를 CE(각질화 외피)의 구조 단백질과 결합시키며, 이로 인해 각질세포는 강한 기계적·화학적 저항성을 가지게 된다. 라멜라 소체에서 방출된 지질과 함께 필라그린은 각질층의 세포외 지질 기질 형성에도 기여한다.In addition, filaggrin binds intermediate keratin filaments to structural proteins of the CE (keratinized epithelium), which gives keratinocytes strong mechanical and chemical resistance. Together with lipids released from lamellar bodies, filaggrin also contributes to the formation of the extracellular lipid matrix of the stratum corneum.

특히, 필라그린 분해산물인 UCA(Urocanic acid)와 PCA(Pyrroliodone-5-carboxylic acid)는 피부의 수분을 유지하고, pH를 산성으로 유지하며, UV 방사선으로부터 피부를 보호한다. 또한, UCA는 항미생물 작용과 면역 조절에서도 중요한 역할을 한다.In particular, UCA (Urocanic acid) and PCA (Pyrroliodone-5-carboxylic acid), which are filaggrin degradation products, maintain moisture in the skin, maintain acidic pH, and protect the skin from UV radiation. In addition, UCA plays an important role in antimicrobial action and immune regulation.

이에 본 발명자들은 튜불린 저해제(tubulin inhibitor)가 표피세포에서의 필라그린의 발현을 증가시키고, 표피세포의 분화를 촉진함을 확인하였다. 또한, 더욱 놀랍게도 튜불린 저해제가 염증 신호를 억제하고, 광노화를 억제하며, 콜라겐 분해 기전을 억제하며, 미백 효과까지 보유하고 있음을 확인하고 본 발명을 완성하였다. Accordingly, the inventors of the present invention confirmed that a tubulin inhibitor increases the expression of filaggrin in epidermal cells and promotes the differentiation of epidermal cells. In addition, more surprisingly, the inventors confirmed that a tubulin inhibitor suppresses inflammatory signals, suppresses photoaging, suppresses collagen decomposition mechanisms, and even has a whitening effect, thereby completing the present invention.

따라서, 본 발명의 목적은 피부 질환의 예방 또는 치료용 약학적 조성물, 의약외품 조성물을 제공하는 것이다. 또한, 본 발명의 목적은 피부 질환의 예방 또는 개선용 화장료 조성물 및 피부 보습, 미백, 주름개선, 여드름 완화, 피부 장벽 강화, 또는 피부 케라티노사이트 (keratinocyte) 분화용 화장료 조성물을 제공하는 것이다. Accordingly, the purpose of the present invention is to provide a pharmaceutical composition or a quasi-drug composition for preventing or treating skin diseases. In addition, the purpose of the present invention is to provide a cosmetic composition for preventing or improving skin diseases and a cosmetic composition for moisturizing, whitening, improving wrinkles, alleviating acne, strengthening the skin barrier, or differentiating skin keratinocytes.

상기 목적을 달성하기 위하여, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 치료용 약학적 조성물을 제공한다. To achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating skin diseases, which contains a tubulin inhibitor as an active ingredient.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 의약외품 조성물, 및 피부 질환의 예방 또는 개선용 화장료 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or improving skin diseases, and a cosmetic composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 보습, 미백, 주름개선, 여드름 완화, 피부 장벽 강화, 또는 피부 케라티노사이트 (keratinocyte) 분화용 화장료 조성물을 제공한다. In addition, the present invention provides a cosmetic composition for skin moisturizing, whitening, wrinkle improvement, acne relief, skin barrier strengthening, or skin keratinocyte differentiation, which contains a tubulin inhibitor as an active ingredient.

본 발명의 튜불린 저해제는 표피세포에서 필라그린 발현량을 증가시키고, 피부 분화를 촉진하며, TNF-α에 의해 유도된 NF-kB 신호 전달 과정을 억제하며, 광노화 억제 및 주름개선 효과를 나타내며, 미백효과를 나타낸다. 이에, 본 발명의 튜불린 저해제는 피부질환의 예방, 치료 또는 개선과 더불어, 피부 보습, 미백, 주름개선, 여드름 완화, 피부 장벽 강화, 또는 피부 케라티노사이트 (keratinocyte) 분화 등의 활성을 동시에 나타내는 유효성분으로 활용될 수 있다. The tubulin inhibitor of the present invention increases the expression of filaggrin in epidermal cells, promotes skin differentiation, inhibits the NF-kB signaling process induced by TNF-α, exhibits photoaging inhibition and wrinkle improvement effects, and exhibits a whitening effect. Accordingly, the tubulin inhibitor of the present invention can be utilized as an effective ingredient that simultaneously exhibits activities such as prevention, treatment, or improvement of skin diseases, as well as skin moisturizing, whitening, wrinkle improvement, acne relief, skin barrier strengthening, or skin keratinocyte differentiation.

도 1은 튜불린 저해제가 인간 표피 세포주(NHEK)에서 필라그린 발현량에 미치는 효과에 관한 것이다. 튜불린 저해제 처리에 따라 필라그린 발현량이 증가하는 결과를 나타낸다.Figure 1 shows the effect of a tubulin inhibitor on filaggrin expression in a human epidermal cell line (NHEK). The results show that filaggrin expression increases with treatment with a tubulin inhibitor.

도 2는 튜불린 저해제가 인간 표피 세포주(NHEK)에서 세포 분화도에 미치는 효과에 관한 것이다. 튜불린 저해제 처리 후 세포 분화가 촉진되는 결과를 나타낸다.Figure 2 shows the effect of tubulin inhibitors on cell differentiation in human epidermal keratinocyte cell lines (NHEK). The results show that cell differentiation is promoted after treatment with tubulin inhibitors.

도 3은 튜불린 저해제의 NF-kB 신호 전달 억제 효과를 확인하기 위한 실험 결과에 관한 것이다. 튜불린 저해제 처리 후 NF-kB 신호 전달이 억제되는 결과를 나타낸다.Figure 3 shows the results of an experiment to confirm the inhibitory effect of a tubulin inhibitor on NF-kB signal transduction. It shows the results of inhibiting NF-kB signal transduction after treatment with a tubulin inhibitor.

도 4는 튜불린 저해제의 광노화로 유도된 MMP-1, MMP-3, MMP-9 발현량 감소 효과에 관한 것이다. 튜불린 저해제는 자외선 유발 MMP 발현량을 억제하는 결과를 나타낸다.Figure 4 shows the effect of tubulin inhibitors on reducing the expression levels of MMP-1, MMP-3, and MMP-9 induced by photoaging. Tubulin inhibitors show results of suppressing the expression levels of MMPs induced by UV rays.

도 5는 튜불린 저해제의 Tyrosinase 활성 억제 및 미백 효과에 관한 것이다. 튜불린 저해제가 Tyrosinase 활성을 억제하여 멜라닌 생성을 줄이는 결과를 나타낸다.Figure 5 is about the inhibition of tyrosinase activity and whitening effect of a tubulin inhibitor. It shows that a tubulin inhibitor inhibits tyrosinase activity and reduces melanin production.

이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.

본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating skin diseases, comprising a tubulin inhibitor as an active ingredient.

또한 본 발명은 치료적 유효량의 튜불린 저해제를 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 피부　질환을 예방 또는 치료하는 방법을 제공한다. The present invention also provides a method for preventing or treating a skin disease, comprising the step of administering a therapeutically effective amount of a tubulin inhibitor to a subject in need thereof.

튜불린 저해제 (튜불린 억제제)는 미세소관(microtubule)의 주요 구성 요소인 튜불린 단백질(tubulin)의 기능을 조절하거나 억제하는 약물군을 의미한다. 미세소관은 세포 내에서 중요한 역할을 하는 세포 골격의 일부로, 세포 분열, 세포 이동, 세포 내 수송 등의 과정에 필수적인 구조이다. Tubulin inhibitors (tubulin inhibitors) refer to a group of drugs that regulate or inhibit the function of tubulin, a major component of microtubules. Microtubules are part of the cytoskeleton that plays an important role in cells and are essential structures for processes such as cell division, cell movement, and intracellular transport.

본 발명에서 튜불린 저해제는 이러한 종전 기능과는 달리, 표피세포에서의 필라그린의 발현량 증가 및 표피세포 분화에 따른 피부 증식에 활성을 나타내며, TNF-α에 의해 유도된 NF-kB 신호 전달 과정을 억제하며, 광노화 억제 및 주름개선 효과를 나타내며, 미백효과를 나타내었다. In the present invention, unlike the previous functions, the tubulin inhibitor exhibits activity in increasing the expression of filaggrin in epidermal cells and in skin proliferation according to epidermal cell differentiation, inhibits the NF-kB signaling process induced by TNF-α, exhibits photoaging inhibition and wrinkle improvement effects, and exhibits a whitening effect.

본 발명에서 상기 튜불린 저해제는 그 종류를 제한하지 않으나, 예를 들어, 빈카 알칼로이드(vinca　alkaloid), 탁산(taxane), 크립토피신 52 (Crytophycin 52), 할리콘드린 (Halichondrins), 돌라스타틴 (Dolastatins), 헤미아스테를린 (Hemiasterlins), 콤브레스타틴-A4 (Combretastatin-A4), 2-메톡시에스트라디올 (2-Methoxyestradiol), E7010 (E7010), 플리나불린 (Plinabuline), 에포틸론 (Epothilone), 및 디스코더몰리드 (Discodermolide)으로 이루어진 군으로부터 하나 이상 선택된 것일 수 있다. In the present invention, the tubulin inhibitor is not limited in type, but may be at least one selected from the group consisting of, for example, vinca alkaloid, taxane, cryptophycin 52, Halichondrins, dolastatins, hemisterlins, combretastatin-A4, 2-methoxyestradiol, E7010, plinabulin, epothilone, and discodermolide.

본 발명의 상기 빈카 알칼로이드는 바람직하게는 빈블라스틴 (Vinblastine), 빈크리스틴 (Vincristine), 비노렐빈 (Vinorelbine), 또는 빈플루닌 (Vinflunine)일 수 있다.The vinca alkaloid of the present invention may preferably be Vinblastine, Vincristine, Vinorelbine, or Vinflunine.

또한, 상기 탁센은 파클리탁셀 (Paclitaxel) 또는 도세탁셀 (Docetaxel)일 수 있다. Additionally, the taxane may be paclitaxel or docetaxel.

본 발명의 튜불린 저해제는 그의 약제학적으로 허용 가능한 염, 이성질체, 또는 유도체, 동일 또는 유사한 효과를 나타내는 유사체를 모두 포함하는 개념이다. The tubulin inhibitor of the present invention is a concept that includes all pharmaceutically acceptable salts, isomers, derivatives, and analogs exhibiting the same or similar effects.

　발명에서, 약제학적으로 허용가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 일예로 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 및 황산 등으로 제조된 무기산염, 아세트산, 트라이플루오로아세트산, 시트르산, 말레산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만델산, 프로피온산, 시트르산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트라이메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등을 들 수 있으나, 이에 한정되는 것은 아니다.　In the invention, pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, and examples thereof include inorganic ion salts manufactured with calcium, potassium, sodium and magnesium, inorganic acid salts manufactured with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid and sulfuric acid, organic acid salts manufactured with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like, sulfonic acid salts manufactured with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid, and glycine, arginine, Examples thereof include, but are not limited to, amino acid salts manufactured from lysine, etc., and amine salts manufactured from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.

상기 튜불린 저해제는 추출물로부터 유래하거나, 생물학적으로 생산되거나, 화학적으로 합성될 수 있으며, 그 유래 및 제조 방법에 제한되지 않는다. The above tubulin inhibitor may be derived from an extract, produced biologically, or synthesized chemically, and is not limited in its origin and production method.

본 발명에서 피부 질환은 피부의 구조적, 기능적 이상으로 인해 발생하는 질환군으로 염증, 감염, 알레르기, 면역 이상 등 다양한 원인에 의해 유발될 수 있는 피부에서 발생하는 비정상적 상태를 포괄하는 개념이다. In the present invention, skin disease is a group of diseases caused by structural and functional abnormalities of the skin, and is a concept encompassing abnormal conditions occurring in the skin that can be caused by various causes such as inflammation, infection, allergy, and immune abnormality.

본 발명에서 피부질환은 예를 들어, 아토피성 피부염, 피부 열손상, 소양증, 여드름, 건선, 알레르기성 피부염, 접촉성 피부염, 박탈성 피부염, 지루성 피부염, 지루성 두피염, 편평태선, 장미증, 색소 장애, 멜라닌과다증, 홍반, 창상, 궤양, 욕창, 루푸스, 피부 주름 관련 질환, 및 광손상에 의한 피부질환으로 이루어진 군으로부터 하나 이상 선택된 것일 수 있으며, 그 종류를 제한하지 않는다.In the present invention, the skin disease may be at least one selected from the group consisting of, for example, atopic dermatitis, skin thermal damage, pruritus, acne, psoriasis, allergic dermatitis, contact dermatitis, exfoliative dermatitis, seborrheic dermatitis, seborrheic dermatitis, lichen planus, rosacea, pigmentation disorders, hypermelanosis, erythema, wounds, ulcers, bedsores, lupus, skin wrinkle-related diseases, and skin diseases caused by photodamage, without limitation in type.

상기 피부 주름관련 질환은 탄력섬유증, 피부의 비박화(thinning of the skin), 피부 위축증(skin atrophy), 콜라겐 섬유(collagen fiber) 및 탄성 섬유(elastic fiber)의 감소, 피부 탄력성의 손실(loss of skin elasticity), 건조(dryness), 주름형성(wrinkle formation) 또는 조기 피부 노화(premature skin aging)일 수 있다.The above skin wrinkle-related diseases may be elasticity fibrosis, thinning of the skin, skin atrophy, decrease in collagen fibers and elastic fibers, loss of skin elasticity, dryness, wrinkle formation, or premature skin aging.

또한, 상기 광손상에 의한 피부질환은 검버섯(lentigines), 주근깨(freckles), 저색소 침착 (hypopigmentation) 과색소 침착(hyperpigmentation), 급성 또는 만성 UV 방사선으로 인한 광손상, 또는 광민감화일 수 있다.Additionally, the skin diseases caused by the photodamage may be lentigines, freckles, hypopigmentation, hyperpigmentation, photodamage due to acute or chronic UV radiation, or photosensitivity.

또한, 본 발명의 피부질환은 편평세포 암종, 기저 세포 암종, 양성 상피 종양, 및 방사선 피부염일 수 있다.Additionally, the skin disease of the present invention may be squamous cell carcinoma, basal cell carcinoma, benign epithelial tumor, and radiation dermatitis.

또한, 본 발명의 피부질환은 상기 피부질환은 지방층염, 굳은살, 백반증, 두드러기, 모낭염, 피지 모공 각화증, 습진, 티눈, 기미, 발진, 무좀, 반점, 튼살, 주근깨, 땀띠, 피부 건조증, 동창, 화농, 곰보, 두피염 또는 건선성 관절염일 수 있다. In addition, the skin disease of the present invention may be panniculitis, calluses, vitiligo, urticaria, folliculitis, sebaceous keratosis pilaris, eczema, styes, freckles, blemishes, rashes, athlete's foot, spots, stretch marks, freckles, prickly heat, dry skin, chilblains, suppuration, keratosis pilaris, dermatitis, or psoriatic arthritis.

또한, 본 발명은 상기 튜불린 저해제와 더불어, 칼슘, 콜히친, 타피나로프(tapinarof), 핑골리모드, 및 토파시티닙으로 이루어진 군으로부터 선택된 화합물을 추가로 포함할 수 있다. In addition, the present invention may further comprise, in addition to the tubulin inhibitor, a compound selected from the group consisting of calcium, colchicine, tapinarof, fingolimod, and tofacitinib.

상기 칼슘, 콜히친, 타피나로프(tapinarof), 핑골리모드, 및 토파시티닙으로 이루어진 군으로부터 선택된 화합물은 튜불린 저해제와 병용 또는 복합될 수 있으며, 투여는 동시 또는 순차적일 수 있다. A compound selected from the group consisting of calcium, colchicine, tapinarof, fingolimod, and tofacitinib may be used in combination or complex with a tubulin inhibitor, and administration may be simultaneous or sequential.

상기 칼슘, 콜히친, 타피나로프(tapinarof), 핑골리모드, 또는 토파시티닙은 그의 염, 이성질체, 또는 유도체, 동일 또는 유사한 효과를 나타내는 유사체를 모두 포함하는 개념이다.The above calcium, colchicine, tapinarof, fingolimod, or tofacitinib is a concept that includes all of its salts, isomers, or derivatives, and analogues having the same or similar effects.

본 발명에서 상기 튜불린 저해제는 유효성분으로서, 피부 질환의 예방 또는 치료용 약학적 조성물에 제공될 수 있다. In the present invention, the tubulin inhibitor can be provided as an active ingredient in a pharmaceutical composition for preventing or treating skin diseases.

본 명세서에서 용어 "예방"은 질병의 발생을 억제하는 것을 포함할 수 있다.The term “prevention” as used herein may include inhibiting the occurrence of a disease.

본 명세서에서 용어 "치료"는 질병의 발전의 억제, 경감, 또는 제거를 포함한다. The term “treatment” as used herein includes inhibition, alleviation, or elimination of the development of a disease.

본 명세서에서 용어 "유효성분으로 포함"은 본 명세서에서 언급한 효과를 나타낼 수 있는 정도로 본 명세서의 튜불린 저해제가 첨가되는 것을 의미하고, 약물전달 및 안정화 등을 위하여 다양한 성분을 부성분으로 첨가하여 다양한 형태로 제형화(formulation)되는 것을 포함하는 의미이다.The term "included as an active ingredient" in this specification means that the tubulin inhibitor of this specification is added to an extent that it can exhibit the effect mentioned in this specification, and includes formulation in various forms by adding various components as auxiliary components for drug delivery and stabilization, etc.

상기 약학적 조성물은 상기 튜불린 저해제를 약학적 유효량으로 포함할 수 있다.The pharmaceutical composition may contain the tubulin inhibitor in a pharmaceutically effective amount.

본 명세서에서 용어 "약학적 유효량"은 유효성분의 효능 또는 활성을 달성하는 데 충분한 양을 의미한다.The term “pharmaceutically effective amount” as used herein means an amount sufficient to achieve the efficacy or activity of an active ingredient.

상기 약학적 조성물은 약제학적으로 허용가능한 희석제 또는 담체를 추가적으로 포함할 수 있다. 상기 희석제는 유당, 옥수수 전분, 대두유, 미정질 셀룰로오스, 만니톨, 또는 그 조합일 수 있다. 상기 담체는 부형제, 붕해제, 결합제, 활택제, 또는 그 조합일 수 있다. 상기 부형제는 미결정 셀룰로오스, 유당, 저치환도 히드록시셀룰로오스, 또는 그 조합일 수 있다. 상기 붕해제는 카르복시메틸셀룰로오스 칼슘, 전분글리콜산 나트륨, 무수인산일수소 칼슘, 또는 그 조합일 수 있다. 상기 결합제는 폴리비닐피롤리돈, 저치환도 히드록시프로필셀룰로오스, 히드록시프로필셀룰로오스, 또는 그 조합일 수 있다. 상기 활택제는 스테아린산 마그네슘, 이산화규소, 탈크, 또는 그 조합일 수 있다.The pharmaceutical composition may additionally comprise a pharmaceutically acceptable diluent or carrier. The diluent may be lactose, corn starch, soybean oil, microcrystalline cellulose, mannitol, or a combination thereof. The carrier may be an excipient, a disintegrant, a binder, a glidant, or a combination thereof. The excipient may be microcrystalline cellulose, lactose, low-substituted hydroxycellulose, or a combination thereof. The disintegrant may be calcium carboxymethylcellulose, sodium starch glycolate, calcium dihydrogen phosphate, or a combination thereof. The binder may be polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, or a combination thereof. The glidant may be magnesium stearate, silicon dioxide, talc, or a combination thereof.

상기 약학적 조성물은 경구 또는 비경구 투여 제형으로 제형화될 수 있다. 경구 투여 제형은 과립제, 산제, 액제, 정제, 캅셀제, 건조시럽제, 또는 그 조합일 수 있다. 비경구 투여 제형은 주사제, 연고제, 에어로졸, 스프레이, 패치 등일 수 있으며, 그 제형은 제한하지 않는다. The above pharmaceutical composition may be formulated as an oral or parenteral dosage form. The oral dosage form may be a granule, powder, solution, tablet, capsule, dry syrup, or a combination thereof. The parenteral dosage form may be an injection, ointment, aerosol, spray, patch, etc., and the dosage form is not limited.

일 예에 따른 약학 조성물의 투여량은 예를 들면, 포유동물에 하루 동안 약 0.0001 내지 10000mg/kg, 0.0001 내지 5000mg/kg, 0.0001 내지 1000mg/kg, 0.0001 내지 900mg/kg, 0.0001 내지 800mg/kg, 0.0001 내지 700mg/kg, 0.0001 내지 600mg/kg, 0.0001 내지 500mg/kg, 0.0001 내지 400mg/kg, 0.0001 내지 300mg/kg, 0.0001 내지 200mg/kg, 1 내지 1000mg/kg, 1 내지 900mg/kg, 1 내지 800mg/kg, 1 내지 700mg/kg, 1 내지 600mg/kg, 1 내지 500mg/kg, 1 내지 450mg/kg, 1 내지 400mg/kg, 1 내지 350mg/kg, 1 내지 300mg/kg, 1 내지 250mg/kg, 10 내지 1000mg/kg, 10 내지 900mg/kg, 10 내지 800mg/kg, 10 내지 700mg/kg, 10 내지 600mg/kg, 10 내지 500mg/kg, 10 내지 450mg/kg, 10 내지 400mg/kg, 10 내지 350mg/kg, 10 내지 300mg/kg, 10 내지 250mg/kg, 100 내지 1000mg/kg, 100 내지 900mg/kg, 100 내지 800mg/kg, 100 내지 700mg/kg, 100 내지 600mg/kg, 100 내지 500mg/kg, 100 내지 450mg/kg, 100 내지 400mg/kg, 100 내지 350mg/kg, 100 내지 300mg/kg, 100 내지 250mg/kg, 200 내지 1000mg/kg, 200 내지 900mg/kg, 200 내지 800mg/kg, 200 내지 700mg/kg, 200 내지 600mg/kg, 200 내지 500mg/kg, 200 내지 450mg/kg, 200 내지 400mg/kg, 200 내지 350mg/kg, 200 내지 300mg/kg, 또는 200 내지 250mg/kg으로 투여할 수 있으나 이에 제한되는 것은 아니다. 본 출원의 약학 조성물의 투여 빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 출원의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition according to one example is, for example, about 0.0001 to 10,000 mg/kg, 0.0001 to 5,000 mg/kg, 0.0001 to 1,000 mg/kg, 0.0001 to 900 mg/kg, 0.0001 to 800 mg/kg, 0.0001 to 700 mg/kg, 0.0001 to 600 mg/kg, 0.0001 to 500 mg/kg, 0.0001 to 400 mg/kg, 0.0001 to 300 mg/kg, 0.0001 to 200 mg/kg, 1 to 1,000 mg/kg, 1 to 900 mg/kg, 1 to 800 mg/kg, 1 to 700 mg/kg, 1 to 600 mg/kg, 1 to 500 mg/kg, 1 to 450 mg/kg, 1 to 400 mg/kg, 1 to 350 mg/kg, 1 to 300 mg/kg, 1 to 250 mg/kg, 10 to 1000 mg/kg, 10 to 900 mg/kg, 10 to 800 mg/kg, 10 to 700 mg/kg, 10 to 600 mg/kg, 10 to 500 mg/kg, 10 to 450 mg/kg, 10 to 400 mg/kg, 10 to 350 mg/kg, 10 to 300 mg/kg, 10 to 250 mg/kg, 100 to 1000 mg/kg, 100 to 900 mg/kg, 100 to 800 mg/kg, 100 to 700 mg/kg, 100 to 600 mg/kg, 100 to 500 mg/kg, 100 to 450 mg/kg, 100 to 400 mg/kg, 100 to 350 mg/kg, 100 to 300 mg/kg, 100 to 250 mg/kg, 200 to 1000 mg/kg, 200 to 900 mg/kg, 200 to 800 mg/kg, 200 to 700 mg/kg, 200 to 600 mg/kg, 200 to 500 mg/kg, 200 to 450 mg/kg, 200 to 400 mg/kg, 200 to 350 mg/kg, 200 to It can be administered at 300 mg/kg, or 200 to 250 mg/kg, but is not limited thereto. The frequency of administration of the pharmaceutical composition of the present application is not particularly limited thereto, but can be administered once a day or administered several times in divided doses. The above dosage does not limit the scope of the present application in any way.

본 명세서에서 제공되는 약학 조성물의 투여 대상은 인간, 개, 고양이, 말, 소, 돼지, 염소, 토끼, 마우스, 래트 등을 포함하는 포유동물 또는 이로부터 분리된 세포, 조직, 또는 이의 배양물일 수 있으며, 일 예에서 상기 대상은 앞서 설명한 바와 같은 피부질환의 예방, 개선, 및/또는 치료를 필요로 하거나, 피부질환을 가지는 개체 (인간 등의 포유동물) 또는 이로부터 분리된 세포, 조직, 또는 이의 배양물일 수 있다.The subject of administration of the pharmaceutical composition provided in the present specification may be a mammal including a human, a dog, a cat, a horse, a cow, a pig, a goat, a rabbit, a mouse, a rat, etc., or a cell, tissue, or culture thereof isolated therefrom. In one example, the subject may be a subject (a mammal such as a human) in need of prevention, improvement, and/or treatment of a skin disease as described above, or a cell, tissue, or culture thereof isolated therefrom.

일 예에 따른 약학 조성물은 상기 튜불린 저해제를 1 내지 80중량%, 5 내지 80중량%, 5 내지 75중량%, 5 내지 70중량%, 5 내지 65중량%, 50 내지 70중량%, 55내지 65중량%, 60 내지 65중량%, 10 내지 60중량%, 15 내지 60 중량%, 20 내지 60 중량%, 1 내지 50중량%, 5 내지 50중량%, 10 내지 50중량%, 15 내지 50 중량%, 20 내지 50 중량%, 1 내지 40중량%, 5 내지 40중량%, 10 내지 40중량%, 15 내지 40 중량%, 20 내지 40 중량%, 1 내지 30중량%, 5 내지 30중량%, 10 내지 30중량%, 15 내지 30 중량%, 20 내지 30 중량%, 1 내지 25중량%, 5 내지 25중량%, 10 내지 25중량%, 15 내지 25중량%, 20 내지 25중량%, 또는 23 내지 25중량%로 포함할 수 있다.According to an example, a pharmaceutical composition comprises 1 to 80 wt%, 5 to 80 wt%, 5 to 75 wt%, 5 to 70 wt%, 5 to 65 wt%, 50 to 70 wt%, 55 to 65 wt%, 60 to 65 wt%, 10 to 60 wt%, 15 to 60 wt%, 20 to 60 wt%, 1 to 50 wt%, 5 to 50 wt%, 10 to 50 wt%, 15 to 50 wt%, 20 to 50 wt%, 1 to 40 wt%, 5 to 40 wt%, 10 to 40 wt%, 15 to 40 wt%, 20 to 40 wt%, 1 to 30 wt%, 5 to 30 wt%, 10 to It can contain 30 wt%, 15 to 30 wt%, 20 to 30 wt%, 1 to 25 wt%, 5 to 25 wt%, 10 to 25 wt%, 15 to 25 wt%, 20 to 25 wt%, or 23 to 25 wt%.

대안적으로, 상기 조성물은　피부외용제 조성물일 수 있다.Alternatively, the composition may be a composition for external use in the skin.

상기　피부외용제는 크림, 겔, 연고,　피부　유화제,　피부　현탁액, 경피전달성 패치, 약물 함유 붕대, 로션, 스프레이 또는 그 조합일 수 있으나, 이에 한정되는 것은 아니다.The above skin external preparation may be, but is not limited to, a cream, gel, ointment, skin emulsifier, skin suspension, transdermal patch, drug-containing bandage, lotion, spray, or a combination thereof.

본 발명에 있어서　피부외용제는 통상 화장품이나 의약품 등의　피부　외용제에 사용되는 성분, 예를 들면 수성성분, 유성성분, 분말성분, 알코올류, 보습제, 증점제, 자외선흡수제, 미백제, 방부제, 산화방지제, 계면활성제, 향료, 색제, 각종　피부　영양제, 금속이온봉쇄제, 당류, 또는 이들의 조합과 필요에 따라서 적절하게 배합될 수 있다.In the present invention, the external skin preparation may be appropriately mixed with ingredients commonly used in external skin preparations such as cosmetics or medicines, such as aqueous ingredients, oily ingredients, powder ingredients, alcohols, moisturizers, thickeners, ultraviolet absorbers, whitening agents, preservatives, antioxidants, surfactants, fragrances, colorants, various skin nutrients, metal ion sequestrants, sugars, or combinations thereof, as needed.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 의약외품 조성물을 제공한다. In addition, the present invention provides a pharmaceutical composition for preventing or improving skin diseases, which contains a tubulin inhibitor as an active ingredient.

본 발명에서 의약외품은 질병의 치료 또는 예방에 관련한 의약품이 아닌 모든 제품을 지칭한다. In the present invention, non-medicinal products refer to all products other than pharmaceutical products related to the treatment or prevention of diseases.

본 발명에서 의약외품은 질병의 치료 또는 예방에 관련한 의약품이 아닌 모든 제품을 지칭한다. 상기 의약외품은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미하는 것으로, 예를 들어 약사법에 따르면 의약외품이란 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람ㆍ동물의 질병 치료나 예방에 쓰이는 섬유ㆍ고무 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않으며, 기구 또는 기계가 아닌 것과 이와 유사한 것, 감염병을 막기 위한 살균ㆍ살충제 등이 이에 포함될 수 있으나, 이에 한정되는 것은 아니다.In the present invention, quasi-drugs refer to all products other than drugs related to the treatment or prevention of diseases. The quasi-drugs above refer to products that are used for the purpose of diagnosing, treating, improving, alleviating, managing or preventing diseases of humans or animals, and have a milder effect than drugs. For example, according to the Pharmaceutical Affairs Act, quasi-drugs are products other than those used for the purpose of drugs, and may include, but are not limited to, fiber and rubber products used for the treatment or prevention of diseases of humans or animals, non-applied or non-direct effects on the human body, non-applied instruments or machines and similar thereto, sterilizers and insecticides for preventing infectious diseases, etc.

본 발명의 의약외품 조성물의 종류나 제형은 특별히 제한되지 아니하나, 바람직하게는 소독 청결제, 샤워폼, 가그린, 물티슈, 세제 비누, 핸드 워시, 가습기 충진제, 마스크, 연고제 또는 필터 충진제 등일 수 있다.The type or formulation of the pharmaceutical composition of the present invention is not particularly limited, but may preferably be a disinfectant, a shower foam, a garglin, a wet tissue, a detergent soap, a hand wash, a humidifier filler, a mask, an ointment, or a filter filler.

본 발명의 조성물을 피부 보습 용도로 의약외품에 포함시킬 경우, 상기 조성물을 그대로 포함하여 사용하거나 다른 의약외품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효 성분의 혼합량은 사용 목적에 따라 적합하게 결정할 수 있으며, 본 발명에 의한 의약외품 조성물은 상기 튜불린 저해제를 조성물 총 중량에 대하여 0.01~20 중량%로 함유할 수 있다.When the composition of the present invention is included in an over-the-counter drug for skin moisturizing purposes, the composition may be used as is or together with other over-the-counter drug ingredients, and may be used appropriately according to a conventional method. The mixing amount of the effective ingredients may be appropriately determined depending on the intended use, and the over-the-counter drug composition according to the present invention may contain the tubulin inhibitor in an amount of 0.01 to 20 wt% based on the total weight of the composition.

또한, 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 화장료 조성물을 제공한다. In addition, the present invention provides a cosmetic composition for preventing or improving skin diseases, which contains a tubulin inhibitor as an active ingredient.

본 명세서에서 용어 "개선"은 상태의 완화 또는 치료와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미할 수 있다.The term "improvement" herein may mean any action that at least reduces the severity of a symptom, for example, a parameter associated with alleviating or curing a condition.

상기 튜불린 저해제는 화장료 조성물 총 중량 대비 0.0001 내지 80 중량%, 0.01 내지 70 중량%, 0.01 내지 60 중량%, 0.01 내지 50 중량%, 0.01 내지 40 중량%, 0.01 내지 30 중량%, 0.1 내지 70 중량%, 0.1 내지 60 중량%, 0.1 내지 50 중량%, 0.1 내지 40 중량%, 0.1 내지 30 중량%, 0.5 내지 70 중량%, 0.5 내지 60 중량%, 0.5 내지 50 중량%, 0.5 내지 40 중량%, 0.5 내지 30 중량%, 1 내지 70 중량%, 1 내지 60 중량%, 1 내지 50 중량%, 1 내지 40 중량%, 또는 1 내지 30%, 예를 들어, 30 중량%로 포함될 수 있으나, 이에 제한되지 않는다.The tubulin inhibitor is present in an amount of 0.0001 to 80 wt%, 0.01 to 70 wt%, 0.01 to 60 wt%, 0.01 to 50 wt%, 0.01 to 40 wt%, 0.01 to 30 wt%, 0.1 to 70 wt%, 0.1 to 60 wt%, 0.1 to 50 wt%, 0.1 to 40 wt%, 0.1 to 30 wt%, 0.5 to 70 wt%, 0.5 to 60 wt%, 0.5 to 50 wt%, 0.5 to 40 wt%, 0.5 to 30 wt%, 1 to 70 wt%, 1 to 60 wt%, 1 to 50 wt%, 1 to 40 wt%, or 1 to 30%, based on the total weight of the cosmetic composition. For example, it may be included at 30 wt%, but is not limited thereto.

상기 화장료 조성물은 특정 제형에 특별히 한정되지 않으며, 목적하는 바에 따라 제형을 적절히 선택할 수 있다. 상기 화장료 조성물은, 예를 들어, 가용화 제형, 유화 제형, 또는 분산 제형을 갖는 것일 수 있다. 상기 화장료 조성물은 유연화장수, 영양화장수, 마사지크림, 영양크림, 에센스, 팩, 젤, 앰플 또는　피부　점착 타입의 화장료 제형을 갖는 것일 수 있으나, 이에 한정되는 것은 아니다.The above cosmetic composition is not particularly limited to a specific formulation, and the formulation can be appropriately selected depending on the purpose. The above cosmetic composition may have, for example, a solubilized formulation, an emulsified formulation, or a dispersed formulation. The above cosmetic composition may have a cosmetic formulation of a flexible toner, a nourishing toner, a massage cream, a nourishing cream, an essence, a pack, a gel, an ampoule, or a skin adhesive type, but is not limited thereto.

상기 화장료 조성물은 본 명세서에 개시된 유효성분 이외에 화장료 조성물에 통상적으로 이용되는 성분들을 추가로 포함할 수 있으며, 예를 들면, 항산화제, 안정화제, 용해화제, 계면활성제, 분산제, 유화제, 방부제, 비타민, 안료 및 향료와 같은 통상적인 보조제 및 담체를 포함할 수 있다.The above cosmetic composition may additionally contain ingredients commonly used in cosmetic compositions in addition to the effective ingredients disclosed herein, and may include, for example, conventional auxiliary agents and carriers such as antioxidants, stabilizers, solubilizers, surfactants, dispersants, emulsifiers, preservatives, vitamins, pigments, and fragrances.

또한 본 발명은 튜불린 저해제를 유효성분으로 포함하는 피부 보습, 미백, 주름개선, 여드름 완화, 피부 장벽 강화, 또는 피부 케라티노사이트 (keratinocyte) 분화용 화장료 조성물을 제공한다. In addition, the present invention provides a cosmetic composition for skin moisturizing, whitening, wrinkle improvement, acne relief, skin barrier strengthening, or skin keratinocyte differentiation, containing a tubulin inhibitor as an active ingredient.

본 명세서에서 용어 "피부　보습"은　피부　수분을 유지하거나 수분 손실을 방지하는 모든 작용을 의미할 수 있다.The term “skin moisturizing” as used herein may mean any action that maintains skin moisture or prevents moisture loss.

본 명세서에서 용어 "미백"은 피부 톤의 밝기를 개선하거나, 멜라닌 생성을 억제하여 색소 침착을 완화하는 것을 의미할 수 있다.The term “whitening” as used herein may mean improving the brightness of skin tone or alleviating pigmentation by inhibiting melanin production.

본 명세서에서 용어 "주름개선"은 피부 탄력 증진, 주름의 깊이 감소, 또는 피부 표면의 매끄러움을 증가시키는 것을 의미할 수 있다.The term "wrinkle improvement" as used herein may mean improving skin elasticity, reducing the depth of wrinkles, or increasing the smoothness of the skin surface.

본 명세서에서 용어 "여드름 완화"는 여드름의 염증, 발적, 혹은 과도한 피지 생성을 억제하거나, 여드름 병변의 치유를 촉진하는 것을 의미할 수 있다.The term "acne relief" as used herein may mean suppressing inflammation, redness, or excessive sebum production of acne, or promoting healing of acne lesions.

본 명세서에서 용어 "피부　장벽 강화"는　피부　가장 바깥쪽에 위치하여 수분과 영양 손실을 막아주는　피부　장벽의 기능이 증진되는 모든 작용을 의미할 수 있다.In this specification, the term "strengthening the skin barrier" may mean any action that enhances the function of the skin barrier, which is located at the outermost part of the skin and prevents moisture and nutrient loss.

본 명세서에서 용어 "피부 케라티노사이트 (keratinocyte) 분화"는 케라티노사이트가 성숙하여 각질층을 형성하는 과정을 촉진하거나, 이를 통해 피부 장벽의 기능을 강화하는 것을 의미할 수 있다.The term "skin keratinocyte differentiation" as used herein may mean promoting the process in which keratinocytes mature to form the stratum corneum, or thereby strengthening the function of the skin barrier.

본 발명의 또 다른 양상은 유효량의 상기 튜불린 저해제를 그를 필요로 하는 개체에게 투여하는 단계를 포함하는　피부　질환을 예방, 개선, 또는 치료하는 방법을 제공한다.Another aspect of the present invention provides a method for preventing, improving, or treating a skin disease, comprising administering an effective amount of the tubulin inhibitor to a subject in need thereof.

용어 "유효량"이란 상기에서 언급한 효과를 나타낼 수 있을 정도로 유효한 양을 의미한다.The term "effective amount" means an amount effective enough to produce the effects mentioned above.

상기 개체는 포유동물, 예를 들면, 사람, 소, 말, 돼지, 개, 양, 염소, 또는 고양이일 수 있다. 상기 개체는　피부　질환의 예방, 개선 또는 치료 효과를 필요로 하는 개체일 수 있다.The subject may be a mammal, for example, a human, a cow, a horse, a pig, a dog, a sheep, a goat, or a cat. The subject may be an object in need of a preventive, ameliorating, or therapeutic effect for a skin disease.

본 명세서에서 용어, "투여하는"은 "도입하는", 및 "이식하는"과 상호교환적으로 사용되고, 일 구체예에 따른 조성물의 원하는 부위로의 적어도 부분적 국소화를 초래하는 방법 또는 경로에 의한 개체 내로의 일 구체예에 따른 조성물의 배치를 의미할 수 있다.As used herein, the term "administering" is used interchangeably with "introducing" and "implanting" and may mean placement of a composition according to one embodiment into a subject by a method or route that results in at least partial localization of the composition to a desired site according to one embodiment.

투여는 당업계에 알려진 방법에 의한 것일 수 있다. 투여 경로, 투여 횟수 등의 투여 방법은 통상의 기술자가 적절히 선택할 수 있다. 투여는 예를 들면, 정맥내, 근육내, 경구, 경피 (transdermal), 점막, 코 안 (intranasal), 구강내, 기관내 (intratracheal) 또는 피하 투여와 같은 경로로, 임의의 수단에 의하여 개체로 직접적으로 투여될 수 있다. 상기 투여는 전신적으로 또는 국부적으로 투여될 수 있다. 상기 투여는　피부에의 도포를 포함할 수 있다.Administration may be by a method known in the art. The administration method, such as the route of administration and the number of administrations, may be appropriately selected by a person skilled in the art. Administration may be directly administered to a subject by any means, for example, intravenous, intramuscular, oral, transdermal, mucosal, intranasal, intrabuccal, intratracheal or subcutaneous administration. The administration may be systemic or local. The administration may include application to the skin.

본 발명에 있어서 투여는 일 구체예에 따른 조성물을 개체당 일당 0.1 ㎎ 내지 1,000 ㎎, 예를 들면, 0.1 ㎎ 내지 500 ㎎, 0.1 ㎎ 내지 100 ㎎, 0.1 ㎎ 내지 50 ㎎, 0.1 ㎎ 내지 25 ㎎, 1 ㎎ 내지 1,000 ㎎, 1 ㎎ 내지 500 ㎎, 1 ㎎ 내지 100 ㎎, 1 ㎎ 내지 50 ㎎, 1 ㎎ 내지 25 ㎎, 5 ㎎ 내지 1,000 ㎎, 5 ㎎ 내지 500 ㎎, 5 ㎎ 내지 100 ㎎, 5 ㎎ 내지 50 ㎎, 5 ㎎ 내지 25 ㎎, 10 ㎎ 내지 1,000 ㎎, 10 ㎎ 내지 500 ㎎, 10 ㎎ 내지 100 ㎎, 10 ㎎ 내지 50 ㎎, 또는 10 ㎎ 내지 25 ㎎을 투여하는 것일 수 있다. 다만, 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성별, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있고, 당업자라면 이러한 요인들을 고려하여 투여량을 적절히 조절할 수 있다. 투여 횟수는 1일 1회 또는 임상적으로 용인가능한 부작용의 범위 내에서 2회 이상이 가능하고, 투여 부위에 대해서도 1개소 또는 2개소 이상에 투여할 수 있으며, 매일 또는 2 내지 5일 간격으로 총 투여 일수는 한번 치료 시 1일에서 30일까지 투여될 수 있다. 필요한 경우, 적정 시기 이후에 동일한 치료를 반복할 수 있다. 인간 이외의 동물에 대해서도, kg당 인간과 동일한 투여량으로 하거나, 또는 예를 들면 목적의 동물과 인간과의 기관 (심장 등)의 용적비 (예를 들면, 평균값) 등으로 상기의 투여량을 환산한 양을 투여할 수 있다.In the present invention, administration is 0.1 mg to 1,000 mg per day per individual of the composition according to one specific example, for example, 0.1 mg to 500 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 1 mg to 1,000 mg, 1 mg to 500 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 5 mg to 1,000 mg, 5 mg to 500 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 10 mg to 1,000 mg, 10 mg to 500 mg, 10 mg The dosage may be administered in an amount of 100 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 25 mg. However, the dosage may be prescribed in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity, and a person skilled in the art can appropriately adjust the dosage considering these factors. The number of administrations may be once a day or twice or more within the range of clinically acceptable side effects, and the administration may be administered to one or more sites, and the total number of administration days may be from 1 to 30 days for one treatment at intervals of 2 to 5 days daily. If necessary, the same treatment may be repeated after an appropriate period. For animals other than humans, the same dosage per kg as for humans may be administered, or the dosage may be converted into the above dosage based on, for example, the volume ratio of organs (such as the heart) between the target animal and the human (e.g., average value).

또 다른 양상은　피부　질환의 예방, 개선 또는 치료용 조성물을 제조하는 데 사용하기 위한, 상기 튜불린 저해제의 용도를 제공한다.Another aspect provides a use of the tubulin inhibitor for preparing a composition for preventing, improving or treating a skin disease.

또 다른 양상은　피부　질환의 예방, 개선 또는 치료용 약제를 제조하는 데 사용하기 위한, 상기 튜불린 저해제의 용도를 제공한다.Another aspect provides a use of the tubulin inhibitor for the manufacture of a medicament for preventing, ameliorating or treating a skin disease.

또 다른 양상은 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 식품 조성물을 제공한다. Another aspect provides a food composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient.

본 발명의 일 실시예에 따른　식품　조성물은 액상 또는 고체 상태의 제형일 수 있고, 정제, 캡슐제, 연질캡슐제, 환제, 과립제, 음료(드링크제), 다이어트바, 초콜렛, 카라멜 제형 또는 과자류 제형일 수 있으며, 그 제형이 특별히 한정되는 것은 아니다. 본 발명의　식품　조성물은 상기 유효 성분 외에도 필요에 따라 부형제, 당류, 향료, 색소, 유지류, 단백질 등을 적의 함유할 수 있다.The food composition according to one embodiment of the present invention may be in a liquid or solid form, and may be in the form of a tablet, capsule, soft capsule, pill, granule, beverage (drink), diet bar, chocolate, caramel or confectionery, and the form is not particularly limited. In addition to the above-mentioned effective ingredients, the food composition of the present invention may contain excipients, sugars, flavorings, colorings, fats, proteins, etc. as needed.

중복되는 내용은 본 명세서의 복잡성을 고려하여 생략하며, 본 명세서에서 달리 정의되지 않은 용어들은 본 발명이 속하는 기술분야에서 통상적으로 사용되는 의미를 갖는 것이다.Duplicate contents are omitted in consideration of the complexity of this specification, and terms not otherwise defined in this specification have meanings commonly used in the technical field to which the present invention belongs.

이하, 본 발명을 실시예에 의해 상세히 설명한다. 단 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by examples. However, the following examples are only intended to illustrate the present invention, and the content of the present invention is not limited to the following examples.

[실험예 1] 균주 [Experimental Example 1] Strain

인간 표피 세포주(Normal Human Epidermal Keratinocyte; NHEK)는 인간 태아 경피 세포주로, ATCC에서 분양 받아 사용하였다. 1차 배양(primary culture)을 통해 얻은 세포이며 질병 조건이 아닌 통상 조건에서 튜불린 저해제에 의한 세포 내 생화학적 변화 확인을 위해 사용되었다.Normal Human Epidermal Keratinocyte (NHEK) cell line is a human fetal keratinocyte cell line, and was provided by ATCC. The cells were obtained through primary culture and used to confirm intracellular biochemical changes caused by tubulin inhibitors under normal conditions, not disease conditions.

태아 인간 배아 신장 세포주(human embryonic kidney cell, HEK)를 ATCC에서 분양 받아 사용하였다. 질병 조건이 아닌 통상 조건에서 튜불린 저해제에 의한 세포 내 생화학적 변화 확인을 위해 사용되었다.Human embryonic kidney cells (HEK) were obtained from ATCC and used to confirm intracellular biochemical changes caused by tubulin inhibitors under normal conditions, not disease conditions.

[실험예 2][Experimental Example 2]

1.1 세포기반 프로모터 활성 측정을 이용한 필라그린 발현량 측정1.1 Measurement of filaggrin expression using cell-based promoter activity measurement

인간 표피 세포주(NHEK)에 Fugene4K 시약(promega사)을 사용하여 필라그린 프로모터가 달린 루시퍼 발광 유전자를 삽입한 후, 24시간 후에 각 튜불린 저해제를 1.0 μM 농도로 처리하였다. 약물 처리 24시간 후, 루시퍼 발광을 정도를 측정하는 키트(promega사)를 이용하여 각 튜불린 저해제 처리에 따른 필라그린 발현량을 측정하였다. 대조군으로는 처리한 화합물과 같은 용량의 DMSO를 사용하였다. After inserting the luciferase gene with the filaggrin promoter into human epidermal keratinocytes (NHEK) using Fugene4K reagent (Promega), each tubulin inhibitor was treated at a concentration of 1.0 μM 24 hours later. After 24 hours of drug treatment, the level of filaggrin expression according to the treatment with each tubulin inhibitor was measured using a kit for measuring the level of luciferase luminescence (Promega). DMSO at the same volume as the treated compound was used as a control.

1.21.2 위상차 현미경 사진을 이용한 세포 분화도 측정 관찰Observation of cell differentiation measurement using phase contrast microscopy

인간 표피 세포주(Normal Human Epidermal Keratinocyte; NHEK)에 각 튜불린 저해제를 1.0uM 농도로 처리 후 매일 세포 분화도를 위상차 현미경으로 관찰하였다. After treating human epidermal cell lines (Normal Human Epidermal Keratinocyte; NHEK) with each tubulin inhibitor at a concentration of 1.0 uM, cell differentiation was observed daily using a phase contrast microscope.

세포 분화 5일차에 위상차 현미경 카메라로 촬영하였으며, 그 결과를 도2에 나타내었다. On the fifth day of cell differentiation, images were taken using a phase contrast microscope camera, and the results are shown in Figure 2.

[시험예 3] 세포기반 프로모터 활성 측정을 이용한 염증 신호 기전 억제 확인[Experimental Example 3] Confirmation of Inflammatory Signaling Mechanism Inhibition Using Cell-Based Promoter Activity Measurement

DNA 전사인자인 NF-κB는 세포 기질에 존재하며 NF-κB를 억제하는 IκB와 결합한 형태로 존재한다. NF-κB는 선천, 후천적 면역 반응과 관련되어, 많은 염증성 질환에서 나타나는 대표적인 pro-inflammatory cytokine이다.NF-κB, a DNA transcription factor, exists in the cytosol and exists in a bound form with IκB, which inhibits NF-κB. NF-κB is related to innate and acquired immune responses and is a representative pro-inflammatory cytokine that appears in many inflammatory diseases.

NF-κB 기전은 염증반응 조절, 면역체계 조절(immune modulation), 세포고사(apoptosis), 세포증식, 상피세포의 분화(epithelial differentiation) 등에 관여하는 단백질군(protein family)으로 다양한 유전자들의 발현을 조절하며 세포내의 신호전달 체계의 중심축을 이루고 있다. The NF-κB mechanism is a protein family involved in regulating inflammatory responses, immune modulation, apoptosis, cell proliferation, and epithelial differentiation. It regulates the expression of various genes and forms the central axis of the intracellular signaling system.

태아 인간 배아 신장 세포주(human embryonic kidney cell, HEK)에 Fugene4K 시약(promega사)을 사용하여 NFkb 프로모터가 달린 루시퍼 발광 유전자를 삽입한 후, 6시간 후 TNF-α를 처리 염증을 유도, NfKb 신호 전달을 유도하였다. 18시간 후, 각 튜불린 저해제를 1.0 μM 농도로 처리하였다. After inserting a luciferase gene with the NFkb promoter into human embryonic kidney cells (HEK) using Fugene4K reagent (Promega), inflammation was induced by treating with TNF-α after 6 hours, and NfKb signal transduction was induced. After 18 hours, each tubulin inhibitor was treated at a concentration of 1.0 μM.

약물 처리 24시간 후, 루시퍼 발광을 정도를 측정하는 키트(promega사)를 이용하여 각 튜불린 저해제 처리에 따른 NfkB 신호기전 억제 효과를 측정하였다. 이에 더해, 2mM CaCl2, 1μM 콜히친(colchicine), 1μM의 타피나로프(tapinarof), 1μM의 핑골리모드(Fingolimod), 1μM의 토파시티닙(Tofacitinib)과 튜불린 저해제를 병용 처리하였을 때, 튜불린 저해제를 단독 처리한 실험군보다 NfkB 신호기전 억제 효과가 상승되는지 여부됨을 확인하였다. After 24 hours of drug treatment, the NfkB signaling pathway inhibition effect according to each tubulin inhibitor treatment was measured using a kit (Promega) that measures the degree of luciferase luminescence. In addition, when 2 mM CaCl 2 , 1 μM colchicine, 1 μM tapinarof, 1 μM fingolimod, and 1 μM tofacitinib were co-treated with tubulin inhibitors, it was confirmed whether the NfkB signaling pathway inhibition effect was increased compared to the experimental group treated with the tubulin inhibitor alone.

[시험예 4] 튜불린 저해제의 콜라겐 감소 기전 억제 효과[Experimental Example 4] Inhibitory effect of tubulin inhibitor on collagen reduction mechanism

광노화 (Photoaging)는 피부가 태양의 자외선에 노출되어 발생하는 피부 노화현상을 말한다. 이것은 점진적인 인체 기능의 감퇴로 인한 생물학적 노화 (senescence 또는 biological aging)과는 구별되는 노화의 형태로, 일반적으로 피부 주름과 건조함, 탄력섬유증, 색소침착 등의 주요 원인으로 작용한다.Photoaging is the skin aging phenomenon that occurs when the skin is exposed to the sun's ultraviolet rays. It is a form of aging that is distinct from biological aging (senescence or biological aging) caused by the gradual decline in human functions, and is generally the main cause of skin wrinkles, dryness, elastic fiber loss, and pigmentation.

태양은 UV-A와 UV-B 두 가지 유형의 자외선을 배출하며 파장은 UV-A가 320~400nm, UV-B가 290~320nm이다. 이러한 UV가 손상시키는 조직 중 대표적으로 콜라겐이 있다. 콜라겐은 결합조직의 주 성분으로 뼈와 피부에 주로 존재하며, 크게 5가지 타입으로 분류된다. 피부 결합 조직 내에서 발견되는 가장 풍부한 콜라겐으로 타입 1이 있으며, 그 다음으로 타입 3이 많다.The sun emits two types of ultraviolet rays, UV-A and UV-B, with wavelengths of 320–400 nm for UV-A and 290–320 nm for UV-B. Among the tissues that these UV rays damage, collagen is a representative example. Collagen is the main component of connective tissue and is mainly found in bones and skin, and is broadly classified into five types. Type 1 is the most abundant collagen found in skin connective tissue, followed by Type 3.

Matrix Metalloproteinases (MMP)는 인체 결합조직의 주 성분인 콜라겐 등을 분해하는 단백질 분해효소로, UV자외선에 의해 그 발현량이 증가된다. 따라서 피부가 자외선에 노출되면 이러한 Matrix Metalloproteinases(MMP)의 발현이 증가하여 피부 진피층의 콜라겐을 파괴하고 피부 주름과 색소 침착 등 광노화가 진행되는 것이다.Matrix Metalloproteinases (MMPs) are protein-decomposing enzymes that break down collagen, a major component of human connective tissue, and their expression level increases due to UV rays. Therefore, when the skin is exposed to UV rays, the expression of these Matrix Metalloproteinases (MMPs) increases, destroying collagen in the dermal layer of the skin and causing photoaging such as wrinkles and pigmentation.

인간피부세포 NHEK에 튜불린 저해제 또는 대조군이 도포 6시간 후, UB 자외선을 30분 조사하였다. 피부세포로부터 RNeasy mini kit (Qiagen사)을 이용해 세포 내 RNA를 추출하였다. 추출한 RNA를 ImProm-II TM Reverse Transcription kit (Promega사)를 이용하여 cDNA로 역전사한 후, Real-Time PCR Detection System (Bio-Rad사, CFX96)을 사용하여 피부세포에 존재하는 MMP-1, MMP-3, MMP-9 발현량을 정량적 PCR (quantitative PCR; qPCR) 방법으로 측정하였다After 6 hours of application of tubulin inhibitor or control group to human skin cells NHEK, UB UV was irradiated for 30 minutes. Intracellular RNA was extracted from skin cells using RNeasy mini kit (Qiagen). The extracted RNA was reverse transcribed into cDNA using ImProm-II TM Reverse Transcription kit (Promega), and the expression levels of MMP-1, MMP-3, and MMP-9 in skin cells were measured by quantitative PCR (qPCR) using Real-Time PCR Detection System (Bio-Rad, CFX96).

[시험예 5] Tyrosinase 활성 측정을 이용한 미백 기능 확인[Experimental Example 5] Confirmation of whitening function using tyrosinase activity measurement

본 발명의 튜불린 저해제가 미백기능이 존재하는지 여부를 확인하기 위하여 Tyrosinase 활성 측정을 수행하였다. Tyrosine을 산소가 존재하는 곳에서 산화하여 멜라닌을 생성하는 효소로, Tyrosinase의 활성이 저해되면 멜리닌 생성이 억제된다. Tyrosinase를 통해 Tyrosine이 산화되면서 주황색을 띠지만, Tyrosinase 활성이 저해되면 Tyrosinase을 통한 Tyrosine의 산화반응이 줄어들기 때문에 Tyrosinase 활성이 저해되는 정도에 따라 점점 연해지면서 투명색을 띤다. 이때 감소하는 흡광도 값을 490nm에서 측정하여 Tyrosinase inhibition 정도를 평가하였다. Tyrosinase activity was measured to confirm whether the tubulin inhibitor of the present invention has a whitening function. Tyrosine is an enzyme that oxidizes in the presence of oxygen to produce melanin, and when the activity of tyrosinase is inhibited, melanin production is inhibited. Tyrosine is oxidized through tyrosinase and turns orange, but tyrosinase When activity is inhibited, the oxidation reaction of tyrosine through tyrosinase decreases, so the color gradually becomes lighter and transparent depending on the degree of tyrosinase activity inhibition. The degree of tyrosinase inhibition was evaluated by measuring the decreasing absorbance value at 490 nm.

[실시예 1] 튜불린 저해제 처리에 의한 인간 표피세포주에서의 필라그린 발현량 및 세포 분화도[Example 1] Filaggrin expression level and cell differentiation in human epidermal cell lines treated with tubulin inhibitor

배양 중인 인간 표피 세포주(NHEK)에 튜불린 저해제를 처리하여, cell-based reporter assay와 RT-PCR을 통해서 필라그린 발현량을 측정하였다.The expression level of filaggrin was measured using cell-based reporter assay and RT-PCR by treating cultured human epidermal keratinocyte (NHEK) cell lines with tubulin inhibitors.

각 튜불린 저해제는 1.0 μM 농도로 NHEK에 처리하였으며, 필라그린 발현 및 세포 분화의 비교를 위해 대조군으로 처리 약물과 동일한 용량의 DMSO를 NHEK에 처리하였으며, 처리 24시간 경과 후, 필라그린 발현량과 세포 분화도를 관찰하였다.Each tubulin inhibitor was treated with NHEK at a concentration of 1.0 μM, and as a control, DMSO was treated with the same dose of the treatment drug to compare filaggrin expression and cell differentiation, and after 24 hours of treatment, the amount of filaggrin expression and the degree of cell differentiation were observed.

그 결과는 도 1 및 도 2에 도시하였다.The results are shown in Figures 1 and 2.

도 1 a에서 확인할 수 있는 바와 같이, 필라그린 발현량이 튜불린 저해제 처리 군에서 증가하였다. 또한, 도 2 a에서 확인할 수 있는 바와 같이, 튜불린 저해제 처리 군에서 세포 분화도가 현저히 증가하는 것을 확인하였다. As can be seen in Fig. 1a, the expression level of filaggrin increased in the tubulin inhibitor treatment group. In addition, as can be seen in Fig. 2a, it was confirmed that the degree of cell differentiation significantly increased in the tubulin inhibitor treatment group.

또한, 튜불린 저해제 병용의 효과를 확인하기 위하여, 각 튜불린 저해제와 2mM CaCl2, 1 μM 콜히친(colchicine), 1μM의 타피나로프(tapinarof), 1μM의 핑골리모드(Fingolimod), 1μM의 토파시티닙(Tofacitinib)과 튜불린 저해제를 병용 처리하였을 때, 튜불린 저해제를 단독 처리한 실험군보다 필라그린 발현량의 증가 (도1a 내지 도1b) 및 세포분화능 (도2b 내지 도2c)이 상승됨을 확인하였다. In addition, to confirm the effect of combined use of tubulin inhibitors, when each tubulin inhibitor was combined with 2 mM CaCl2, 1 μM colchicine, 1 μM tapinarof, 1 μM fingolimod, and 1 μM tofacitinib, it was confirmed that the filaggrin expression level (Figs. 1a to 1b) and cell differentiation ability (Figs. 2b to 2c) increased compared to the experimental group treated with the tubulin inhibitor alone.

[실시예 2] 튜불린 저해제의 염증기전 억제 확인[Example 2] Confirmation of inhibition of inflammation mechanism by tubulin inhibitor

cell-based reporter assay를 통해서 인간 표피 세포주(NHEK)에 TNF-α를 처리하여 NF-kB 활성화를 유도한 뒤, 튜불린 저해제를 1.0 μM 농도로 처리하면 NF-kB 신호전달 과정을 억제함을 확인하고, 그 결과를 도 3a에 나타내었다. Through a cell-based reporter assay, it was confirmed that NF-kB activation was induced by treating human epidermal cell lines (NHEK) with TNF-α, and then the NF-kB signaling process was inhibited by treating with a tubulin inhibitor at a concentration of 1.0 μM. The results are shown in Fig. 3a.

도 3a에서 확인할 수 있는 바와 같이, 본 발명에 따른 튜불린 저해제 처리는 TNF-α 만을처리한 대조군에 비해 NF-kB의 신호 전달을 억제하였다. TPCA1 물질은 NF-kB 신호 전달 저해제로 잘 알려진 positive control로 사용되었다. As can be seen in Fig. 3a, the tubulin inhibitor treatment according to the present invention inhibited the signal transduction of NF-kB compared to the control group treated only with TNF-α. TPCA1, a well-known NF-kB signal transduction inhibitor, was used as a positive control.

이에 더해, 2mM CaCl2, 1μM 콜히친(colchicine), 1μM의 타피나로프(tapinarof), 1μM의 핑골리모드(Fingolimod), 1μM의 토파시티닙(Tofacitinib)과 튜불린 저해제를 병용 처리하였을 때, 튜불린 저해제를 단독 처리한 실험군보다 NfkB 신호기전 억제 효과가 상승됨을 확인하였다 (도3a 내지 b). In addition, when the cells were co-treated with 2 mM CaCl 2 , 1 μM colchicine, 1 μM tapinarof, 1 μM fingolimod, 1 μM tofacitinib, and a tubulin inhibitor, the NfkB signaling pathway inhibition effect was confirmed to be enhanced compared to the experimental group treated with the tubulin inhibitor alone (Fig. 3a to b).

[실시예 3] 튜불린 저해제의 콜라겐 감소 기전 억제 확인[Example 3] Confirmation of the inhibition mechanism of collagen reduction by tubulin inhibitors

인간세포 NHEK에 튜불린 저해제를 도포하고 30분후 UV 자외선을 조사하여 광노화 (특히, 주름 개선)를 유도하였다. 튜불린 저해제를 비교 및 검증하기 위해서 아무런 처리를 하지 않은 negative control 군과 UV-A만을 조사한 positive control을 실험에 반영하였다.A tubulin inhibitor was applied to human NHEK cells and irradiated with UV light 30 minutes later to induce photoaging (especially, improvement of wrinkles). In order to compare and verify the tubulin inhibitor, a negative control group that was not treated and a positive control group that was irradiated with UV-A only were included in the experiment.

도포 및 UV 자외선 실험 종료 후 피부세포에서 RNA를 추출하였다. 추출한 RNA를 cDNA로 역전사한 후, Real-time PCR기계를 사용하여 피부조직에 존재하는 MMP-1과 MMP-3, MMP-9의 양을 정량적 PCR (quantitative PCR, qPCR) 방법으로 측정하였다.After application and UV ultraviolet irradiation experiments, RNA was extracted from skin cells. The extracted RNA was reverse transcribed into cDNA, and the amounts of MMP-1, MMP-3, and MMP-9 present in skin tissue were measured using a real-time PCR machine using the quantitative PCR (qPCR) method.

튜불린 저해제의 광노화 억제 효과는 위에서 설명한 Matrix Metalloproteinases (MMP) 단백질 발현량의 변화를 측정하였다. 즉, 자외선만을 조사한 대조군과 튜불린 저해제를 도포한 후 자외선을 조사한 실험군, 튜불린 저해제와 2mM CaCl2, 1 μM 콜히친(colchicine), 1μM의 타피나로프(tapinarof), 1μM의 핑골리모드(Fingolimod), 1μM의 토파시티닙(Tofacitinib)의 병용 처리군 각각에서 MMP 단백질의 발현량을 측정하여 튜불린 저해제의 도포로 MMP 단백질의 발현량이 억제되는 정도를 측정하였다. The photoaging inhibitory effect of tubulin inhibitors was measured by measuring the change in the expression level of Matrix Metalloproteinases (MMP) proteins described above. That is, the expression level of MMP proteins was measured in each of the control group that was irradiated with UV rays only, the experimental group that was applied with tubulin inhibitors and then irradiated with UV rays, and the group that was treated with a combination of tubulin inhibitors and 2 mM CaCl 2 , 1 μM colchicine, 1 μM tapinarof, 1 μM fingolimod, and 1 μM tofacitinib, to determine the degree to which the expression level of MMP proteins was suppressed by application of the tubulin inhibitor.

그 결과를 도 4a 내지 도 4f에 나타내었다.The results are shown in Figures 4a to 4f.

MMP-1과 MMP-9은 피부조직에서 주로 발현되는 타입1과 타입3 콜라겐의 분해를 촉진하는 효소이고, MMP-3는 타입1 콜라겐을 분해하고 MMP-1의 발현량 변화를 조절하는 조절 효소로서, 광노화에 매우 중요한 영향을 미치는 MMP단백질이다.MMP-1 and MMP-9 are enzymes that promote the decomposition of type 1 and type 3 collagen, which are mainly expressed in skin tissue, and MMP-3 is a regulatory enzyme that decomposes type 1 collagen and controls changes in the expression level of MMP-1, and is an MMP protein that has a very important effect on photoaging.

도 4a, 도 4c, 도 4e에서 확인할 수 있는 바와 같이, 튜불린 저해제를 피부에 도포한 경우 자외선만을 조사한 대조군에 비해 MMP-1, MMP-3, MMP-9 모두 약 50%로 발현량이 감소함을 확인하였다. 이와 같이 튜불린 저해제 도포로 MatrixMetalloproteinases (MMP) 단백질 발현량이 억제됨이 검증되었으며, 전체적으로 UV 자외선에 의한 광노화 억제효과를 확인할 수 있었다. 각 튜불린 저해제 처리에 따라 UV-B 조사로 높아진 MMP-1, MMP-3, MMP-9 발현량이 억제되는 효과를 측정하였다. As can be confirmed in FIGS. 4a, 4c, and 4e, when the tubulin inhibitor was applied to the skin, the expression levels of MMP-1, MMP-3, and MMP-9 were all reduced by about 50% compared to the control group that was only irradiated with UV rays. In this way, it was verified that the application of the tubulin inhibitor suppressed the expression levels of Matrix Metalloproteinases (MMP), and the overall UV-induced photoaging suppression effect was confirmed. The suppression effect of the increased expression levels of MMP-1, MMP-3, and MMP-9 due to UV-B irradiation according to each tubulin inhibitor treatment was measured.

이와 더불어, 2mM CaCl2, 1 μM 콜히친(colchicine), 1μM의 타피나로프(tapinarof), 1μM의 핑골리모드(Fingolimod), 1μM의 토파시티닙(Tofacitinib)과 튜불린 저해제를 병용 처리하였을 때, 튜불린 저해제를 단독 처리한 실험군보다 MMP-1, MMP-3, MMP-9 발현량 억제 효과가 상승됨을 확인하였다 (도 4a 내지 도 4f). In addition, when 2 mM CaCl 2 , 1 μM colchicine, 1 μM tapinarof, 1 μM fingolimod, 1 μM tofacitinib, and a tubulin inhibitor were co-treated, it was confirmed that the inhibitory effect on the expression of MMP-1, MMP-3, and MMP-9 was increased compared to the experimental group treated with the tubulin inhibitor alone (Figs. 4a to 4f).

[실시예 4] 튜불린 저해제의 색소 침착 개선 효과 검증[Example 4] Verification of the effect of tubulin inhibitor on improving pigmentation

Tyrosinase 활성 저해 실험을 통해서, 기질인 L-tyrosine 2mM에 각 튜불린 저해제를 1.0 μM 농도로 처리하여 490nm 흡광도에서 측정한 후, 다시 tyrosinase 효소를 넣고 37ºC에서 반응시켰다. 다시 490nm 흡광도에서 측정한 후 흡광도 값을 계산하여 각 튜불린 저해제가 Tyrosinase 활성을 저해하는 정도를 확인하였다. Tyrosinase 활성을 억제하는 것으로 알려진 Kojic acid를 비교군으로 사용하였다. 이를 통하여 각 튜불린 저해제가 멜리닌 생성을 억제하는 정도를 알 수 있다. 그 결과를 도 5a 내지 도 5b에 나타내었다. Through a tyrosinase activity inhibition experiment, each tubulin inhibitor was treated at a concentration of 1.0 μM with 2 mM of L-tyrosine as a substrate, and the absorbance was measured at 490 nm. Then, tyrosinase enzyme was added again and the reaction was performed at 37ºC. After measuring the absorbance at 490 nm again, the absorbance value was calculated to confirm the degree to which each tubulin inhibitor inhibits tyrosinase activity. Kojic acid, known to inhibit tyrosinase activity, was used as a comparison group. Through this, the degree to which each tubulin inhibitor inhibits melanin production can be known. The results are shown in Figs. 5a and 5b.

도 5a에서 나타난 바와 같이, 각 튜불린 저해제가 Tyrosinase 활성 저해를 통하여 멜라닌 생성을 억제하는 활성이 존재한다.As shown in Figure 5a, each tubulin inhibitor has the activity of inhibiting melanin production through inhibition of tyrosinase activity.

또한, 도 5a 내지 도 5b에서 확인할 수 있는 바와 같이, 2mM CaCl2, 1 μM 콜히친(colchicine), 1μM의 타피나로프(tapinarof), 1μM의 핑골리모드(Fingolimod), 1μM의 토파시티닙(Tofacitinib)과 튜불린 저해제를 병용 처리하였을 때, 튜불린 저해제를 단독 처리한 실험군보다 Tyrosinase 활성을 저해하는 효과가 상승됨을 확인하였다. In addition, as can be confirmed in FIGS. 5a and 5b, when 2 mM CaCl 2 , 1 μM colchicine, 1 μM tapinarof, 1 μM fingolimod, 1 μM tofacitinib, and a tubulin inhibitor were co-treated, the effect of inhibiting tyrosinase activity was confirmed to be increased compared to the experimental group treated with the tubulin inhibitor alone.

Claims (14)

튜불린 저해제(tubulin inhibitor)를 유효성분으로 포함하는 피부 질환의 예방 또는 치료용 약학적 조성물. A pharmaceutical composition for preventing or treating skin diseases, comprising a tubulin inhibitor as an active ingredient. 청구항 2에 있어서, 상기 튜불린 저해제는 빈카 알칼로이드(vinca　alkaloid), 탁산(taxane), 크립토피신 52 (Crytophycin 52), 할리콘드린 (Halichondrins), 돌라스타틴 (Dolastatins), 헤미아스테를린 (Hemiasterlins), 콤브레스타틴-A4 (Combretastatin-A4), 2-메톡시에스트라디올 (2-Methoxyestradiol), E7010 (E7010), 플리나불린 (Plinabuline), 에포틸론 (Epothilone), 디스코더몰리드 (Discodermolide) 및 상기 화합물의 약제학적으로 허용 가능한 염으로 이루어진 군으로부터 하나 이상 선택된 것인, 조성물. A composition according to claim 2, wherein the tubulin inhibitor is at least one selected from the group consisting of vinca alkaloid, taxane, cryptophycin 52, halichondrins, dolastatins, hemiasterlins, combretastatin-A4, 2-methoxyestradiol, E7010, plinabulin, epothilone, discodermolide, and pharmaceutically acceptable salts of the above compounds. 청구항 2에 있어서, 상기 빈카 알칼로이드(vinca　alkaloid)는 빈블라스틴 (Vinblastine), 빈크리스틴 (Vincristine), 비노렐빈 (Vinorelbine), 빈플루닌 (Vinflunine), 및 상기 화합물의 약제학적으로 허용 가능한 염으로 이루어진 군으로부터 하나 이상 선택된 것인, 조성물. A composition according to claim 2, wherein the vinca alkaloid is at least one selected from the group consisting of Vinblastine, Vincristine, Vinorelbine, Vinflunine, and pharmaceutically acceptable salts of the above compounds. 청구항 2에 있어서, 상기 탁센은 파클리탁셀 (Paclitaxel), 도세탁셀 (Docetaxel), 및 상기 화합물의 약제학적으로 허용 가능한 염으로 이루어진 군으로부터 하나 이상 선택된 것인, 조성물. A composition according to claim 2, wherein the taxane is at least one selected from the group consisting of paclitaxel, docetaxel, and pharmaceutically acceptable salts of the above compounds. 청구항 1에 있어서, 상기 피부 질환은 아토피성 피부염, 피부 열손상, 소양증, 여드름, 건선, 알레르기성 피부염, 접촉성 피부염, 박탈성 피부염, 지루성 피부염, 지루성 두피염, 편평태선, 장미증, 색소 장애, 멜라닌과다증, 홍반, 창상, 궤양, 욕창, 루푸스, 피부 주름 관련 질환, 및 광손상에 의한 피부질환으로 이루어진 군으로부터 하나 이상 선택된 것인, 조성물. A composition according to claim 1, wherein the skin disease is at least one selected from the group consisting of atopic dermatitis, skin thermal damage, pruritus, acne, psoriasis, allergic dermatitis, contact dermatitis, exfoliative dermatitis, seborrheic dermatitis, seborrheic dermatitis, lichen planus, rosacea, pigmentation disorders, hypermelanosis, erythema, wounds, ulcers, bedsores, lupus, skin wrinkle-related diseases, and skin diseases caused by photodamage. 청구항 5에 있어서, 상기 피부 주름관련 질환은 탄력섬유증, 피부의 비박화(thinning of the skin), 피부 위축증(skin atrophy), 콜라겐 섬유(collagen fiber) 및 탄성 섬유(elastic fiber)의 감소, 피부 탄력성의 손실(loss of skin elasticity), 건조(dryness), 주름형성(wrinkle formation) 및 조기 피부 노화(premature skin aging)로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 조성물. A composition according to claim 5, wherein the skin wrinkle-related disease is at least one selected from the group consisting of elasticity fibrosis, thinning of the skin, skin atrophy, reduction of collagen fibers and elastic fibers, loss of skin elasticity, dryness, wrinkle formation, and premature skin aging. 청구항 5에 있어서, 상기 광손상에 의한 피부질환은 검버섯(lentigines), 주근깨(freckles), 저색소 침착 (hypopigmentation) 과색소 침착(hyperpigmentation), 급성 또는 만성 UV 방사선으로 인한 광손상, 및 광민감화로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 조성물. A composition according to claim 5, wherein the skin disease caused by photodamage is at least one selected from the group consisting of lentigines, freckles, hypopigmentation, hyperpigmentation, photodamage caused by acute or chronic UV radiation, and photosensitization. 청구항 1에 있어서, 상기 피부질환은 편평세포 암종, 기저 세포 암종, 양성 상피 종양, 및 방사선 피부염으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 조성물. A composition according to claim 1, wherein the skin disease is at least one selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, benign epithelial tumor, and radiation dermatitis. 청구항 1에 있어서, 상기 피부질환은 지방층염, 굳은살, 백반증, 두드러기, 모낭염, 피지 모공 각화증, 습진, 티눈, 기미, 발진, 무좀, 반점, 튼살, 주근깨, 땀띠, 피부 건조증, 동창, 화농, 곰보, 두피염 및 건선성 관절염으로 이루어진 군으로부터 선택되는 어느 하나 이상인 것인, 조성물. A composition according to claim 1, wherein the skin disease is at least one selected from the group consisting of panniculitis, calluses, vitiligo, urticaria, folliculitis, seborrheic keratosis pilaris, eczema, styes, freckles, blemishes, rashes, athlete's foot, spots, stretch marks, prickly heat, dry skin, chilblains, suppuration, keratoses, dermatitis, and psoriatic arthritis. 청구항 1에 있어서, 상기 조성물은 칼슘, 콜히친, 타피나로프(tapinarof), 핑골리모드, 및 토파시티닙으로 이루어진 군으로부터 선택된 화합물을 추가로 포함하는 것인, 조성물. A composition according to claim 1, wherein the composition further comprises a compound selected from the group consisting of calcium, colchicine, tapinarof, fingolimod, and tofacitinib. 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 의약외품 조성물.A pharmaceutical composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient. 튜불린 저해제를 유효성분으로 포함하는 피부 질환의 예방 또는 개선용 화장료 조성물.A cosmetic composition for preventing or improving skin diseases, comprising a tubulin inhibitor as an active ingredient. 튜불린 저해제를 유효성분으로 포함하는 피부 보습, 미백, 주름개선, 여드름 완화, 피부 장벽 강화, 또는 피부 케라티노사이트 (keratinocyte) 분화용 화장료 조성물.A cosmetic composition for moisturizing the skin, whitening, improving wrinkles, alleviating acne, strengthening the skin barrier, or differentiating skin keratinocytes, containing a tubulin inhibitor as an active ingredient. 치료적 유효량의 튜불린 저해제를 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 피부　질환을 예방 또는 치료하는 방법.A method for preventing or treating a skin disease, comprising the step of administering a therapeutically effective amount of a tubulin inhibitor to a subject in need thereof.
PCT/KR2025/000257 2024-01-05 2025-01-06 Composition comprising tubulin inhibitor for preventing or treating skin diseases Pending WO2025147178A1 (en)

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