JP2021070661A - Composition for inhibiting tslp gene expression, for inhibiting il-33 gene expression, or for promoting filaggrin production - Google Patents
Composition for inhibiting tslp gene expression, for inhibiting il-33 gene expression, or for promoting filaggrin production Download PDFInfo
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- JP2021070661A JP2021070661A JP2019199175A JP2019199175A JP2021070661A JP 2021070661 A JP2021070661 A JP 2021070661A JP 2019199175 A JP2019199175 A JP 2019199175A JP 2019199175 A JP2019199175 A JP 2019199175A JP 2021070661 A JP2021070661 A JP 2021070661A
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Abstract
Description
本発明は、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用組成物、ＩＬ−３３遺伝子発現抑制用組成物、又はフィラグリン産生促進用組成物に関する。 The present invention relates to a composition for suppressing thymic interstitial lymphocyte neoplasia (TSLP) gene expression, a composition for suppressing IL-33 gene expression, or a composition for promoting filaggrin production.
胸腺間質性リンパ球新生因子（ＴＳＬＰ）は、胸腺、皮膚、腸、扁桃、肺の上皮細胞、肺線維芽細胞、間質性細胞等が発現するサイトカインである（非特許文献１）。これらの細胞では、炎症を惹起する刺激に応答して、ＴＳＬＰが産生されることが知られている。ＴＳＬＰは、樹状細胞、マスト細胞等の活性化を通じて、アレルギー性の炎症応答を引き起こすことが知られている。 Thymus interstitial lymphocyte neoplastic factor (TSLP) is a cytokine expressed by thymus, skin, intestines, tonsils, lung epithelial cells, pulmonary fibroblasts, interstitial cells, and the like (Non-Patent Document 1). It is known that these cells produce TSLP in response to stimuli that induce inflammation. TSLP is known to induce an allergic inflammatory response through activation of dendritic cells, mast cells and the like.
例えば、アトピー性皮膚炎では、皮膚バリア機能異常や掻破によって、上皮細胞でＴＳＬＰが誘導される。そしてＴＳＬＰはＴｈ２リンパ球を介して炎症を誘導するだけでなく、ＴＲＰＡを介して掻痒を誘導し、バリア機能をさらに悪化させる要因となる。そのため、ＴＳＬＰは、アトピー性皮膚炎をはじめとする炎症性皮膚疾患において、薬剤ターゲットの一つとして注目されている（非特許文献２）。 For example, in atopic dermatitis, TSLP is induced in epithelial cells by skin barrier dysfunction or scratching. Then, TSLP not only induces inflammation via Th2 lymphocytes, but also induces pruritus via TRPA, which is a factor that further aggravates the barrier function. Therefore, TSLP is attracting attention as one of the drug targets in inflammatory skin diseases such as atopic dermatitis (Non-Patent Document 2).
その他にも、喘息等の慢性炎症にＴＳＬＰが関与することが知られている。 In addition, it is known that TSLP is involved in chronic inflammation such as asthma.
インターロイキン−３３（ＩＬ−３３）は、炎症に関連するインターロイキン−１ファミリーに属するサイトカインである。ＩＬ−３３は、上皮細胞や血管内皮細胞で恒常的に発現しており、感染、物理的又は化学的ストレス等によって細胞外に放出される。放出されたＩＬ−３３は、その受容体を発現する免疫系細胞を介してアレルギー性の炎症応答を引き起こすことが知られている。 Interleukin-33 (IL-33) is a cytokine belonging to the interleukin-1 family associated with inflammation. IL-33 is constitutively expressed in epithelial cells and vascular endothelial cells, and is released extracellularly by infection, physical or chemical stress, or the like. The released IL-33 is known to provoke an allergic inflammatory response via immune system cells that express its receptor.
例えば、ＩＬ−３３は、アトピー性皮膚炎の病変部Ｔｈ２細胞の遊走を通じて、アトピー性皮膚炎の発症に関わることが知られている（非特許文献２）。 For example, IL-33 is known to be involved in the development of atopic dermatitis through the migration of Th2 cells in lesions of atopic dermatitis (Non-Patent Document 2).
そのほかにも、乾癬、喘息、関節リウマチ、全身性硬化症、潰瘍性大腸炎、クローン病、多発性硬化症、強直性脊椎炎、肝繊維症等の炎症性疾患にＩＬ−３３が関与することが示唆されている。 In addition, IL-33 is involved in inflammatory diseases such as psoriasis, asthma, rheumatoid arthritis, systemic sclerosis, ulcerative colitis, Crohn's disease, multiple sclerosis, ankylosing spondylitis, and liver fibrosis. Is suggested.
炎症性皮膚疾患や喘息等の炎症にはステロイド製剤が用いられる。ステロイド製剤はＩＬ−３３による炎症を抑制する。しかし、ステロイド製剤の継続使用では、表皮のバリア機能の低下や、ステロイド抵抗性が生じることが知られている。また、ＴＳＬＰとＩＬ−３３の両方の発現量の増加が、重症の喘息においてステロイド抵抗性に関与することも知られている（非特許文献３）。そこで、ステロイドとは別の、ＴＳＬＰ又はＩＬ−３３の発現を抑制する薬剤が望まれていた。 Steroid preparations are used for inflammation such as inflammatory skin diseases and asthma. Steroid preparations suppress inflammation caused by IL-33. However, it is known that continuous use of steroid preparations causes a decrease in the barrier function of the epidermis and steroid resistance. It is also known that an increase in the expression level of both TSLP and IL-33 is involved in steroid resistance in severe asthma (Non-Patent Document 3). Therefore, a drug that suppresses the expression of TSLP or IL-33, which is different from steroids, has been desired.
その一方で、皮膚の炎症においては、炎症を抑える他に、表皮のバリア機能を改善して、皮膚の乾燥や外部から皮膚内への刺激因子の侵入を防ぐことも重要である。表皮のバリア機能に関わる代表的なタンパク質の一つがフィラグリンである。フィラグリンは、表皮の顆粒細胞で産生される塩基性タンパク質である。ヒトにおいては、フィラグリンは分子量約４００ｋＤａのプロフィラグリンとして産生された後、プロフィラグリンの脱リン酸化とプロテアーゼによる分解を経て、３７ｋＤａのフィラグリンモノマーとなる。フィラグリンモノマーはケラチンフィラメント同士を凝集させる線維間凝集物質として働く。さらに、角層の外層部では、フィラグリンは分解されて、アミノ酸、ウロカニン酸糖を含む天然保湿因子（ＮＭＦ）となる。 On the other hand, in skin inflammation, in addition to suppressing inflammation, it is also important to improve the barrier function of the epidermis to prevent the skin from drying out and the invasion of stimulants from the outside into the skin. One of the typical proteins involved in the barrier function of the epidermis is filaggrin. Filaggrin is a basic protein produced by granule cells of the epidermis. In humans, filaggrin is produced as profilaggrin having a molecular weight of about 400 kDa, and then undergoes dephosphorylation of profilaggrin and decomposition by protease to become a filaggrin monomer of 37 kDa. The filaggrin monomer acts as an interfiber aggregating substance that aggregates keratin filaments. Furthermore, in the outer layer of the stratum corneum, filaggrin is decomposed into a natural moisturizing factor (NMF) containing an amino acid, urocanic acid sugar.
従って、炎症性皮膚疾患等の改善のために、フィラグリンの産生を促進することも重要な課題の一つであった。 Therefore, it was one of the important issues to promote the production of filaggrin for the improvement of inflammatory skin diseases and the like.
本発明は、新たなＴＳＬＰ遺伝子発現抑制用組成物、ＩＬ−３３遺伝子発現抑制用組成物、又はフィラグリン産生促進用組成物の提供に関する。 The present invention relates to the provision of a novel composition for suppressing TSLP gene expression, a composition for suppressing IL-33 gene expression, or a composition for promoting filaggrin production.
本発明者らは、鋭意検討を行った結果、トレハロース又はその誘導体で対象を処置又は処理することにより、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子及びＩＬ−３３遺伝子の発現が抑制されることを見出した。
また、本発明者らは、トレハロース又はその誘導体で対象を処置又は処理することにより、フィラグリンの産生が促進されることを見出した。
本発明は、これらの知見に基づいて完成されたものである。
As a result of diligent studies, the present inventors suppressed the expression of the thymic interstitial lymphocyte neoplastic factor (TSLP) gene and the IL-33 gene by treating or treating the subject with trehalose or a derivative thereof. I found that.
The present inventors have also found that treatment or treatment of a subject with trehalose or a derivative thereof promotes the production of filaggrin.
The present invention has been completed based on these findings.
本発明は、トレハロース又はその誘導体を含有する、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用、ＩＬ−３３遺伝子発現抑制用、又はフィラグリン産生促進用である、組成物に関する。
また、本発明は、トレハロース又はその誘導体を有効成分として含有する、炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれ、を改善又は予防するための医薬組成物に関する。
The present invention relates to a composition containing trehalose or a derivative thereof, for suppressing thymic interstitial lymphocyte neoplasia (TSLP) gene expression, for suppressing IL-33 gene expression, or for promoting filaggrin production.
The present invention also relates to a pharmaceutical composition containing trehalose or a derivative thereof as an active ingredient for improving or preventing inflammatory skin diseases, scars, or cracks or cracks in the skin.
本発明の組成物により、細胞におけるＴＳＬＰ遺伝子及びＩＬ−３３遺伝子の発現が抑制される。従って、本発明の組成物は、ＴＳＬＰ関連状態又はＩＬ−３３関連状態の改善又は予防に有用である。
また本発明の組成物により、細胞におけるフィラグリンの産生が促進される。さらに産生されたフィラグリンの一部は分解して天然保湿因子（ＮＭＦ）となる。従って、本発明の組成物は、皮膚バリア機能低下状態の改善又は予防に有用である。
The composition of the present invention suppresses the expression of the TSLP gene and the IL-33 gene in cells. Therefore, the compositions of the present invention are useful for ameliorating or preventing TSLP-related or IL-33-related conditions.
In addition, the composition of the present invention promotes the production of filaggrin in cells. Furthermore, a part of the produced filaggrin is decomposed into a natural moisturizing factor (NMF). Therefore, the composition of the present invention is useful for improving or preventing a state of reduced skin barrier function.
本発明の構成の医薬組成物は、炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれを改善又は予防する。従って、本発明の医薬組成物は、これら皮膚の状態の処置に有用である。 The pharmaceutical composition of the constitution of the present invention improves or prevents inflammatory skin diseases, scars, or cracks or cracks in the skin. Therefore, the pharmaceutical compositions of the present invention are useful in treating these skin conditions.
本明細書において、「改善」とは、疾患、症状、健康状態若しくは審美的状態の治癒、好転若しくは緩和、又は、疾患、症状、健康状態若しくは審美的状態の悪化の防止若しくは遅延、あるいは、疾患若しくは症状の進行の逆転、防止若しくは遅延を表す。
本明細書において、「予防」とは、疾患若しくは症状の発症の防止、又は疾患若しくは症状の発症のリスクを低下させることを表す。
As used herein, "improvement" means cure, improvement or alleviation of a disease, symptom, health condition or aesthetic condition, or prevention or delay of deterioration of a disease, symptom, health condition or aesthetic condition, or disease. Or it represents the reversal, prevention or delay of the progression of the symptom.
As used herein, "prevention" means preventing the onset of a disease or symptomatology or reducing the risk of developing a disease or symptomatology.
本明細書において、「対象」とは、本発明の組成物又は医薬組成物によって処理又は処置される、個体、器官、組織又は細胞を表す。 As used herein, the term "subject" refers to an individual, organ, tissue or cell treated or treated with the composition or pharmaceutical composition of the present invention.
本明細書において、「瘢痕」（Scar）とは、身体の任意の組織の損傷又は疾患の部位に生じた線維性組織を表す。瘢痕には肥厚性瘢痕及びケロイドが包含される。 As used herein, the term "scar" refers to fibrous tissue that develops at the site of injury or disease of any tissue in the body. Scars include hypertrophic scars and keloids.
本明細書において、「トレハロース」とは、２つのα−グルコースが１，１−グリコシド結合した二糖類であり、α，α−トレハロースとも呼ばれる。本明細書のトレハロースは無水物、二水和物等の水和物を包含する。 As used herein, "trehalose" is a disaccharide in which two α-glucoses are 1,1-glycosidically bonded, and is also referred to as α, α-trehalose. Trehalose herein includes hydrates such as anhydrides and dihydrates.
本明細書において、「トレハロース誘導体」とは、トレハロースの糖質誘導体であり、分子内にα，α−トレハロース構造に１個以上の糖モノマーが縮合した糖質である。トレハロース誘導体の具体例としては、特に限定されないが、例えば、特開平７−１４３８７６号公報、特開平８−７３５０４号公報、特許第３１８２６７９号公報、特開２０００−２２８９８０号公報などに記載される、α−マルトシルα−グルコシド、α−イソマルトシルα−グルコシドなどのモノ−グルコシルα，α−トレハロース；α−マルトトリオシルα−グルコシド（別名α−マルトシルα，α−トレハロース）、α−マルトシルα−マルトシド、α−イソマルトシルα−マルトシド、α−イソマルトシルα−イソマルトシドなどのジ−グルコシルα，α−トレハロース；α−マルトテトラオシルα−グルコシド（別名α−マルトトリオシルα，α−トレハロース）、α−マルトシルα−マルトトリオシド、α−パノシルα−マルトシドなどのトリ−グルコシルα，α−トレハロース；α−マルトペンタオシルα−グルコシド（別名α−マルトテトラオシルα，α−トレハロース）、α−マルトトリオシルα−マルトトリオシド、α−パノシルα−マルトトリオシドなどのテトラ−グルコシルα，α−トレハロースなど、グルコース重合度が３〜６のα，α−トレハロースの糖質誘導体が挙げられる。
トレハロース又はその誘導体の由来や製法は特に限定されず、天然物由来であっても化学合成された物であってもよいが、リポ多糖（ＬＰＳ）その他の細胞毒性をもたらす物質の含有量が、細胞増殖を妨げない量以下であることが好ましい。
本明細書において、「トレハロース換算量」とは、トレハロース及びその誘導体から、水和水及びトレハロース以外の糖部分を差し引いた、トレハロース部分に相当する質量を表す。
In the present specification, the "trehalose derivative" is a trehalose sugar derivative, which is a sugar in which one or more sugar monomers are condensed in an α, α-trehalose structure in the molecule. Specific examples of the trehalose derivative are not particularly limited, but are described in, for example, JP-A-7-143876, JP-A-8-73504, Patent No. 3182679, JP-A-2000-228980 and the like. Mono-glucosyl α, α-trehalose such as α-maltosyl α-glucoside, α-isomaltosyl α-glucoside; α-maltotriosyl α-glucoside (also known as α-maltosyl α, α-trehalose), α-maltosyl α-trehalose Di-glucosyl α, α-trehalose such as α-isomaltosyl α-maltoside, α-isomaltosyl α-isomaltoside; α-maltotetraosyl α-glucoside (also known as α-maltotriosyl α, α-trehalose), α- Tri-glucosyl α, α-trehalose such as maltosyl α-maltotrioside, α-panosyl α-maltoside; α-maltopentaosyl α-glucoside (also known as α-maltotetraosyl α, α-trehalose), α- Examples thereof include sugar derivatives of α and α-trehalose having a glucose polymerization degree of 3 to 6, such as tetra-glucosyl α and α-trehalose such as maltotriosyl α-maltotrioside and α-panosyl α-maltotrioside.
The origin and production method of trehalose or its derivative are not particularly limited, and it may be derived from a natural product or chemically synthesized, but the content of lipopolysaccharide (LPS) or other substance causing cytotoxicity is high. The amount is preferably less than or equal to the amount that does not interfere with cell proliferation.
In the present specification, the "trehalose equivalent amount" represents the mass corresponding to the trehalose moiety obtained by subtracting the sugar moiety other than hydrated water and trehalose from trehalose and its derivative.
本明細書において、含有量の単位「質量％」は、「ｇ／１００ｇ」と同義である。
本明細書において、「ｖ／ｖ％」は、体積百分率を表し、「ｍＬ／１００ｍＬ」と同義である。
In the present specification, the unit of content "mass%" is synonymous with "g / 100g".
In the present specification, "v / v%" represents a volume percentage and is synonymous with "mL / 100 mL".
［ＴＳＬＰ遺伝子発現抑制用、ＩＬ−３３遺伝子発現抑制用、又はフィラグリン産生促進用である、組成物］
本発明の組成物は、トレハロース及びトレハロース誘導体からなる群より選ばれる１種又は２種以上の化合物を含有することを特徴とする。
トレハロース又はトレハロース誘導体は、下記の実施例で示されるように、ＴＳＬＰ遺伝子の発現抑制効果、ＩＬ−３３遺伝子の発現抑制効果、及びフィラグリンの産生促進効果を有する。
[Composition for suppressing TSLP gene expression, for suppressing IL-33 gene expression, or for promoting filaggrin production]
The composition of the present invention is characterized by containing one or more compounds selected from the group consisting of trehalose and trehalose derivatives.
Trehalose or a trehalose derivative has an effect of suppressing the expression of the TSLP gene, an effect of suppressing the expression of the IL-33 gene, and an effect of promoting the production of filaggrin, as shown in the following examples.
（用途）
本発明の組成物は、ＴＳＬＰの発現量増加が関与する生理的状態である、ＴＳＬＰ関連状態の改善に有用である。ＴＳＬＰ関連状態としては、特に限定されないが、例えば、炎症性皮膚疾患、瘢痕、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、好酸球性食道炎等が挙げられる。
(Use)
The composition of the present invention is useful for improving a TSLP-related condition, which is a physiological condition in which an increase in the expression level of TSLP is involved. TSLP-related conditions are not particularly limited, and include, for example, inflammatory skin diseases, scars, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), and eosinophilic esophagus. Examples include flames.
本発明の組成物は、ＩＬ−３３の発現量増加が関与する生理的状態である、ＩＬ−３３関連状態の改善に有用である。ＩＬ−３３関連状態としては、特に限定されないが、例えば、炎症性皮膚疾患、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、アナフィラキシーショック、天疱瘡、類天疱瘡、強皮症、強直性脊椎炎、肝線維症、肺線維症、急性腎障害、血管炎、癌等が挙げられる。 The composition of the present invention is useful for improving IL-33-related conditions, which are physiological conditions in which an increase in the expression level of IL-33 is involved. IL-33-related conditions are not particularly limited, but are, for example, inflammatory skin diseases, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, asthma, chronic obstructive pulmonary disease, systemic lupus erythematosus, and ulcerative colitis. , Crohn's disease, anaphylactic shock, herbitis, aspergillus, scleroderma, tonic spondylitis, liver fibrosis, pulmonary fibrosis, acute nephropathy, vasculitis, cancer and the like.
本明細書において、炎症性皮膚疾患としては、特に限定されないが、国際疾病分類であるＩＣＤ−１０に例示される、アトピー性皮膚炎、脂漏性皮膚炎、おむつ皮膚炎、アレルギー性接触皮膚炎、刺激性接触皮膚炎（医薬品の接触等による皮膚炎を含む）、詳細不明の接触皮膚炎、剥脱性皮膚炎、摂取物質による皮膚炎、慢性単純性苔癬及び痒疹、掻痒症、又はその他の皮膚炎が挙げられる。 In the present specification, the inflammatory dermatitis is not particularly limited, but is exemplified by the international disease classification ICD-10, atopic dermatitis, seborrheic dermatitis, diaper dermatitis, allergic contact dermatitis. , Irritant contact dermatitis (including dermatitis caused by contact with drugs), unspecified contact dermatitis, exfoliative dermatitis, dermatitis caused by ingested substances, chronic simple lichen and prurigo, prurigo, or other Dermatitis can be mentioned.
本発明の組成物は、フィラグリンの分解によって生じる天然保湿因子（ＮＭＦ）の産生を促進するのにも有用である。さらに、本発明の組成物は、フィラグリン産生促進効果とＮＭＦ産生促進効果を通じて、皮膚バリア機能の低下を抑制する用途にも有用である。皮膚バリア機能の低下に起因する状態としては、特に限定されないが、例えばアトピー性皮膚炎等の炎症性皮膚疾患、ひび割れ、あかぎれ等が挙げられる。 The compositions of the present invention are also useful in promoting the production of natural moisturizing factor (NMF) produced by the decomposition of filaggrin. Furthermore, the composition of the present invention is also useful for applications that suppress a decrease in skin barrier function through a filaggrin production promoting effect and an NMF production promoting effect. The condition caused by the deterioration of the skin barrier function is not particularly limited, and examples thereof include inflammatory skin diseases such as atopic dermatitis, cracks, and cracks.
（対象）
本発明の組成物が対象とする個体又は器官、組織若しくは細胞の由来は、特に限定されないが、好ましくは哺乳動物、より好ましくはヒトである。
本発明が対象とする器官又は組織は、好ましくは皮膚であり、より好ましくは皮膚上皮（表皮）である。
本発明の組成物が対象とする細胞は、特に限定されないが、好ましくは上皮細胞、より好ましくは皮膚上皮細胞（表皮細胞）である。ここで、対象となる細胞は、単離された器官又は組織に由来する細胞や単離細胞、幹細胞等から分化して得られた細胞、又は個体、器官若しくは組織中に存在する細胞であってもよい。
(Target)
The origin of the individual or organ, tissue or cell targeted by the composition of the present invention is not particularly limited, but is preferably a mammal, more preferably a human.
The organ or tissue targeted by the present invention is preferably the skin, more preferably the cutaneous epithelium (epithelium).
The target cell of the composition of the present invention is not particularly limited, but is preferably an epithelial cell, more preferably a cutaneous epithelial cell (epidermal cell). Here, the target cell is a cell derived from an isolated organ or tissue, a cell obtained by differentiating from an isolated cell, a stem cell, or the like, or a cell existing in an individual, an organ, or a tissue. May be good.
（用量）
本発明の組成物のトレハロース及びその誘導体の総含有量は、当該組成物の形態、対象、使用目的等によって適宜調整される。
本発明の効果を顕著に奏する観点から、本発明の組成物は、上記の本発明の対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であり、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上となるように調製される。
また、本発明の組成物は、特に限定されないが、上記の本発明の対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、例えば３００ｍｇ／ｍＬ以下であり、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下となるように調製される。
本明細書において、特定量の成分が「細胞に適用される」とは、その細胞（組織、器官又は個体中のものを含む）が特定量の成分に曝露されることを表す。
(dose)
The total content of trehalose and its derivatives in the composition of the present invention is appropriately adjusted according to the form, subject, purpose of use and the like of the composition.
From the viewpoint of remarkably exerting the effect of the present invention, the composition of the present invention has a total concentration of trehalose and a derivative thereof applied to the above-mentioned target cells of the present invention of 10 mg / mL or more in terms of trehalose. It is prepared so as to be preferably 20 mg / mL or more, more preferably 30 mg / mL or more, and further preferably 50 mg / mL or more.
The composition of the present invention is not particularly limited, but the total concentration of trehalose and its derivatives applied to the above-mentioned target cells of the present invention is, for example, 300 mg / mL or less in terms of trehalose. It is prepared so as to be preferably 200 mg / mL or less, more preferably 150 mg / mL or less, still more preferably 100 mg / mL or less.
As used herein, the term "applied to a cell" of a particular amount of a component means that the cell (including those in a tissue, organ or individual) is exposed to the particular amount of the component.
（形態）
本発明の組成物の形態は、特に限定されないが、例えば、医薬品、医薬部外品、化粧品、食品等である。
また、本発明の組成物は、例えば、細胞培養用品として、コラーゲンゲル、コラーゲンスポンジ等の細胞支持体、培地、培地添加用サプリメント、血清等；研究用試薬等であり得る。
本発明の組成物の形態は、好ましくは医薬品、医薬部外品又は化粧品である。
(form)
The form of the composition of the present invention is not particularly limited, and examples thereof include pharmaceuticals, quasi-drugs, cosmetics, and foods.
Further, the composition of the present invention may be, for example, a cell culture product such as a cell support such as collagen gel or collagen sponge, a medium, a supplement for adding a medium, serum or the like; a research reagent or the like.
The form of the composition of the present invention is preferably a pharmaceutical product, a quasi drug or a cosmetic product.
本発明の組成物を医薬品、医薬部外品又は化粧品に用いる場合、基剤又は担体、保存剤、乳化剤、着色剤、防腐剤、界面活性剤、紫外線吸収剤、酸化防止剤、保湿剤、紫外線吸収剤、香料、防腐防黴剤、体質顔料、着色顔料、アルコール、多価アルコール、水、油剤、増粘剤、粉体、キレート剤、酵素、動植物エキス類、ｐＨ調整剤等の成分のうち、１種単独又は２種以上を組み合わせて含んでいてもよい。本発明の組成物が医薬品又は医薬部外品の形態である場合、その具体的な形態は、下記の［医薬組成物］に記載した形態と同じである。 When the composition of the present invention is used in pharmaceuticals, non-pharmaceutical products or cosmetics, bases or carriers, preservatives, emulsifiers, colorants, preservatives, surfactants, UV absorbers, antioxidants, moisturizers, UV rays Among the components such as absorbents, fragrances, antiseptic and fungicides, extender pigments, coloring pigments, alcohols, polyhydric alcohols, water, oils, thickeners, powders, chelating agents, enzymes, animal and plant extracts, pH adjusters, etc. It may contain one kind alone or a combination of two or more kinds. When the composition of the present invention is in the form of a pharmaceutical product or a quasi-drug, the specific form thereof is the same as that described in [Pharmaceutical Composition] below.
［医薬組成物］
本発明の医薬組成物は、トレハロース及びトレハロース誘導体からなる群より選ばれる１種又は２種以上の化合物を有効成分として含有することを特徴とする。
ここで、「医薬組成物」とは、医薬品及び医薬部外品を包含する。
本発明の医薬組成物は、上記の組成物と同じくＴＳＬＰ遺伝子発現抑制効果、ＩＬ−３３遺伝子発現抑制効果、及びフィラグリン産生促進効果を有する。
[Pharmaceutical composition]
The pharmaceutical composition of the present invention is characterized by containing one or more compounds selected from the group consisting of trehalose and trehalose derivatives as an active ingredient.
Here, the "pharmaceutical composition" includes pharmaceuticals and quasi-drugs.
The pharmaceutical composition of the present invention has a TSLP gene expression-suppressing effect, an IL-33 gene expression-suppressing effect, and a filaggrin production-promoting effect, similarly to the above composition.
（対象）
本発明の医薬組成物が対象とする個体は、特に限定されないが、好ましくは哺乳動物、より好ましくはヒトである。
(Target)
The individual targeted by the pharmaceutical composition of the present invention is not particularly limited, but is preferably a mammal, more preferably a human.
（適用症）
本発明の医薬組成物は、上記のＴＳＬＰ関連状態、ＩＬ−３３関連状態、又は皮膚バリア機能低下状態の改善に有用である。即ち、本発明の医薬組成物が処置又は予防に用いられ得る具体的な疾患としては、炎症性皮膚疾患、瘢痕、皮膚のひび割れ若しくはあかぎれ、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、好酸球性食道炎、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、アナフィラキシーショック、天疱瘡、類点疱瘡、強皮症、強直性脊椎炎、肝線維症、肺線維症、急性腎障害、血管炎、又は癌が挙げられる。中でも、本発明の医薬組成物は、炎症性皮膚疾患、瘢痕又は皮膚のひび割れ若しくはあかぎれの処置又は予防に好適に用いられる。
(Indication)
The pharmaceutical composition of the present invention is useful for improving the above-mentioned TSLP-related state, IL-33-related state, or skin barrier function-reduced state. That is, specific diseases in which the pharmaceutical composition of the present invention can be used for treatment or prevention include inflammatory skin diseases, scars, cracks or cracks in the skin, allergic conjunctivitis, allergic rhinitis, allergic scleroderma, and the like. Asthma, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, systemic erythematosus, ulcerative colitis, Crohn's disease, anaphylactic shock, vesicles, vesicles, scleroderma, tonic spondylitis, liver Examples include fibrosis, pulmonary fibrosis, acute nephropathy, vasculitis, or cancer. Above all, the pharmaceutical composition of the present invention is suitably used for the treatment or prevention of inflammatory skin diseases, scars or cracks or cracks in the skin.
（用量）
本発明の医薬組成物のトレハロース及びその誘導体の総含有量は、その剤形及び使用目的によって適宜調整され得るが、医薬組成物の全量に対して、トレハロース換算量で、例えば５質量％以上であり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上である。
トレハロース及びその誘導体の総含有量は、医薬組成物の全量に対して、トレハロース換算量で、例えば、８０質量％以下、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である。
(dose)
The total content of trehalose and its derivatives of the pharmaceutical composition of the present invention can be appropriately adjusted depending on the dosage form and purpose of use thereof, but is, for example, 5% by mass or more in terms of trehalose with respect to the total amount of the pharmaceutical composition. Yes, preferably 6% by mass or more, more preferably 8% by mass or more, still more preferably 10% by mass or more.
The total content of trehalose and its derivatives is, for example, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less in terms of trehalose equivalent amount with respect to the total amount of the pharmaceutical composition. , 30% by mass or less, 20% by mass or less, or 15% by mass or less.
なお、医薬組成物が貼付剤である場合における医薬組成物の全量とは、外用剤のうち、患部に吸収され得る部分の総重量である。即ち、医薬組成物中の支持体、ライナー（剥離体）、テープ、布等の有効成分を含まない材料を除いた、残部の総重量である。 When the pharmaceutical composition is a patch, the total amount of the pharmaceutical composition is the total weight of the portion of the external preparation that can be absorbed by the affected area. That is, it is the total weight of the balance excluding the active ingredient-free materials such as the support, liner (peeling body), tape, and cloth in the pharmaceutical composition.
（剤形）
本発明の医薬組成物の剤型としては、例えば、皮膚外用製剤（例：外用固形剤、外用液剤、スプレー剤、軟膏剤、クリーム剤、ゲル剤、貼付剤等）、眼科用製剤（例：点眼剤、眼軟膏剤等）、経口投与用製剤（例：錠剤、カプセル剤、顆粒剤、散剤、経口液剤、シロップ剤、経口ゼリー剤等）、口腔用製剤（例：口腔用錠剤、口腔用スプレー剤、口腔用半固形剤、含嗽剤等）、注射用製剤（例：注射剤等）、透析用製剤（例：透析用剤等）、吸入用製剤（例：吸入剤等）、耳科用製剤（例：点耳剤等）、鼻科用製剤（例：点鼻剤等）、直腸用製剤（例：坐剤、直腸用半固形剤、腸注剤等）、及び膣用製剤（例：膣錠、膣用坐剤等）等が挙げられる。
(Dosage form)
Examples of the dosage form of the pharmaceutical composition of the present invention include skin external preparations (eg, external solids, external liquids, sprays, ointments, creams, gels, patches, etc.) and ophthalmic preparations (eg, patches). Eye drops, eye ointments, etc.), Orally-administered preparations (eg, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), Oral preparations (eg, oral tablets, oral preparations, etc.) Sprays, oral semi-solids, mouthwashes, etc.), injection formulations (eg, injections, etc.), dialysis preparations (eg, dialysis agents, etc.), inhalation preparations (eg, inhalants, etc.), otologic products Pharmaceutical preparations (eg, ear drops, etc.), nasal preparations (eg, nasal drops, etc.), rectal preparations (eg, suppositories, rectal semi-solid preparations, enteric injections, etc.), and vaginal preparations (eg, nasal drops, etc.) Examples: vaginal tablets, suppositories for vagina, etc.).
本発明の医薬組成物は、好ましくは外用製剤であり、より好ましくは皮膚外用製剤である。
本発明の医薬組成物が皮膚外用製剤の場合、その剤形は、好ましくは軟膏剤、クリーム剤、ゲル剤、又は貼付剤である。皮膚外用製剤の剤形を以下に示す。
The pharmaceutical composition of the present invention is preferably an external preparation, more preferably a skin external preparation.
When the pharmaceutical composition of the present invention is an external preparation for skin, the dosage form is preferably an ointment, a cream, a gel, or a patch. The dosage form of the external preparation for skin is shown below.
＜皮膚外用製剤の剤形＞
（１）外用固形剤
外用固形剤は、頭皮を含む皮膚又は爪に、塗布又は散布する固形の製剤であり、外用散剤等が含まれる。外用散剤とは、粉末状の外用固形剤をいう。
（２）外用液剤
外用液剤は、頭皮を含む皮膚又は爪に塗布する液状の製剤であり、リニメント剤、ローション剤等が含まれる。リニメント剤とは、皮膚にすり込んで用いる液状又は泥状の外用液剤をいう。ローション剤とは、有効成分を水性の液に溶解又は乳化もしくは微細に分散させた外用液剤をいう。
（３）スプレー剤
スプレー剤は、有効成分を霧状、粉末状、泡沫状、又はペースト状等として皮膚に噴霧する製剤であり、外用エアゾール剤、ポンプスプレー剤等が含まれる。
（４）軟膏剤
軟膏剤は、皮膚に塗布する、有効成分を基剤に溶解又は分散させた半固形の製剤であり、油脂性軟膏剤、水溶性軟膏剤等が含まれる。
（５）クリーム剤
クリーム剤は、皮膚に塗布する、水中油型又は油中水型に乳化した半固形の製剤であり、油中水型に乳化した親油性の製剤については油性クリーム剤とも呼ばれることもある。
（６）ゲル剤
ゲル剤は、皮膚に塗布するゲル状の製剤であり、水性ゲル剤、油性ゲル剤等が含まれる。
（７）貼付剤
貼付剤は、皮膚に貼付する製剤であり、テープ剤、パップ剤等が含まれる。貼付剤は、通常、高分子化合物又はこれらの混合物を基剤とし、有効成分を基剤と混和し均質として、支持体又はライナー（剥離体）に展延して成形されたものをいう。貼付剤には、必要に応じて、粘着剤や吸収促進剤等の添加剤を用いることもできる。テープ剤とは、ほとんど水を含まない基剤を用いる貼付剤をいい、プラスター剤、硬膏剤等が含まれる。テープ剤は、通常、樹脂、プラスチック、ゴム等の非水溶性の天然又は合成高分子化合物を基剤とし、有効成分をそのまま、又は有効成分に添加剤を加え、全体を均質とし、布に展延又はプラスチック製フィルム等に展延もしくは封入して成形することにより製造することができる。パップ剤とは、水を含む基剤を用いる貼付剤をいう。
<Dosage form of topical skin preparation>
(1) External solid agent The external solid agent is a solid preparation that is applied or sprayed on the skin or nails including the scalp, and includes an external powder and the like. The external powder is a powdered external solid.
(2) External liquid agent The external liquid agent is a liquid preparation to be applied to the skin or nails including the scalp, and includes a liniment agent, a lotion agent and the like. The liniment agent is a liquid or muddy external liquid agent that is used by rubbing it on the skin. The lotion agent refers to an external liquid agent in which the active ingredient is dissolved, emulsified, or finely dispersed in an aqueous liquid.
(3) Spray agent The spray agent is a preparation that sprays the active ingredient onto the skin in the form of a mist, powder, foam, paste, etc., and includes an external aerosol agent, a pump spray agent, and the like.
(4) Ointment The ointment is a semi-solid preparation to which the active ingredient is dissolved or dispersed in a base, which is applied to the skin, and includes an oily ointment, a water-soluble ointment and the like.
(5) Cream agent A cream agent is a semi-solid preparation emulsified into an oil-in-water type or a water-in-oil type to be applied to the skin, and a lipophilic preparation emulsified in a water-in-oil type is also called an oil-based cream agent. Sometimes.
(6) Gel agent The gel agent is a gel-like preparation to be applied to the skin, and includes an aqueous gel agent, an oil-based gel agent and the like.
(7) Patching agent The patching agent is a preparation to be attached to the skin, and includes a tape agent, a poultice, and the like. The patch is usually formed by using a polymer compound or a mixture thereof as a base, mixing the active ingredient with the base to make it homogeneous, and spreading it on a support or a liner (peeling body). If necessary, an additive such as a pressure-sensitive adhesive or an absorption accelerator can be used as the patch. The tape agent is a patch that uses a base that contains almost no water, and includes plasters, ointments, and the like. The tape agent is usually based on a water-insoluble natural or synthetic polymer compound such as resin, plastic, rubber, etc., and the active ingredient is used as it is, or an additive is added to the active ingredient to homogenize the whole and spread on a cloth. It can be manufactured by spreading or enclosing it in a rolled or plastic film or the like and molding it. The poultice is a patch that uses a base containing water.
（基剤又は担体）
本発明の医薬組成物は、有効成分である当該物質を、通常、各種の添加剤又は溶媒等の薬学的に許容される基剤又は担体と共に製剤化したうえで、全身的又は局所的に、経口又は非経口の形（例えば、外用）で投与される。
ここで、薬学的に許容される担体とは、一般的に医薬品の製剤に用いられる、有効成分以外の物質を意味する。薬学的に許容される担体は、その製剤の投与量において薬理作用を示さず、無害で、有効成分の治療効果を妨げないものが好ましい。また、薬学的に許容される担体は、有効成分及び製剤の有用性を高める、製剤化を容易にする、品質の安定化を図る、又は使用性を向上させる等の目的で用いることもできる。具体的には、薬事日報社２０１６年刊「医薬品添加物事典２０１６」（日本医薬品添加剤協会編集）等に記載されているような物質を、適宜目的に応じて選択すればよい。
(Base or carrier)
In the pharmaceutical composition of the present invention, the substance as an active ingredient is usually formulated with a pharmaceutically acceptable base or carrier such as various additives or solvents, and then systemically or locally. It is administered in oral or parenteral form (eg, topical).
Here, the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used in the preparation of a pharmaceutical product. The pharmaceutically acceptable carrier preferably has no pharmacological action at the dose of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. In addition, a pharmaceutically acceptable carrier can be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the formulation, stabilizing the quality, improving the usability, and the like. Specifically, substances such as those described in Yakuji Nippo Co., Ltd. 2016 "Pharmaceutical Additives Dictionary 2016" (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.
本発明の医薬組成物が皮膚外用製剤である場合、用いられる基剤又は担体としては、特に限定されないが、例えば、油溶性の基剤又は担体として、ワセリン、精製ワセリン、パラフィン、流動パラフィン、ラノリン、精製ラノリン、炭化水素、高級アルコール類、植物油、動物油等の脂肪油；脂肪酸エステル類、プラスチベース、グリコール類、高級脂肪酸等が挙げられる。また、特に限定されないが、水溶性の基材又は担体として、マクロゴール２００、マクロゴール４００、マクロゴール１５００、マクロゴール１５４０、マクロゴール４０００、マクロゴール２００００等のマクロゴール類（ポリエチレングリコール類）；濃グリセリン、プロピレングリコール等の多価アルコール類；ポビドン、ポリビニルアルコール等の水溶性高分子等が挙げられる。さらに、基剤又は担体としては、特に限定されないが、例えば、水溶性溶媒としてエタノール、イソプロピルアルコール、水、グリセリン、プロピレングリコール、ポリエチレングリコール類等、油溶性溶媒としてセバシン酸ジエチル、アジピン酸ジイソプロピル、トリ（カプリル・カプリン酸）グリセリン等の液状の油等が挙げられる。
当該皮膚外用製剤には、これらの基剤又は担体から、１種又は２種以上を適宜選択して用いることができる。
When the pharmaceutical composition of the present invention is an external preparation for skin, the base or carrier used is not particularly limited, but for example, as an oil-soluble base or carrier, petrolatum, purified petrolatum, paraffin, liquid paraffin, lanolin, etc. , Refined lanolin, hydrocarbons, higher alcohols, vegetable oils, animal oils and other fatty oils; fatty acid esters, plastic bases, glycols, higher fatty acids and the like. Further, although not particularly limited, as a water-soluble base material or carrier, macrogols (polyethylene glycols) such as macrogol 200, macrogol 400, macrogol 1500, macrogol 1540, macrogol 4000, and macrogol 20000; Polyhydric alcohols such as concentrated glycerin and propylene glycol; water-soluble polymers such as povidone and polyvinyl alcohol can be mentioned. Further, the base or carrier is not particularly limited, but for example, ethanol, isopropyl alcohol, water, glycerin, propylene glycol, polyethylene glycol and the like are used as water-soluble solvents, and diethyl sebacate, diisopropyl adipate and tris are used as oil-soluble solvents. (Capryl capric acid) Liquid oil such as glycerin and the like can be mentioned.
One or more of these bases or carriers can be appropriately selected and used for the external preparation for skin.
（その他成分）
本発明の医薬組成物には、必要に応じて、さらに懸濁剤、増粘剤、安定化剤、湿潤剤、保存剤、乳化剤、懸濁化剤、ｐＨ調整剤等の１種又は２種以上を含有してもよい。
(Other ingredients)
The pharmaceutical composition of the present invention further includes one or two kinds of suspending agent, thickener, stabilizer, wetting agent, preservative, emulsifier, suspending agent, pH adjuster and the like, if necessary. The above may be contained.
（用法）
本発明の医薬組成物が皮膚外用製剤である場合は、対象の年齢、性別等、に応じて適宜変更し得るが、例えば、１日数回（例えば、約１〜５回、好ましくは１〜３回）、適量（例えば、約０．０５〜５ｇ）を患部に投与（塗布等）することができる。
(Usage)
When the pharmaceutical composition of the present invention is a preparation for external use on the skin, it can be appropriately changed according to the age, sex, etc. of the subject, but for example, several times a day (for example, about 1 to 5 times, preferably 1 to 3 times). An appropriate amount (for example, about 0.05 to 5 g) can be administered (applied, etc.) to the affected area.
本発明の医薬組成物が皮膚外用製剤である場合は、製剤の塗布による１０ｃｍ２当たりの１回の投与量は、特に限定されないが、例えば、トレハロース換算量で、０．１ｍｇ以上、好ましくは１ｍｇ以上、より好ましくは５ｍｇ以上、更に好ましくは１０ｍｇ以上、更により好ましくは１００ｍｇ以上であり、５，０００ｍｇ以下、好ましくは１，０００ｍｇ以下、より好ましくは５００ｍｇ以下である。 When the pharmaceutical composition of the present invention is a preparation for external use on the skin, the single dose per 10 cm 2 by applying the preparation is not particularly limited, but for example, in terms of trehalose equivalent, 0.1 mg or more, preferably 1 mg. The above is more preferably 5 mg or more, still more preferably 10 mg or more, still more preferably 100 mg or more, and 5,000 mg or less, preferably 1,000 mg or less, more preferably 500 mg or less.
（他の医薬との組み合わせ）
本発明の医薬組成物は、ステロイド製剤と併用することができる。本発明の医薬組成物は、フィラグリン産生促進を通じて皮膚のバリア機能を改善する。そのため、このような併用は、ステロイド製剤による皮膚のバリア機能の低下を改善する観点から、皮膚疾患、好ましくは皮膚炎症性疾患に対して好適である。
本発明の医薬組成物は、ＴＳＬＰとＩＬ−３３の両方を抑制する。そのため、このような併用は、ＴＳＬＰ及びＩＬ−３３の発現量増加によってもたらされるステロイド抵抗性を改善する観点から、喘息又は慢性閉塞性肺疾患、好ましくは重度喘息に対して好適である。
(Combination with other medicines)
The pharmaceutical composition of the present invention can be used in combination with a steroid preparation. The pharmaceutical composition of the present invention improves the barrier function of the skin through promotion of filaggrin production. Therefore, such a combination is suitable for skin diseases, preferably skin inflammatory diseases, from the viewpoint of improving the deterioration of the barrier function of the skin due to the steroid preparation.
The pharmaceutical composition of the present invention suppresses both TSLP and IL-33. Therefore, such a combination is suitable for asthma or chronic obstructive pulmonary disease, preferably severe asthma, from the viewpoint of improving the steroid resistance caused by the increased expression level of TSLP and IL-33.
以下に、本発明及び本発明の好ましい実施態様を示す。
＜１＞
トレハロース及びその誘導体からなる群より選ばれる１種又は２種以上の化合物を含有する、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用、ＩＬ−３３遺伝子発現抑制用、又はフィラグリン産生促進用である、組成物。
＜２＞
ＴＳＬＰ関連状態、ＩＬ−３３関連状態、又は皮膚バリア機能低下状態を改善又は予防するための、＜１＞に記載の組成物。
＜３＞
処置又は処理する対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であって、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上、
３００ｍｇ／ｍＬ以下であって、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下となるように調製された、＜１＞又は＜２＞に記載の組成物。
＜４＞
対象が、哺乳動物、好ましくはヒトの、個体又は器官、組織若しくは細胞である、＜１＞〜＜３＞のいずれか１に記載の組成物。
＜５＞
医薬品、医薬部外品、化粧品、食品、細胞培養用品、又は研究用試薬である、＜１＞〜＜４＞のいずれか１に記載の組成物。
＜６＞
炎症性皮膚疾患、瘢痕、皮膚のひび割れ若しくはあかぎれ、アレルギー性結膜炎、アレルギー性鼻炎、アレルギー性副鼻腔炎、喘息、慢性閉塞性肺疾患（ＣＯＰＤ）、好酸球性食道炎、全身性エリテマトーデス、潰瘍性大腸炎、クローン病、アナフィラキシーショック、天疱瘡、類点疱瘡、強皮症、強直性脊椎炎、肝線維症、肺線維症、急性腎障害、血管炎、又は癌を、改善又は予防するための、＜１＞〜＜５＞のいずれか１に記載の組成物。
＜７＞
トレハロース及びその誘導体の総含有量が、組成物の全量に対して、トレハロース換算量で、５質量％以上であり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上、
８０質量％以下であり、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である、＜１＞〜＜６＞のいずれか１に記載の組成物。
The present invention and preferred embodiments of the present invention are shown below.
<1>
For suppressing thymic interstitial lymphocyte neoplasia (TSLP) gene expression, for suppressing IL-33 gene expression, or promoting phyllagrin production, which contains one or more compounds selected from the group consisting of trehalose and its derivatives. For the composition.
<2>
The composition according to <1> for improving or preventing a TSLP-related state, an IL-33-related state, or a skin barrier function-deteriorated state.
<3>
The total concentration of trehalose and its derivatives applied to the cells to be treated or treated is 10 mg / mL or more, preferably 20 mg / mL or more, more preferably 30 mg / mL or more, in terms of trehalose equivalent. More preferably, 50 mg / mL or more,
The composition according to <1> or <2>, which is prepared so as to be 300 mg / mL or less, preferably 200 mg / mL or less, more preferably 150 mg / mL or less, still more preferably 100 mg / mL or less. ..
<4>
The composition according to any one of <1> to <3>, wherein the subject is a mammal, preferably a human, an individual or organ, tissue or cell.
<5>
The composition according to any one of <1> to <4>, which is a pharmaceutical product, a quasi drug, a cosmetic product, a food product, a cell culture product, or a research reagent.
<6>
Inflammatory skin diseases, scars, cracks or cracks in the skin, allergic conjunctivitis, allergic rhinitis, allergic sinusitis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis, systemic erythematosus, ulcers To improve or prevent sexual colitis, Crohn's disease, anaphylactic shock, scleroderma, vesicles, scleroderma, tonic spondylitis, liver fibrosis, pulmonary fibrosis, acute nephropathy, angiitis, or cancer The composition according to any one of <1> to <5>.
<7>
The total content of trehalose and its derivatives is 5% by mass or more, preferably 6% by mass or more, more preferably 8% by mass or more, still more preferably 10% by mass, in terms of trehalose equivalent, based on the total amount of the composition. %that's all,
80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, or 15% by mass or less, <1> to <6> The composition according to any one of.
＜８＞
トレハロース及びその誘導体からなる群より選ばれる１種又は２種以上の化合物を有効成分として含有する、炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれ、を改善又は予防するための医薬組成物。
＜９＞
トレハロース及びその誘導体の総含有量が、医薬組成物の全量に対して、トレハロース換算量で、５質量％以上であり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上、
８０質量％以下であり、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である、＜８＞に記載の医薬組成物。
＜１０＞
皮膚外用製剤であって、好ましくは外用固形剤、外用液剤、スプレー剤、軟膏剤、クリーム剤、ゲル剤、又は貼付剤である、＜８＞又は＜９＞に記載の医薬組成物。
<8>
A pharmaceutical composition for improving or preventing inflammatory skin diseases, scars, or cracks or cracks in the skin, which contains one or more compounds selected from the group consisting of trehalose and its derivatives as an active ingredient.
<9>
The total content of trehalose and its derivatives is 5% by mass or more, preferably 6% by mass or more, more preferably 8% by mass or more, still more preferably 10 in terms of trehalose, based on the total amount of the pharmaceutical composition. Mass% or more,
80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, or 15% by mass or less, according to <8>. Pharmaceutical composition.
<10>
The pharmaceutical composition according to <8> or <9>, which is an external preparation for skin, preferably an external solid agent, an external liquid agent, a spray agent, an ointment agent, a cream agent, a gel agent, or a patch.
＜１１＞
胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制、ＩＬ−３３遺伝子発現抑制、又はフィラグリン産生促進のための、トレハロース又はその誘導体の使用。
＜１２＞
処置又は処理する対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であって、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上、
３００ｍｇ／ｍＬ以下であって、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下である、＜１１＞に記載の使用。
<11>
Use of trehalose or a derivative thereof for suppressing thymic interstitial lymphocyte neoplasia (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production.
<12>
The total concentration of trehalose and its derivatives applied to the cells to be treated or treated is 10 mg / mL or more, preferably 20 mg / mL or more, more preferably 30 mg / mL or more, in terms of trehalose equivalent. More preferably, 50 mg / mL or more,
The use according to <11>, which is 300 mg / mL or less, preferably 200 mg / mL or less, more preferably 150 mg / mL or less, still more preferably 100 mg / mL or less.
＜１３＞
ＴＳＬＰ関連状態、ＩＬ−３３関連状態、又は皮膚バリア機能低下状態を改善又は予防するために用いるトレハロース又はその誘導体。
＜１４＞
炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれの処置のために用いるトレハロース又はその誘導体。
＜１５＞
上記＜１３＞又は＜１４＞において、使用濃度は、トレハロース換算量で、５質量％以上でり、好ましくは６質量％以上、より好ましくは８質量％以上、更に好ましくは１０質量％以上、
８０質量％以下であり、７０質量％以下、６０質量％以下、５０質量％以下、４０質量％以下、３０質量％以下、２０質量％以下、又は１５質量％以下である、トレハロース又はその誘導体。
<13>
Trehalose or its derivatives used to improve or prevent TSLP-related conditions, IL-33-related conditions, or skin barrier dysfunction conditions.
<14>
Trehalose or its derivatives used for the treatment of inflammatory skin diseases, scars, or cracks or cracks in the skin.
<15>
In the above <13> or <14>, the concentration used is 5% by mass or more in terms of trehalose, preferably 6% by mass or more, more preferably 8% by mass or more, still more preferably 10% by mass or more.
Trehalose or a derivative thereof, which is 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, or 15% by mass or less.
＜１６＞
胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制、ＩＬ−３３遺伝子発現抑制、又はフィラグリン産生促進の方法であって、それを必要とする対象にトレハロース又はその誘導体を有効量で投与することを含む、方法。
＜１７＞
対象となる細胞に適用されるトレハロース及びその誘導体の総和の濃度が、トレハロース換算量で、１０ｍｇ／ｍＬ以上であって、好ましくは２０ｍｇ／ｍＬ以上、より好ましくは３０ｍｇ／ｍＬ以上、更に好ましくは５０ｍｇ／ｍＬ以上、３００ｍｇ／ｍＬ以下であって、好ましくは２００ｍｇ／ｍＬ以下、より好ましくは１５０ｍｇ／ｍＬ以下、更に好ましくは１００ｍｇ／ｍＬ以下である、＜１６＞に記載の方法。
<16>
A method of suppressing thymic interstitial lymphocyte neoplasia (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production, in which trehalose or a derivative thereof is administered in an effective amount to a subject who requires it. Including methods.
<17>
The total concentration of trehalose and its derivatives applied to the target cells is 10 mg / mL or more, preferably 20 mg / mL or more, more preferably 30 mg / mL or more, still more preferably 50 mg in terms of trehalose equivalent. The method according to <16>, wherein it is / mL or more and 300 mg / mL or less, preferably 200 mg / mL or less, more preferably 150 mg / mL or less, still more preferably 100 mg / mL or less.
＜１８＞
ＴＳＬＰ関連状態、ＩＬ−３３関連状態、又は皮膚バリア機能低下状態を改善又は予防するための方法であって、それを必要とする対象にトレハロース又はその誘導体を有効量で投与することを含む、方法。
＜１９＞
炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれの処置又は予防のための方法であって、それを必要とする対象にトレハロース又はその誘導体を有効量で投与することを含む、方法。
＜２０＞
製剤の塗布による１０ｃｍ２当たりの１回の投与量は、トレハロース換算量で、０．１ｍｇ以上であって、好ましくは１ｍｇ以上、より好ましくは５ｍｇ以上、更に好ましくは１０ｍｇ以上、更に好ましくは１００ｍｇ以上、５，０００ｍｇ以下であって、好ましくは１，０００ｍｇ以下、より好ましくは５００ｍｇ以下、である、＜１８＞又は＜１９＞に記載の方法。
＜２１＞
前記処置又は予防が、胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制、ＩＬ−３３遺伝子発現抑制、又はフィラグリン産生促進によって行われる、＜１８＞〜＜２０＞のいずれか１に記載の方法。
<18>
A method for improving or preventing a TSLP-related condition, an IL-33-related condition, or a skin barrier hypofunction condition, which comprises administering an effective amount of trehalose or a derivative thereof to a subject in need thereof. ..
<19>
A method for the treatment or prevention of inflammatory skin diseases, scars, or cracks or cracks in the skin, which comprises administering an effective amount of trehalose or a derivative thereof to a subject in need thereof.
<20>
The single dose per 10 cm 2 by application of the preparation is 0.1 mg or more in terms of trehalose, preferably 1 mg or more, more preferably 5 mg or more, still more preferably 10 mg or more, still more preferably 100 mg or more. The method according to <18> or <19>, wherein the amount is 5,000 mg or less, preferably 1,000 mg or less, and more preferably 500 mg or less.
<21>
The treatment or prevention according to any one of <18> to <20>, wherein the treatment or prevention is performed by suppressing the expression of the thymic interstitial lymphocyte neoplastic factor (TSLP) gene, suppressing the expression of the IL-33 gene, or promoting the production of filaggrin. Method.
＜２２＞
胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現抑制用、ＩＬ−３３遺伝子発現抑制用、又はフィラグリン産生促進用の医薬を製造するための、トレハロース又はその誘導体の使用。
＜２３＞
炎症性皮膚疾患、瘢痕、又は皮膚のひび割れ若しくはあかぎれの処置又は予防用の医薬を製造するための、トレハロース又はその誘導体の使用。
<22>
Use of trehalose or a derivative thereof for producing a drug for suppressing thymic interstitial lymphocyte neoplastic factor (TSLP) gene expression, suppressing IL-33 gene expression, or promoting filaggrin production.
<23>
Use of trehalose or its derivatives to produce pharmaceuticals for the treatment or prevention of inflammatory skin diseases, scars, or cracks or cracks in the skin.
［試験例１．トレハロースの遺伝子発現に対する効果の検証］
下記のように、正常ヒト皮膚上皮細胞を用いて、トレハロースによる遺伝子発現に与える効果をｉｎ ｖｉｔｒｏで検証した。
[Test Example 1. Verification of the effect of trehalose on gene expression]
As described below, the effect of trehalose on gene expression was examined in vitro using normal human skin epithelial cells.
（方法）
（１）ＭＣＤＢ Ｔｙｐｅ−ＩＩ培地（特許第３０６６６２４号公報の増殖培地２）に対して、６．６ｇ／Ｌ ＨＥＰＥＳ、０．０６ｍＭ ＣａＣｌ２、１００ｍｇ／Ｌカナマイシン、１．２ｇ／Ｌ ＮａＨＣＯ３、０．１μＭ インスリン、１００μＭモノエタノールアミン、１００μＭ ｏ−ホスホエタノールアミン、０．５μｇ／ｍＬヒドロコルチゾン、５０ｍｇタンパク質／ｍＬウシ脳視床下部抽出液（ＢＨＥ）を含有する培地（ｐＨ７．２）を調製した。正常ヒト皮膚上皮細胞（ＮＨＫ）を、前記培地中で、コンフルエントになるまで３７℃で単層培養した。
（２）（１）の培地を、０、３０又は１００ｍｇ／ｍＬのトレハロースを含有する培地に置換して、３７℃で４８時間インキュベートした。
（３）各条件の細胞を回収し、RNeasy Mini Kit（QIAGEN社製）を用いてｍＲＮＡを抽出した。ｍＲＮＡからiScript cDNA Synthesis kit（B10-RAD社製）を用いてｃＤＮＡを調製した。各処理はそれぞれのマニュアルに従って行った。
（４）（３）で得られたｃＤＮＡに対して、ＴＳＬＰ、フィラグリン、及びＩＬ−３３遺伝子に対するＴａｑＭａｎ ＰＣＲ用プライマー（Thermo fisher Scientific社製、プライマーコード：Hs00263639-m1（TSLP）、Hs00856927-g1（フィラグリン）、Hs04931857-m1（IL-33））を用いて、定量ＰＣＲ（ｑＰＣＲ）を行った。反応には、Fast Start Universl Probe Master (Rox)（Roche社製）、StepOnePlue Real time PCR system（Applied Biosystems社製）を用いた。各条件で用いたサンプル数は３であった。
(Method)
(1) 6.6 g / L HEPES, 0.06 mM CaCl 2 , 100 mg / L canamycin, 1.2 g / L NaHCO 3 , 0 with respect to MCDB Type-II medium (proliferation medium 2 of Japanese Patent No. 3066624). A medium (pH 7.2) containing 1 μM insulin, 100 μM monoethanolamine, 100 μM o-phosphoethanolamine, 0.5 μg / mL hydrocortisone, and 50 mg protein / mL bovine hypothalamic extract (BHE) was prepared. Normal human cutaneous epithelial cells (NHK) were monolayer-cultured in the medium at 37 ° C. until confluent.
(2) The medium of (1) was replaced with a medium containing 0, 30 or 100 mg / mL trehalose, and incubated at 37 ° C. for 48 hours.
(3) Cells under each condition were collected, and mRNA was extracted using RNeasy Mini Kit (manufactured by QIAGEN). cDNA was prepared from mRNA using the iScript cDNA Synthesis kit (manufactured by B10-RAD). Each process was performed according to the respective manual.
(4) For the cDNA obtained in (3), TaqMan PCR primers for TSLP, phyllagrin, and IL-33 genes (manufactured by Thermo fisher Scientific, primer code: Hs00263639-m1 (TSLP), Hs00856927-g1 ( Quantitative PCR (qPCR) was performed using Philagulin) and Hs04931857-m1 (IL-33). For the reaction, Fast Start Universl Probe Master (Rox) (manufactured by Roche) and StepOnePlue Real time PCR system (manufactured by Applied Biosystems) were used. The number of samples used in each condition was 3.
（結果）
ｑＰＣＲの結果を図１に示す。３０ｍｇ／ｍＬ又は１００ｍｇ／ｍＬトレハロースで処理した場合、トレハロースなしの対照（vehicle）に比べてＴＳＬＰ遺伝子及びＩＬ−３３遺伝子のｍＲＮＡ発現量が顕著に減少した。
また、フィラグリン遺伝子については、１００ｍｇ／ｍＬトレハロース処理によってｍＲＮＡ発現量が顕著に増加した。３０ｍｇ／ｍＬトレハロースで処理した場合にも、トレハロースなしの培地で処理した場合に対してフィラグリン遺伝子のｍＲＮＡの発現量が５倍程度に増加した。
(result)
The result of qPCR is shown in FIG. When treated with 30 mg / mL or 100 mg / mL trehalose, the mRNA expression levels of the TSLP gene and the IL-33 gene were significantly reduced as compared with the control (vehicle) without trehalose.
Regarding the filaggrin gene, the mRNA expression level was significantly increased by treatment with 100 mg / mL trehalose. Even when treated with 30 mg / mL trehalose, the expression level of filaggrin gene mRNA increased about 5-fold as compared with the case of treatment with a medium without trehalose.
以上から、トレハロースは皮膚上皮細胞のＴＳＬＰ遺伝子及びＩＬ−３３遺伝子の発現を抑制し、またフィラグリン遺伝子の発現を促進することが明らかとなった。 From the above, it was clarified that trehalose suppresses the expression of TSLP gene and IL-33 gene in skin epithelial cells and promotes the expression of filaggrin gene.
［試験例２．トレハロースのフィラグリン産生促進効果の検証］
下記のように、皮膚組織のｉｎ ｖｉｔｒｏモデルである三次元培養皮膚に対して、トレハロースを含有するクリーム剤を塗布して、そのフィラグリン産生効果を検証した。
[Test Example 2. Verification of the effect of trehalose on promoting filaggrin production]
As described below, a cream containing trehalose was applied to three-dimensional cultured skin, which is an in vitro model of skin tissue, and its filaggrin production effect was verified.
（方法）
＜１．三次元培養皮膚の作製＞
（１）まず、以下の表１の組成でゲル溶液Ｉを作製した。
(Method)
<1. Preparation of 3D cultured skin>
(1) First, a gel solution I was prepared with the composition shown in Table 1 below.
（２）続いて、得られたゲル約１ｍＬをセルカルチャーインサートであるトランズウェル−コルコラーゲンコートインサート（カタログ番号： ３４９２、Costar社製；ポアサイズ：３.０μｍ、表面積：４．６７ｃｍ２）に注ぎ、インキュベーターに５分以上静置した。５×１０５個／ｍＬの細胞密度で正常ヒト皮膚線維芽細胞（ＮＨＤＦ、Cambrex社製）を懸濁した、１０ｖ／ｖ％ＦＣＳ及び１ｖ／ｖ％ＡＢＡＭ（Antibiotics-Antimycotic solution, 100x，ThermoFisher Scientific社製）を含むＤＭＥＭ５ｍＬを、２９ｍＬのゲル溶液Ｉに加えた。この細胞を含むゲル溶液約３．５ｍＬを上記セルカルチャーインサートに加え、３７℃インキュベーターに３０分間静置してゲル化した。 (2) Subsequently, about 1 mL of the obtained gel is poured into a cell culture insert, Transwell-Colcollagen coated insert (catalog number: 3492, manufactured by Costar; pore size: 3.0 μm, surface area: 4.67 cm 2). , The mixture was allowed to stand in the incubator for 5 minutes or more. 10v / v% FCS and 1v / v% ABAM (Antibiotics-Antimycotic solution, 100x, ThermoFisher Scientific) in which normal human skin fibroblasts (NHDF, manufactured by Cambrex) were suspended at a cell density of 5 × 10 5 cells / mL. 5 mL of DMEM containing) was added to 29 mL of Gel Solution I. About 3.5 mL of a gel solution containing these cells was added to the above cell culture insert, and the mixture was allowed to stand in a 37 ° C. incubator for 30 minutes for gelation.
（３）次に、上記のＮＨＤＦを含むコラーゲンゲル（層状の真皮細胞構造体）を、５０μｇ／ｍｌアスコルビン酸、１０ｖ／ｖ％ＦＣＳ、１ｖ／ｖ％ＡＢＡＭを含むＤＭＥＭ培地を用いて５日間前培養した後、コラーゲンゲル表面にＭＣＤＢ培地に懸濁したヒト正常皮膚上皮細胞を１．２８×１０５個／ｃｍ２となるように播種し、セルカルチャーインサートの外液及びインサート内にＭＣＤＢ Ｔｙｐｅ−ＩＩ培地（特許第３０６６６２４号公報の増殖培地２）とＥＧＭを等量混ぜた培地を加えて、３７℃で２日間培養した。なお、ＥＧＭの組成は表２のとおりである。 (3) Next, the above NHDF-containing collagen gel (layered dermal cell structure) was used 5 days before using DMEM medium containing 50 μg / ml ascorbic acid, 10 v / v% FCS, and 1 v / v% ABAM. After culturing, human normal skin epithelial cells suspended in MCDB medium were seeded on the surface of the collagen gel so as to be 1.28 × 10 5 cells / cm 2, and MCDB Type- was seeded in the external solution of the cell culture insert and in the insert. A medium in which an equal amount of EGM was mixed with II medium (proliferation medium 2 of Japanese Patent No. 3066624) was added, and the cells were cultured at 37 ° C. for 2 days. The composition of EGM is shown in Table 2.
（４）角化培地（ＣＭ培地）に交換し、セルカルチャーインサートの多孔質膜が角化培地の気液界面に位置するようにセルカルチャーインサートを配置した。その状態で３７℃、７〜１４日間気液界面培養することにより分化誘導を行い、三次元培養皮膚を得た。なお、培養開始から２日ごとに培地交換を行った。なお、ＣＭ培地の組成は表３のとおりである。 (4) The cell culture insert was replaced with a keratinized medium (CM medium), and the cell culture insert was placed so that the porous membrane of the cell culture insert was located at the gas-liquid interface of the keratinized medium. In that state, differentiation was induced by gas-liquid interface culture at 37 ° C. for 7 to 14 days to obtain three-dimensional cultured skin. The medium was changed every two days from the start of the culture. The composition of the CM medium is as shown in Table 3.
＜２．培養皮膚の処置＞
（５）塗布用のサンプルとして、基剤にVanicream Moisturizing Skin Cream（Vanicream社製）を使用し、基剤のみのクリーム（ビヒクル）、トレハロースを１００ｍｇ／ｍＬ含有するクリーム、及びヘパリン類似物質（Heparinoid）を３０ｍｇ／ｍＬ含有するクリームを調製した。これら３種類のクリーム１００ｍｇを、（４）で得られた三次元培養皮膚の表皮上（面積：４．６７ｃｍ２）に塗布し、（４）と同じ培地で、さらに３７℃１週間インキュベートした。
<2. Treatment of cultured skin>
(5) As a sample for application, Vanicream Moisturizing Skin Cream (manufactured by Vanicream) is used as a base, and a cream containing only a base (vehicle), a cream containing 100 mg / mL of trehalose, and a heparinoid. A cream containing 30 mg / mL was prepared. 100 mg of these three types of cream was applied on the epidermis (area: 4.67 cm 2 ) of the three-dimensional cultured skin obtained in (4), and incubated in the same medium as in (4) for another 37 ° C. for 1 week.
＜３．培養皮膚の染色＞
（６）（５）で得られた三次元培養皮膚の組織切片を作製した。得られた組織切片を常法によりヘマトキシリン・エオジン（ＨＥ）染色を行った。また、得られた組織切片に、一次抗体として抗フィラグリン抗体（抗FillagrinマウスIgG抗体(AKH1)、Santa Cruz社製、製品番号sc-66192）を用いて、フィラグリン染色を行った。
<3. Dyeing of cultured skin>
(6) Tissue sections of the three-dimensional cultured skin obtained in (5) were prepared. The obtained tissue sections were stained with hematoxylin and eosin (HE) by a conventional method. In addition, the obtained tissue section was stained with filaggrin using an anti-filaggrin antibody (anti-Fillagrin mouse IgG antibody (AKH1), manufactured by Santa Cruz, product number sc-66192) as a primary antibody.
（結果）
得られたそれぞれの三次元培養皮膚の組織切片の染色像を、図２に示した。フィラグリン染色像に示されるように、１００ｍｇ／ｍＬトレハロース含有クリームで処理した場合、３０ｍｇ／ｍＬヘパリン類似物質で処置を行った場合やビヒクルと比べて、フィラグリンの層の厚みが増し、またフィラグリン量が増加していることが分かった。従って、トレハロースが表皮組織のフィラグリン量を増加させることが明らかとなった。
(result)
The stained image of the tissue section of each of the obtained three-dimensional cultured skin is shown in FIG. As shown in the filaggrin-stained image, when treated with a cream containing 100 mg / mL trehalose, the thickness of the layer of filaggrin is increased and the amount of filaggrin is increased as compared with the case of treatment with a 30 mg / mL heparinoid or a vehicle. It turned out to be increasing. Therefore, it was revealed that trehalose increases the amount of filaggrin in epidermal tissue.
［試験例３．皮膚病変に対する効果の検証（ヒトを対象とした評価）］
以下では、塗布剤として、Gauglitzらの総説（Molecular Medicine, 2011, Vol.17, No.1-2, p.113-125）のSilicone gel sheetingに類似したゲルにトレハロースを添加し、患者に処置を行った例を示す。具体的には、塗布剤として、１０％トレハロースジェル（トレハロースを終濃度１００ｍｇ／ｍＬとなるように、アイ・ティー・オー社製のＩＴＯジェルベースに加え、１０００ｒｐｍの撹拌機で混合したもの）を用いた。当該ジェルは、水、グリセリン、カルボマー、ポリアクリル酸ナトリウム、メチルパラベン、プロピルパラベンを含有する。
[Test Example 3. Verification of effect on skin lesions (evaluation for humans)]
In the following, as a coating agent, trehalose is added to a gel similar to Silicone gel sheeting in the review by Gauglitz et al. (Molecular Medicine, 2011, Vol.17, No.1-2, p.113-125) to treat patients. Is shown as an example. Specifically, as a coating agent, 10% trehalose gel (trehalose is added to an ITO gel base manufactured by ITO gel so as to have a final concentration of 100 mg / mL and mixed with a stirrer at 1000 rpm). Using. The gel contains water, glycerin, carbomer, sodium polyacrylate, methylparaben, propylparaben.
（１．瘢痕に対する効果の検証）
表４に記載の患者の瘢痕部に、１０％トレハロースジェルを、１日１回入浴後に適量（約１〜約１０ｍｇ／ｃｍ２）塗布してもらった。塗布後に患部はラップで覆われ、固定された。処置前及び表４に記載する処置後の各時点の瘢痕の状態を、瘢痕・ケロイド治療研究会が定めるガイドラインであるＪＳＷ Ｓｃａｒ Ｓｃａｌｅ ２０１１に従ってスコア化した。処方及びスコア付けは、患者の同意を得て医師が行った。結果を同じ表４に示した。また、症例１及び３の瘢痕の経過を示す写真を図３に示した。トレハロース含有製剤の塗布により、いずれの症例においても、瘢痕の状態が通常よりも速やかに改善していた。
(1. Verification of effect on scars)
10% trehalose gel was applied to the scars of the patients shown in Table 4 once a day after bathing in an appropriate amount (about 1 to about 10 mg / cm 2). After application, the affected area was covered with a wrap and fixed. The condition of scars before treatment and at each time point after treatment shown in Table 4 was scored according to JSW Scar Scale 2011, which is a guideline established by the Japan Scar Workshop for Treatment of Scars and Keloids. Prescription and scoring were performed by a physician with the consent of the patient. The results are shown in the same Table 4. In addition, photographs showing the course of scarring in cases 1 and 3 are shown in FIG. The application of the trehalose-containing preparation improved the scar condition more rapidly than usual in all cases.
ＴＳＬＰは、瘢痕組織で発現量が増加し、瘢痕組織への線維芽細胞の浸潤を増加させることが示唆されている（Journal of Investigative Dermatology, Vol. 136, No. 2, 507-515 (2016)）。試験例１の結果を考慮すると、トレハロースがＴＳＬＰの発現を抑制することによって、線維芽細胞が瘢痕組織へ浸潤するのを抑制し、その結果瘢痕組織の線維化を抑制したと推察される。 TSLP has been suggested to increase expression in scar tissue and increase fibroblast infiltration into scar tissue (Journal of Investigative Dermatology, Vol. 136, No. 2, 507-515 (2016)). ). Considering the results of Test Example 1, it is presumed that trehalose suppressed the expression of TSLP, thereby suppressing the infiltration of fibroblasts into the scar tissue, and as a result, suppressed the fibrosis of the scar tissue.
（２．炎症性皮膚疾患に対する効果の検証）
表５に記載の患者の患部に、１０％トレハロースジェルを、各症例で示した回数で、適量（約１〜約１０ｍｇ／ｃｍ２）を単純塗布してもらった。処方及び評価は、患者又は保護者の同意を得て医師が行った。処置後の患部の評価結果を、同じ表５に記載した。また、症例７の経過を示す写真を図４に示した。上記症例の皮膚の炎症は、保湿のみでは回復しないレベルのものであったが、１０％トレハロースジェルの塗布により、いずれの症例も症状が顕著に改善していた。
(2. Verification of effect on inflammatory skin diseases)
The affected areas of the patients listed in Table 5 were simply applied with an appropriate amount (about 1 to about 10 mg / cm 2 ) of 10% trehalose gel at the number of times shown in each case. Prescription and evaluation were performed by a physician with the consent of the patient or guardian. The evaluation results of the affected area after the treatment are shown in the same Table 5. In addition, a photograph showing the progress of Case 7 is shown in FIG. The skin inflammation in the above cases was at a level that could not be recovered by moisturizing alone, but the application of 10% trehalose gel significantly improved the symptoms in all cases.
上記結果と試験例１及び２の結果を合わせて考慮すると、トレハロースがＴＳＬＰ遺伝子及びＩＬ−３３遺伝子の発現抑制によって皮膚の炎症を抑えたと推察される。さらに、トレハロースがフィラグリン産生を促進した結果、皮膚バリア機能が改善し、皮膚の乾燥及び刺激因子の侵入による炎症悪化を防いだものと推察される。 Considering the above results together with the results of Test Examples 1 and 2, it is inferred that trehalose suppressed skin inflammation by suppressing the expression of the TSLP gene and the IL-33 gene. Furthermore, it is speculated that as a result of trehalose promoting filaggrin production, the skin barrier function was improved and inflammation was prevented from worsening due to skin dryness and invasion of irritants.
（３．表皮の荒れに対する効果の検証）
両手指先に同程度のひび割れが見られた２名（症例８：５０代女性、症例９：３歳男性）を対象とした。症例８では、１日１回（夜）、対象の右親指は上記と同じ１０％トレハロースジェルを塗布した後ラップで覆い、対象の左親指は白色ワセリン（商品名：プロペト）を塗布した後ラップで覆ってもらった。日中は、両手ともに白色ワセリンを塗布してもらった。症例９では、対象の右手には上記と同じ１０％トレハロースジェルを適量塗布した後、白色ワセリンを塗布してもらった。対象の左手には白色ワセリンのみを適量塗布してもらった。これらの塗布は、毎日就寝前１回とした。日中は両手ともに０．３％ヘパリン類似物質油性クリームを塗布してもらった。処方及び評価は、患者又は保護者の同意を得て医師が行った。
(3. Verification of the effect on rough epidermis)
Two subjects (case 8: female in their 50s, case 9: 3-year-old male) who had similar cracks on their fingertips were included. In case 8, the subject's right thumb was covered with plastic wrap after applying the same 10% trehalose gel as above, and the subject's left thumb was coated with white petrolatum (trade name: Propet) and then wrapped. I had it covered with. During the day, both hands were coated with white petrolatum. In Case 9, the subject's right hand was coated with the same 10% trehalose gel as above, followed by white petrolatum. Only white petrolatum was applied to the left hand of the subject in an appropriate amount. These applications were applied once daily before bedtime. During the day, both hands were coated with 0.3% heparinoid oil cream. Prescription and evaluation were performed by a physician with the consent of the patient or guardian.
その結果、症例８では、処置から２週間後に１０％トレハロースジェルで処置をした右手側のひび割れはほとんど見られなかったが、対照の左手側にはひび割れが残っていた。また、症例９では、処置５日後に同様に右手側のひび割れはほぼ閉塞したが、対照の左手側はひび割れが顕著に残っていた（図５）。ワセリンには保湿効果があることから、トレハロースによるひび割れの状態の改善は、保湿以外の効果も寄与しているといえる。 As a result, in Case 8, almost no cracks were observed on the right hand side treated with 10% trehalose gel 2 weeks after the treatment, but cracks remained on the left hand side of the control. Further, in case 9, the crack on the right hand side was almost occluded 5 days after the treatment, but the crack remained remarkably on the left hand side of the control (FIG. 5). Since petrolatum has a moisturizing effect, it can be said that the improvement of the cracked state by trehalose contributes to effects other than moisturizing.
上記結果に試験例１及び２の結果を合わせて考慮すると、トレハロースのフィラグリン産生促進効果によってバリア機能が改善して皮膚の乾燥が抑えられ、最終的にひび割れの状態が改善したものと推察される。さらに、トレハロースのＴＳＬＰ遺伝子及びＩＬ−３３遺伝子発現の抑制によるひび割れ部分の炎症抑制効果もまた、ひび割れの状態の改善に寄与したものと推察される。 Considering the results of Test Examples 1 and 2 together with the above results, it is presumed that the barrier function was improved by the filaggrin production promoting effect of trehalose, the dryness of the skin was suppressed, and finally the state of cracks was improved. .. Furthermore, it is presumed that the anti-inflammatory effect of the cracked portion by suppressing the expression of the TSLP gene and IL-33 gene of trehalose also contributed to the improvement of the cracked state.
Claims (3)
A pharmaceutical composition for improving or preventing inflammatory skin diseases, scars, or cracks or cracks in the skin, which contains one or more compounds selected from the group consisting of trehalose and its derivatives as an active ingredient.
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