WO2019124603A1 - Composition destinée à prévenir ou à traiter une chéloïde contenant iwr-1 à titre de principe actif - Google Patents

Composition destinée à prévenir ou à traiter une chéloïde contenant iwr-1 à titre de principe actif Download PDF

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Publication number
WO2019124603A1
WO2019124603A1 PCT/KR2017/015359 KR2017015359W WO2019124603A1 WO 2019124603 A1 WO2019124603 A1 WO 2019124603A1 KR 2017015359 W KR2017015359 W KR 2017015359W WO 2019124603 A1 WO2019124603 A1 WO 2019124603A1
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iwr
keloid
preventing
mmp
active ingredient
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PCT/KR2017/015359
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English (en)
Korean (ko)
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윤태진
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경상대학교병원
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Publication of WO2019124603A1 publication Critical patent/WO2019124603A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • composition for preventing or treating keloid containing IWR-1 as an active ingredient is provided.
  • Keloid disease is a benign skin fibro-proliferative tumor characterized by excessive accumulation of extracellular matrix proteins leading to an excess of collagen formation. Abnormal skin scar formation can occur after injury in genetically sensitive individuals.
  • Existing therapies include the following: closed dressings, compression therapy, intra-lesion steroid injections, cryosurgery, surgical resection, laser therapy, radiation therapy, canallog (triamcinolone), interferon therapy, bleomycin, 5- Verapamil, imiquimodem cream, and combinations thereof.
  • closed dressings of both silicone and non-silicone based have been used extensively as clinical options for keloids over the past three decades, since all of these methods lead to very limited efficacy, new therapies for keloids It is widely recognized.
  • the present invention provides a composition containing IWR-1 as an active ingredient as a pharmaceutical composition and a cosmetic composition for preventing or treating keloid.
  • the present invention can provide a pharmaceutical composition for preventing or treating keloid containing IWR-1 as an active ingredient.
  • the present invention can provide a cosmetic composition for preventing or improving keloid containing IWR-1 as an active ingredient.
  • IWR-1 inhibits proliferation and migration of keloid fibroblasts without the influence of the TGF-beta signaling system, increases the expression of collagen degrading factor MMP and inhibits collagen synthesis
  • the composition containing the IWR-1 as an active ingredient can be provided as a pharmaceutical composition and a cosmetic composition for preventing or treating fibrosing diseases such as keloid.
  • FIG. 1A shows the chemical structure of IWR-1.
  • Fig. 1B shows the results of confirming the cytotoxicity of IWR-1 in fibroblasts.
  • IWR-1 at a concentration of 0 to 50 ⁇ M was incubated with human normal fibroblasts (NF) (KF) for 24 hours, and LDH activity in the culture medium.
  • FIG. 1C shows the effect of IWR-1 on endogenous Wnt / ⁇ -catenin signal.
  • TOPflash or FOPflash reporter adenovirus was detected overnight (* P ⁇ 0.01) after transfection and treating IWR-1 at a concentration of 0 to 20 [mu] M for 24 hours and then confirming luciferase activity.
  • FIG. 2A shows the results of confirming the cell proliferation effect of IWR-1.
  • human normal skin fibroblasts (NF) and keloid fibroblasts (KF) were treated with 0 to 20 ⁇ M of IWR-
  • FIG. 2B shows the effect of IWR-1 on cell migration by confirming the level of confluence of NF and KF after the production of a scratch wound.
  • FIG. 3 shows the results of confirming the effect of IWR-1 on collagen production.
  • Fig. 3A shows the results of treatment of human normal skin fibroblasts (NF) and keloid fibroblasts (KF) with 20 [mu] M IWR-
  • FIG. 3B is a Western blot analysis showing the expression levels of collagen-1 ⁇ 1 and collagen-1 ⁇ 2 proteins.
  • Collagen type I protein (collagen- 1 ⁇ 1 and collagen-1 ⁇ 2)
  • the right photograph shows the expression level of collagen type I protein at 0, 24 and 48 hours in 20 ⁇ M of IWR-1 treated cells
  • 3C is an ELISA analysis (* P ⁇ 0.01) showing the level of procollagen secreted in the culture medium after culturing the cells for 20 hours at a concentration of 20 ⁇ M for 48 hours,
  • NF or KF The IWR-1 of 20 ⁇ M contained in the collagen gel is the result confirming the excellent shrinkage seven days after the treatment compared to the control as a result of confirming the degree of shrinkage Gel IWR-1 is treated group (* P ⁇ 0.01).
  • FIG. 4A shows the effect of IWR-1 on TGF- ⁇ 1 / Smad signal and myofibroblast differentiation.
  • FIG. 4A shows the results of pretreatment of 20 ⁇ M of IWR-1 in NF and KF for 1 hour, Western blot analysis of Smad phosphorylation and ⁇ -SMA expression levels after stimulation with ng / ml TGF- ⁇ 1 showed that IWR-1 did not affect the phosphorylation of Smad protein induced by TGF- ⁇ 1 , FIG.
  • FIG. 5A shows the effect of MMP (matrix metalloproteinase) production on IGF-1 in normal human fibroblast (NF) and keloid fibroblast (KF) extracts treated with 20 ⁇ M IWR-1 for 48 hours.
  • MMP matrix metalloproteinase
  • FIG. 5B shows the result of RT-PCR analysis of the mRNA levels of MMP-1, MMP-3 and MMP-13, wherein GAPDH was used as an internal control and the expression of MMPs was increased by IWR- 5C was the result of gelatinization analysis of electrophoresis after enriching the cell culture medium.
  • the band of about 90 kDa was predicted as MMP9
  • the low molecular weight band can be predicted by MMP13.
  • the present invention can provide a pharmaceutical composition for preventing or treating keloid containing IWR-1 as an active ingredient.
  • the IWR-1 can inhibit proliferation and migration of fibroblasts.
  • the IWR-1 can inhibit collagen synthesis.
  • the most important feature of fibrosis disease is the increase in collagen synthesis and accumulation.
  • the effect of IWR-1 on collagen synthesis was confirmed by Western blot analysis. As a result, The collagen synthesis effect was significantly reduced in normal and keloid tissues. Also, referring to FIG. 3C, which confirms the amount of procollagen released from fibroblasts, it was confirmed that the release of procollagen was significantly reduced by IWR-1 treatment in both NF and KF, in accordance with the collagen synthesis effect as described above.
  • IWR-1 may be one that increases the production of matrix metalloproteinase (MMP), a collagen degrading factor.
  • MMP matrix metalloproteinase
  • IWR-1 expresses MMP-1, MMP-3, and MMP-13, respectively, as shown in FIG. 5A.
  • MMP-1, MMP-3 and MMP-13 secretion levels were significantly increased in the cell culture medium by IWR-1 treatment.
  • the pharmaceutical composition may contain 0.001 to 50 parts by weight of IWR-1, based on 100 parts by weight of the total amount of the pharmaceutical composition.
  • the pharmaceutical composition for preventing or treating keloid containing the IWR-1 as an active ingredient can be administered orally or parenterally in the form of injections, granules, powders, tablets, pills, capsules, suppositories, , Emulsions, drops, and liquid preparations can be used.
  • the pharmaceutical composition for the prevention or treatment of keloids containing IWR-1 as an active ingredient may be formulated with a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant , At least one additive selected from the group consisting of lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, binders and lubricants.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.
  • the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.
  • As the suppository base witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
  • the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
  • the preferred dosage of the above IWR-1 may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art.
  • the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto.
  • the administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
  • the 'subject' may be a mammal including a human, but is not limited thereto.
  • the present invention can provide a cosmetic composition for preventing or improving keloid containing IWR-1 as an active ingredient.
  • the cosmetic composition may contain, in addition to the active ingredient IWR-1, conventional additives such as stabilizers, solubilizers, vitamins, pigments and flavors, and carriers.
  • conventional additives such as stabilizers, solubilizers, vitamins, pigments and flavors, and carriers.
  • the cosmetic composition may be prepared in any form conventionally produced in the art and may be in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, oil, powder foundation, emulsion foundation, Wax foundation, spray, and the like.
  • the present invention is not limited thereto. More specifically, it can be manufactured in the form of a sun cream, a flexible lotion, a convergent lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a pack, a spray or a powder.
  • the formulation is a paste, cream or gel
  • an animal oil a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide
  • a carrier component a carrier component that may be used as a carrier component .
  • lactose When the formulation is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component.
  • talc In the case of a spray, in particular, chlorofluorohydrocarbons, propane / Or propellants such as dimethyl ether.
  • a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, - butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitan.
  • a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, a microcrystalline cellulose , Aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
  • IWR-1 was purchased from Selleckchem (Houston, Tex.). Collagen-1 alpha 1, collagen-1 alpha 2, MMP-1, MMP-3 and alpha-SMA (Santa Cruz Biotechnology, Santa Cruz, Calif.) As primary antibodies; MMP-13 (Abcam, Cambridge, Mass.); (Rhodamine phalloidin) was transformed into Invitrogen (Eugene, St. Louis, Mo.), p-Smad2, Smad2, p-Smad3, Smad3 (Cell Signaling Technology, Beverly, MA) OR).
  • Keloid tissue was collected from patients between 20 and 65 years of age (mean 32.0 ⁇ 15.1 years). Normal fibroblasts (NF) and keloid-induced dermal fibroblasts (KF) were cultured by modification of the previously reported method (Peihua Zhang, et al., 2014).
  • PBS phosphate-buffered saline
  • Fibroblasts were obtained from tissue cultured for one week. The cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal calf serum (FBS) and 1% penicillin-streptomycin (Life Technologies Corporation, Grand Island, NY) ; Welgene, Daegu, Korea).
  • DMEM Dulbecco's Modified Eagle's Medium
  • FBS fetal calf serum
  • penicillin-streptomycin Life Technologies Corporation, Grand Island, NY
  • Lactate dehydrogenase (LDH) analysis was performed to confirm cytotoxicity.
  • Cells were seeded at a density of 2 ⁇ 10 4 / well on a 24-well culture plate and treated with various concentrations of IWR-1. After 24 hours, the culture medium was collected and LDH activity was determined by a cytotoxicity detection kit (Roche, Indianapolis, IN) .
  • NF or KF was dispensed into 60 mm dishes at the same cell number and treated with various concentrations of IWR-1 after 24 hours.
  • the cells were separated from the culture dish at fixed intervals and the number of cells was counted using a hemocytometer.
  • the TOPflash reporter adenovirus contains three copies of the motif with optimal TCF binding leading to luciferase expression.
  • MOI multiplicity of infection
  • IWR-1 was treated with various concentrations of IWR-1 for 24 hours, scratched with a microwave pet tip to create artificial wounds, and the gap closure was monitored before and after treatment under a phase contrast microscope to determine the percentage of gap closure Respectively.
  • a sample containing the same amount of protein was loaded on SDS-polyacrylamide gel and transferred to a nitrocellulose membrane. After blocking with 5% skim milk, the cells were incubated with the appropriate primary antibody and incubated with secondary antibody conjugated with the corresponding horseradish peroxidase.
  • Cell contraction assay kit (Cell Biolabs Inc., San Diego, Calif.) was used to perform gel shrinkage analysis according to the manufacturer's instructions.
  • M-MLV Molecular Rule Leukemia Virus
  • cDNA was used as a template for amplification, and primers of the following sequences were used: MMP-1, 5'-GATGGGAGGCAAGTTGAAAA and 5'-CCAGGTCCATCAAAAGGAGA; MMP-3, 5'-TGCTTTGTCCTTTGATGCTG and 5'-ATCGATTTTCCTCACGGTTG; MMP-13, 5'-TAAGGAGCATGGCGACTTCT and 5'-GTCTGGCGTTTTTGGATGTT; GAPDH, 5'-GTCAGTGGTGGACCTGACCT and 5'-AGGGGTCTACATGGCAACTG.
  • IWR-1 at a concentration of 20 ⁇ M in serum-free medium was treated with fibroblasts for 48 hours.
  • the supernatant was concentrated and gelatinization was performed with the reported method (Substrate-zymography: A still worthwhile method for gelatinases analysis in biological samples).
  • the gel was washed twice with 2.5% tryptone X-100 solution at room temperature for 30 minutes and then washed in a buffer containing 0.05 M Tris-HCl (pH 7.5), 0.15 M NaCl and 0.01 M CaCl 2 at 37 ° C for 24 hours Lt; / RTI >
  • the gel was then stained with 30% methanol, 10% acetic acid and 0.1% (w / v) Coomassie Brilliant Blue R250 and stained with 30% methanol and 10% acetic acid to clarify the band in the background gel, Activity was visualized.
  • NF normal skin fibroblasts
  • KF keloid fibroblasts
  • IWR-1 may cause some damage to the plasma membrane. Therefore, IWR-1 was further treated to 20 ⁇ M in fibroblasts.
  • IWR-1 was originally developed as a low-molecular inhibitor of Wnt / ⁇ -catenin signaling, confirming that IWR-1 indeed blocks intracellular Wnt / ⁇ -catenin signaling in fibroblasts.
  • TOPflash reporter the most well-known analytical tool for Wnt / ⁇ -catenin signal validation, was used.
  • basal TOPflash activity was found to be a major cause of keloid, with KF being higher than NF.
  • TOPflash reporter was transfected into fibroblasts and then treated with IWR-1.
  • IWR-1 inhibited TOPflash activity in a dose-dependent manner in both NF and KF. From the above results, a potential effect on fibroblast Wnt /? - catenin signal was confirmed.
  • Fibrosis diseases such as keloids increase the proliferation and migration of fibroblasts, thus confirming the effect of IWR-1 on fibroblast proliferation and migration.
  • IWR-1 effectively inhibits collagen production of fibroblasts, thus, in the treatment of fibrosing disease, IWR-1 can be proposed as a potential therapeutic agent.
  • TGF- ⁇ / Smad signal plays an important role in keloid development by promoting fibroblast proliferation and collagen synthesis.
  • IWR-1 IWR-1 on TGF- ⁇ / Smad signal in NF and KF cells.
  • IWR-1 significantly inhibits collagen gel shrinkage, thereby confirming whether IWR-1 can affect the shrinking protein ⁇ -SMA, which plays an important role in muscle differentiation.
  • IWR-1 treatment did not affect ⁇ -SMA expression regardless of TGF- ⁇ stimulation.
  • IWR-1 inhibits myoblast differentiation in stress fiber formation without affecting Smad signal.
  • IWR-1 increased intracellular protein levels of MMP-1, MMP-3 and MMP-13 and similar results showed that MMP-1, MMP-3 and MMP- -13 secretion was significantly increased.
  • RT-PCR was performed to confirm whether IWR-1 can increase the expression of MMP gene.
  • IWR-1 increased mRNA levels of MMP-1, MMP-3 and MMP-13.

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Abstract

La présente invention concerne une composition destinée à prévenir ou à traiter une chéloïde, contenant IWR-1 à titre de principe actif. La composition contenant IWR-1 à titre de principe actif peut être proposée sous la forme d'une composition pharmaceutique et d'une composition cosmétique pour prévenir ou traiter les maladies fibrotiques comme la chéloïde, dans la mesure où il a été confirmé que ledit IWR-1 exerce des effets d'inhibition de la prolifération et de la migration des fibroblastes chéloïdiens sans affecter le système de signalisation du TGF-β, et d'inhibition de la synthèse du collagène tout en augmentant l'expression de MMP qui est un facteur de dégradation du collagène.
PCT/KR2017/015359 2017-12-22 2017-12-22 Composition destinée à prévenir ou à traiter une chéloïde contenant iwr-1 à titre de principe actif WO2019124603A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110014229A (ko) * 2008-05-27 2011-02-10 더 보드 오브 리전츠 오브 더 유니버시티 오브 텍사스 시스템 Ｗｎｔ 단백질 신호전달 억제제
KR20130131290A (ko) * 2010-06-29 2013-12-03 아이알엠 엘엘씨 Ｗｎｔ 신호전달 경로를 조절하기 위한 조성물 및 방법
JP2017521499A (ja) * 2014-07-17 2017-08-03 バイオキュリティー ホールディングス インコーポレイテッド 放射線、酸化セリウムナノ粒子、及び化学療法剤の併用によるがんの治療
JP2017526676A (ja) * 2014-08-27 2017-09-14 オンコメッド ファーマシューティカルズ インコーポレイテッド がんの処置のための併用療法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110014229A (ko) * 2008-05-27 2011-02-10 더 보드 오브 리전츠 오브 더 유니버시티 오브 텍사스 시스템 Ｗｎｔ 단백질 신호전달 억제제
KR20130131290A (ko) * 2010-06-29 2013-12-03 아이알엠 엘엘씨 Ｗｎｔ 신호전달 경로를 조절하기 위한 조성물 및 방법
JP2017521499A (ja) * 2014-07-17 2017-08-03 バイオキュリティー ホールディングス インコーポレイテッド 放射線、酸化セリウムナノ粒子、及び化学療法剤の併用によるがんの治療
JP2017526676A (ja) * 2014-08-27 2017-09-14 オンコメッド ファーマシューティカルズ インコーポレイテッド がんの処置のための併用療法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHOU, MING-WEI ET AL.: "Inhibition of Collagen Synthesis by IWR-1 in Normal and Keloid-derived Skin Bibroblasts", LIFE SCIENCES, vol. 173, 7 December 2016 (2016-12-07), pages 86 - 93, XP029939033, DOI: doi:10.1016/j.lfs.2016.12.003 *

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