JP2020193915A - Method of evaluating skin condition of infants - Google Patents
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Abstract
Description
本発明は、乳幼児の皮膚の状態を評価する方法に関する。 The present invention relates to a method for evaluating the skin condition of an infant.
皮膚炎の発症の有無などの乳幼児の皮膚の状態は、皮膚を目視して判断することによりある程度の評価ができる。しかし、いうまでもなく、皮膚の見た目の判断では、乳幼児の皮膚の状態を分子レベルで科学的にかつ定量的に評価することができない。 The condition of the infant's skin, such as the presence or absence of the onset of dermatitis, can be evaluated to some extent by visually judging the skin. However, needless to say, it is not possible to scientifically and quantitatively evaluate the skin condition of infants at the molecular level by judging the appearance of the skin.
乳幼児の皮膚に頻発するトラブルとしておむつ皮膚炎がある。乳幼児は皮膚炎によるかゆみ、苦痛などの自覚症状を明確に言葉として訴えることができず、保護者によって認識されることが多く、保護者の意識、判断の遅れから、適切な処置を受けずに悪化してしまう場合も多かった。 Diaper dermatitis is a frequent problem on the skin of infants. Infants cannot clearly complain of subjective symptoms such as itching and pain due to dermatitis and are often recognized by their parents, and due to the delay in their awareness and judgment, they do not receive appropriate treatment. In many cases, it got worse.
したがって、皮膚炎の発症を悪化する前や発症前に適切に処置することは、重要であり、それを客観的に判定する方法が望まれていた。斯かる状況の下、本出願人は、おむつ皮膚炎を発症する皮膚に関する検証から、おむつ皮膚炎を有する乳幼児角層とおむつ皮膚炎を有さない乳幼児角層のそれぞれの細胞間脂質成分の組成に相違があり、当該細胞間脂質中の特定のセラミド成分の成分量比を指標として乳幼児の皮膚の状態を評価できることを見出している（特許文献１）。 Therefore, it is important to take appropriate measures before the onset of dermatitis is exacerbated or before the onset of dermatitis, and a method for objectively determining it has been desired. Under such circumstances, Applicants have examined the composition of the intercellular lipid components of the infant horny layer with diaper dermatitis and the infant horny layer without diaper dermatitis based on the verification of the skin developing diaper dermatitis. It has been found that the skin condition of infants can be evaluated by using the component amount ratio of a specific ceramide component in the intercellular lipid as an index (Patent Document 1).
皮膚は、体内からの水分や生体成分の損失、並びに外部からの異物の進入を防ぐ機能を有している。このような機能は、一般に「皮膚のバリア機能」と呼ばれている。皮膚のバリア機能は、主に皮膚の最外層に存在する角層が担っている。角層は角質細胞とその間を埋める細胞間脂質から成り、レンガモルタル構造と呼ばれている。角層の細胞間脂質は、多層状構造（ラメラ構造）を形成し、角層のバリア機能において重要な役割を担っているとされる。肌荒れや加齢などにより角層の細胞間脂質の構造が変化すると、皮膚のバリア機能が低下することが知られている（非特許文献１）。１２８名の日本人女性の頬を対象とした試験では、加齢に伴って細胞間脂質の側方充填構造が低下することが報告されている（非特許文献２）。
健常男性３７名の前腕屈側部を対象としてＴＥＷＬとラマン分光スペクトル中の脂質分子に由来するピークの強度を測定したところ、相関関係を示すことが報告されている（特許文献２）。
The skin has a function of preventing the loss of water and biological components from the body and the invasion of foreign substances from the outside. Such a function is generally called "skin barrier function". The barrier function of the skin is mainly carried out by the stratum corneum, which exists in the outermost layer of the skin. The stratum corneum consists of keratinocytes and the intercellular lipids that fill the space between them, and is called the brick mortar structure. Intercellular lipids in the stratum corneum form a multi-layered structure (lamellar structure) and are said to play an important role in the barrier function of the stratum corneum. It is known that when the structure of intercellular lipids in the stratum corneum changes due to rough skin or aging, the barrier function of the skin deteriorates (Non-Patent Document 1). In a study on the cheeks of 128 Japanese women, it was reported that the lateral packing structure of intercellular lipids decreased with age (Non-Patent Document 2).
When the intensities of peaks derived from TEWL and lipid molecules in the Raman spectroscopic spectrum were measured in 37 healthy men on the flexion side of the forearm, it was reported that they showed a correlation (Patent Document 2).
しかしながら、おむつ皮膚炎を起こした乳幼児の皮膚状態と細胞間脂質の会合状態との関係は全く報告されていない。細胞間脂質の会合状態と乳幼児の皮膚状態の関連を明らかにすることで、ＴＥＷＬでは推し量ることのできない細胞間脂質の状態を知ることができる。細胞間脂質の情報は、リピドミクスによる分析が主流だが、侵襲性があること、詳細な分析には時間がかかることが欠点として挙げられる。このため、乳幼児の皮疹のように、頻繁に消失・出現する皮膚に対しては、非侵襲的、かつ、その場でタイムリーに皮膚状態を評価できることは、乳幼児の皮疹における皮膚状態を理解し、かつその悪化を防ぐ上で非常に有益であると考えられる。 However, no relationship has been reported between the skin condition of infants with diaper dermatitis and the association of intercellular lipids. By clarifying the relationship between the associative state of intercellular lipids and the skin state of infants, it is possible to know the state of intercellular lipids that cannot be estimated by TEWL. The mainstream analysis of intercellular lipid information is by lipidomics, but its drawbacks are that it is invasive and that detailed analysis takes time. Therefore, it is possible to evaluate the skin condition on the spot in a non-invasive and timely manner for the skin that frequently disappears and appears, such as the skin condition of the infant's skin. And it is considered to be very beneficial in preventing its deterioration.
本発明は、乳幼児の皮膚の状態を非侵襲で、簡便かつ的確に評価する、乳幼児の皮膚の状態の評価方法を提供することに関する。 The present invention relates to a method for evaluating an infant's skin condition, which non-invasively, simply and accurately evaluates the infant's skin condition.
本発明者らは、おむつかぶれの症状が見られる乳幼児の皮膚角層の細胞間脂質の構造と機能を解析し、かぶれとの関連性を調べたところ、おむつかぶれ群では経皮水分蒸散量（ＴＥＷＬ)が有意に高く、おむつかぶれ群の皮疹部は非かぶれ群の同一部位と比較し、細胞間脂質の分子会合状態（横方向）の秩序度が有意に低く、細胞間脂質の分子会合状態がおむつ皮膚炎等の乳幼児の皮膚状態を評価するための指標となり得ることを見出した。 The present inventors analyzed the structure and function of intercellular lipids in the skin stratum corneum of infants with diaper rash symptoms and investigated the relationship with rash. As a result, the amount of percutaneous water evaporation in the diaper rash group ( TEWL) is significantly higher, and the eruption part of the diaper rash group has a significantly lower order of intercellular lipid molecular association state (lateral direction) than the same site of the non-rash group, and the intercellular lipid molecular association state. It was found that diaper dermatitis can be an index for evaluating the skin condition of infants such as diaper dermatitis.
すなわち、本発明は、被験乳幼児の皮膚炎部位又はその近傍部位における皮膚角層の細胞間脂質の分子会合状態を測定し、その測定値を基準値と比較する工程を含む、乳幼児の皮膚状態の評価方法、を提供する。
また本発明は、被験物質を塗布又は摂取する工程、皮膚角層の細胞間脂質の会合状態を測定し、基準値と比較する工程を含む、皮膚炎の改善若しくは予防、又は乳幼児の皮膚の状態の維持に対する、被験物質の有効性を評価する方法、を提供する。
That is, the present invention comprises a step of measuring the molecular association state of intercellular lipids in the stratum corneum of the skin at the dermatitis site or a site in the vicinity thereof of the test infant and comparing the measured value with the reference value. An evaluation method, is provided.
The present invention also includes a step of applying or ingesting a test substance, a step of measuring the association state of intercellular lipids in the stratum corneum of the skin and comparing it with a reference value, for improving or preventing dermatitis, or a skin condition of an infant. Provided is a method for assessing the effectiveness of a test substance for maintenance of.
本発明の方法によれば、おむつ皮膚炎等の乳幼児の皮膚の状態を、非侵襲で、簡便かつ的確に評価することが可能となる。これにより、例えば、保護者は、皮膚炎の状態を客観的指標に基いて把握できるため、必要に応じて患部を清潔に保つこと、保湿を心がけること、刺激の少ないおむつ用品を選択すること等のかぶれ対策を講じることができ、皮膚炎の発症を未然に防止できる。また皮膚炎を発症している場合は、その治療効果や治癒状況を的確に判断することができる。
また、本発明の方法によれば、乳幼児の排尿部、肛門部、臀部、鼠蹊部、腰部等の皮膚に適用する外用剤、内服剤、身体洗浄剤、入浴剤、おむつ用品等のかぶれリスクへの影響を評価することができる。
According to the method of the present invention, it is possible to easily and accurately evaluate the skin condition of an infant such as diaper dermatitis in a non-invasive manner. As a result, for example, parents can grasp the condition of dermatitis based on an objective index, so that the affected area should be kept clean, moisturized, and diaper products that are less irritating should be selected as necessary. It is possible to take measures against rashes and prevent the onset of dermatitis. In addition, if dermatitis has developed, its therapeutic effect and healing status can be accurately determined.
In addition, according to the method of the present invention, there is a risk of rashes on the skin of infants such as urination, anus, buttocks, inguinal region, and lumbar region, such as external preparations, internal preparations, body cleansers, bath salts, and diaper products. The effect of can be evaluated.
乳幼児の皮膚状態の評価方法は、被験乳幼児の皮膚炎部位又はその近傍部位における皮膚角層の細胞間脂質の分子会合状態を測定し、基準値と比較する工程を含むものである。 The method for evaluating the skin condition of an infant includes a step of measuring the molecular association state of intercellular lipids in the skin stratum corneum at the dermatitis site or a site in the vicinity thereof of the test infant and comparing it with a reference value.
後記実施例に示すように、皮膚科専門医師によりおむつ皮膚炎を有すると診断された群（以下、かぶれ群）の皮疹部では経皮水分蒸散量（ＴＥＷＬ）と角層水分量が有意に高かったことから皮膚炎の発症部位（以下、「皮疹部」ともいう）はバリア機能が低下していることが認められた。そして、かぶれ群の皮疹部は非かぶれ群の同一部位と比較し、角層（深さ３−６μｍ）における細胞間脂質の分子会合状態が有意に低く、おむつかぶれの皮膚炎のバリア機能の低下に細胞間脂質の分子会合状態が関係していることが示された。したがって、角層の細胞間脂質の分子会合状態を指標として、皮膚炎に関連する皮膚状態を評価できると考えられる。とりわけ、見た目からは皮膚炎を発症しているか否かの判断が難しい、軽微又は軽度な皮膚炎の皮膚状態の評価に用いることが好ましく、軽微又は軽度な刺激性接触皮膚炎の評価に用いることが好ましい。ここで軽微又は軽度な刺激性接触皮膚炎とは、後出の表１のおむつ皮膚炎重症度評価基準に基く重症度のスコアが１又は２であることを意味する。 As shown in the examples below, the amount of transdermal water evaporation (TEWL) and the amount of water in the stratum corneum were significantly higher in the eruption part of the group diagnosed as having diaper dermatitis by a dermatologist (hereinafter referred to as the rash group). Therefore, it was confirmed that the barrier function of the onset site of dermatitis (hereinafter, also referred to as "rash area") was reduced. The eruption part of the rash group has a significantly lower molecular association state of intercellular lipids in the stratum corneum (depth 3-6 μm) compared to the same part of the non-rash group, and the barrier function of dermatitis of diaper rash is reduced. It was shown that the molecular association state of intercellular lipids is related to. Therefore, it is considered that the skin condition related to dermatitis can be evaluated by using the molecular association state of intercellular lipids in the stratum corneum as an index. In particular, it is preferably used for evaluation of the skin condition of mild or mild dermatitis, which is difficult to judge from the appearance whether or not dermatitis has developed, and is used for evaluation of mild or mild irritant contact dermatitis. Is preferable. Here, mild or mild irritant contact dermatitis means that the severity score based on the diaper dermatitis severity evaluation criteria shown in Table 1 below is 1 or 2.
本発明において、「被験乳幼児」とは、ヒトの乳幼児を指し、例えば生後３か月〜３６か月、好ましくは生後３か月〜２４か月、より好ましくは生後４か月〜６か月までの乳幼児を指す。 In the present invention, the “test infant” refers to a human infant, for example, from 3 months to 36 months after birth, preferably from 3 months to 24 months after birth, and more preferably from 4 months to 6 months after birth. Refers to infants.
本発明において、乳幼児の皮膚の状態が評価される部位は、角層の細胞間脂質の分子会合状態が測定される部位であって、皮膚炎部位又はその近傍部位である。
ここで、「皮膚炎部位」とは、皮膚炎の発症部位、すなわち皮疹部を指し、その近傍部位には、皮疹部と隣接する無疹部（皮膚炎の症状が見られない部位）が包含されるが、皮疹部であるのが好ましい。ここで皮疹部と隣接する無疹部とは、例えば皮疹部外縁から３ｃｍ以内、好ましくは１ｃｍ〜３ｃｍにある領域を指す。なお、皮疹部以外の一見正常と思われる無疹部の皮膚状態を評価すれば、皮膚炎の発症の有無、皮膚炎の発症の可能性、皮膚炎の病態の進行度、皮膚炎の治癒の程度や治療効果などが判定できる。
In the present invention, the site where the skin condition of an infant is evaluated is a site where the molecular association state of intercellular lipids in the stratum corneum is measured, and is a dermatitis site or a site in the vicinity thereof.
Here, the "dermatitis site" refers to the onset site of dermatitis, that is, the rash area, and the rash area adjacent to the dermatitis area (the site where no dermatitis symptom is observed) is included in the vicinity thereof. However, it is preferably the rash area. Here, the non-rash portion adjacent to the rash portion refers to a region within 3 cm, preferably 1 cm to 3 cm, from the outer edge of the rash portion, for example. If the skin condition of the seemingly normal non-rash area other than the rash area is evaluated, the presence or absence of dermatitis, the possibility of developing dermatitis, the degree of progression of dermatitis, and the cure of dermatitis The degree and therapeutic effect can be determined.
本発明において、「皮膚炎」とは、一般的な技術用語として用いられる「湿疹」と同義である。臨床的には、皮膚炎を発症すると、丘疹、紅斑、落屑、浸潤、などを呈する。
皮膚炎の原因としては、刺激性物質やアレルゲンなどの外的因子により発症する皮膚炎と、アトピー素因などの内的因子により発症する皮膚炎とに大別される。実際には、これら両方の要素により皮膚炎が発症する場合も多い。また、これらの要素に加えて、IV型アレルギーなどの免疫反応により、特徴的な描像を形成する場合もある。
In the present invention, "dermatitis" is synonymous with "eczema" used as a general technical term. Clinically, when dermatitis develops, it presents with papules, erythema, desquamation, infiltration, and the like.
The causes of dermatitis are roughly classified into dermatitis caused by external factors such as irritants and allergens and dermatitis caused by internal factors such as atopic predisposition. In practice, both of these factors often cause dermatitis. In addition to these factors, an immune response such as type IV allergy may form a characteristic picture.
皮膚炎の具体例としては、接触皮膚炎、アトピー性皮膚炎、脂漏性皮膚炎、はたけ、貨幣状湿疹、感染性湿疹様皮膚炎、自家感作性皮膚炎、皮脂欠乏性皮膚炎、白色粃糠疹、手足の湿疹、単純性苔癬、うっ滞性皮膚炎が挙げられる。
このうち、本発明では接触皮膚炎を好ましく指す。ここで「接触皮膚炎」とは、皮膚に接触した物質（例えば、おむつなどの吸収性物品、衣類やタオルなどの繊維製品、ティシュペーパー、トイレットペーパーなどの紙製品、おしりふきやウェットティッシュなどの不織布、糞尿や菌由来の刺激物質、洗剤、せっけん、化粧品などの日常生活用品に含まれる化学物質、食品、金属、植物、ほこりなど）の刺激によって生じる皮膚炎（刺激性接触皮膚炎）と、アレルギー反応によって生じる皮膚炎とに大別される。本発明は特に、刺激性接触皮膚炎の評価に好適に用いることができる。
Specific examples of dermatitis include contact dermatitis, atopic dermatitis, seborrheic dermatitis, flakes, monetary eczema, infectious eczema-like dermatitis, autosensitizing dermatitis, sebaceous dermatitis, and white color. Examples include porridge, eczema of limbs, simple lichen, and stagnant dermatitis.
Of these, contact dermatitis is preferably referred to in the present invention. Here, "contact dermatitis" refers to substances that come into contact with the skin (for example, absorbent articles such as diapers, textile products such as clothing and towels, paper products such as tissue paper and toilet paper, and non-woven fabrics such as wipes and wet tissues. , Dermatitis (irritant contact dermatitis) caused by irritation of irritants derived from manure and bacteria, chemical substances contained in daily life products such as detergents, soaps, cosmetics, foods, metals, plants, dust, etc., and allergies It is roughly classified into dermatitis caused by reaction. The present invention can be particularly suitably used for the evaluation of irritant contact dermatitis.
刺激性接触皮膚炎のうち、おむつなどの吸収性物品と乳幼児の皮膚とが接触したときに生じるおむつ皮膚炎の評価に特に好適である。このようなおむつ皮膚炎の生じやすい部位としては、排尿部、肛門部、臀部、鼠蹊部、腰部、並びにこれらの近傍部などが挙げられる。よって本発明は、排尿部、肛門部、臀部、鼠蹊部、腰部、並びにこれらの近傍部の皮膚の状態の評価に好適である。 Among irritant contact dermatitis, it is particularly suitable for evaluation of diaper dermatitis that occurs when an absorbent article such as a diaper comes into contact with the skin of an infant. Examples of sites where such diaper dermatitis is likely to occur include a urinary part, an anus, buttocks, inguinal region, lumbar region, and a portion in the vicinity thereof. Therefore, the present invention is suitable for evaluating the skin condition of the urinary part, the anus part, the buttocks, the inguinal region, the lumbar region, and the vicinity thereof.
本発明の「皮膚状態の評価」における「皮膚状態」とは、上記皮膚炎との関係における皮膚状態を意味し、具体的には、上記皮膚炎の発症の有無、上記皮膚炎の進行度、上記皮膚炎発症の可能性の有無、上記皮膚炎の治癒状況、上記皮膚炎に対する治療もしくは予防効果が挙げられる。 The "skin condition" in the "evaluation of the skin condition" of the present invention means the skin condition in relation to the dermatitis, and specifically, the presence or absence of the onset of the dermatitis, the degree of progression of the dermatitis, and the like. The presence or absence of the onset of dermatitis, the healing status of the dermatitis, and the therapeutic or preventive effect on the dermatitis can be mentioned.
本発明においては、皮膚角層の細胞間脂質の分子会合状態が測定されるが、ここで、「細胞間脂質の分子会合状態」（「細胞間脂質の分子会合構造」とも称される）とは、細胞間脂質のパッキング状態を意味し、詳細には、ラメラ構造を形成する細胞間脂質において、ラメラ方向に直行する横断面での炭素鎖の並び方すなわち側方充填構造を指す。斯かる側方充填構造は、密に炭素鎖が充填されている直方晶構造と、疎に炭素鎖が充填されている六方晶構造が知られており、本発明の細胞間脂質の分子会合状態にはそれらの構造を包含する。
なお、細胞間脂質は、角質細胞の周囲を取り囲む脂質であり、セラミド、コレステロール、脂肪酸などからなる。細胞間脂質はラメラ構造を形成し、長周期ラメラ構造と短周期ラメラ構造が存在する（Van Smeden J, Janssens M, Gooris GS, Bouwstra JA. The important role of stratum corneum lipids for the cutaneous barrier function. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 2014; 1841; 295-313.）。しかし、本発明においては、その構造は限定されるものではない。
In the present invention, the molecular association state of intercellular lipids in the stratum corneum is measured, and here, it is referred to as "molecular association state of intercellular lipids" (also referred to as "molecular association structure of intercellular lipids"). Means the packed state of the intercellular lipid, and more specifically, refers to the arrangement of carbon chains in the cross section orthogonal to the lamella direction, that is, the lateral packed structure in the intercellular lipid forming the lamella structure. As such a laterally packed structure, a rectangular structure in which carbon chains are densely packed and a hexagonal structure in which carbon chains are sparsely packed are known, and the molecular association state of the intercellular lipid of the present invention. Includes those structures.
The intercellular lipid is a lipid that surrounds the keratinocytes, and is composed of ceramide, cholesterol, fatty acid, and the like. Intercellular lipids form a lamellar structure, with long-period lamellar structure and short-period lamellar structure (Van Smeden J, Janssens M, Gooris GS, Bouwstra JA. The important role of stratum corneum lipids for the cutaneous barrier function. Biochimica et Biophysica Acta --Molecular and Cell Biology of Lipids. 2014; 1841; 295-313.). However, in the present invention, the structure is not limited.
細胞間脂質の分子会合状態は、Ｘ線回析、電子線回析、フーリエ変換ＩＲ（ＦＴ−ＩＲ）、電子顕微鏡観察、ラマン分光法などを用いて測定することができるが、本発明においては、皮膚から試料を剥離することなく非侵襲で測定できる点及びハイスループットである点から、共焦点ラマン分光法を用いて測定するのが好ましい。細胞間脂質は周囲の環境から影響を受けやすいため、共焦点ラマン分光法を用いると角層をそのまま測定できるという利点も挙げられる。
ラマン分光法を用いて角層のスペクトルを測定し、それに基づき細胞間脂質の分子会合状態を評価する手段は、例えば特開２０１３−６１２８４号公報に記載の方法に従って行うことができる。
すなわち、ラマン分光により皮膚の角層のスペクトルを測定し、測定したスペクトルから含水脱脂角層の寄与分を除去し、細胞間脂質に特異的な信号（ＣＨ２対称伸縮振動に由来するスペクトル中２８５０ｃｍ−１付近で検出される信号、及び／又はＣＨ２逆対称伸縮振動に由来するスペクトル中２８８０ｃｍ−１付近で検出される信号）を抽出したスペクトルを得、これに基づいて細胞間脂質の分子会合状態を評価することができる。
ヒトの角層のラマンスペクトルを測定した場合、細胞間脂質のＣＨ２伸縮振動由来の信号（２８５０ｃｍ−１付近の信号と２８８０ｃｍ−１付近に出現）と、タンパク質のＣＨ３伸縮振動に由来する信号（２９３０ｃｍ−１付近に出現）は、一部が重複した波数領域で観察される。そのため、タンパク質、脂質及び水を主要構成成分とする角層のラマンスペクトルを測定すると、タンパク質及び脂質にそれぞれ由来とする信号が重畳したスペクトルが得られる。そこで、角層のラマンスペクトルからタンパク質のＣＨ３伸縮振動の影響を除去して、細胞間脂質由来の信号を正確に抽出する必要がある。特開２０１３−６１２８４号公報に記載の通り、角層から細胞間脂質などの油性成分とアミノ酸などの水溶性成分を除去した後の脱脂角層に含水させた含水脱脂角層モデルのラマンスペクトルを解析すると、該ラマンスペクトル中のＣＨ３伸縮振動に由来する信号の極大吸収波長が、角層のラマンスペクトル中のＣＨ３伸縮振動に由来する信号の極大吸収波長とほぼ一致する。よって、同公報に従って角層のラマンスペクトルから含水脱脂角層の寄与分を除去することで、細胞間脂質に特異的な信号を抽出することができる。この場合、角層のラマンスペクトルの信号強度と含水脱脂角層モデルのラマンスペクトルの信号強度は必ずしも一致しないため、ラマンスペクトル中２９３０ｃｍ−１付近に出現する、ＣＨ３伸縮振動由来の信号強度に基づき、両スペクトルを規格化してから抽出することで、細胞間脂質に特異的な信号を正確に抽出することができる。このように抽出した細胞間脂質に関する２つの信号を指標として、細胞間脂質の分子会合構造を評価することができる。
The molecular association state of intercellular lipids can be measured by using X-ray diffraction, electron beam diffraction, Fourier transform IR (FT-IR), electron microscope observation, Raman spectroscopy, etc., but in the present invention, it can be measured. It is preferable to measure using confocal Raman spectroscopy because it can be measured non-invasively without peeling the sample from the skin and has high throughput. Since intercellular lipids are easily affected by the surrounding environment, confocal Raman spectroscopy has the advantage that the stratum corneum can be measured as it is.
The means for measuring the spectrum of the stratum corneum using Raman spectroscopy and evaluating the molecular association state of intercellular lipids based on the spectrum can be carried out, for example, according to the method described in JP2013-61284A.
That is, the spectrum of the stratum corneum of the skin is measured by Raman spectroscopy, the contribution of the hydrous degreased stratum corneum is removed from the measured spectrum, and the signal specific to the intercellular lipid (2850 cm in the spectrum derived from CH 2 symmetric stretching vibration). signal is detected in the vicinity of -1, and / or CH 2 give the antisymmetric stretching vibration spectrum extracted signal) which is detected in the vicinity of the spectrum in 2880Cm -1 derived from the molecular association of intercellular lipids based on this The condition can be evaluated.
When the Raman spectrum of the human stratum corneum was measured, a signal derived from CH 2 stretching vibration of intercellular lipids (a signal near 2850 cm -1 and a signal appearing near 2880 cm -1 ) and a signal derived from CH 3 stretching vibration of protein (Appears near 2930 cm -1 ) is observed in a partially overlapping wavenumber region. Therefore, when the Raman spectrum of the stratum corneum containing proteins, lipids and water as the main constituents is measured, a spectrum in which signals derived from the proteins and lipids are superimposed can be obtained. Therefore, it is necessary to remove the influence of CH 3 stretching vibration of the protein from the Raman spectrum of the stratum corneum and accurately extract the signal derived from the intercellular lipid. As described in Japanese Patent Application Laid-Open No. 2013-61284, a Raman spectrum of a hydrous degreased stratum corneum model obtained by removing oily components such as intercellular lipids and water-soluble components such as amino acids from the stratum corneum and then impregnating the degreased stratum corneum with water. When analyzed, the maximum absorption wavelength of the signal derived from the CH 3 expansion and contraction vibration in the Raman spectrum substantially coincides with the maximum absorption wavelength of the signal derived from the CH 3 expansion and contraction vibration in the Raman spectrum of the stratum corneum. Therefore, by removing the contribution of the hydrous degreasing stratum corneum from the Raman spectrum of the stratum corneum according to the same publication, a signal specific to the intercellular lipid can be extracted. In this case, since the signal intensity of the Raman spectrum of the stratum corneum and the signal intensity of the Raman spectrum of the hydrous degreased stratum corneum model do not always match, it is based on the signal intensity derived from CH 3 stretching vibration that appears near 2930 cm -1 in the Raman spectrum. By standardizing both spectra and then extracting, a signal specific to the intercellular lipid can be accurately extracted. The molecular association structure of the intercellular lipid can be evaluated using the two signals related to the intercellular lipid extracted in this way as indexes.
細胞間脂質がラメラ構造を形成し測定部位における細胞間脂質の分子間相互作用が大きくなると細胞間脂質を構成するアルキル鎖の運動性が低下し、２８８０ｃｍ−１付近の信号が大きくなる。これに対して、測定部位における細胞間脂質の分子間相互作用が小さくなると細胞間脂質を構成するアルキル鎖の運動性が上昇し、２８８０ｃｍ−１付近の信号が小さくなる。以下に示す２８５０ｃｍ−１付近の信号に対する２８８０ｃｍ−１付近の信号の強度比（以下、Ｒ値と表記）が、細胞間脂質を構成するアルキル鎖の運動性や細胞間脂質の結晶構造を反映することが知られている（P.R.Carey ラマン分光学―基礎と生化学への応用 共立出版 1984）。 When the intercellular lipid forms a lamellar structure and the intermolecular interaction of the intercellular lipid at the measurement site increases, the motility of the alkyl chain constituting the intercellular lipid decreases, and the signal near 2880 cm -1 becomes large. On the other hand, when the intermolecular interaction of the intercellular lipid at the measurement site becomes small, the motility of the alkyl chain constituting the intercellular lipid increases, and the signal near 2880 cm -1 becomes small. The intensity ratio of the signal near 2880 cm -1 (hereinafter referred to as R value) to the signal near 2850 cm -1 shown below reflects the motility of the alkyl chain constituting the intercellular lipid and the crystal structure of the intercellular lipid. It is known (PRCarey Raman spectroscopy-Basics and Applications to Biochemistry Kyoritsu Shuppan 1984).
Ｒ値を算出し、層構造形成の有無、細胞間脂質の会合状態、細胞間脂質を構成するアルキル鎖の運動性、細胞間脂質の結晶構造などを評価する。Ｒ値が大きくなると、細胞間脂質の分子会合状態は秩序度が高い状態（パッキングが密）であり、Ｒ値が小さくなると、細胞間脂質の分子会合状態は秩序度が低い状態（パッキングが疎）となる。
よって、本発明における細胞間脂質の分子会合状態は、斯かるＲ値を指標として評価することができる。
The R value is calculated to evaluate the presence or absence of layer structure formation, the association state of intercellular lipids, the motility of alkyl chains constituting the intercellular lipids, the crystal structure of the intercellular lipids, and the like. When the R value is large, the molecular association state of intercellular lipids is in a highly ordered state (packing is dense), and when the R value is small, the molecular association state of intercellular lipids is in a low order state (packing is loose). ).
Therefore, the molecular association state of the intercellular lipid in the present invention can be evaluated using such an R value as an index.
当該細胞間脂質の分子会合状態は、角層を含む皮膚の任意の深さ（例えば皮膚表面からの深さが０〜３０μｍ）において測定されるが、本発明においては、皮膚表面からの深さが２〜１５μｍ（角層全層の厚さ（角層厚）を１００％とした場合における、皮膚表面から１４〜１００％程度の深さ範囲に相当）、好ましくは２〜８μｍ（同、１４〜５６％程度の深さ範囲に相当）、より好ましくは３〜６μｍ（同、２１〜４２％程度の深さ範囲に相当）における角層の細胞間脂質の分子会合状態を測定するのが好ましい。なお、角層厚としては、ラマン分光法により取得される角層中の水分量データに基づく水分プロファイルを２本の１次直線で近似した時、該２本の直線の交点における深さを用いることができる。
細胞間脂質の会合状態は温度により影響を受けることが知られているので、ラマン分光により皮膚の角層のスペクトルを測定する前に、皮膚温を一定に保持するために、被験者を定温条件下で順化させることが好ましい。また測定時には皮膚温を測定し、皮膚温が一定であることを確認するのが好ましい。
The molecular association state of the intercellular lipid is measured at an arbitrary depth of the skin including the stratum corneum (for example, the depth from the skin surface is 0 to 30 μm), but in the present invention, the depth from the skin surface. Is 2 to 15 μm (corresponding to a depth range of about 14 to 100% from the skin surface when the thickness of the entire stratum corneum (the thickness of the stratum corneum) is 100%), preferably 2 to 8 μm (14). It is preferable to measure the molecular association state of intercellular lipids in the stratum corneum at a depth range of about 56%), more preferably 3 to 6 μm (corresponding to a depth range of about 21 to 42%). .. As the thickness of the stratum corneum, when the moisture profile based on the water content data in the stratum corneum acquired by Raman spectroscopy is approximated by two linear lines, the depth at the intersection of the two straight lines is used. be able to.
Since it is known that the association state of intercellular lipids is affected by temperature, subjects are subjected to constant temperature conditions in order to keep the skin temperature constant before measuring the spectrum of the stratum corneum of the skin by Raman spectroscopy. It is preferable to acclimatize with. Further, it is preferable to measure the skin temperature at the time of measurement to confirm that the skin temperature is constant.
測定された細胞間脂質の分子会合状態は、基準値と比較することにより、乳幼児の皮膚状態が評価される。
基準値は、例えば、細胞間脂質の分子会合状態と、乳幼児の皮膚の状態との関連づけから以下のように設定することができる。
乳幼児の皮膚の状態を、目視評価や機器分析等の手段により評価する。その評価結果に基づき、皮膚の状態が健常と判断される被験体から構成される健常群と、皮膚炎と判断される被験体から構成される皮膚炎群を作成する。これとは別途、前述の方法により細胞間脂質の分子会合状態（Ｒ値）を測定する。そして皮膚の状態の評価結果とＲ値との相関性に基づき、皮膚の状態を評価するのに適した基準値を決定される。具体的には、各群に属する乳幼児のＲ値の統計解析結果に基づき、各群を特徴づけるＲ値の数値範囲を決定する。この数値範囲は、各群の平均値を中心とした上下の一定範囲に設定することにより決定する。ここで「一定範囲」とは、標準偏差（ＳＤ）等の統計数値や、１／２ＳＤ値、１／３ＳＤ値などを用いてもよいし、予め設定した任意の数値を用いてもよい。そして、各群を特徴づける数値範囲の上限又は下限を、基準値とする。
The measured molecular association state of intercellular lipids is compared with the reference value to evaluate the skin condition of infants.
The reference value can be set as follows, for example, from the relationship between the molecular association state of intercellular lipids and the skin state of infants.
The skin condition of infants is evaluated by means such as visual evaluation and instrumental analysis. Based on the evaluation result, a healthy group composed of subjects whose skin condition is judged to be healthy and a dermatitis group composed of subjects judged to be dermatitis are created. Separately from this, the molecular association state (R value) of intercellular lipids is measured by the above-mentioned method. Then, a reference value suitable for evaluating the skin condition is determined based on the correlation between the evaluation result of the skin condition and the R value. Specifically, the numerical range of the R value that characterizes each group is determined based on the statistical analysis result of the R value of the infant belonging to each group. This numerical range is determined by setting a certain range above and below the average value of each group. Here, as the "fixed range", a statistical value such as standard deviation (SD), a 1 / 2SD value, a 1 / 3SD value, or the like may be used, or an arbitrary value set in advance may be used. Then, the upper limit or the lower limit of the numerical range that characterizes each group is set as a reference value.
例えば、Ｒ値の数値範囲を規定する「一定範囲」として１／３ＳＤ値を用いた場合、健常群のＲ値の数値範囲の下限（例えば、皮膚表面から深さ３μｍにおけるラマン分光スペクトルから算出されるＲ値の場合は１．１７７）又は皮膚炎群Ｒ値の数値範囲の上限（例えば、皮膚表面から深さ３μｍにおけるラマン分光スペクトルから算出されるＲ値の場合は１．１３１）のいずれかを基準値とし、測定された被験乳児において測定されたＲ値が基準値以上の場合を「健常である」と評価し、Ｒ値が基準値未満の場合を「皮膚炎の可能性がある」又は「皮膚炎の可能性が高い」と評価できる。 For example, when the 1/3 SD value is used as the "constant range" that defines the numerical range of the R value, it is calculated from the lower limit of the numerical range of the R value in the healthy group (for example, the Raman spectral spectrum at a depth of 3 μm from the skin surface). 1.177) or the upper limit of the numerical range of the dermatitis group R value (for example, 1.131 for the R value calculated from the Raman spectral spectrum at a depth of 3 μm from the skin surface). When the measured R value of the measured infant is equal to or higher than the standard value, it is evaluated as "healthy", and when the R value is less than the standard value, "there is a possibility of dermatitis". Or, it can be evaluated as "there is a high possibility of dermatitis".
斯くして、本発明の方法によれば、おむつ皮膚炎等の乳幼児の皮膚の状態を、非侵襲で、簡便かつ的確に評価することができる。経皮水分蒸散量（ＴＥＷＬ）を測定することにより、皮膚バリア機能を評価する方法もあるが、ＴＥＷＬの測定では、動きを制止させて安静を保ち、長時間の測定の間、測定用プローブを水平な状態を保って非常に微弱な圧力で皮膚に接触させ続ける必要があることから、乳幼児を対象とした場合非常に困難を伴う。さらに、発汗などによる皮膚表面の残留物の影響も受けやすい。これに対して、ラマン分光による測定が可能な本発明の方法では、測定用プローブを測定部位の皮膚にしっかり密着するように、比較的短時間押し当てるだけで測定が可能であり、また表面の残留物の影響を受けずに皮膚内部の情報を得ることができるため、乳幼児を対象とした皮膚状態の評価に適した方法と云える。
なお、本発明における「評価」とは、乳幼児の皮膚の状態に関する情報提供行為であり、医師による診断等の医療行為を包含するものではない。
Thus, according to the method of the present invention, the skin condition of an infant such as diaper dermatitis can be evaluated easily and accurately in a non-invasive manner. There is also a method of evaluating the skin barrier function by measuring the amount of transdermal water evaporation (TEWL), but in the measurement of TEWL, the movement is stopped to keep the patient at rest, and the measurement probe is used during a long measurement. It is very difficult for infants because it is necessary to keep it level and keep it in contact with the skin with very weak pressure. In addition, it is also susceptible to skin surface residues due to sweating and the like. On the other hand, in the method of the present invention capable of measurement by Raman spectroscopy, measurement can be performed by simply pressing the measurement probe firmly against the skin of the measurement site for a relatively short time, and the surface surface. Since it is possible to obtain information on the inside of the skin without being affected by the residue, it can be said to be a method suitable for evaluating the skin condition of infants.
The "evaluation" in the present invention is an act of providing information on the skin condition of an infant, and does not include a medical practice such as a diagnosis by a doctor.
また、本発明の乳幼児の皮膚の状態の評価方法によれば、皮膚外用剤の塗布試験や、何らかの機能性食品や医薬品、医薬部外品の摂取試験等において、これらの被験物質の塗布又は摂取後の皮膚角層の細胞間脂質の分子会合状態を測定し、基準値と比較することにより、その被験物質の皮膚炎の改善若しくは予防、又は乳幼児の皮膚の状態の維持に対する有効性を評価すること、或いはそれに基づいて当該被験物質を有効成分として選択することができる。この場合、基準値としては、例えば被験物質の塗布又は摂取前の皮膚角層の細胞間脂質の分子会合状態の測定値を用いればよい。
ここで、「皮膚の状態の維持」とは、皮膚炎が改善又は予防された健康な皮膚の状態を、定常的に維持することをいう。また、「予防」とは、個体における疾患若しくは症状の発症の防止若しくは遅延、又は個体の疾患若しくは症状の発症の危険性を低下させることをいう。具体的には、細胞間脂質の分子会合状態（Ｒ値）を、前述の基準値より大きい状態に維持することを指す。
In addition, according to the method for evaluating the skin condition of infants of the present invention, application or ingestion of these test substances in an application test of an external preparation for skin, an ingestion test of some functional food, a drug, a quasi drug, etc. By measuring the molecular association state of the intercellular lipids in the subsequent skin stratum corneum and comparing it with the reference value, the effectiveness of the test substance for improving or preventing dermatitis or maintaining the skin condition of infants is evaluated. This, or based on that, the test substance can be selected as the active ingredient. In this case, as the reference value, for example, the measured value of the molecular association state of the intercellular lipid in the stratum corneum of the skin before application or ingestion of the test substance may be used.
Here, "maintenance of skin condition" means to constantly maintain a healthy skin condition in which dermatitis is improved or prevented. In addition, "prevention" means preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of developing a disease or symptom in an individual. Specifically, it refers to maintaining the molecular association state (R value) of intercellular lipids in a state larger than the above-mentioned reference value.
以下、本発明を実施例に基づきさらに詳細に説明するが、本発明はこれに限定されるものではない。
１．方法
（１）被験乳幼児
月齢が４−６ヶ月齢の日本人男児及び女児について、以下の基準により、非かぶれ群１３名（男６名、女７名）、かぶれ群１０名（男７名、女３名）を選抜した。
＜被験者のリクルート基準＞
おむつかぶれなし児：おむつ被覆部位に紅斑・丘疹・落屑・浸潤がない児。
おむつかぶれ児：下記表１のおむつ皮膚炎重症度評価基準に基づき皮膚科専門医師が重症度を評価し、そのスコアが３又は４の乳幼児で、かつ共焦点ラマンで測定可能な肛門から臀部にかけて比較的広範囲にかぶれがある児。
Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.
1. 1. Method (1) Test infants For Japanese boys and girls aged 4-6 months, 13 non-rash groups (6 men, 7 women) and 10 rash groups (7 men, 7 men) were based on the following criteria. 3 women) were selected.
<Subject recruitment criteria>
Children without diaper rash: Children without erythema, papules, desquamation, or infiltration on the diaper covering area.
Children with diaper rash: From the anus to the buttocks, which is evaluated by a dermatologist based on the diaper dermatitis severity evaluation criteria in Table 1 below and has a score of 3 or 4, and can be measured by confocal Raman. A child with a relatively widespread rash.
（２）評価部位
おむつ被覆部位として臀部、排尿部及び肛門部を含む範囲を評価部位とした。
（３）皮膚計測
温度２４度、湿度４０％に制御した環境可変室内において、新しいおむつを軽く着用した状態で２０分間皮膚を馴化させた。その後、皮膚温をInfrared Thermometer IR-TA Series（Chino社製）を用いて、角層水分量をCorneometer CM825（Courage and Khazaka社製 MPA5）を用いて、経皮水分蒸散量をTewameter TM300（Courage and Khazaka社製 MPA5）を用いて各部位（かぶれ児は臀部の皮疹部、非かぶれ児は臀部の無疹部）の測定を行った。角層水分量の測定は各部位につき１０点ずつ、経皮水分蒸散量の測定は各部位につき３点ずつ測定して平均値を算出した。
共焦点ラマンの計測は、共焦点ラマン分光装置 Raman spectroscopy Model3510（River Diagnostic社製）を用い、下記の測定条件にて臀部から肛門部にかけての部位１箇所について、３回以上測定し、角層内の脂質のパッキングの指標であるＲ値の平均値を算出した。
（測定条件）
励起波長：６７１ｎｍ
積算時間：１０秒／１スペクトル
対物レンズ：４０倍、ＮＡ＝１．２
深さ方向スキャン条件：皮膚表面から３μｍ毎にスキャン
(2) Evaluation site The evaluation site was the area including the buttocks, urination, and anus as the diaper covering site.
(3) Skin measurement In a variable environment room where the temperature was controlled to 24 degrees and the humidity was controlled to 40%, the skin was acclimated for 20 minutes while wearing a new diaper lightly. After that, the skin temperature was measured using the Infrared Thermometer IR-TA Series (Chino), the stratum corneum water content was measured using the Corneometer CM825 (Courage and Khazaka MPA5), and the percutaneous water evaporation was measured using the Tewameter TM300 (Courage and). Using Khazaka MPA5), each site (rash on the buttocks for rash children and rash on the buttocks for non-rash children) was measured. The average value was calculated by measuring the amount of water in the stratum corneum at 10 points for each part and measuring the amount of transpiration of transdermal water at 3 points for each part.
Confocal Raman is measured using a confocal Raman spectrometer Raman spectroscopy Model3510 (manufactured by River Diagnostic) three or more times for one site from the buttocks to the anus under the following measurement conditions, and within the stratum corneum. The average value of the R value, which is an index of the lipid packing of the above, was calculated.
(Measurement condition)
Excitation wavelength: 671 nm
Integration time: 10 seconds / 1 spectrum Objective lens: 40x, NA = 1.2
Depth direction scan condition: Scan every 3 μm from the skin surface
２．結果
（１）角層性状
皮疹の評価結果と皮膚計測結果を表２に示す。非かぶれ群無疹部と比較して、皮疹スコアが有意に高いかぶれ群皮疹部では、経皮水分蒸散量と角層水分量が有意に高かったことから皮疹部はバリア機能が低下していることがわかった。皮膚温については、有意な差は認められなかった。
2. 2. Results (1) Table 2 shows the evaluation results and skin measurement results for stratum corneum rash. The rash score was significantly higher in the rash group than in the non-rash group. In the rash group, the barrier function was reduced because the transdermal water evaporation and the stratum corneum water content were significantly higher. I understand. There was no significant difference in skin temperature.
（２）角層内の脂質のパッキング性（共焦点ラマン分光法）
角層内Ｒ値のプロファイルは、かぶれ群皮疹部が非かぶれ群無疹部に対して深さ３μｍ（角層全層の厚さ（角層厚）を１００％とした場合における、皮膚表面より２１％付近の深さに相当）、と６μｍ（角層全層の厚さ（角層厚）を１００％とした場合における、皮膚表面より４２％付近の深さに相当）のＲ値が低かった。皮膚温は、脂質のパッキング性に影響を与えることが知られているが、上述の通り、今回、かぶれ群皮疹部と非かぶれ群で皮膚温に差がなかったため温度以外の要因、つまり、皮膚炎の皮膚状態に基づく細胞間脂質の状態の相違をＲ値で評価することができたと考える。
(2) Lipid packing property in the stratum corneum (confocal Raman spectroscopy)
The profile of the R value in the stratum corneum is from the skin surface when the rash group rash part has a depth of 3 μm (the thickness of the entire stratum corneum (horny layer thickness) is 100%) with respect to the non-rash group rash part. The R values of 6 μm (corresponding to a depth of about 42% from the skin surface when the thickness of the entire stratum corneum (thickness of the stratum corneum) is 100%) are low. It was. It is known that skin temperature affects the packing property of lipids, but as mentioned above, since there was no difference in skin temperature between the rash group and the non-rash group, factors other than temperature, that is, the skin It is considered that the difference in the state of intercellular lipids based on the skin state of inflammation could be evaluated by the R value.
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