JP6671671B1 - Preventive and / or therapeutic drug for allergic rhinitis - Google Patents
Preventive and / or therapeutic drug for allergic rhinitis Download PDFInfo
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- JP6671671B1 JP6671671B1 JP2019070996A JP2019070996A JP6671671B1 JP 6671671 B1 JP6671671 B1 JP 6671671B1 JP 2019070996 A JP2019070996 A JP 2019070996A JP 2019070996 A JP2019070996 A JP 2019070996A JP 6671671 B1 JP6671671 B1 JP 6671671B1
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- allergic rhinitis
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Abstract
【課題】アレルギー性鼻炎の予防及び／又は治療のための経口投与用医薬やアレルギー性鼻炎の発症を予防し、及び／又は症状を改善するための食品を提供すること。【解決手段】本発明は、少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙ（Ｇｌｙ−Ｘ−Ｙはアミノ酸配列であり、Ｘ及びＹは独立にＧｌｙ以外のアミノ酸残基を示す）を含むコラーゲン加水分解物を含む、アレルギー性鼻炎の予防及び／又は治療薬を提供する。本発明は、また、前記コラーゲン加水分解物を含む、アレルギー性鼻炎の発症予防用及び／又は症状改善用食品を提供する。【選択図】図１PROBLEM TO BE SOLVED: To provide a drug for oral administration for the prevention and / or treatment of allergic rhinitis and a food for preventing the onset of allergic rhinitis and / or improving the symptoms. The present invention provides a collagen hydrolyzate containing at least one tripeptide Gly-XY (Gly-XY is an amino acid sequence, and X and Y independently represent amino acid residues other than Gly). Provided is a preventive and / or therapeutic drug for allergic rhinitis, which contains a degradation product. The present invention also provides a food for preventing the onset of allergic rhinitis and / or for improving the symptoms, which contains the collagen hydrolyzate. [Selection diagram] Fig. 1
Description
本発明は、アレルギー性鼻炎の予防及び／又は治療薬に関する。より詳しくは、本発明は、コラーゲン加水分解物を含む、アレルギー性鼻炎の予防及び／又は治療薬に関する。さらに本発明は、コラーゲン加水分解物を含む、アレルギー性鼻炎の発症予防用及び／又は症状改善用食品に関する。 The present invention relates to a preventive and / or therapeutic agent for allergic rhinitis. More specifically, the present invention relates to a preventive and / or therapeutic agent for allergic rhinitis, comprising a collagen hydrolyzate. Furthermore, the present invention relates to a food for preventing the onset of allergic rhinitis and / or improving the symptoms, comprising a collagen hydrolyzate.
アレルギー性鼻炎は、鼻腔粘膜にＩ型のアレルギー反応が生じる疾患である。通年性アレルギー性鼻炎と季節性アレルギー性鼻炎（花粉症）に大別され、いずれも反復性のくしゃみ、水様性鼻漏、及び鼻閉を３主徴とする。日本におけるアレルギー性鼻炎の罹患率は３０〜４０％とも言われ、その高い有病率より「国民病」とも称される。アレルギー性鼻炎の症状（くしゃみ、水様性鼻漏、鼻閉）は、嗅覚障害、睡眠障害、集中力の低下等を引き起こし、患者の生活に少なからず支障をきたす。 Allergic rhinitis is a disease in which a type I allergic reaction occurs in the nasal mucosa. It is roughly classified into perennial allergic rhinitis and seasonal allergic rhinitis (hay fever), all of which are characterized by recurrent sneezing, watery rhinorrhea, and nasal congestion. The prevalence of allergic rhinitis in Japan is said to be 30 to 40%, and due to its high prevalence, it is also called "national disease". Symptoms of allergic rhinitis (sneezing, watery rhinorrhea, nasal congestion) cause olfactory disturbance, sleep disturbance, decrease in concentration, etc., and impair the patient's life to a considerable extent.
一方、コラーゲンたんぱく質は、生体中の全たんぱく質の３割を占める主要な成分である。そのアミノ酸配列は、グリシン（Ｇｌｙ）が３残基ごとに繰り返す特徴をもつ。動物や魚に含まれるコラーゲンを、加熱・抽出・精製することによって得られたゼラチンを、さらに加水分解することでコラーゲン加水分解物を製造することができる。あるいは、生体原料を直接的に酵素処理する手法で製造される場合もある。また、加水分解の方法や程度によって分子量のコントロールが可能であることから、市場には多様な分子量のコラーゲン加水分解物が流通している。コラーゲン加水分解物は、加水分解コラーゲン、ゼラチン加水分解物、コラーゲンペプチドなどとも呼ばれている。 On the other hand, collagen protein is a major component which accounts for 30% of all proteins in the living body. The amino acid sequence has the characteristic that glycine (Gly) repeats every three residues. A collagen hydrolyzate can be produced by further hydrolyzing gelatin obtained by heating, extracting and purifying collagen contained in animals and fish. Alternatively, it may be produced by a technique of directly treating a biological material with an enzyme. Moreover, since the molecular weight can be controlled by the method and degree of hydrolysis, collagen hydrolysates having various molecular weights are distributed on the market. Collagen hydrolyzate is also called hydrolyzed collagen, gelatin hydrolyzate, collagen peptide and the like.
コラーゲン加水分解物やコラーゲン由来のペプチド類の経口摂取による薬理効果が報告されている。例えば、コラーゲンペプチドが血液流動性改善効果を示すこと（特許文献１）、コラーゲンやゼラチンをブロメラインなどの蛋白質分解酵素で処理して得られる分解物が骨組織の機能維持および骨折の予防に有効であること（特許文献２）、並びにコラーゲン加水分解物が新陳代謝促進作用を有することが報告されている（特許文献３）。 Pharmacological effects of oral ingestion of collagen hydrolysates and collagen-derived peptides have been reported. For example, a collagen peptide shows an effect of improving blood fluidity (Patent Document 1), and a degradation product obtained by treating collagen or gelatin with a protease such as bromelain is effective for maintaining bone tissue function and preventing bone fracture. There is a report (Patent Literature 2), and that a collagen hydrolyzate has a metabolism promoting action (Patent Literature 3).
更に、特許文献４は、Ｈｙｐ−Ｇｌｙ、Ｐｒｏ−Ａｌａ−Ｇｌｙ、Ｇｌｙ−Ｐｒｏ、Ｇｌｕ−Ｈｙｐ−Ｇｌｙ、（Ｐｒｏ−Ｈｙｐ−Ｇｌｙ）5、（Ｐｒｏ−Ｈｙｐ−Ｇｌｙ）2、Ｐｒｏ−Ｈｙｐ−Ｇｌｙ、Ｇｌｕ−Ｈｙｐ、Ａｌａ−Ｈｙｐ−Ｇｌｙ、Ｓｅｒ−Ｈｙｐ−ＧｌｙおよびＰｈｅ−Ｈｙｐからなる群から選択されるペプチドまたはその薬学上許容される塩を含有する、美白促進剤またはアトピー性皮膚炎改善剤を開示する。また、白田ら（非特許文献１）は、コラーゲン由来トリペプチドがアトピー性皮膚炎の炎症を抑制する作用を有することを記載する。さらに、特許文献５は、コラーゲン由来ペプチド類を有効成分として含有するキマーゼ阻害用組成物を開示する。 Further, Patent Document 4 discloses Hy-Gly, Pro-Ala-Gly, Gly-Pro, Glu-Hyp-Gly, (Pro-Hyp-Gly) 5 , (Pro-Hyp-Gly) 2 , and Pro-Hyp-Gly. , A peptide selected from the group consisting of Glu-Hyp, Ala-Hyp-Gly, Ser-Hyp-Gly and Phe-Hyp or a pharmaceutically acceptable salt thereof, a whitening accelerator or an atopic dermatitis ameliorating agent Is disclosed. (Non-Patent Document 1) describe that a collagen-derived tripeptide has an action of suppressing inflammation of atopic dermatitis. Further, Patent Document 5 discloses a composition for inhibiting chymase, which contains collagen-derived peptides as an active ingredient.
アレルギー性鼻炎を引き起こす抗原として、ダニ、花粉などが挙げられる。感作陽性者の鼻粘膜上に抗原が吸入され、鼻粘膜表層に分布するマスト細胞表面のＩｇＥ抗体と結合すると、抗原抗体反応が起こる。その結果放出されたヒスタミン、ロイコトエリンなどの様々な化学伝達物質が鼻粘膜の知覚神経終末や血管と反応することで、アレルギー性鼻炎の症状（くしゃみ、水様性鼻漏、鼻閉（鼻粘膜腫脹））が引き起こされる。その後、ＩＬ−５、ＩＬ−４、ＩＬ−１３などのＴｈ２サイトカイン、種々のケミカルメディエーター等によって、好酸球をはじめとするさまざまな炎症細胞の浸潤が起こる。鼻粘膜のアレルギー性炎症の進行と同時に様々な刺激に対する鼻粘膜の反応性が亢進するといわれる。アレルギー性鼻炎の原因抗原の特定には、血清中特異的ＩｇＥ抗体値検査が用いられる。 Antigens that cause allergic rhinitis include mites, pollen and the like. When the antigen is inhaled onto the nasal mucosa of a sensitized positive person and binds to the IgE antibody on the mast cell surface distributed on the surface layer of the nasal mucosa, an antigen-antibody reaction occurs. Various chemical mediators, such as histamine and leukotoelin, released as a result react with sensory nerve endings and blood vessels in the nasal mucosa to produce symptoms of allergic rhinitis (sneezing, watery rhinorrhea, nasal congestion (nasal mucosal swelling) )) Is caused. Thereafter, infiltration of various inflammatory cells including eosinophils is caused by Th2 cytokines such as IL-5, IL-4 and IL-13, various chemical mediators and the like. It is said that the responsiveness of the nasal mucosa to various stimuli increases simultaneously with the progression of allergic inflammation of the nasal mucosa. A serum-specific IgE antibody level test is used to identify the antigen responsible for allergic rhinitis.
アレルギー性鼻炎の主要な治療法は、抗原回避、薬物療法、手術療法、及び免疫療法の４つである（非特許文献２）。抗原回避は、患者の行動が制限されるという問題がある。薬物療法は広く用いられているが対症療法に留まり、投与を中止すれば短期間で再発する。手術療法は、薬物療法への抵抗性症例に用いられるが、患者の負担は小さくなく、再発の可能性がある。また、根治的な治療を目指して開発されたアレルゲンエキスの舌下免疫療法は、安全性が高く、長期寛解が可能であると言われている。しかし、国内において治療対象となるのはスギ花粉又はダニへのアレルギーに限られる上、長期間（３年から５年の継続が望ましい）の治療が必要である。従って、患者の負担がより小さく、より短期に、アレルギー性鼻炎を予防及び／又は治療できる治療法が求められている。 There are four main treatments for allergic rhinitis: antigen avoidance, drug therapy, surgery, and immunotherapy (Non-Patent Document 2). Antigen evasion has the problem that patient behavior is restricted. Pharmacotherapy is widely used but remains symptomatic and relapses shortly after discontinuation. Surgery is used for cases of resistance to drug therapy, but the burden on the patient is not small and recurrence is possible. In addition, it is said that sublingual immunotherapy of an allergen extract, which has been developed for radical treatment, has high safety and is capable of long-term remission. However, treatment in Japan is limited to allergy to cedar pollen or mites, and requires long-term treatment (preferably for 3 to 5 years). Therefore, there is a need for a treatment that can prevent and / or treat allergic rhinitis in a shorter period of time with less burden on the patient.
上記特許文献４は、特定のコラーゲンペプチドがフィラグリン遺伝子発現を促進させ皮膚バリア機能を高めることにより、アトピー性皮膚炎が改善されることを記載する。非特許文献１は、コラーゲン由来トリペプチドがアトピー性皮膚炎の炎症を抑制する作用を有する可能性があること、及びアトピー性皮膚炎様の炎症を生じているヒトケラチノサイトにおいて、コラーゲン由来トリペプチド処理により、ＴＡＲＣの発現が抑制されたことを記載する。 Patent Document 4 describes that atopic dermatitis is improved by promoting the expression of filaggrin gene by a specific collagen peptide to enhance the skin barrier function. Non-Patent Document 1 discloses that collagen-derived tripeptide may have an effect of suppressing inflammation of atopic dermatitis, and treatment of collagen-derived tripeptide in human keratinocytes having atopic dermatitis-like inflammation Describes that the expression of TARC was suppressed.
アトピー性皮膚炎は、強いかゆみ、皮膚バリアの破たん、免疫暴走の３つの病態が関連する皮膚疾患であり、その定義ではアレルギーの存在は必須ではなく、診断にアレルギーの証明が必須となるアレルギー性鼻炎とは異なる（非特許文献３）。アトピー性皮膚炎の発症に特に重要であるのは皮膚の乾燥による皮膚バリア機能の破たんであることが知られている。特許文献４に記載のペプチドは、皮膚バリアの改善によりアトピー性皮膚炎の発症の可能性を低減するものであるため、皮膚に生じるアレルギーにのみ有効であると考えられる。 Atopic dermatitis is a skin disease that is associated with three conditions: strong itch, broken skin barrier, and immune runaway. The definition of allergy does not require the presence of allergy, and allergy requires proof of allergy for diagnosis. It is different from rhinitis (Non-Patent Document 3). It is known that what is particularly important for the development of atopic dermatitis is the breakdown of the skin barrier function due to drying of the skin. The peptide described in Patent Literature 4 is considered to be effective only for allergies occurring in the skin because it improves the skin barrier and reduces the possibility of developing atopic dermatitis.
また、特許文献４には、ＯＶＡ腹腔内投与したマウスにコラーゲンペプチド投与した結果、血中ＩｇＥが低下したことが記載されている。特許文献４の実施例で測定しているＩｇＥは「総ＩｇＥ」と呼ばれるもので、ＯＶＡ抗原に限らず、皮膚から入るハウスダストやダニなどあらゆるものに反応して上昇しうるため、抗体活性が明確ではないＩｇＥといえる。そのため、特許文献４に記載のコラーゲンペプチド混合物の摂取による体内のＩｇＥ値の抑制については、皮膚バリアが高まり、皮膚内にアレルゲンが侵入しなくなることで、結果的に血中のＩｇＥ値低下が生じている可能性がある。なお、アトピー性皮膚炎の診断では血中のＩｇＥ値は参考にされる程度である。 In addition, Patent Document 4 describes that as a result of administration of a collagen peptide to a mouse to which OVA was intraperitoneally administered, blood IgE was reduced. The IgE measured in the examples of Patent Document 4 is called “total IgE”, and is not limited to OVA antigen, and can increase in response to any substance such as house dust and ticks entering from the skin. It is unclear IgE. Therefore, regarding suppression of the IgE level in the body by ingestion of the collagen peptide mixture described in Patent Document 4, the skin barrier is increased and the allergen does not penetrate into the skin, resulting in a decrease in blood IgE level. Could be. In the diagnosis of atopic dermatitis, the IgE value in blood is of a reference level.
アトピー性皮膚炎では、血清中のＴＡＲＣ（thymus and activation-regulated chemokine）値が重症度を反映するため、重症度評価に用いられている。一方で、アレルギー性鼻炎では、鼻粘膜等局所的にＴＡＲＣ値が上昇することが知られるのみであり、血清中ＴＡＲＣ値はアレルギー性鼻炎の重症度を反映するとは考えられていない。 In atopic dermatitis, the serum TARC (thymus and activation-regulated chemokine) value in serum reflects the severity and is therefore used for severity evaluation. On the other hand, in allergic rhinitis, it is only known that the TARC value locally increases, such as in the nasal mucosa, and the serum TARC value is not considered to reflect the severity of allergic rhinitis.
アレルギー性鼻炎とアトピー性皮膚炎は同じＩ型アレルギーに分類されるが、両者は抗原の種類、抗原との感作の起こる部位が異なっている。また、以上のように、アレルギー性鼻炎とアトピー性皮膚炎は、発生部位、症状の種類が異なっており、検査方法も治療薬も異なる。従って、特許文献４に記載のコラーゲンペプチド及び非特許文献１に記載のコラーゲン由来トリペプチドが、アレルギー性鼻炎の治療等に有用であるかは知られていない。 Allergic rhinitis and atopic dermatitis are classified into the same type I allergy, but they differ in the type of antigen and the site of sensitization with the antigen. In addition, as described above, allergic rhinitis and atopic dermatitis have different sites of occurrence and different types of symptoms, and have different test methods and therapeutic agents. Therefore, it is not known whether the collagen peptide described in Patent Document 4 and the collagen-derived tripeptide described in Non-Patent Document 1 are useful for treating allergic rhinitis and the like.
上記特許文献５は、コラーゲン由来ペプチド類を有効成分として含有するキマーゼ阻害用組成物を開示し、キマーゼに由来する疾患の予防・治療に用いられることが記載されている。キマーゼに由来する疾患として鼻炎が挙げられているが、特許文献５に記載のキマーゼ阻害用組成物はキマーゼによって発症した全身的な諸症状の一つとして発生する鼻炎を、キマーゼの阻害を通して改善するものである。特許文献５に記載のキマーゼ阻害用組成物が、アレルギー性鼻炎の症状の改善に有効であるかは知られていない。 Patent Document 5 discloses a composition for inhibiting chymase containing a collagen-derived peptide as an active ingredient, and describes that the composition is used for prevention and treatment of a disease derived from chymase. Although rhinitis is cited as a disease derived from chymase, the composition for chymase inhibition described in Patent Literature 5 improves rhinitis which occurs as one of systemic symptoms caused by chymase through inhibition of chymase. Things. It is not known whether the composition for chymase inhibition described in Patent Document 5 is effective for improving the symptoms of allergic rhinitis.
以上のように、従来のコラーゲン加水分解物において、アレルギー性鼻炎の予防、治療、症状改善などに効果があるものは報告されていない。そこで本発明の目的は、アレルギー性鼻炎の予防及び／又は治療のための経口投与用医薬やアレルギー性鼻炎の発症を予防し、及び／又は症状を改善するための食品を提供することである。 As described above, none of the conventional collagen hydrolysates has been reported to be effective in preventing, treating, or improving symptoms of allergic rhinitis. Therefore, an object of the present invention is to provide a medicament for oral administration for preventing and / or treating allergic rhinitis and a food for preventing the onset of allergic rhinitis and / or improving symptoms.
本発明者らは、上記課題を解決するために鋭意検討を重ねた結果、トリペプチドＧｌｙ−Ｘ−Ｙを含むコラーゲン加水分解物を投与したアレルギー性鼻炎モデルマウス（ＣＴＰ投与群）では、くしゃみや鼻掻きの回数が減少し、アレルギー性鼻炎の症状が改善されることを見出した。また、ＣＴＰ投与群では、抗原を鼻腔に連日投与しても、くしゃみ回数や鼻掻き回数が増加しなかったことから、アレルギー性鼻炎の発症が予防されたと考えられた。また、ＣＴＰ投与群では、血中の抗原特異的ＩｇＥ値の増加の抑制も観察され、アレルギー反応そのものが抑制されていることが判明した。このような知見に基づいて本発明は完成された。 The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, in the allergic rhinitis model mouse (CTP administration group) to which a collagen hydrolyzate containing the tripeptide Gly-XY was administered, sneezing and It has been found that the number of times of nasal scratching is reduced and the symptoms of allergic rhinitis are improved. In addition, in the CTP-administered group, even if the antigen was administered to the nasal cavity every day, the number of sneezes and the number of nasal scratches did not increase, indicating that the onset of allergic rhinitis was prevented. In the CTP administration group, suppression of an increase in the antigen-specific IgE value in blood was also observed, indicating that the allergic reaction itself was suppressed. The present invention has been completed based on such findings.
本発明によれば以下の発明が提供される。
［１］少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙ（Ｇｌｙ−Ｘ−Ｙはアミノ酸配列であり、Ｘ及びＹは独立にＧｌｙ以外のアミノ酸残基を示す）を含むコラーゲン加水分解物を含む、アレルギー性鼻炎の予防及び／又は治療薬。
［２］前記コラーゲン加水分解物に含まれる少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙが、Ｇｌｙ−Ｐｒｏ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｐｒｏ、Ｇｌｙ−Ｐｒｏ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ｈｙｐ、Ｇｌy−Ａｌａ−Ｐｒｏ、Ｇｌｙ−Ｌｅｕ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ａｒｇ、Ｇｌｙ−Ｓｅｒ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ｌｙｓ、Ｇｌｙ−Ａｌａ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ｌｙｓ、Ｇｌｙ−Ｐｒｏ−Ｓｅｒ、Ｇｌｙ−Ｐｈｅ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｇｌｎ、Ｇｌｙ−Ａｌａ−Ａｌａ、Ｇｌｙ−Ｐｒｏ−Ｖａｌ、Ｇｌｙ−Ａｓｐ−Ａｌａ、Ｇｌｙ−Ｇｌｕ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ａｓｐ、及びＧｌｙ−Ａｒｇ−Ｈｙｐからなる群から選択されるいずれかである、［１］に記載の予防及び／又は治療薬。
［３］前記コラーゲン加水分解物がジペプチドをさらに含む、［１］又は［２］に記載の予防及び／又は治療薬。
［４］前記コラーゲン加水分解物中のトリペプチド及びジペプチドの含有率が少なくとも１０質量％である、［１］〜［３］の何れか一に記載の予防及び／又は治療薬。
［５］アレルギー性鼻炎のアレルゲンが花粉、室内塵及びダニの何れかである、［１］〜［４］のいずれか一に記載のアレルギー性鼻炎の予防及び／又は治療薬。
［６］［１］〜［４］のいずれかに記載のコラーゲン加水分解物を含む、アレルギー性鼻炎の発症予防用及び／又は症状改善用食品。
［７］アレルギー性鼻炎のアレルゲンが花粉、室内塵及びダニの何れかである、［６］に記載のアレルギー性鼻炎の発症予防用及び／又は症状改善用食品。
According to the present invention, the following inventions are provided.
[1] including a collagen hydrolyzate containing at least one kind of tripeptide Gly-XY (Gly-XY is an amino acid sequence, and X and Y independently represent amino acid residues other than Gly). An agent for preventing and / or treating allergic rhinitis.
[2] At least one kind of tripeptide Gly-XY contained in the collagen hydrolyzate is Gly-Pro-Hyp, Gly-Pro-Pro, Gly-Pro-Ala, Gly-Ala-Hyp, Gly- Ala-Pro, Gly-Leu-Hyp, Gly-Glu-Hyp, Gly-Glu-Arg, Gly-Pro-Arg, Gly-Ser-Hyp, Gly-Ala-Lys, Gly-Ala-Arg, Gly-Pro- Lys, Gly-Pro-Ser, Gly-Phe-Hyp, Gly-Pro-Gln, Gly-Ala-Ala, Gly-Pro-Val, Gly-Asp-Ala, Gly-Glu-Ala, Gly-Ala-Asp, And any one selected from the group consisting of Gly-Arg-Hyp, described in [1]. Prophylactic and / or therapeutic agents mentioned.
[3] The prophylactic and / or therapeutic agent according to [1] or [2], wherein the collagen hydrolyzate further contains a dipeptide.
[4] The prophylactic and / or therapeutic agent according to any one of [1] to [3], wherein the content of the tripeptide and the dipeptide in the collagen hydrolyzate is at least 10% by mass.
[5] The preventive and / or therapeutic drug for allergic rhinitis according to any one of [1] to [4], wherein the allergic rhinitis allergen is any of pollen, house dust, and mite.
[6] A food for preventing onset and / or improving symptoms of allergic rhinitis, comprising the collagen hydrolyzate according to any one of [1] to [4].
[7] The food for preventing the onset of allergic rhinitis and / or improving the symptoms according to [6], wherein the allergen of allergic rhinitis is any of pollen, house dust, and mite.
本発明によれば、アレルギー性鼻炎の新たな予防及び／又は治療薬、並びにアレルギー性鼻炎の発症の予防、症状の改善、又は症状の増悪を抑制するための新たな食品を提供することができる。アレルギー性鼻炎の症状の改善とＩｇＥ値の増加抑制の２つの効果を従来の薬物療法で得ようとする場合、最低でも２種類の投薬が必要になる。たとえば、症状の改善のためにはケミカルメディエーター遊離抑制薬あるいはケミカルメディエーター受容体拮抗薬を投与する必要があり、ＩｇＥ値の増加抑制のためにはＴｈ２サイトカイン阻害剤の２種を投薬する必要がある。本発明によれば、異なる薬理作用をもつ複数の処方薬を服用したのに匹敵する効果を得ることができる。 According to the present invention, it is possible to provide a new preventive and / or therapeutic agent for allergic rhinitis and a new food for preventing the onset of allergic rhinitis, ameliorating symptoms, or suppressing exacerbation of symptoms. . In order to achieve the two effects of improving the symptoms of allergic rhinitis and suppressing an increase in the IgE level by conventional drug therapy, at least two types of medication are required. For example, it is necessary to administer a chemical mediator release inhibitor or a chemical mediator receptor antagonist in order to improve symptoms, and it is necessary to administer two Th2 cytokine inhibitors in order to suppress an increase in IgE level. . According to the present invention, an effect equivalent to taking a plurality of prescription drugs having different pharmacological actions can be obtained.
以下に記載する本発明の説明は、代表的な実施形態や具体例に基づいてなされることがあるが、本発明はそのような実施形態に限定されるものではない。なお、本明細書において「〜」を用いて表される数値範囲は「〜」の前後に記載される数値を下限値および上限値として含む範囲を意味する。また、本明細書において、特に記載しない限り、「％」等は質量基準であり、数値範囲はその端点を含むものとして記載される。 The description of the present invention described below may be made based on representative embodiments or specific examples, but the present invention is not limited to such embodiments. In this specification, a numerical range represented by using “to” means a range including numerical values described before and after “to” as a lower limit and an upper limit. In this specification, unless otherwise specified, “%” and the like are based on mass, and numerical ranges are described as including the endpoints.
本発明は、少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙ（Ｇｌｙ−Ｘ−Ｙはアミノ酸配列であり、Ｘ及びＹは独立にＧｌｙ以外のアミノ酸残基を示す）を含むコラーゲン加水分解物を含む、アレルギー性鼻炎の予防及び／又は治療薬を提供する。本明細書中、常法に従って、ペプチドのアミノ酸配列をそのＮ末端のアミノ酸残基が左側に位置し、Ｃ末端のアミノ酸残基が右側に位置するように示す。 The present invention includes a collagen hydrolyzate containing at least one tripeptide Gly-XY (Gly-XY is an amino acid sequence, and X and Y independently represent amino acid residues other than Gly). And a preventive and / or therapeutic agent for allergic rhinitis. In the present specification, the amino acid sequence of the peptide is shown in accordance with a conventional method such that the N-terminal amino acid residue is located on the left side and the C-terminal amino acid residue is located on the right side.
本明細書の「アレルギー性鼻炎」は、鼻腔粘膜にＩ型のアレルギー反応、すなわちＩｇＥ依存型反応が生じる疾患である。アレルギー性鼻炎の症状は、反復性のくしゃみ、水様性鼻漏、鼻閉などである。アレルギー性鼻炎は、純粋にＩｇＥに依存するアレルギーであり、アレルゲンが付着した局所（鼻付近）のみに症状が現れる。本発明によれば、アレルギー性鼻炎を予防及び／又は治療することができる。 As used herein, “allergic rhinitis” is a disease in which a type I allergic reaction, ie, an IgE-dependent reaction, occurs in the nasal mucosa. Symptoms of allergic rhinitis include recurrent sneezing, watery rhinorrhea, and nasal congestion. Allergic rhinitis is an allergy that is purely dependent on IgE, and the symptoms appear only in the local area (near the nose) where the allergen is attached. According to the present invention, allergic rhinitis can be prevented and / or treated.
少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙを含むコラーゲン加水分解物は、特に製造方法が限定されるものではなく、例えば、タンパク質加水分解法、化学合成法、酵素法、発酵法などによって製造することができる。具体的には、ゼラチンまたはコラーゲンの酵素消化精製物であってもよいし、ゼラチンまたはコラーゲンの酵素消化精製物に化学合成したペプチドを添加したものであってよい。コラーゲン加水分解物は、例えば特許第３１４６２５１号公報に記載の方法で調製でき、ある程度精製したコラーゲンあるいは変性コラーゲン（ゼラチン）などを原材料として、プロテアーゼ、ペプチダーゼ等の酵素で加水分解することによって得られる。 The production method of the collagen hydrolyzate containing at least one kind of tripeptide Gly-XY is not particularly limited, and is produced by, for example, a protein hydrolysis method, a chemical synthesis method, an enzyme method, a fermentation method, or the like. be able to. Specifically, it may be an enzymatically digested purified product of gelatin or collagen, or a product obtained by adding a chemically synthesized peptide to an enzymatically digested purified product of gelatin or collagen. The collagen hydrolyzate can be prepared, for example, by the method described in Japanese Patent No. 3146251, and is obtained by hydrolyzing collagen or denatured collagen (gelatin) which has been purified to some extent, with an enzyme such as protease or peptidase.
少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙを含むコラーゲン加水分解物は、Ｉ型コラーゲンのペプチド結合をグリシンのアミノ末端で切断する細菌コラゲナーゼを用いて加水分解することによって得てもよい。コラーゲン加水分解物に含まれるアミノ酸配列：Ｇｌｙ−Ｘ−Ｙからなるトリペプチドの種類は、加水分解の原料となるコラーゲンの種類や加水分解に使用するコラゲナーゼの種類や加水分解条件等により変化しうる。上記コラーゲン加水分解物は、アミノ酸配列：Ｇｌｙ−Ｘ−Ｙからなるトリペプチドを、少なくとも１質量％、少なくとも２質量％、少なくとも３質量％、少なくとも４質量％、少なくとも５質量％、少なくとも１０質量％、少なくとも１５質量％、少なくとも２０質量％、少なくとも２５質量％、少なくとも３０質量％、又は少なくとも３５質量％含むことができる。コラーゲン加水分解物中上記トリペプチドの含有率は、例えば１〜４０質量％、１〜３５質量％、１〜３０質量％、１〜２５質量％、１〜２０質量％、２〜２０質量％、又は５〜２０質量％の範囲であってもよい。コラーゲン加水分解物中のトリペプチド含有率は、例えば特許第４０９９５４１号公報に記載の方法を用いて、高めることができる。 A collagen hydrolyzate containing at least one tripeptide Gly-XY may be obtained by hydrolysis using a bacterial collagenase that cleaves the peptide bond of type I collagen at the amino terminus of glycine. The type of the tripeptide consisting of the amino acid sequence Gly-XY contained in the collagen hydrolyzate can vary depending on the type of collagen used as a raw material for hydrolysis, the type of collagenase used for hydrolysis, hydrolysis conditions, and the like. . The collagen hydrolyzate contains at least 1% by mass, at least 2% by mass, at least 3% by mass, at least 4% by mass, at least 5% by mass, at least 10% by mass of a tripeptide consisting of the amino acid sequence: Gly-XY. , At least 15%, at least 20%, at least 25%, at least 30%, or at least 35% by weight. The content of the tripeptide in the collagen hydrolyzate is, for example, 1 to 40% by mass, 1 to 35% by mass, 1 to 30% by mass, 1 to 25% by mass, 1 to 20% by mass, 2 to 20% by mass, Or it may be in the range of 5 to 20% by mass. The tripeptide content in the collagen hydrolyzate can be increased using, for example, the method described in Japanese Patent No. 4099541.
上記コラーゲン加水分解物に含まれる少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙは、Ｇｌｙ−Ｐｒｏ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｐｒｏ、Ｇｌｙ−Ｐｒｏ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ｈｙｐ、Ｇｌy−Ａｌａ−Ｐｒｏ、Ｇｌｙ−Ｌｅｕ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ａｒｇ、Ｇｌｙ−Ｓｅｒ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ｌｙｓ、Ｇｌｙ−Ａｌａ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ｌｙｓ、Ｇｌｙ−Ｐｒｏ−Ｓｅｒ、Ｇｌｙ−Ｐｈｅ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｇｌｎ、Ｇｌｙ−Ａｌａ−Ａｌａ、Ｇｌｙ−Ｐｒｏ−Ｖａｌ、Ｇｌｙ−Ａｓｐ−Ａｌａ、Ｇｌｙ−Ｇｌｕ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ａｓｐ、及びＧｌｙ−Ａｒｇ−Ｈｙｐからなる群から選択されるいずれかであってもよい。 At least one tripeptide Gly-XY contained in the collagen hydrolyzate is Gly-Pro-Hyp, Gly-Pro-Pro, Gly-Pro-Ala, Gly-Ala-Hyp, Gly-Ala-Pro. , Gly-Leu-Hyp, Gly-Glu-Hyp, Gly-Glu-Arg, Gly-Pro-Arg, Gly-Ser-Hyp, Gly-Ala-Lys, Gly-Ala-Alg, Gly-Pro-Lys, Gly -Pro-Ser, Gly-Phe-Hyp, Gly-Pro-Gln, Gly-Ala-Ala, Gly-Pro-Val, Gly-Asp-Ala, Gly-Glu-Ala, Gly-Ala-Asp, and Gly- Any one selected from the group consisting of Arg-Hyp may be used.
本発明のアレルギー性鼻炎の予防及び／又は治療薬に含まれるコラーゲン加水分解物は、例えば５００〜３０００の範囲の平均分子量を有することができ、分子量が４００より大きい高分子画分を５０〜９５％と、分子量４００以下の低分子画分を５〜５０％含むことができる。低分子画分の主成分はトリペプチド類及びジペプチド類である。分子量が８００より大きい高分子画分は、アミノ酸残基４個以上からなるペプチドからなり、最大でも分子量が１００００程度である。 The collagen hydrolyzate contained in the prophylactic and / or therapeutic agent for allergic rhinitis of the present invention can have an average molecular weight in the range of, for example, 500 to 3000, and a high molecular fraction having a molecular weight of more than 400 in a range of 50 to 95. % And a low molecular fraction having a molecular weight of 400 or less can be contained at 5 to 50%. The main components of the low molecular fraction are tripeptides and dipeptides. The high molecular fraction having a molecular weight of more than 800 is composed of a peptide consisting of four or more amino acid residues, and has a maximum molecular weight of about 10,000.
上記コラーゲン加水分解物は、トリペプチド類及びジペプチド類を合わせて、コラーゲン加水分解物中に少なくとも１０質量％、少なくとも１５質量％、少なくとも２０質量％、少なくとも２５質量％、少なくとも３０質量％、又は少なくとも３５質量％含むことができる。コラーゲン加水分解物中トリペプチド類及びジペプチド類の含有率は、例えば１０〜５０質量％、１０〜４５質量％、１０〜４０質量％、１０〜３５質量％、１０〜３０質量％、１０〜２５質量％、又は１０〜２０質量％の範囲であってもよい。 The collagen hydrolyzate, when combined with the tripeptides and dipeptides, is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or at least 35% by mass. The content of tripeptides and dipeptides in the collagen hydrolyzate is, for example, 10 to 50% by mass, 10 to 45% by mass, 10 to 40% by mass, 10 to 35% by mass, 10 to 30% by mass, 10 to 25% by mass. %, Or in the range of 10 to 20% by weight.
上記コラーゲン加水分解物は、トリペプチドＧｌｙ−Ｘ−Ｙ以外に、任意のコラーゲン由来トリペプチド又はジペプチドを含んでもよい。例えば、上記コラーゲン加水分解物は、Ｐｒｏ−Ｈｙｐ−Ｇｌｙ、Ａｌａ−Ｈｙｐ−Ｇｌｙ、Ｇｌｙ−Ｐｒｏ、Ｐｒｏ−Ｈｙｐ、Ｈｙｐ−Ｇｌｙ、Ａｌａ−Ｈｙｐ、Ｐｒｏ−Ａｌａ、及びＣｙｃｌｏ（Ｇｌｙ−Ｐｒｏ）からなる群から選択されるいずれかをさらに含むことができる。Ｃｙｃｌｏ（Ｇｌｙ−Ｐｒｏ）は、Ｇｌｙ−Ｐｒｏが環状化したものである。 The collagen hydrolyzate may contain any collagen-derived tripeptide or dipeptide in addition to the tripeptide Gly-XY. For example, the collagen hydrolyzate consists of Pro-Hyp-Gly, Ala-Hyp-Gly, Gly-Pro, Pro-Hyp, Hyp-Gly, Ala-Hyp, Pro-Ala, and Cyclo (Gly-Pro). It can further include any selected from the group. Cyclo (Gly-Pro) is a cyclized version of Gly-Pro.
本発明の一態様では、トリペプチドのアミノ酸配列：Ｇｌｙ−Ｘ−Ｙにおいて、Ｘはアミノ酸残基Ｐｒｏ又はＡｌａを示し、ＹはＧｌｙ以外のアミノ酸残基を示すトリペプチドであってもよい。コラーゲンのアミノ酸組成は、グリシン（Ｇｌｙ）が全アミノ酸残基の約１／３を占め、次にプロリン（Ｐｒｏ）とアラニン（Ａｌａ）が多いため、上記アミノ酸配列の位置Ｘのアミノ酸残基は、プロリン（Ｐｒｏ）又はアラニン（Ａｌａ）であることが多い。 In one embodiment of the present invention, in the amino acid sequence of the tripeptide: Gly-XY, X represents an amino acid residue Pro or Ala, and Y may be a tripeptide representing an amino acid residue other than Gly. In the amino acid composition of collagen, glycine (Gly) occupies about 1/3 of all amino acid residues, followed by proline (Pro) and alanine (Ala), so that the amino acid residue at position X in the above amino acid sequence is It is often proline (Pro) or alanine (Ala).
上記アミノ酸配列：Ｇｌｙ−Ｘ−Ｙにおいて、Ｘはアミノ酸残基Ｐｒｏ又はＡｌａを示し、ＹはＧｌｙ以外のアミノ酸残基を示し、トリペプチドは、Ｇｌｙ−Ｐｒｏ−Ａｌａ、Ｇｌｙ−Ｐｒｏ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ｇｌｎ、Ｇｌｙ−Ｐｒｏ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｌｙｓ、Ｇｌｙ−Ｐｒｏ−Ｐｒｏ、Ｇｌｙ−Ｐｒｏ−Ｓｅｒ、Ｇｌｙ−Ｐｒｏ−Ｖａｌ、Ｇｌｙ−Ａｌａ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ａｒｇ、Ｇｌｙ−Ａｌａ−Ａｓｐ、Ｇｌｙ−Ａｌａ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ｌｙｓ、及びＧｌy−Ａｌａ−Ｐｒｏからなる群から選択されるいずれかであってもよい。 In the above amino acid sequence: Gly-XY, X represents an amino acid residue Pro or Ala, Y represents an amino acid residue other than Gly, and tripeptides are Gly-Pro-Ala, Gly-Pro-Arg, and Gly. -Pro-Gln, Gly-Pro-Hyp, Gly-Pro-Lys, Gly-Pro-Pro, Gly-Pro-Ser, Gly-Pro-Val, Gly-Ala-Ala, Gly-Ala-Alg, Gly-Ala -Asp, Gly-Ala-Hyp, Gly-Ala-Lys, and Gly-Ala-Pro.
上記コラーゲン加水分解物は、本願明細書に具体的に列挙したコラーゲン由来トリペプチド又はジペプチドの他に、任意のコラーゲン由来トリペプチド又はジペプチドを含むことができる。 The collagen hydrolyzate can include any collagen-derived tripeptide or dipeptide in addition to the collagen-derived tripeptide or dipeptide specifically listed in the present specification.
コラーゲン加水分解物に含まれる高分子画分および低分子画分の含有率は、高速液体クロマトグラフ（ＨＰＬＣ）によるサイズ排除クロマトグラフィーで分析することができる。分析条件の例を以下に記載する。例えば、カラムとしてＳｕｐｅｒｄｅｘ Ｐｅｐｔｉｄｅ ＨＲ １０／３０（ＧＥヘルスケア）を用いることができ、１．５Ｍの塩化ナトリウムおよび５０ｍＭの塩化カルシウムを含む０．１Ｍ Ｔｒｉｓ−ＨＣｌ（ｐＨ ７．４）水溶液を１．０ｍＬ／ｍｉｎの速度で流すことができる。これに、０．１％濃度で溶媒に溶解したコラーゲン加水分解物溶液を注入し、２１４ｎｍの吸収を検出することで得られるクロマトグラムの面積値から高分子画分および低分子画分の含有率を算出することができる。 The content of the high molecular fraction and the low molecular fraction contained in the collagen hydrolyzate can be analyzed by size exclusion chromatography using high performance liquid chromatography (HPLC). Examples of the analysis conditions are described below. For example, Superdex Peptide HR 10/30 (GE Healthcare) can be used as a column, and a 0.1 M aqueous solution of Tris-HCl (pH 7.4) containing 1.5 M sodium chloride and 50 mM calcium chloride can be used. It can flow at a rate of 0 mL / min. To this, a collagen hydrolyzate solution dissolved in a solvent at a concentration of 0.1% is injected, and the content of the high molecular fraction and the low molecular fraction is determined from the area value of the chromatogram obtained by detecting the absorption at 214 nm. Can be calculated.
コラーゲン加水分解物に含まれるトリペプチド又はジペプチドの同定は、特に限定されないが、例えば、ＨＰＬＣ、ＬＣ−ＭＳ、ＬＣ−ＭＳ／ＭＳを使用して行うことができる。 The identification of the tripeptide or dipeptide contained in the collagen hydrolyzate is not particularly limited, but can be performed using, for example, HPLC, LC-MS, LC-MS / MS.
本発明のコラーゲン加水分解物は、非抗原性および低アレルゲン性コラーゲン加水分解物であるが、さらに種々の方法による精製処理に供することもできる。（Shinmoto H. et al., 2001, Food Sci. Technol. Res., Vol 7, No. 4, 331-332）。 The collagen hydrolyzate of the present invention is a non-antigenic and low allergenic collagen hydrolyzate, but can be further subjected to purification treatment by various methods. (Shinmoto H. et al., 2001, Food Sci. Technol. Res., Vol 7, No. 4, 331-332).
本発明によるアレルギー性鼻炎の予防、治療及び／又は症状の改善効果は、上記コラーゲン加水分解物の摂取によって血中に出現するペプチドのうち、１種、又は２種以上の複合での薬理作用によると考えられる。コラーゲン由来の配列を保有するトリペプチド類やジペプチド類を摂取した場合、トリペプチド類やジペプチド類が高い血中移行性を示すことに加えて、摂取されたトリペプチド類の消化分解により生成した代謝物ジペプチドも高濃度で血中に出現することが報告されている（Yamamoto S. et al., 2015, Bioscience, Biotechnology, and Biochemistry, Vol. 79, No. 12, 2026-2033; Yamamoto S. et al., 2016, Biol. Pharm. Bull. 39, 428-434; Sontakke S. B. et al., 2016, J. Agric. Food Chem. 64, 7127-7133）。 The effect of preventing, treating and / or improving symptoms of allergic rhinitis according to the present invention is due to the pharmacological action of one or two or more of the peptides that appear in the blood upon ingestion of the collagen hydrolyzate. it is conceivable that. When ingesting tripeptides or dipeptides having a sequence derived from collagen, the tripeptides or dipeptides show high blood transportability, as well as metabolism generated by digestion and decomposition of the ingested tripeptides. Dipeptides have also been reported to appear in blood at high concentrations (Yamamoto S. et al., 2015, Bioscience, Biotechnology, and Biochemistry, Vol. 79, No. 12, 2026-2033; Yamamoto S. et. al., 2016, Biol. Pharm. Bull. 39, 428-434; Sontakke SB et al., 2016, J. Agric. Food Chem. 64, 7127-7133).
すなわち、コラーゲン加水分解物を摂取すると、血中代謝物としてトリペプチド類及びジペプチド類が出現し、次にそれらが組織へと移行して生理活性を発揮することで薬理作用が現れることから、はじめからトリペプチド類などを含有するコラーゲン加水分解物では、トリペプチド類及びジペプチド類の吸収性がより向上することで、より高い薬理活性が得られると考えられる。 In other words, when collagen hydrolyzate is ingested, tripeptides and dipeptides appear as metabolites in the blood, and then migrate to tissues to exert physiological activities, thereby exhibiting a pharmacological action. Therefore, it is considered that a collagen hydrolyzate containing tripeptides and the like can obtain higher pharmacological activity by further improving the absorbability of tripeptides and dipeptides.
更には、平均分子量５０００のゼラチン加水分解物を摂取した場合、血中には多様なトリペプチド類、あるいはジペプチド類が代謝物として出現することが報告されている（Iwai K. et al., J. Agric. Food Chem. 2005, 53, 6531-6536; Ichikawa S. et al., International Journal of Food Sciences and Nutrition, February 2010; 61(1): 52-60）。それらの代謝物はゼラチン加水分解物中の高分子画分のペプチドから生成したものであると考えられる。このことから、本発明のコラーゲン加水分解物の高分子画分のペプチドも薬理活性を有する成分の前駆体として重要な成分であると考えられる。 Furthermore, it has been reported that various tripeptides or dipeptides appear as metabolites in blood when a gelatin hydrolyzate having an average molecular weight of 5000 is ingested (Iwai K. et al., J Agric. Food Chem. 2005, 53, 6531-6536; Ichikawa S. et al., International Journal of Food Sciences and Nutrition, February 2010; 61 (1): 52-60). These metabolites are believed to have been formed from peptides of the high molecular fraction in the gelatin hydrolysate. From this, it is considered that the peptide of the high molecular fraction of the collagen hydrolyzate of the present invention is also an important component as a precursor of the pharmacologically active component.
本発明のアレルギー性鼻炎の予防及び／又は治療薬は、種々の剤型とすることができる。例えば、経口投与剤としては錠剤、顆粒剤、散材、カプセル剤、ソフトカプセル剤等の固形剤、溶液剤、懸濁剤、乳化剤等の液剤、凍結乾燥剤等が挙げられる。局所薬としては、噴霧剤が挙げられる。トリペプチドＧｌｙ−Ｘ−Ｙは鼻粘膜から吸収されるためである。本発明のアレルギー性鼻炎の予防及び／又は治療薬は、コラーゲン加水分解物の他に、医薬として許容される添加物を含むことができる。医薬として許容される添加物は、例えば安定化剤、滑剤、湿潤剤、乳化剤、結合剤、ｐＨ調整剤、保存剤等である。 The preventive and / or therapeutic agent for allergic rhinitis of the present invention can be in various dosage forms. For example, examples of the oral administration preparation include solid preparations such as tablets, granules, powders, capsules and soft capsules, liquid preparations such as solutions, suspensions and emulsifiers, and lyophilized preparations. Topicals include sprays. This is because the tripeptide Gly-XY is absorbed from the nasal mucosa. The preventive and / or therapeutic agent for allergic rhinitis of the present invention can contain a pharmaceutically acceptable additive in addition to the collagen hydrolyzate. Pharmaceutically acceptable additives are, for example, stabilizers, lubricants, wetting agents, emulsifiers, binders, pH adjusters, preservatives and the like.
本発明のアレルギー性鼻炎の予防及び／又は治療薬は、有効成分であるコラーゲン加水分解物を、コラーゲン加水分解物に含まれるトリペプチド類及びジペプチド類の濃度によっても異なるが、例えば、トリペプチド類及びジペプチド類を１５質量％含有するコラーゲン加水分解物の場合、１日につき体重１ｋｇあたり１０〜１０００ｍｇ、好ましくは１００〜１０００ｍｇ、より好ましくは３００〜１０００ｍｇ、１日１回または数回に分けて投与することができる。投与量は、ペプチドの特性、罹患者の年齢、体重、症状の違い、症状の程度、剤型等により適宜調節することができる。 The preventive and / or therapeutic agent for allergic rhinitis of the present invention differs from the collagen hydrolyzate as an active ingredient depending on the concentration of tripeptides and dipeptides contained in the collagen hydrolyzate. And in the case of collagen hydrolyzate containing 15% by mass of dipeptides, 10 to 1000 mg, preferably 100 to 1000 mg, more preferably 300 to 1000 mg per kg of body weight per day, administered once or several times a day can do. The dose can be appropriately adjusted depending on the characteristics of the peptide, the age and weight of the affected patient, the difference in symptoms, the degree of symptoms, the dosage form, and the like.
また、コラーゲン加水分解物、あるいは上記のトリペプチド類、ジペプチド類は生体構成成分であると共に、すでに長年の使用経験があるコラーゲン加水分解物に含有されている成分であることから、安全性が高いと考えられる。 In addition, collagen hydrolyzate, or the above-mentioned tripeptides and dipeptides are biological components, and because they are components contained in collagen hydrolysates that have already been used for many years, safety is high. it is conceivable that.
アレルギー性鼻炎の原因物質（アレルゲン、抗原）として、花粉、室内塵、ダニ等が知られている。花粉症は、花粉を原因物質とする季節性アレルギー性鼻炎である。春のスギやヒノキの花粉症の罹患者は非常に多く、そのほか、夏のイネ科の植物や秋のブタクサなどの花粉症がある。花粉症を引き起こす花粉の例としては、スギ、ヒノキ、アカマツ、イチョウ、ネズ、ケヤキ、シラカンバ、オオヤシャブシ、コナラ、クリ、オリーブ、ハンノキ、カモガヤなどのイネ科、ヨモギやブタクサなどのキク科の花粉などがある。室内塵、ダニ等は、季節を問わず現れる通年性アレルギー性鼻炎の原因物質となる。室内塵は、ハウスダストともいい、ダニの死骸やフン、ペットの毛、花粉、真菌などを含むほこりである。通年性アレルギー性鼻炎の原因となる主なダニの例は、コナヒョウヒダニやヤケヒョウヒダニなどである。本発明の予防及び／又は治療薬は、原因物質が花粉、室内塵及びダニの何れかであるアレルギー性鼻炎の予防及び／又は治療に有効である。 As pollutants (allergens, antigens) of allergic rhinitis, pollen, house dust, mites and the like are known. Pollen allergy is seasonal allergic rhinitis caused by pollen. The susceptibility of cedar and cypress to hay fever in spring is extremely large, and there are also hay fever such as grasses in summer and ragweed in autumn. Examples of pollen that cause hay fever include cedar, cypress, red pine, ginkgo, rat, zelkova, birch, oyster shark, oak, chestnut, olive, alder, duckweed and other asteraceae, and asteraceae such as mugwort and ragweed. and so on. House dust, mites, and the like are the causative substances of perennial allergic rhinitis that appears regardless of the season. House dust is also called house dust, and is dust including dead mites and dung, pet hair, pollen, fungi, and the like. Examples of major mites that cause perennial allergic rhinitis are Dermatophagoides farinae and Dermatophagoides pteronyssinus. The prophylactic and / or therapeutic agent of the present invention is effective in preventing and / or treating allergic rhinitis in which the causative substance is any of pollen, house dust, and mite.
[食品、機能性表示食品、特定保健用食品]
本発明は、上記のコラーゲン加水分解物を含む、アレルギー性鼻炎の発症予防用及び／又は症状改善用食品を包含する。前述のように、日本におけるアレルギー性鼻炎の罹患率は３０〜４０％と非常に高い。本発明の食品は、アレルギー性鼻炎の発症の予防及び症状の改善に有効であり、アレルギー性鼻炎の発症の予防及び症状の改善を必要とする多くの人々に用いることができる。
[Food, Functional food, Food for specified health use]
The present invention includes a food for preventing the onset of allergic rhinitis and / or improving the symptoms, comprising the above-mentioned collagen hydrolyzate. As mentioned above, the prevalence of allergic rhinitis in Japan is as high as 30 to 40%. The food of the present invention is effective for prevention of onset of allergic rhinitis and improvement of symptoms, and can be used for many people who need to prevent onset of allergic rhinitis and improve symptoms.
本発明の食品に含まれるコラーゲン加水分解物は、上記のアレルギー性鼻炎の予防及び／又は治療薬に含まれるものと同様である。具体的には、本発明のアレルギー性鼻炎の発症予防用及び／又は症状改善用食品に含まれるコラーゲン加水分解物は、少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙ（Ｇｌｙ−Ｘ−Ｙはアミノ酸配列であり、Ｘ及びＹは独立にＧｌｙ以外のアミノ酸残基を示す）を含むことができる。 The collagen hydrolyzate contained in the food of the present invention is the same as that contained in the above preventive and / or therapeutic drug for allergic rhinitis. Specifically, the collagen hydrolyzate contained in the food for preventing the onset of allergic rhinitis and / or improving the symptoms of the present invention contains at least one kind of tripeptide Gly-XY (Gly-XY is an amino acid). X and Y independently represent amino acid residues other than Gly).
上記コラーゲン加水分解物に含まれる少なくとも１種類のトリペプチドＧｌｙ−Ｘ−Ｙは、Ｇｌｙ−Ｐｒｏ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｐｒｏ、Ｇｌｙ−Ｐｒｏ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ｈｙｐ、Ｇｌy−Ａｌａ−Ｐｒｏ、Ｇｌｙ−Ｌｅｕ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ａｒｇ、Ｇｌｙ−Ｓｅｒ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ｌｙｓ、Ｇｌｙ−Ａｌａ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ｌｙｓ、Ｇｌｙ−Ｐｒｏ−Ｓｅｒ、Ｇｌｙ−Ｐｈｅ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｇｌｎ、Ｇｌｙ−Ａｌａ−Ａｌａ、Ｇｌｙ−Ｐｒｏ−Ｖａｌ、Ｇｌｙ−Ａｓｐ−Ａｌａ、Ｇｌｙ−Ｇｌｕ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ａｓｐ、及びＧｌｙ−Ａｒｇ−Ｈｙｐからなる群から選択されるいずれかであってもよい。 At least one tripeptide Gly-XY contained in the collagen hydrolyzate is Gly-Pro-Hyp, Gly-Pro-Pro, Gly-Pro-Ala, Gly-Ala-Hyp, Gly-Ala-Pro. , Gly-Leu-Hyp, Gly-Glu-Hyp, Gly-Glu-Arg, Gly-Pro-Arg, Gly-Ser-Hyp, Gly-Ala-Lys, Gly-Ala-Alg, Gly-Pro-Lys, Gly -Pro-Ser, Gly-Phe-Hyp, Gly-Pro-Gln, Gly-Ala-Ala, Gly-Pro-Val, Gly-Asp-Ala, Gly-Glu-Ala, Gly-Ala-Asp, and Gly- Any one selected from the group consisting of Arg-Hyp may be used.
上記コラーゲン加水分解物は、トリペプチドＧｌｙ−Ｘ−Ｙ以外に、任意のコラーゲン由来トリペプチド又はジペプチドを含んでもよい。例えば、上記コラーゲン加水分解物は、Ｐｒｏ−Ｈｙｐ−Ｇｌｙ、Ａｌａ−Ｈｙｐ−Ｇｌｙ、Ｇｌｙ−Ｐｒｏ、Ｐｒｏ−Ｈｙｐ、Ｈｙｐ−Ｇｌｙ、Ａｌａ−Ｈｙｐ、Ｐｒｏ−Ａｌａ、及びＣｙｃｌｏ（Ｇｌｙ−Ｐｒｏ）からなる群から選択されるいずれかをさらに含むことができる。 The collagen hydrolyzate may contain any collagen-derived tripeptide or dipeptide in addition to the tripeptide Gly-XY. For example, the collagen hydrolyzate consists of Pro-Hyp-Gly, Ala-Hyp-Gly, Gly-Pro, Pro-Hyp, Hyp-Gly, Ala-Hyp, Pro-Ala, and Cyclo (Gly-Pro). It can further include any selected from the group.
上記トリペプチドのアミノ酸配列：Ｇｌｙ−Ｘ−Ｙにおいて、Ｘはアミノ酸残基Ｐｒｏ又はＡｌａを示し、ＹはＧｌｙ以外のアミノ酸残基を示すアミノ酸配列からなるものであってもよく、具体的には、Ｇｌｙ−Ｐｒｏ−Ａｌａ、Ｇｌｙ−Ｐｒｏ−Ａｒｇ、Ｇｌｙ−Ｐｒｏ−Ｇｌｎ、Ｇｌｙ−Ｐｒｏ−Ｈｙｐ、Ｇｌｙ−Ｐｒｏ−Ｌｙｓ、Ｇｌｙ−Ｐｒｏ−Ｐｒｏ、Ｇｌｙ−Ｐｒｏ−Ｓｅｒ、Ｇｌｙ−Ｐｒｏ−Ｖａｌ、Ｇｌｙ−Ａｌａ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ａｒｇ、Ｇｌｙ−Ａｌａ−Ａｓｐ、Ｇｌｙ−Ａｌａ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ｌｙｓ、及びＧｌy−Ａｌａ−Ｐｒｏからなる群から選択されるいずれかであってもよい。 In the amino acid sequence of the above tripeptide: Gly-XY, X represents an amino acid residue Pro or Ala, and Y may consist of an amino acid sequence representing an amino acid residue other than Gly. Gly-Pro-Ala, Gly-Pro-Arg, Gly-Pro-Gln, Gly-Pro-Hyp, Gly-Pro-Lys, Gly-Pro-Pro, Gly-Pro-Ser, Gly-Pro-Val, Gly -Ala-Ala, Gly-Ala-Arg, Gly-Ala-Asp, Gly-Ala-Hyp, Gly-Ala-Lys, and Gly-Ala-Pro may be any one selected from the group consisting of:
本発明において食品は、経口摂取可能な任意の形態であればよく、例えば、溶液、懸濁液、粉末、固体成形物などであってもよい。本発明の食品としては、上記コラーゲン加水分解物を含む錠剤、顆粒剤、カプセル剤、ソフトカプセル剤及びドリンク剤等のサプリメント、あるいは上記コラーゲン加水分解物を配合した食品（飲料を含む）を挙げることができる。本発明の一態様において食品は、機能性食品または特定保健用食品である。本発明の食品は、アレルギー性鼻炎の発症の予防及び症状の改善に有効であることから、アレルギー性鼻炎の発症の予防及び症状の改善を必要とする多くの人々に用いることができる。 In the present invention, the food may be in any form that can be taken orally, and may be, for example, a solution, a suspension, a powder, a solid molded product, or the like. Examples of the food of the present invention include supplements such as tablets, granules, capsules, soft capsules and drinks containing the above-mentioned collagen hydrolyzate, or foods (including beverages) containing the above-mentioned collagen hydrolyzate. it can. In one embodiment of the present invention, the food is a functional food or a food for specified health use. Since the food of the present invention is effective in preventing the onset of allergic rhinitis and improving symptoms, it can be used for many people who need to prevent the onset of allergic rhinitis and improve symptoms.
本発明の食品に含まれるコラーゲン加水分解物は、トリペプチドＧｌｙ−Ｘ−Ｙを、少なくとも１質量％、少なくとも２質量％、少なくとも３質量％、少なくとも４質量％、少なくとも５質量％、少なくとも１０質量％、少なくとも１５質量％、少なくとも２０質量％、少なくとも２５質量％、少なくとも３０質量％、又は少なくとも３５質量％含むことができる。コラーゲン加水分解物中上記トリペプチドの含有率は、例えば１〜４０質量％、１〜３５質量％、１〜３０質量％、１〜２５質量％、１〜２０質量％、２〜２０質量％、又は５〜２０質量％の範囲であってもよい。 The collagen hydrolyzate contained in the food of the present invention contains at least 1% by mass, at least 2% by mass, at least 3% by mass, at least 4% by mass, at least 5% by mass, at least 10% by mass of the tripeptide Gly-XY. %, At least 15%, at least 20%, at least 25%, at least 30%, or at least 35% by weight. The content of the tripeptide in the collagen hydrolyzate is, for example, 1 to 40% by mass, 1 to 35% by mass, 1 to 30% by mass, 1 to 25% by mass, 1 to 20% by mass, 2 to 20% by mass, Or it may be in the range of 5 to 20% by mass.
トリペプチドＧｌｙ−Ｘ−Ｙの濃度が低いコラーゲン加水分解物では、トリペプチドＧｌｙ−Ｘ−Ｙ以外の成分、特に、加水分解の程度が低い高分子量の成分が多くなり、食品への添加に支障をきたす場合もある。そこで、所望の効能とコスト（費用）、さらには食品への添加のし易さ等を考慮して、使用するトリペプチドＧｌｙ−Ｘ−Ｙを含有するコラーゲン加水分解物の純度を決めることが適当である。例えば、機能性食品においては、価格をある程度抑制したい場合があり、そのような場合には、トリペプチドＧｌｙ−Ｘ−Ｙの含有率は、好ましくは１０〜２５質量％であることが適当である。但し、特定保健用食品では、効果の発現をより確実にしたい場合があり、そのような場合には、トリペプチドＧｌｙ−Ｘ−Ｙの含有率は、好ましくは２５〜４０質量％であることが適当である。 In the collagen hydrolyzate having a low concentration of the tripeptide Gly-XY, components other than the tripeptide Gly-XY, particularly, high-molecular-weight components having a low degree of hydrolysis increase, which hinders addition to food. May be caused. Therefore, it is appropriate to determine the purity of the collagen hydrolyzate containing the tripeptide Gly-XY to be used in consideration of the desired effect and cost (cost), and the ease of addition to food. It is. For example, in the case of functional foods, it may be desirable to suppress the price to some extent. In such a case, the content of the tripeptide Gly-XY is preferably from 10 to 25% by mass. . However, in the case of foods for specified health use, there are cases where it is desired to more reliably exert the effect. In such a case, the content of the tripeptide Gly-XY is preferably 25 to 40% by mass. Appropriate.
本発明の食品に含まれるコラーゲン加水分解物は、トリペプチド類及びジペプチド類を合わせて、コラーゲン加水分解物中に少なくとも１０質量％、少なくとも１５質量％、少なくとも２０質量％、少なくとも２５質量％、少なくとも３０質量％、又は少なくとも３５質量％含むことができる。コラーゲン加水分解物中トリペプチド類及びジペプチド類の含有率は、例えば１０〜５０質量％、１０〜４５質量％、１０〜４０質量％、１０〜３５質量％、１０〜３０質量％、１０〜２５質量％、又は１０〜２０質量％の範囲であってもよい。 Collagen hydrolyzate contained in the food of the present invention is at least 10% by mass, at least 15% by mass, at least 20% by mass, at least 25% by mass, at least 30% by weight, or at least 35% by weight. The content of tripeptides and dipeptides in the collagen hydrolyzate is, for example, 10 to 50% by mass, 10 to 45% by mass, 10 to 40% by mass, 10 to 35% by mass, 10 to 30% by mass, 10 to 25% by mass. %, Or in the range of 10 to 20% by weight.
本発明の食品は、コラーゲン加水分解物を、コラーゲン加水分解物に含まれるトリペプチド類及びジペプチド類の濃度によっても異なるが、例えば、トリペプチド類及びジペプチド類を１５質量％含有するコラーゲン加水分解物の場合、１日につき体重１ｋｇあたり１０〜１０００ｍｇ、好ましくは１００〜１０００ｍｇ、より好ましくは３００〜１０００ｍｇ、１日１回または数回に分けて経口摂取することができる。 The food of the present invention differs depending on the concentration of tripeptides and dipeptides contained in the collagen hydrolyzate. For example, a collagen hydrolyzate containing 15% by mass of tripeptides and dipeptides In the case of the above, it can be taken orally in 10 to 1000 mg, preferably 100 to 1000 mg, more preferably 300 to 1000 mg per kg of body weight per day, once or several times a day.
コラーゲン加水分解物、あるいは上記のトリペプチド類、ジペプチド類は生体構成成分であると共に、すでに長年の使用経験があるコラーゲン加水分解物に含有されている成分であることから、安全性が高いと考えられる。 Collagen hydrolyzate, or the above-mentioned tripeptides and dipeptides are considered to be highly safe because they are components contained in the collagen hydrolyzate that has been used for many years, as well as being a biological component. Can be
本発明の食品は、原因物質が花粉、室内塵及びダニの何れかであるアレルギー性鼻炎の発症の予防及び症状の改善にも有効であることから、アレルギー性鼻炎の発症の予防及び症状の改善を必要とする多くの人々に用いることができる。 The food of the present invention is also effective in preventing the onset and improving symptoms of allergic rhinitis in which the causative substance is any of pollen, house dust, and mite, thus preventing the onset of allergic rhinitis and improving the symptoms. Can be used for many people in need.
以下に説明する本発明の実施例は例示のみを目的とし、本発明の技術的範囲を限定するものではない。本発明の技術的範囲は特許請求の範囲の記載によってのみ限定される。本発明の趣旨を逸脱しないことを条件として、本発明の変更、例えば、本発明の構成要件の追加、削除および置換を行うことができる。 The embodiments of the present invention described below are for the purpose of illustration only, and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the claims. Modifications of the present invention, for example, additions, deletions, and replacements of constituent elements of the present invention, can be made on condition that they do not depart from the gist of the present invention.
実施例１
（１）試験溶液の調製
試験物質としてコラーゲン加水分解物「コラーゲン・トリペプチド」（ゼライス株式会社にて作成）を使用した。上記コラーゲン加水分解物の平均分子量は約１５００であり、トリペプチド類及びジペプチド類が主成分である低分子画分を約１５％と、トリペプチドよりも分子量が大きい、アミノ酸４個以上の加水分解物からなる高分子画分を約８５％含む。
ＬＣ−ＭＳ法により、上記コラーゲン加水分解物に含まれるペプチドを分析した。実験条件は以下のとおりである。装置としてＡＣＱＵＩＴＹ ＵＹＰＬＣ Ｈ−Ｃｌａｓｓ Ｓｙｓｔｅｍ ｗｉｔｈ ＳＱ Ｄｅｔｅｃｔｏｒ２（ウォーターズ社）、カラムとしてＡＣＣＱ−ＴＡＧ ＵＬＴＡ Ｃ１８（ウォーターズ社、直径２．１×１００ｍｍ、粒子径１．７μｍ）を用いた。溶媒Ａに０．１％ギ酸水溶液を、溶媒Ｂとして０．１％ギ酸を含む５０％アセトニトリル水溶液を用い、カラム温度４５℃の条件で０．６ｍＬ／ｍｉｎの速度で溶媒を流した。グラジエント条件として、０〜５分まで溶媒Ａを１００％、５〜１０分まで溶媒Ｂを徐々に２５％まで上昇させた。これに０．１％で溶媒Ａに溶解したコラーゲン加水分解物水溶液を注入し、各トリペプチドの質量を検出することで分析した。
Example 1
(1) Preparation of test solution As a test substance, a collagen hydrolyzate “collagen tripeptide” (produced by ZELICE Co., Ltd.) was used. The above collagen hydrolyzate has an average molecular weight of about 1500, a low molecular fraction containing tripeptides and dipeptides as a main component of about 15%, and hydrolysis of 4 or more amino acids having a molecular weight larger than that of the tripeptide. About 85% of the high molecular fraction of the product.
The peptides contained in the collagen hydrolyzate were analyzed by LC-MS. The experimental conditions are as follows. ACQUITY UYPLC H-Class System with SQ Detector 2 (Waters) was used as an apparatus, and ACCQ-TAG ULTA C18 (Waters, diameter 2.1 × 100 mm, particle diameter 1.7 μm) was used as a column. A 0.1% formic acid aqueous solution was used as the solvent A, and a 50% acetonitrile aqueous solution containing 0.1% formic acid was used as the solvent B. The solvent was flowed at a rate of 0.6 mL / min at a column temperature of 45 ° C. As gradient conditions, the solvent A was gradually increased to 100% from 0 to 5 minutes, and the solvent B was gradually increased to 25% from 5 to 10 minutes. An aqueous solution of collagen hydrolyzate dissolved in solvent A at 0.1% was injected into this, and analysis was performed by detecting the mass of each tripeptide.
ＬＣ−ＭＳ法により、表１に記載のトリペプチド類及びジペプチド類が検出された。
表１に記載のペプチドほか、Ｇｌｙ−Ａｌａ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ｐｒｏ、Ｇｌｙ−Ｐｒｏ−Ｖａｌ、Ｇｌｙ−Ｐｒｏ−Ｌｙｓ、Ｇｌｙ−Ｓｅｒ−Ｈｙｐ、Ｇｌｙ−Ａｌａ−Ａｌａ、Ｇｌｙ−Ｇｌｕ−Ｈｙｐ、Ｇｌｙ−Ｐｈｅ−Ｈｙｐ、Ｇｌｙ−Ｇｌｕ−Ａｒｇ、Ｇｌｙ−Ａｌａ−Ｌｙｓ、Ｇｌｙ−Ａｓｐ−Ａｌａ、Ｇｌｙ−Ｇｌｕ−Ａｌａ、Ｇｌｙ−Ａｌａ−Ａｓｐ、Ｇｌｙ−Ａｒｇ−Ｈｙｐ、Ｐｒｏ−Ｈｙｐ−Ｇｌｙ、Ａｌａ−Ｈｙｐ−Ｇｌｙが、各々０．００１％〜０．０５％の範囲で検出された。 In addition to the peptides described in Table 1, Gly-Ala-Hyp, Gly-Ala-Pro, Gly-Pro-Val, Gly-Pro-Lys, Gly-Ser-Hyp, Gly-Ala-Ala, Gly-Glu-Hyp, Gly-Phe-Hyp, Gly-Glu-Arg, Gly-Ala-Lys, Gly-Asp-Ala, Gly-Glu-Ala, Gly-Ala-Asp, Gly-Arg-Hyp, Pro-Hyp-Gly, Ala- Hyp-Gly was detected in the range of 0.001% to 0.05%, respectively.
上記コラーゲン加水分解物において検出されたトリペプチド類及びジペプチド類の合計は、コラーゲン加水分解物中約１５質量％であった。そのうち、トリペプチド類は、コラーゲン加水分解物中約１３質量％であった。上記コラーゲン加水分解物を水道水１００ｍＬあたり、５０ｍｇ（以下、ＬＤ（Ｌｏｗ Ｄｏｓｅ）溶液）又は１８０ｍｇ（以下、ＨＤ（Ｈｉｇｈ Ｄｏｓｅ）溶液）溶解したものを、試験溶液として、以下の実施例で用いた。 The total of tripeptides and dipeptides detected in the collagen hydrolyzate was about 15% by mass in the collagen hydrolyzate. Among them, tripeptides accounted for about 13% by mass in the collagen hydrolyzate. The above-mentioned collagen hydrolyzate dissolved in 50 mg (hereinafter, LD (Low Dose) solution) or 180 mg (hereinafter, HD (High Dose) solution) per 100 mL of tap water was used as a test solution in the following Examples. .
実施例２
＜アレルギー性鼻炎モデルマウス（アレルゲン感作マウス）による試験＞
（１）アレルギー性鼻炎モデルマウスの作成
６週齢のＢＡＬＢ／ｃ 雌性マウス（日本クレア株式会社）を、室温２４±２℃、湿度５１±１３％、明暗サイクル（明期７：００−１９：００）の条件下である動物飼育室で飼育した。餌および水は自由摂取とし、餌は固形飼料ＣＥ−２（日本クレア株式会社）を使用した。
Example 2
<Test using allergic rhinitis model mouse (allergen-sensitized mouse)>
(1) Preparation of allergic rhinitis model mouse A 6-week-old BALB / c female mouse (CLEA Japan) was subjected to room temperature 24 ± 2 ° C., humidity 51 ± 13%, light-dark cycle (light period 7: 00-19: (00) in an animal breeding room. Food and water were freely available, and solid feed CE-2 (CLEA Japan) was used.
マウス購入から１週間後をＤａｙ０とし、卵白アルブミン（Ｇｒａｄｅ Ｖ、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ社）１μｇと水酸化アルミニウムゲル（ＡＬＵＭ、ＬＳＬ）１００μｇを、２００μＬの生理食塩水に溶解し、Ｄａｙ０とＤａｙ５に腹腔内投与することにより全身感作を行った。その後、Ｄａｙ１４からＤａｙ３５まで卵白アルブミン溶液（１００ｍｇ／ｍＬ 生理食塩水）を両鼻腔に２μＬずつ、マイクロピペットを用いて連日投与した。 One week after the mouse was purchased, it was designated as Day 0, and 1 μg of ovalbumin (Grade V, Sigma-Aldrich) and 100 μg of aluminum hydroxide gel (ALUM, LSL) were dissolved in 200 μL of physiological saline, and intraperitoneally on Day 0 and Day 5. The whole body was sensitized by administration. Thereafter, from Day 14 to Day 35, an ovalbumin solution (100 mg / mL physiological saline) was administered to both nasal passages by 2 μL each day using a micropipette.
（２）試験溶液の投与
実施例１で調製した試験溶液を、Ｄａｙ０からＤａｙ３５まで給水瓶からマウスに自由摂取させた。なお、ＬＤ溶液を投与した群をＬＤ群、ＨＤ溶液を投与した群をＨＤ群とした。以下、両群を合わせてＣＴＰ投与群と記載する。コントロール群には水道水を摂取させた。試験溶液は毎日新しいものに取り替えた。マウス１匹の体重を約２３ｇ、１日の飲水量を約４．５ｍＬとすると、試験物質の一日投与量は、体重１ｋｇあたりＬＤ群で約９８ｍｇ／ｋｇ／ｄａｙ、ＨＤ群で約３５２ｍｇ／ｋｇ／ｄａｙとなる。
(2) Administration of Test Solution Mice were allowed to freely ingest the test solution prepared in Example 1 from the water bottle from Day 0 to Day 35. The group to which the LD solution was administered was referred to as an LD group, and the group to which the HD solution was administered was referred to as an HD group. Hereinafter, both groups are collectively referred to as a CTP administration group. The control group received tap water. The test solution was replaced with a new one every day. Assuming that the weight of one mouse is about 23 g and the daily drinking water is about 4.5 mL, the daily dose of the test substance is about 98 mg / kg / day in the LD group and about 352 mg / kg in the HD group per kg of body weight. kg / day.
（３）鼻炎症状の観察
鼻炎症状の観察前に、マウスを観察用ケージ（２１×３１×１３ｃｍ3）に１０分間放置して馴化した。その後、卵白アルブミン溶液（１００ｍｇ/ｍＬ 生理食塩水）を２μＬずつ両鼻腔に点鼻投与後、観察用ケージに戻し、くしゃみと鼻掻き回数を１０分間計測した。鼻炎症状の観察はＤａｙ０から実験終了まで、週に１回行った。
(3) Observation of rhinitis symptoms Before observation of rhinitis symptoms, the mice were acclimated by leaving them in observation cages (21 × 31 × 13 cm 3 ) for 10 minutes. Thereafter, 2 μL of an ovalbumin solution (100 mg / mL physiological saline) was instilled into both nasal cavities, returned to the observation cage, and the number of sneezing and nasal scratching was counted for 10 minutes. The observation of rhinitis was performed once a week from Day 0 to the end of the experiment.
（４）卵白アルブミン特異的ＩｇＥ抗体の測定
Ｄａｙ０とＤａｙ３５にマウスの尾静脈より、ヘパリン処理したヘマトクリット毛細管を用いて血液を採取した。ヘマトクリット遠心機（ＫＵＢＯＴＡ３２００）を用いて血液を遠心分離（12000 rpm、５分間）し、血漿を−３０℃で保存した。その後、ＥＩＡキット（Ｃａｙｍａｎ Ｃｈｅｍｉｃａｌ社）を用いて、卵白アルブミン特異的ＩｇＥ抗体の濃度を測定した。
(4) Measurement of ovalbumin-specific IgE antibody Blood was collected from Day 0 and Day 35 from the tail vein of the mouse using heparin-treated hematocrit capillary tubes. Blood was centrifuged (12000 rpm, 5 minutes) using a hematocrit centrifuge (KUBOTA3200), and the plasma was stored at -30 ° C. Thereafter, the concentration of the ovalbumin-specific IgE antibody was measured using an EIA kit (Cayman Chemical).
（５）統計方法
データは平均値±標準誤差で表示し、統計処理として、一元配置分散分析とTukey-Kramer法による多重比較を行った。有意差の基準は、Ｐ＜０．０５とした。
(5) Statistical method The data were expressed as mean ± standard error, and as statistical processing, one-way analysis of variance and multiple comparisons by the Tukey-Kramer method were performed. The criterion for significant difference was P <0.05.
結果を、図１に示す。結果から示されるように、コントロール群ではアレルギー性鼻炎症状が経時的に増悪しているが、コントロール群に比較し、ＣＴＰ投与群ではアレルギー性鼻炎症状の増悪が抑制された。特に、ＨＤ群は、くしゃみ回数や鼻掻き回数がともに、コントロール群に比較し、有意に少ないことが示された。Ｄａｙ１４からＤａｙ３５まで卵白アルブミン溶液を連日投与しているが、ＨＤ群では、Ｄａｙ０からＤａｙ７までと比較して、Ｄａｙ１４以降も、くしゃみ回数や鼻掻き回数が増加していないことから、アレルギー性鼻炎の発症が予防されたと解釈することができる。 The results are shown in FIG. As can be seen from the results, the allergic rhinitis state worsened over time in the control group, but the exacerbation of the allergic rhinitis state was suppressed in the CTP-administered group compared to the control group. In particular, the HD group showed that both the number of times of sneezing and the number of times of nasal scratching were significantly lower than those of the control group. Ovalbumin solution is administered daily from Day 14 to Day 35, but in the HD group, compared to Day 0 to Day 7, the number of sneezes and the number of nasal scratches after Day 14 are not increased. It can be interpreted that the onset was prevented.
さらに、図２に示すように、コントロール群のマウスでは、Ｄａｙ３５において、血漿中の卵白アルブミン特異的ＩｇＥ抗体濃度が顕著に増加したのに対し、ＣＴＰ投与群のマウスは、コントロール群に比較し、その濃度の増加が抑制されていた。特にＨＤ群はより優れた抑制効果を示した。また、ＣＴＰ投与群では、Ｄａｙ１４からＤａｙ３５まで卵白アルブミン溶液を連日投与しても、血漿中の卵白アルブミン特異的ＩｇＥ抗体濃度の増加が抑制されることが示された。ＣＴＰ投与群における血漿中の卵白アルブミン特異的ＩｇＥ抗体濃度の増加の抑制は、ＣＴＰ投与群におけるくしゃみや鼻掻きのアレルギー性鼻炎症状の増悪の抑制と一致する結果である。 Further, as shown in FIG. 2, in the mice of the control group, the concentration of the ovalbumin-specific IgE antibody in the plasma was significantly increased at Day 35, whereas the mice of the CTP administration group were compared with the control group. The increase in the concentration was suppressed. In particular, the HD group showed a more excellent inhibitory effect. In addition, in the CTP-administered group, it was shown that even if the ovalbumin solution was administered daily from Day 14 to Day 35, the increase in the concentration of the ovalbumin-specific IgE antibody in the plasma was suppressed. The suppression of the increase in the concentration of ovalbumin-specific IgE antibodies in the plasma in the CTP administration group is a result consistent with the suppression of the exacerbation of allergic rhinitis symptoms such as sneezing and nasal scratching in the CTP administration group.
図３に示すように、コントロール群ではＤａｙ０と比較してＤａｙ３５のマウス体重が減少したのに対し、ＣＴＰ群ではＤａｙ０と比較してＤａｙ３５のマウス体重の増加が見られた。７週齢の雌性マウスは、３５日間で通常１４％程度体重が増加する。くしゃみはヒトにおいても１回で２ｋｃａｌを消費するほどの、非常に消耗性の強い症状であり、正常な体重の増加を阻害する。ＣＴＰ投与群でも正常な体重増加のレベルには戻らなかったものの、減少から増加に転じていることから、くしゃみ等による体力の消耗が抑えられたと考えられる。
以上の試験結果から、トリペプチドを含むコラーゲン加水分解物は、アレルギー性鼻炎の症状の改善及び／治療効果を有することが示された。
As shown in FIG. 3, the weight of the mouse of Day 35 was decreased in the control group as compared to Day 0, whereas the weight of the mouse of Day 35 was increased in the CTP group as compared to Day 0. Seven-week-old female mice usually gain about 14% in weight over 35 days. Sneezing is a very debilitating symptom that consumes 2 kcal at a time even in humans, and inhibits normal weight gain. The CTP administration group did not return to the normal level of weight gain, but turned from a decrease to an increase, suggesting that the exhaustion of physical strength due to sneezing and the like was suppressed.
From the above test results, it was shown that the collagen hydrolyzate containing the tripeptide has the effect of improving and / or treating the symptoms of allergic rhinitis.
Claims (11)
Priority Applications (1)
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| CN114315960A (en) * | 2021-12-31 | 2022-04-12 | 深圳市维琪医药研发有限公司 | Modified peptide, and cosmetic composition or medicinal composition and application thereof |
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| CN114315960A (en) * | 2021-12-31 | 2022-04-12 | 深圳市维琪医药研发有限公司 | Modified peptide, and cosmetic composition or medicinal composition and application thereof |
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