JP2006219454A - Oral agent for treatment or prevention of cutaneous disease - Google Patents

Oral agent for treatment or prevention of cutaneous disease Download PDF

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JP2006219454A
JP2006219454A JP2005036235A JP2005036235A JP2006219454A JP 2006219454 A JP2006219454 A JP 2006219454A JP 2005036235 A JP2005036235 A JP 2005036235A JP 2005036235 A JP2005036235 A JP 2005036235A JP 2006219454 A JP2006219454 A JP 2006219454A
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dgla
food
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dihomo
linolenic acid
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JP5546087B2 (en
JP2006219454A5 (en
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Norifumi Tateishi
法史 立石
Hiroshi Kawashima
洋 河島
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Suntory Ltd
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Priority to PCT/JP2006/302787 priority patent/WO2006085687A1/en
Priority to US11/884,199 priority patent/US9006287B2/en
Priority to CA2599112A priority patent/CA2599112C/en
Priority to EP19183855.6A priority patent/EP3581178B1/en
Priority to EP06713928.7A priority patent/EP1852114B1/en
Priority to CN2012100164426A priority patent/CN102600174A/en
Priority to CN 200610003112 priority patent/CN101019853B/en
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a new composition for the prevention or treatment of cutaneous diseases such as atopic dermatitis. <P>SOLUTION: The invention provides a composition containing dihomo-γ-linolenic acid (DGLA), having preventing or treating effect on cutaneous diseases and usable as foods, medicines, etc. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

本発明は、アトピー性皮膚炎、接触性皮膚炎等のアレルギー性皮膚炎、湿疹、UVによる皮膚障害等の各種皮膚疾患に対して予防または治療効果を有する食品成分またはそれを含有する食品組成物に関する。さらに具体的には当該成分の効果を最大限発揮するための最適な用量を提供することに関する。   The present invention relates to a food component having a preventive or therapeutic effect on various skin diseases such as allergic dermatitis such as atopic dermatitis and contact dermatitis, eczema, and skin disorders caused by UV, or a food composition containing the same About. More specifically, it relates to providing an optimal dose for maximizing the effect of the component.

多種多様の脂肪酸を構造学的観点から分類する際、その分子内に20個程度の炭素からなる長鎖脂肪鎖を有し、かつ不飽和部分(二重結合)を2個以上有するものを多価不飽和脂肪酸(PUFA)と呼ぶ。あるいは、栄養学的観点からはヒトの健康維持のために極めて重要なものである、という位置付けから、一部の脂肪酸に関しては必須脂肪酸(EFA)と表現される場合も多い。EFAの定義は、狭義ではヒトにおいて合成することが出来ず食餌により摂取しなければならないリノール酸(LA)およびα−リノレン酸(ALA)を指し、広義ではそれらの代謝産物であるアラキドン酸(AA)、エイコサペンタエン酸(EPA)、ドコサヘキサエン酸(DHA)も含まれる。これらの中でALAを親脂肪酸として産生される一連の脂肪酸をn3系PUFAと称し、EPAやDHAはこのシリーズに含まれる。   When classifying a wide variety of fatty acids from a structural point of view, many of them have a long-chain fatty chain consisting of about 20 carbons in the molecule and two or more unsaturated moieties (double bonds). Called polyunsaturated fatty acids (PUFA). Or it is often expressed as an essential fatty acid (EFA) for some fatty acids because it is extremely important for maintaining human health from a nutritional point of view. The definition of EFA refers to linoleic acid (LA) and α-linolenic acid (ALA), which cannot be synthesized in humans in the narrow sense and must be ingested by the diet. In the broad sense, their metabolites arachidonic acid (AA ), Eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Among these, a series of fatty acids produced with ALA as the parent fatty acid is called n3 PUFA, and EPA and DHA are included in this series.

一方、図1に示すようにLAを親脂肪酸とする同様のものをn6系PUFAと称し、具体的にはLAからΔ6不飽和化酵素によりγ−リノレン酸(GLA)が、続いて炭素鎖伸長化酵素によりDGLAへ、さらにΔ5不飽和化酵素でAAへと代謝される。   On the other hand, as shown in FIG. 1, a similar one having LA as a parent fatty acid is called n6-type PUFA. Specifically, γ-linolenic acid (GLA) is subsequently produced from LA by Δ6 desaturase, followed by carbon chain elongation. It is metabolized to DGLA by oxidase and to AA by Δ5 desaturase.

これらn6系PUFAの生理学的役割はいずれも詳細に検討されており、なかでもGLAに関しては、皮膚障害(Cosmetic & Toiletries, Nissen HP, 1995, 110, P.71〜)、糖尿病とその合併症(Diabetic Medisine, Jamal GA, 1990, 7, p.319〜)、リウマチ様関節炎(Arthritis Rheumatisum, Zurier RB, 1996, 39, p.1808〜)等に有用であることが示されている。GLAの生理機能における分子メカニズムに関しては、図1に示すようにその活性分子はGLAの炭素鎖伸長代謝物であるDGLAであり、またはDGLAのシクロオキシゲナーゼ代謝産物である1−シリーズのプロスタグランジン(PG1)であり、あるいはDGLAのリポキシゲナーゼ代謝産物である15−ハイドロキシエイコサトリエノイン酸(15-HETrE)である、と推察されている。   The physiological roles of these n6-based PUFAs have been studied in detail. Among them, GLA is associated with skin disorders (Cosmetic & Toiletries, Nissen HP, 1995, 110, P.71), diabetes and its complications ( Diabetic Medisine, Jamal GA, 1990, 7, p. 319-), rheumatoid arthritis (Arthritis Rheumatisum, Zurier RB, 1996, 39, p. 1808-) and the like. Regarding the molecular mechanism in the physiological function of GLA, as shown in FIG. 1, the active molecule is DGLA, which is a carbon chain elongation metabolite of GLA, or 1-series prostaglandin (PG1), which is a cyclooxygenase metabolite of DGLA. Or 15-hydroxyeicosatrienoic acid (15-HETrE), which is a lipoxygenase metabolite of DGLA.

一方、DGLAの生理活性に関しては、in vivoあるいはin vitroでその効果が一部確認されており、in vivoにおいては血小板凝集抑制(British Medical Journal, Kernoff PBA, 1977, 2, p.1441〜)、遅延型足蹠浮腫(Lipids, Taki H, 1993, 28, p.873〜)、血圧上昇抑制(Lipids, Cedric H, 1984, 19, p.699〜)等の作用が、in vitroにおいてはインターロイキンー2、10、腫瘍壊死因子(TNF―α)等のサイトカイン産生抑制作用(Immunology, Maaike MBWD, 2003, 110, p.348〜;The Journal of Immunology, Deniela S, 1989, 143, p.1303〜)、ロイコトリエン産生抑制作用(Archives of Dermatological Research, Iversen L, 1992, 284, p.222〜)、T cell増殖抑制作用(Prostaglandine Leukotrienes and Essential Fatty Acids, Zurier RB, 1999, 60, p.371〜)等が報告されている。   On the other hand, the physiological activity of DGLA has been partially confirmed in vivo or in vitro, and in vivo platelet aggregation inhibition (British Medical Journal, Kernoff PBA, 1977, 2, p.1441), Delayed footpad edema (Lipids, Taki H, 1993, 28, p.873 ~), blood pressure elevation suppression (Lipids, Cedric H, 1984, 19, p.699 ~), etc. -2, 10, Inhibition of cytokine production such as tumor necrosis factor (TNF-α) (Immunology, Maaike MBWD, 2003, 110, p.348 ~; The Journal of Immunology, Deniela S, 1989, 143, p.1303 ~ ), Leukotriene production inhibitory action (Archives of Dermatological Research, Iversen L, 1992, 284, p. 222-), T cell proliferation inhibitory action (Prostaglandine Leukotrienes and Essential Fatty Acids, Zurier RB, 1999, 60, p. 371-) Etc. have been reported.

生物(特に皮膚)の生理機能とPUFAの関係は多くの分野で研究がなされており、例えばラット等の動物をEFA欠乏状態で長期間飼育した場合、皮膚の落屑、水分量の低下、水分喪失量の上昇等、特に皮膚機能の異常を伴うことが判っている。またその他湿疹、接触性皮膚炎、UVによる皮膚ダメージ等の各種皮膚疾患にもPUFAの関与が大きいと推察されている。さらに、GLAが各種疾患の予防や治療に有用であることは先述の通りであるが、中でも皮膚疾患、特にアトピー性皮膚炎においてGLAが有効であることが判明している(American Journal of Clinical Nutrition, Harrobin DF,2000, 71, p367〜)。   The relationship between the physiological function of organisms (especially skin) and PUFA has been studied in many fields. For example, when animals such as rats are kept for a long time in an EFA-deficient state, skin desquamation, water content reduction, water loss It has been found to be accompanied by abnormalities in skin function, such as increased amounts. In addition, it is speculated that PUFA is also heavily involved in various skin diseases such as eczema, contact dermatitis, and skin damage caused by UV. Furthermore, GLA is useful for the prevention and treatment of various diseases as described above, and it has been found that GLA is effective in skin diseases, particularly atopic dermatitis (American Journal of Clinical Nutrition). Harrobin DF, 2000, 71, p367 ~).

始めにアトピー性皮膚炎を罹患する患者血清中のLA量は健常人と比較して増加していることが明らかになり、その時LAからの代謝産物であるDGLAおよびAA量は逆に低下していることが判明した。このことはアトピー性皮膚炎患者においてn6系PUFA代謝経路の中でもLAからGLAへの変換酵素であるΔ6不飽和化酵素の機能が低下している可能性を強く示唆する。
そのためΔ6不飽和酵素の下流にあるPUFAの摂取がこのようなPUPA代謝異常を伴う疾患を改善し得ることが推察され、その中でも天然界に比較的多く存在し、マツヨイグサ、クロスグリ、ルリジサの種子に多く含まれるGLAの摂取よってアトピー性皮膚炎の諸症状を改善できるかが検討された。
First of all, it became clear that the amount of LA in the serum of patients suffering from atopic dermatitis increased compared to that of healthy individuals, and at that time the amounts of metabolites from LA, DGLA and AA, decreased conversely. Turned out to be. This strongly suggests that the function of the Δ6 desaturase, which is an enzyme converting LA to GLA, in the n6 PUFA metabolic pathway may be reduced in patients with atopic dermatitis.
Therefore, it is speculated that ingestion of PUFA downstream of the Δ6 unsaturated enzyme may improve such diseases accompanied by abnormal PUPA metabolism. Among them, there are relatively many in the natural world, and in the seeds of evening primrose, blackcurrant and borage It was investigated whether ingestion of a large amount of GLA could improve various symptoms of atopic dermatitis.

この結果、ヒトでの試験においてGLAの経口摂取(1日あたり約180-1440mg/人)がアトピー性皮膚炎の皮膚炎症状あるいは掻痒感を改善し得る事が報告され、特に1日あたり720あるいは1440mg/人と高用量摂取した患者においてより効果的であった。その時の知見として、GLAが生体中DGLAおよびAA量を増やし、特にDGLA量をより効果的に増加させ得ること、さらに症状改善とDGLAの間で正の相関性があることが確認された(Prostaglandins Leukotrienes and Medicine, Mauku MS, 1982, 9, p.615〜;The Lancet, Wright S, 1982, 20, p.1120〜)。   As a result, it was reported that oral intake of GLA (about 180-1440 mg / person / day) in human studies can improve skin irritation or pruritus in atopic dermatitis, especially 720 or per day. It was more effective in patients who took a high dose of 1440 mg / person. At that time, it was confirmed that GLA can increase DGLA and AA levels in the body, especially DGLA levels more effectively, and that there is a positive correlation between symptom improvement and DGLA (Prostaglandins Leukotrienes and Medicine, Mauku MS, 1982, 9, p.615-; The Lancet, Wright S, 1982, 20, p.1120-).

その有効性はアトピー性皮膚炎モデル動物であるNC/Ngaマウスにおいても確認されており、GLAの経口摂取(1日あたり約1250mg/kg)がアトピー様皮膚炎形成抑制およびIgE産生抑制効果を有することも判明している(第50回日本アレルギー学会総会要旨集,濱田瑞,2000, p.999〜)。以上のように、アトピー性皮膚炎の改善にはn6PUFAの中でGLAの摂取が有用で、好ましくはその活性本体と予想されるDGLAの摂取がより有効であることが推察されている。   Its effectiveness has been confirmed in NC / Nga mice, a model animal for atopic dermatitis, and oral intake of GLA (about 1250 mg / kg per day) has the effect of suppressing atopic dermatitis formation and IgE production. It has also been found (The 50th Annual Meeting of the Japanese Society of Allergy, Mizusada, 2000, p.999-). As described above, for the improvement of atopic dermatitis, it is speculated that the intake of GLA is useful in n6PUFA, and the intake of DGLA, which is expected to be the active body, is more effective.

しかし、上述のアトピー性皮膚炎のようなPUFA代謝異常に対する是正を目的としたGLA摂取において、適切な用量設定がなされていない、という可能性が存在している。モルモットにおいて、GLAを1日あたり約3200mg/kgと大過剰投与した場合、GLAを1日あたり約400mg/kg摂取した時と比較して表皮中DGLA量はむしろ減少する、という投与量と生体PUFA量の亢進が相関しない現象が起こった(Prostaglandins Leukotrienes and Essential Fatty Acids, Navarette R, 1992, 46, p.139〜)。このことから、GLAを大量に摂取した場合には、GLAからDGLAへの変換が阻害を受ける可能性があることが示唆されている。   However, there is a possibility that an appropriate dose is not set in GLA intake for the purpose of correcting PUFA metabolic abnormalities such as the above-mentioned atopic dermatitis. In guinea pigs, when a large excess of GLA was administered at about 3200 mg / kg per day, the amount of DGLA in the epidermis would rather decrease compared to when GLA was ingested at about 400 mg / kg per day, and in vivo PUFA A phenomenon occurred in which the increase in the amount was not correlated (Prostaglandins Leukotrienes and Essential Fatty Acids, Navarette R, 1992, 46, p. 139). This suggests that conversion of GLA to DGLA may be inhibited when a large amount of GLA is ingested.

つまり、仮にGLAを大量摂取した場合には、生体のDGLA量は増加するどころかむしろ低下する可能性があり、アトピー性皮膚炎を増悪させる危険性をはらんでいる。さらに、ヒトでのGLAの代謝には個体差が存在することも知られている。ヒトアトピー性皮膚炎患者にGLAを投与した場合、赤血球膜DGLA量亢進度は患者によって様々であり、その中でDGLA量が亢進している患者群では皮膚炎症状が有意に寛解し、逆にDGLA量が亢進しなかった患者群では皮膚炎症状の改善は認められなかった(British Journal of Dermatology, Henz BM, 1999, 140, p.685〜)。このことは、GLAの摂取がDGLA量を増やすために必ずしも有効ではない事、さらにはアトピー性皮膚炎の治療においてGLAの最適な用量がDGLAの最適な用量であるとは限らないことをも意味している。   That is, if a large amount of GLA is ingested, the amount of DGLA in the living body may decrease rather than increase, and there is a risk of exacerbating atopic dermatitis. Furthermore, it is known that there are individual differences in the metabolism of GLA in humans. When GLA is administered to patients with human atopic dermatitis, the degree of increased erythrocyte membrane DGLA varies from patient to patient, and among those patients with increased DGLA, skin inflammation is significantly ameliorated. In the group of patients whose DGLA level did not increase, improvement of skin inflammation was not observed (British Journal of Dermatology, Henz BM, 1999, 140, p. 685-). This also means that GLA intake is not always effective to increase the amount of DGLA, and that the optimal dose of GLA is not necessarily the optimal dose of DGLA in the treatment of atopic dermatitis. is doing.

一方、DGLAを摂取すると体内DGLA量は用量依存的に増加することが確認されており(第58回日本栄養食糧学会大要旨集,堀川千賀,2004, p.219〜)、仮にDGLAを大量に摂取した場合においても生体DGLA量が低下することは考え難い。さらに、先のGLAによる代謝酵素阻害は元来その酵素活性も比較的高いと認識され、加齢に伴う活性低下なども認められないと考えられていた炭素鎖伸長化酵素も、酵素反応である以上その基質環境やその他因子によって影響を受ける可能性を示している。   On the other hand, ingestion of DGLA has confirmed that the amount of DGLA in the body increases in a dose-dependent manner (58th Annual Meeting of the Japanese Society of Nutrition and Food Science, Chiga Horikawa, 2004, p.219-). It is unlikely that the amount of living DGLA will decrease even when ingested. Furthermore, the inhibition of metabolic enzymes by GLA was originally recognized as having relatively high enzyme activity, and the carbon chain elongation enzyme, which was thought to have no decrease in activity associated with aging, is also an enzyme reaction. The above shows the possibility of being affected by the substrate environment and other factors.

その結果としてGLAを摂取した時のDGLAの増加量は諸条件で変動する可能性が考えられ、GLAの摂取によりアトピー性皮膚炎の治療を適切に制御することは困難であることを強く示唆する。以上、安全性や有効性の点から考えても、アトピー性皮膚炎の治療または予防においてDGLA自体を直接摂取することがGLAを摂取するよりもよりも好ましく、さらにはそこで最も適した用量を供給することが非常に重要と考える。   As a result, the increase in DGLA when GLA is ingested may vary depending on various conditions, strongly suggesting that it is difficult to properly control the treatment of atopic dermatitis by ingesting GLA. . From the viewpoint of safety and efficacy, it is preferable to take DGLA itself more directly than GLA in the treatment or prevention of atopic dermatitis, and to supply the most suitable dose there. I think it is very important.

しかしながら、肉、卵、魚介類にはジホモ−γ−リノレン酸(DGLA)を含んでいるものもあるが、その種類は限られており、菜食主義者など、肉類をあまり食べない人にとって、天然物からのジホモ−γ−リノレン酸(DGLA)の摂取は極めて困難である。また、DGLAは天然に存在はしているもののその量は極めて低く大量調製は困難であったことから、先述のGLAの試験のように実際DGLAを用いてのアトピー性皮膚炎に対する効能検証の実施は極めて困難な状況にあった。つまり、DGLA自体でアトピー性皮膚炎を改善したという直接的な証明は我々の知る限りではなされておらず、また先述の通り、DGLAは動物のin vivo試験あるいは動物、ヒト由来細胞株のin vitro試験で様々な生理作用を有することは示されてはいるものの、そのいずれにおいてもアトピー性皮膚炎を模した試験とは言い難く、実際にDGLAがアトピー性皮膚炎を改善しうるのか、という問いに対しては明確な答えが出ていない。   However, some meats, eggs, and seafood contain dihomo-γ-linolenic acid (DGLA), but the types are limited and natural for those who do not eat meat very much, such as vegetarians. Ingestion of dihomo-γ-linolenic acid (DGLA) from food is extremely difficult. In addition, although DGLA exists in nature, its amount is extremely low and it was difficult to prepare a large amount. Therefore, as in the previous GLA test, the efficacy verification for atopic dermatitis using DGLA was actually conducted. Was in a very difficult situation. In other words, no direct proof that DGLA itself has improved atopic dermatitis has been made to the best of our knowledge, and as mentioned earlier, DGLA has been used in in vivo studies of animals or in vitro of animal and human-derived cell lines. Although it has been shown that the test has various physiological effects, it is difficult to say that it is a test that mimics atopic dermatitis, and whether DGLA can actually improve atopic dermatitis. There is no clear answer to.

発明者らはこれまでに特許第3354581号で示す通り、Δ5不飽和化酵素を欠損する微生物の取得、および本菌株によるDGLA油脂の発酵生産方法を発明することで、構成脂肪酸の約40%がDGLAから成るトリグリセライドSUNTGDを大量調製することを可能にし、DGLAの原料入手に関する困難を克服した。   The inventors have so far obtained a microorganism deficient in Δ5 desaturase and invented a method for fermentative production of DGLA oils and fats by this strain, as shown in Japanese Patent No. 3345811, so that about 40% of the constituent fatty acids are obtained. It made it possible to prepare a large amount of triglyceride SUNTGD consisting of DGLA, and overcame the difficulties in obtaining DGLA raw materials.

特許第3354581号Patent No.3354581 Cosmetic & Toiletries, Nissen HP, 1995, 110, P.71〜Cosmetic & Toiletries, Nissen HP, 1995, 110, P.71〜 Diabetic Medisine, Jamal GA, 1990, 7, p.319〜Diabetic Medisine, Jamal GA, 1990, 7, p.319〜 Arthritis Rheumatisum, Zurier RB, 1996, 39, p.1808〜Arthritis Rheumatisum, Zurier RB, 1996, 39, p.1808〜 British Medical Journal, Kernoff PBA, 1977, 2, p.1441〜British Medical Journal, Kernoff PBA, 1977, 2, p. 1441- Lipids, Taki H, 1993, 28, p.873〜Lipids, Taki H, 1993, 28, p.873〜 Lipids, Cedric H, 1984, 19, p.699〜Lipids, Cedric H, 1984, 19, p.699〜 Immunology, Maaike MBWD, 2003, 110, p.348〜Immunology, Maaike MBWD, 2003, 110, p.348〜 The Journal of Immunology, Deniela S, 1989, 143, p.1303〜The Journal of Immunology, Deniela S, 1989, 143, p.1303〜 Archives of Dermatological Research, Iversen L, 1992, 284, p.222〜Archives of Dermatological Research, Iversen L, 1992, 284, p.222〜

Prostaglandine Leukotrienes and Essential Fatty Acid, Zurier RB, 1999, 60, p.371〜Prostaglandine Leukotrienes and Essential Fatty Acid, Zurier RB, 1999, 60, p.371〜 American Journal of Clinical Nutrition, Harrobin DF,2000, 71, p367〜American Journal of Clinical Nutrition, Harrobin DF, 2000, 71, p367〜 Prostaglandins Leukotrienes and Medicine, Mauku MS, 1982, 9, p.615〜Prostaglandins Leukotrienes and Medicine, Mauku MS, 1982, 9, p.615〜 The Lancet, Wright S, 1982, 20, p.1120〜The Lancet, Wright S, 1982, 20, p.1120〜 第50回日本アレルギー学会総会要旨集,濱田瑞,2000, p.999〜Abstracts of the 50th Annual Meeting of the Japanese Society of Allergy, Mizusada, 2000, p.999- Prostaglandins Leukotrienes Essential Fatty Acids, Navarette R, 1992, 46, p.139〜Prostaglandins Leukotrienes Essential Fatty Acids, Navarette R, 1992, 46, p.139〜 British Journal of Dermatology, Henz BM, 1999, 140, p.685〜British Journal of Dermatology, Henz BM, 1999, 140, p.685 ~ 第58回日本栄養食糧学会大要旨集,堀川千賀,2004, p.219〜58th Annual Meeting of the Japanese Society of Nutrition and Food Science, Chiga Horikawa, 2004, p.219〜 機能性脂質の新展開,鈴木修,2001New development of functional lipids, Osamu Suzuki, 2001 γ−Linolenic Acid, Recent Advances in Biotechnology and Clinical Applications, Hundy YS, 2001γ-Linolenic Acid, Recent Advances in Biotechnology and Clinical Applications, Hundy YS, 2001

本発明の目的は、安全かつより効果的なアトピー性皮膚炎の予防および治療のために、適切な量のDGLAを提供することにある。   An object of the present invention is to provide an appropriate amount of DGLA for safe and more effective prevention and treatment of atopic dermatitis.

本発明はPUFAおよびその関連代謝物が種々の要因で量的・質的な異常を来し、それを原因として好ましくない生体変化が起こること、あるいはその逆に好ましくない生体変化が起こった結果として、PUFAおよびその関連代謝物が量的・質的な異常を来すことが往々にしてあること、このような状況においてPUFAを積極的に摂取して、その状態異常を是正することこそが基本原理であり、特にアトピー性皮膚炎というPUFA状態異常の改善においては、PUFAの中でも特にn6系PUFAであるDGLAが極めて有用で、かつGLAよりも少ない用量でよいことを見出し、本発明を完成した。   In the present invention, PUFA and its related metabolites cause quantitative and qualitative abnormalities due to various factors, and as a result of undesirable biological changes caused by them, and vice versa. Basically, PUFA and related metabolites often cause quantitative and qualitative abnormalities, and in this situation, PUFA is actively taken and the abnormalities are corrected. In principle, especially in the improvement of PUFA abnormalities such as atopic dermatitis, we found that DGLA, which is an n6-based PUFA, is extremely useful among PUFAs, and found that a lower dose than GLA is sufficient, and completed the present invention. .

従って、本発明は、ジホモ−γ−リノレン酸(DGLA)を含んで成り、皮膚疾患に対して予防又は治療効果を有する組成物を提供する。
この組成物は、例えば食品組成物又は医薬組成物である。
前記皮膚炎は、例えばアレルギー性皮膚炎、例えばアトピー性皮膚炎である。
前記組成物中のDGLAの含有量は、例えば、成人1人1日当り5mg〜600mgのジホモ−γ−リノレン酸(DGLA)を摂取するのに適当な量である。例えば、DGLAの摂取量は、成人1人1日当り5mg〜200mg、あるいは5mg〜150mgである。
Accordingly, the present invention provides a composition comprising dihomo-γ-linolenic acid (DGLA) and having a preventive or therapeutic effect on skin diseases.
This composition is, for example, a food composition or a pharmaceutical composition.
The dermatitis is, for example, allergic dermatitis, such as atopic dermatitis.
The content of DGLA in the composition is, for example, an amount suitable for ingesting 5 mg to 600 mg of dihomo-γ-linolenic acid (DGLA) per day per adult. For example, the intake of DGLA is 5 mg to 200 mg per adult per day, or 5 mg to 150 mg.

DGLAは、例えば、グリセライド、リン脂質、糖脂質、アルキルエステル、又は遊離脂肪酸の形態で存在する。前記グリセライドは、例えば、トリグリセライド、ジグリセライド又はモノグリセライドである。好ましくは、前記グリセライドは、トリグリセライド及び/又はジグリセライドである。
組成物は、例えば、丸剤、錠剤又はカプセル剤の形態である。
DGLA exists, for example, in the form of glycerides, phospholipids, glycolipids, alkyl esters, or free fatty acids. The glyceride is, for example, triglyceride, diglyceride, or monoglyceride. Preferably, the glyceride is triglyceride and / or diglyceride.
The composition is, for example, in the form of a pill, tablet or capsule.

本発明の組成物はまた、ジホモ−γ−リノレン酸(DGLA)を含んで成り、皮膚疾患に対して予防又は治療効果を有することを表示した飲食物の形態をとることができる。例えば、ジホモ−γ−リノレン酸(DGLA)を、その摂取量が成人1人1日当り5mg〜600mgである量で含有する、皮膚疾患に対して予防又は治療効果を有する旨の表示を付した飲食物であることが出来る。更に、ジホモ−γ−リノレン酸(DGLA)を、その摂取量が成人1人1日当り5mg〜200mgである量で含有する、皮膚疾患に対して予防又は治療効果を有する旨の表示を付した飲食物、あるいはジホモ−γ−リノレン酸(DGLA)を、その摂取量が成人1人1日当り5mg〜150mgである量で含有する、皮膚疾患に対して予防又は治療効果を有する旨の表示を付した飲食物であることが出来る。   The composition of the present invention can also take the form of a food or drink that comprises dihomo-γ-linolenic acid (DGLA) and displays that it has a preventive or therapeutic effect on skin diseases. For example, a food or drink containing dihomo-γ-linolenic acid (DGLA) in an amount of 5 mg to 600 mg per adult per day, with a label indicating that it has a preventive or therapeutic effect on skin diseases It can be a thing. In addition, food and beverages containing dihomo-γ-linolenic acid (DGLA) in an amount of 5 mg to 200 mg per day per adult, with a label indicating that it has a preventive or therapeutic effect on skin diseases Or dihomo-γ-linolenic acid (DGLA) in an amount of 5 mg to 150 mg per day for an adult, a label indicating that it has a preventive or therapeutic effect on skin diseases Can be food and drink.

DGLA摂取によるアトピー性皮膚炎予防効果はGLAと比較してより低い用量でそれを予防し得ることからも、DGLAがアトピー性皮膚炎予防食品としてより有用性が高い。さらに、その際最も適切な用量を摂取することが有効性の点で極めて重要である。   DGLA is more useful as a food for preventing atopic dermatitis because the effect of preventing DGLA by atopic dermatitis can be prevented at a lower dose compared to GLA. In addition, taking the most appropriate dose is very important in terms of effectiveness.

以下に本発明を詳細に説明する。
食品組成物としては、食餌サプリメント、ならびに(医薬)処方物および調製品、例えば、錠剤、丸剤およびカプセルが挙げられる。さらに、固形または液状食料品、例えば乳製品(マーガリン、バター、牛乳、ヨーグルト)、パン、ケーキ;ドリンク類、例えば飲料(お茶、コーヒー、ココア、チョコレートドリンク)、フルーツジュース、ソフトドリンク(例えば炭酸飲料);菓子;油性食品(スナック、サラダドレッシング、マヨネーズ)、スープ、ソース、炭水化物に富む食品(ご飯、麺類、パスタ)、魚入り食品、ベビーフード(例えば、乳幼児用フォーミュラ、液状または粉末として)、ペットフード、および調理済み食品または電子レンジで調理可能な食品が挙げられる。
The present invention is described in detail below.
Food compositions include dietary supplements, and (pharmaceutical) formulations and preparations such as tablets, pills and capsules. In addition, solid or liquid foodstuffs such as dairy products (margarine, butter, milk, yogurt), bread, cakes; drinks such as beverages (tea, coffee, cocoa, chocolate drinks), fruit juices, soft drinks (eg carbonated drinks) ); Confectionery; oily food (snack, salad dressing, mayonnaise), soup, sauce, carbohydrate rich food (rice, noodles, pasta), fish food, baby food (eg infant formula, as liquid or powder), Examples include pet food and food that can be cooked or cooked in a microwave.

DGLAは任意の適当な起源に由来することが出来る。しかしながら、DGLA含量の高いことの知られている天然油脂源は殆ど無く、ごく微量であれば牛の肝臓、豚の腎臓、卵黄等から抽出することは可能ではある。近年、微生物発酵技術が進歩し、微生物、例えば、真菌類、細菌類または酵母に由来していてもよい。   DGLA can be derived from any suitable source. However, there are almost no natural fat sources known to have a high DGLA content, and it is possible to extract from a beef liver, pig kidney, egg yolk, etc., in a very small amount. In recent years, microbial fermentation technology has advanced and may be derived from microorganisms such as fungi, bacteria or yeast.

適当な真菌類は、ムコラレス(Mucorales)目、例えば、モルティエレラ(Mortierella)、ピチウム(Pythium)またはエントモフトラ(Entomophyhora)に属するものである。DGLAの好ましい起源は、モルティエレラ(Mortierella)由来である。モルティエレラ・アルピナ(Mortierella alpina)由来であればより好ましい。DGLA含有油脂は特許第3354581号で示す通り発明者らはモルティエレラ(Mortierella)を用いた微生物発酵法により構成脂肪酸の約40%がDGLAから成るトリグリセライドを調製することが出来る。   Suitable fungi are those belonging to the order of the Mucorales, for example Mortierella, Pythium or Entomophyhora. A preferred source of DGLA is from Mortierella. More preferably, it is derived from Mortierella alpina. As shown in Japanese Patent No. 334581, the inventors can prepare triglycerides in which about 40% of the constituent fatty acids are composed of DGLA by microbial fermentation using Mortierella.

DGLAに加えて、1種またはそれ以上の付加的なPUFAを供給しても良い。これはDGLAに加えて別のn6系PUFA(例えばLA、GLA、AAなど)であってもよいし、n3系PUFA(例えばEPA、DHA)であってもよい。
本発明に用いるDGLAに変換可能なこの酸の生理的に許容される官能性誘導体としては、DGLAを含むトリグリセライド、ジグリセライド、モノグリセライドとして、あるいはリン脂質、糖脂質として、さらには遊離の脂肪酸、脂肪酸エステル(例えば、メチルまたはエチルエステル)、ステロールエステルとしての形態で有り得る。
In addition to DGLA, one or more additional PUFAs may be supplied. In addition to DGLA, this may be another n6 PUFA (eg, LA, GLA, AA, etc.), or an n3 PUFA (eg, EPA, DHA).
The physiologically acceptable functional derivatives of this acid that can be converted to DGLA for use in the present invention include DGLA-containing triglycerides, diglycerides, monoglycerides, or as phospholipids, glycolipids, and free fatty acids and fatty acid esters. (Eg methyl or ethyl ester), may be in the form of a sterol ester.

好ましくは、PUFAは油中に存在する。これは純粋な油、加工油(例えば、化学的および/または酵素的に処理した油)または濃縮油で有り得る。これら油は10〜100%のPUFAを含有しうるが、所望のPUFA、例えばDGLAの含量は、油が微生物由来であれば油中の5%以上、好ましくは10%以上、より好ましくは25%以上であれば良い。この油は1種またはそれ以上のPUFAをこれら百分率の濃度範囲内で含有し得る。この油は、単独の細胞または微生物に由来する単独油であってもよいし、または他の起源に由来する2種またはそれ以上の油の配合油または混合油であってもよい。この油は、例えば、1種またはそれ以上の添加物、例えば酸化防止剤(例えば、トコフェロール、ビタミンE、トコトリエノール、アスコルビン酸誘導体、パルミチン酸塩またはエステル、アスタキサンチン)やセサミン、CoQ10等を含有していてもよい。   Preferably the PUFA is present in the oil. This can be a pure oil, a processed oil (eg a chemically and / or enzymatically treated oil) or a concentrated oil. These oils may contain 10-100% PUFA, but the content of the desired PUFA, such as DGLA, is 5% or more, preferably 10% or more, more preferably 25% in the oil if the oil is derived from microorganisms. That's all there is to it. The oil may contain one or more PUFAs within these percentage concentration ranges. The oil may be a single oil derived from a single cell or microorganism, or it may be a blended or mixed oil of two or more oils derived from other sources. This oil contains, for example, one or more additives such as antioxidants (eg tocopherol, vitamin E, tocotrienol, ascorbic acid derivatives, palmitate or ester, astaxanthin), sesamin, CoQ10, etc. May be.

本発明は、正常な健康で十分に食事をした個体、つまりPUFAレベルが正常な値を示している個体に対してそのPUFAレベルを向上させ、疾病の予防、健康の保全や維持を目的に用いられる。
しかし、PUFAレベルが低いまたは不足している個体にも用いることが出来る。例えば血中におけるn3系またはn6系PUFAの異常または低いレベルに関連する疾患または状態の予防、防止、改善、治療に用いることが出来る。それゆえ、本発明は、DGLAレベルの低い被験者、例えばLAからGLAおよびDGLAへの変換、GLAからDGLAへの変換が出来ないか、および/あるいは効果的に変換できない被験者への使用を提供する。それゆえ、適当な患者は、Δ6不飽和化酵素および/あるいは炭素鎖伸長化酵素が機能不全、不十分、または欠乏していればよい。
The present invention improves the PUFA level of an individual who has eaten sufficiently with normal health, that is, an individual having a normal PUFA level, and is used for the purpose of disease prevention, health maintenance and maintenance. It is done.
However, it can also be used for individuals with low or insufficient PUFA levels. For example, it can be used for the prevention, prevention, amelioration, or treatment of diseases or conditions associated with abnormal or low levels of n3 or n6 PUFAs in the blood. Therefore, the present invention provides use for subjects with low DGLA levels, such as subjects who cannot convert LA to GLA and DGLA, cannot convert GLA to DGLA, and / or cannot convert effectively. Therefore, a suitable patient need only have dysfunctional, insufficient or deficient Δ6 desaturase and / or carbon chain extender enzymes.

本発明は特に、DGLAレベルの低い人々、例えばアトピー性皮膚炎等の免疫レベルが異常状態にある時、それは免疫レベルが通常より低下あるいは亢進している状態を指し、そのような免疫異常状態にある被験者への使用を提供する。
DGLAレベルの低い状態あるいはDGLAレベルが正常から変動している状態、その他の状態の是正、例えば接触性皮膚炎、湿疹、UVによる皮膚障害等の各種皮膚疾患、慢性関節リウマチ、糖尿病患者、アルコール中毒者、喫煙者等にも使用することが出来る。
In particular, the present invention refers to a state in which the immune level is lowered or increased more than usual when the immune level is abnormal, such as in people with low DGLA levels, for example, atopic dermatitis. Provide use for certain subjects.
Low DGLA level or DGLA level fluctuation from normal, correction of other conditions such as contact dermatitis, eczema, various skin diseases such as UV-induced skin disorders, rheumatoid arthritis, diabetics, alcoholism Can also be used by smokers and smokers.

次に、実施例により本願発明を更に具体的に説明する。
実施例1.
以上のように、DGLAの摂取がアトピー性皮膚炎の予防や治療に有用であることが予想されたため、DGLA油脂である特許第3354581号で示す方法で調製したDGLAを主構成脂肪酸とするトリグリセライドSUNTGDを用いて実験動物におけるその有用性を検討した。今回アトピー性皮膚炎のモデル動物としてNC/Ngaマウスを用いた。本モデル動物は現在最も有用なアトピー性皮膚炎モデルの一つと認識されており、実際にアトピー治療の臨床現場で用いられているステロイド外用剤や免疫抑制外用剤等は本モデル動物においても有効性を示すことが証明されていることから、アトピー性皮膚炎治療薬のスクリーニングにも汎用されている。
Next, the present invention will be described more specifically with reference to examples.
Example 1.
As mentioned above, DGLA intake was expected to be useful for the prevention and treatment of atopic dermatitis. Therefore, triglyceride SUNTGD containing DGLA as a main constituent fatty acid prepared by the method shown in Patent No. 3345801, which is a DGLA oil. We examined its usefulness in experimental animals. In this study, NC / Nga mice were used as model animals for atopic dermatitis. This model animal is currently recognized as one of the most useful atopic dermatitis models, and steroid external preparations and immunosuppressive external preparations that are actually used in clinical settings for atopic treatment are also effective in this model animal. Since it has been proved that it is shown, it is also widely used for screening for therapeutic drugs for atopic dermatitis.

本動物はコンベンショナルな飼育環境下、生後約8週間前後で自然発症的に皮膚炎を発病後、その炎症像は経日的に増悪・慢性化し、肉眼的にも病理組織学的にもヒトのアトピー様皮膚炎症状を呈することで知られている。また、皮膚炎発症に伴った血清中IgEの上昇や病巣部におけるマスト細胞や好酸球、T cell等の免疫担当細胞の顕著な浸潤も本病態の特徴として挙げられる。   This animal developed dermatitis spontaneously around 8 weeks after birth in a conventional rearing environment, and its inflammation became worse and chronic over time. It is known to exhibit atopic-like skin inflammation. In addition, elevated serum IgE associated with the onset of dermatitis and marked infiltration of immunocompetent cells such as mast cells, eosinophils, and T cells in the lesion are also characteristic of this disease state.

この試験ではオスあるいはメスのNC/Ngaマウスを準備し、コンベンショナルな飼育環境下1群7匹で3種類の群を設定した。表1に示す以下の3種類の餌を調製し、離乳後の5週齢目以降、自由摂取にて試験終了となる12週齢目まで与え続けた。群は対照食群、高DGLA食群、低DGLA食群とし、後ろ2群に対しては、SUNTGDを添加し、高DGLA群であれば餌中約1.0%がDGLA(遊離脂肪酸量として算出)、低DGLA群であれば餌中約0.5%がDGLA(遊離脂肪酸量として算出)、となるように設定した。マウス体重が平均20g、平均1日摂餌量が約2gであったことから、この実験におけるDGLA摂取量を算出すると高DGLA群であれば1日あたり約1000mg/kg、低DGLA群であれば1日あたり約500mg/kgであることが推察された。また、いずれの群も餌中の総脂肪酸量は一律5%となるようにした。評価項目はブラインド下の皮膚炎症状の肉眼スコア、掻爬行動、血中IgEとした。   In this study, male / female NC / Nga mice were prepared, and three groups were established with 7 mice per group in a conventional rearing environment. The following three types of food shown in Table 1 were prepared and continued to be fed from the 5th week after weaning until the 12th week when the test was terminated by free consumption. The group is a control diet group, a high DGLA diet group, a low DGLA diet group, and SUNTGD is added to the back 2 groups. In the high DGLA group, about 1.0% of the diet is DGLA (calculated as free fatty acid amount) In the low DGLA group, about 0.5% of the diet was set to be DGLA (calculated as the amount of free fatty acid). Since the average body weight of the mice was 20 g and the average daily food intake was about 2 g, the DGLA intake in this experiment was calculated to be about 1000 mg / kg per day for the high DGLA group and for the low DGLA group. It was estimated that it was about 500 mg / kg per day. In each group, the total amount of fatty acids in the diet was uniformly 5%. Evaluation items were macroscopic score of skin inflammation under the blind, curettage behavior, and blood IgE.

検討の結果、体重推移や一般所見に関する異常をなんら見せることなく、DGLA摂取両群は対照食群と比較して、皮膚炎症状の肉眼スコア(表2)、掻爬行動(表3)、血漿中IgE(表4)の産生量いずれの評価項目においても統計学的に有意な抑制効果を示し、DGLA摂取がアトピー予防に有用である可能性が示唆された。また、この時の血漿中の脂肪酸組成(表5)は食餌の影響を反映して、いずれの臓器においてもDGLA飼料の用量に依存的なDGLA量の増加とLA量の減少が認められ、特に脾臓における脂肪酸組成変動が顕著であり、このことはDGLAが免疫系への生理機能に強い影響を与えることが予想される。さらに、驚くべきことに、本予防効果はDGLAの用量に非依存的、つまり、低DGLA食が高DGLA食群と比較してより強いアトピー予防効果を有する傾向を示した。   As a result of the examination, the DGLA intake group compared to the control diet group without showing any abnormalities related to body weight changes and general findings, and the gross score of skin inflammation (Table 2), curettage behavior (Table 3), plasma The production amount of IgE (Table 4) showed a statistically significant inhibitory effect in any of the evaluation items, suggesting that DGLA intake may be useful for the prevention of atopy. In addition, the fatty acid composition in the plasma (Table 5) at this time reflects the influence of the diet, and in any organ, an increase in the DGLA amount and a decrease in the LA amount depending on the dose of the DGLA feed were observed. The fatty acid composition variation in the spleen is remarkable, which is expected to have a strong influence on the physiological function of the immune system by DGLA. Furthermore, surprisingly, this preventive effect was independent of the dose of DGLA, that is, the low DGLA diet tended to have a stronger atopic preventive effect than the high DGLA diet group.

先述の通り、生体の脂肪酸組成はDGLAに用量依存的な増加が見られたことから、DGLA自身の吸収阻害等による作用の減弱ではないことは明白である。以上のことは、本モデルあるいはヒトにおけるDGLAのアトピー予防効果において、最適な用量の存在、言い換えれば今回用いた低DGLA食飼料の用量よりもさらに低い用量が最も高い抑制効果を示す可能性を強く示唆する。さらに、DGLA食による血漿中DGLA量の変動を特に注目してみると、アトピー性皮膚炎様症状の改善に特に有効であった低DGLA食の場合が血漿リン脂質中DGLAが4.3%、対照食群のそれが1.0%と、存在比率として約4倍あるいは重量%で3%程度増加していることが判り、このような血漿中DGLA量の亢進がアトピー性皮膚炎の治療効果に大きく寄与しているパラメーターのひとつであることが明白となった。   As described above, since the dose-dependent increase in the fatty acid composition of the living body was observed in DGLA, it is clear that the action is not diminished due to absorption inhibition of DGLA itself. The above indicates that there is a strong possibility that the optimal dose of DGLA in atopy prevention effects in this model or in humans, in other words, a dose lower than the low DGLA diet used this time, will have the highest inhibitory effect. Suggest. Furthermore, focusing on the changes in plasma DGLA levels due to the DGLA diet, DGLA in plasma phospholipids was 4.3% for the low DGLA diet, which was particularly effective in improving atopic dermatitis-like symptoms, and the control diet It can be seen that the ratio of the group is 1.0%, which is about 4 times as much as the abundance ratio or about 3% increase in weight%. Such an increase in plasma DGLA level greatly contributes to the therapeutic effect of atopic dermatitis. It became clear that it was one of the parameters.

ヒトにおいてもDGLAを摂取することでこのようなDGLA量の是正を促すことが出来れば、アトピー性皮膚炎を改善することが出来るものと考えられる。また、本モデル動物においては先述の通り、GLAに関しても報告されており(第50回日本アレルギー学会総会要旨集,濱田瑞,2000,p.999〜)、その時の用量は1日あたり約1250mg/kgであったが、今回用いた低DGLA食飼料はその半分以下の1日あたり約500mg/kgであったことからも、GLAよりもDGLAがより効率的にアトピーを予防し得るものと判断される。さらに、別の報告においては、同モデルでn3系PUFAであるALAが検討されており(Prostaglandins Leukotrienes and Essential Fatty Acids, Suzuki R, 2002, 66, p.43)、その正確な投与量はうかがい知る事は出来ないが、少なくともALAを多く含む食餌によって生体赤血球膜中のALAが顕著に上昇するにも関わらず、皮膚炎症状や血中IgEの是正等のアトピー予防効果は認められていない。   It is considered that atopic dermatitis can be improved if humans can promote the correction of DGLA level by ingesting DGLA. In addition, as described above, GLA has also been reported for this model animal (Abstracts of the 50th Annual Meeting of the Japanese Society of Allergy, Mizusada, 2000, p.999-), and the dose at that time is about 1250 mg / day. The low DGLA diet used this time was about 500 mg / kg per day, less than half of that, and it was judged that DGLA can prevent atopy more efficiently than GLA. The In another report, ALA, an n3 PUFA, has been studied in the same model (Prostaglandins Leukotrienes and Essential Fatty Acids, Suzuki R, 2002, 66, p.43), and the exact dosage is known. However, although ALA in the living erythrocyte membrane is significantly increased by a diet containing at least ALA, no atopy prevention effects such as skin inflammation and correction of blood IgE have been observed.

Figure 2006219454
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実施例2.
ヒトにおけるDGLA経口摂取量と、体内DGLAレベルの関係を明らかにするために、DGLA経口摂取量を食事調査で調べるとともに、採血実施後、血清リン脂質中のDGLA量を測定した。対象者は健康な60-70歳の男性11名で、食事内容や食事素材を記した日誌を1週間にわたってつけてもらった。その日誌から、DGLA量を含有することがわかっている肉類、卵類、魚介類について食品素材別の摂取量を求め、「四訂日本食品標準成分表 日本食品脂溶性成分表(1990)」から計算できる食品素材別のDGLA含有量を用いて、各人の1日ごとのDGLA摂取量を計算した。1週間分のDGLA摂取量から、1日平均DGLA摂取量を各人ごとに算出した。
Example 2.
In order to clarify the relationship between DGLA oral intake in humans and DGLA levels in the body, DGLA oral intake was examined by dietary survey, and after blood sampling, the amount of DGLA in serum phospholipids was measured. The subjects were eleven healthy men aged 60-70 years, who had a diary with meals and ingredients for a week. From the diary, the intake of each food material for meat, eggs, and fish and shellfish that are known to contain DGLA is determined. From the “Fourth Japan Food Standard Ingredients Table, Japanese Food Fat-soluble Ingredients Table (1990)” Using the DGLA content by food material that can be calculated, the daily DGLA intake of each person was calculated. From the DGLA intake for one week, the daily average DGLA intake was calculated for each person.

一方、日誌を記した最終日の翌日に採血し、得られた血清のリン脂質画分について、常法に従い脂肪酸組成を分析した。すなわち、血清から常法であるFolch法により脂質成分を抽出し、その脂質を薄層クロマトグラフィーで分画(展開液は、ヘキサン/ジエチルエーテル/=7/3)してリン脂質画分を得た。直接シリカゲル層をかきとり、塩酸メタノール中で50℃3時間反応させ、ヘキサンで抽出することにより、脂肪酸メチルエステル混合物を得た。内部標準には、ペンタデカン酸を用いた。脂肪酸メチルエステル混合物をキャピラリーガスクロマトグラフィーで分析することにより、血清リン脂質の総脂肪酸中のDGLA(重量%)を求めた。   On the other hand, blood was collected on the day after the last day in which a diary was recorded, and the fatty acid composition of the obtained serum phospholipid fraction was analyzed according to a conventional method. That is, lipid components are extracted from serum by the conventional Folch method, and the lipids are fractionated by thin layer chromatography (developing solution is hexane / diethyl ether / = 7/3) to obtain a phospholipid fraction. It was. The silica gel layer was scraped directly, reacted in methanol at 50 ° C. for 3 hours, and extracted with hexane to obtain a fatty acid methyl ester mixture. Pentadecanoic acid was used as an internal standard. By analyzing the fatty acid methyl ester mixture by capillary gas chromatography, DGLA (% by weight) in the total fatty acid of serum phospholipid was determined.

検討の結果、1日平均DGLA経口摂取量と血清リン脂質中のDGLA(重量%)の間には正の相関のあることがわかった。X=1日平均DGLA経口摂取量(mg)、Y=血清リン脂質中のDGLA(重量%)とした時の相関一次式はY=0.0312X+1.361となり、DGLA摂取量が約32mg増えれば血清リン脂質中のDGLAが1重量%増加する関係にあることが判る。またこの検討結果からさらに判ることは、ヒトのほうがマウスよりもDGLA経口摂取後の血中DGLA変化が顕著に起こりやすい、ということである。先のマウスの結果において低DGLA食群を例にとると、体重換算で500mg/kgのDGLAを実質8週間摂取すると血漿リン脂質中DGLA量が3重量%増加することを既に記載した。   As a result of the examination, it was found that there was a positive correlation between daily average DGLA oral intake and DGLA (% by weight) in serum phospholipids. When X = daily average DGLA oral intake (mg), Y = DGLA (% by weight) in serum phospholipids, the linear relationship is Y = 0.0312X + 1.361, and if DGLA intake increases by about 32 mg, serum It can be seen that DGLA in phospholipids has a relationship of 1% by weight. Further, the results of this study further indicate that human DGLA changes are more likely to occur after oral DGLA intake than mice. In the results of the previous mouse, taking the low DGLA diet group as an example, it has already been described that the amount of DGLA in plasma phospholipid increases by 3% by weight when 500 mg / kg DGLA in terms of body weight is ingested for substantially 8 weeks.

今回、ヒトでの検討では体重60kgで換算すると32mg/60kg=0.53 mg/kgのDGLA摂取で血清リン脂質中DGLA量が1重量%増加する計算になる。また、マウスにおいて血漿リン脂質中DGLAが3重量%程度増加するとアトピー性皮膚炎様症状をより効果的に改善したが、逆にヒトにおいて血清リン脂質中DGLA量が3重量%程度増加するようなDGLA必要量を先の式で算出すると、1日あたり約100mg程度である。ヒトのアトピー性皮膚炎を改善し得るGLAの経口摂取量が1日あたり約180-1440mgであることを考えても、DGLAがより少量でアトピーを改善し得る事が強く示唆される。   In human studies, when converted to body weight of 60 kg, the amount of DGLA in serum phospholipids increases by 1% by weight when DGLA intake is 32 mg / 60 kg = 0.53 mg / kg. In addition, when DGLA in plasma phospholipids increased by about 3% by weight in mice, atopic dermatitis-like symptoms were more effectively improved, but conversely, the amount of DGLA in serum phospholipids increased by about 3% by weight in humans. The required amount of DGLA is calculated to be about 100 mg per day. Considering that the oral intake of GLA that can improve human atopic dermatitis is about 180-1440 mg per day, it is strongly suggested that DGLA can improve atopy with a smaller amount.

実施例3.
皮膚疾患の中で太陽光線によっても皮膚はダメージを受けることが知られている。特に波長290-320nmのUV-Bと分類される紫外線は、皮膚の急性的な炎症(sunburn)、色素沈着・日焼け(suntan)、皮膚ガン等の最も大きな原因の一つといわれている。今回、DGLAの皮膚機能へのさらなる可能性を探索するために、モルモットUV-B惹起急性炎症モデルを用いて、DGLAの皮膚急性炎症に対する効果を評価した。本モデルは抗炎症効果を期待した医薬品開発において、薬効スクリーニングに用いられる汎用性の高い動物モデルの中の一つである。
Example 3.
It is known that the skin is damaged by sunlight in skin diseases. In particular, ultraviolet rays classified as UV-B having a wavelength of 290 to 320 nm are said to be one of the largest causes of acute inflammation of the skin (sunburn), pigmentation / suntan, and skin cancer. In this study, we investigated the effects of DGLA on acute skin inflammation using a guinea pig UV-B-induced acute inflammation model to explore further possibilities for DGLA skin function. This model is one of the highly versatile animal models used for drug efficacy screening in drug development with anti-inflammatory effects.

この試験ではオスのHartley系モルモットを準備し、対照食群およびDGLA食群に分けた。各餌は動物の週齢が5週齢から実験終了の7週齢までの計3週間、自由摂取にて与え続けた。今回用いたDGLA食は先に示したマウス飼料の組成とは異なり、餌中の約0.08%がDGLA(遊離脂肪酸として算出)となるように調製した。つまり、モルモット体重平均が約400g、平均1日摂餌量が約30gであったことから、この実験におけるDGLA摂取量を算出すると1日あたり約60mg/kgであることが推察された。3週間の自由摂取期間の後、モルモット背部の体毛を刈毛、剃毛し、伏臥位置で動物を保定後、UV照射器(Dermaray(商標)、M-DMR-I型、エーザイ)およびUV-B管(FL-20S-E-30ランプ、中心波長305nm、東芝)を用いて管から5cmの距離で15分間照射し、急性炎症反応を惹起した。惹起後の皮膚紅斑反応をブラインド下、Draizeの方法に準じてスコアリングした。   In this study, male Hartley guinea pigs were prepared and divided into a control diet group and a DGLA diet group. Each food was fed freely for a total of 3 weeks from the age of the animal to 5 weeks of age to 7 weeks of age when the experiment was completed. The DGLA diet used this time was prepared so that about 0.08% of the diet was DGLA (calculated as free fatty acid), unlike the composition of the mouse feed described above. In other words, since the average guinea pig body weight was about 400 g and the average daily food intake was about 30 g, the DGLA intake in this experiment was estimated to be about 60 mg / kg per day. After a free intake period of 3 weeks, the guinea pig's back hair was shaved and shaved, and the animal was held in the prone position, followed by a UV irradiator (Dermaray ™, M-DMR-I, Eisai) and UV- Using a B tube (FL-20S-E-30 lamp, center wavelength 305 nm, Toshiba), irradiation was performed at a distance of 5 cm from the tube for 15 minutes to induce an acute inflammatory reaction. The erythema reaction after induction was scored according to the Draize method under the blind.

この結果、表6に示すように、DGLA食群はUV-Bに起因する皮膚急性炎症反応を抑制する傾向を示し、特にUV-B曝露後1時間目において統計学的に有意な抑制効果を示した。この時、結果は示さないが、DGLA食群は対照食群と比較して、血漿、皮膚、その他各種臓器のリン脂質中DGLA量が有意に増加することも確認された。以上のことから、DGLA食はUVによる皮膚ダメージの予防に有用であることが明らかとなった。   As a result, as shown in Table 6, the DGLA diet group showed a tendency to suppress the acute skin inflammatory reaction caused by UV-B, and in particular, a statistically significant inhibitory effect at 1 hour after UV-B exposure. Indicated. At this time, although the results are not shown, it was also confirmed that the DGLA diet group significantly increased the amount of DGLA in phospholipids of plasma, skin and other various organs as compared to the control diet group. From the above, it was revealed that the DGLA diet is useful for preventing skin damage caused by UV.

Figure 2006219454
Figure 2006219454

図1は、6n系高度不飽和脂肪酸(PUFA)の代謝経路を示す図である。FIG. 1 is a diagram showing the metabolic pathway of 6n polyunsaturated fatty acids (PUFA).

Claims (14)

ジホモ−γ−リノレン酸(DGLA)を有効成分として含んで成り、皮膚疾患に対して予防又は治療効果を有する組成物。   A composition comprising dihomo-γ-linolenic acid (DGLA) as an active ingredient and having a preventive or therapeutic effect on skin diseases. 食品組成物又は医薬組成物である、請求項1に記載の組成物。   The composition according to claim 1, which is a food composition or a pharmaceutical composition. 前記皮膚炎がアレルギー性皮膚炎である、請求項1又は2に記載の組成物。   The composition according to claim 1 or 2, wherein the dermatitis is allergic dermatitis. 前記アレルギー性皮膚炎が、アトピー性皮膚炎である、請求項1〜3のいずれか1項に記載の組成物。   The composition according to any one of claims 1 to 3, wherein the allergic dermatitis is atopic dermatitis. ジホモ−γ−リノレン酸(DGLA)の摂取量が、成人1人1日当り5mg〜600mgである、請求項1〜4のいずれか1項に記載の組成物。   The composition according to any one of claims 1 to 4, wherein the intake of dihomo-γ-linolenic acid (DGLA) is 5 mg to 600 mg per adult per day. ジホモ−γ−リノレン酸(DGLA)の摂取量が、成人1人1日当り5mg〜200mgである、請求項1〜5のいずれか1項に記載の組成物。   The composition according to any one of claims 1 to 5, wherein the intake of dihomo-γ-linolenic acid (DGLA) is 5 mg to 200 mg per adult per day. ジホモ−γ−リノレン酸(DGLA)の摂取量が、成人1人1日当り5mg〜150mgである、請求項1〜5のいずれか1項に記載の組成物。   The composition according to any one of claims 1 to 5, wherein the intake of dihomo-γ-linolenic acid (DGLA) is 5 mg to 150 mg per day per adult. ジホモ−γ−リノレン酸(DGLA)を含んで成り、皮膚疾患に対して予防又は治療効果を有するものであることを特徴とし、皮膚疾患に対して予防又は治療効果を有する旨の表示を付した飲食物。   It comprises dihomo-γ-linolenic acid (DGLA), has a preventive or therapeutic effect on skin diseases, and is labeled as having a preventive or therapeutic effect on skin diseases. Food and drink. ジホモ−γ−リノレン酸(DGLA)を、その摂取量が成人1人1日当り5mg〜600mgである量で含有する、皮膚疾患に対して予防又は治療効果を有する旨の表示を付した飲食物。   A food or drink containing dihomo-γ-linolenic acid (DGLA) in an amount of intake of 5 mg to 600 mg per day per adult and labeled as having a preventive or therapeutic effect on skin diseases. 前記ジホモ−γ−リノレン酸(DGLA)が、グリセライド、リン脂質、糖脂質、アルキルエステル、又は遊離脂肪酸の形態で存在する、請求項1〜9のいずれか1項に記載の組成物又は飲食物。   The composition or food or drink according to any one of claims 1 to 9, wherein the dihomo-γ-linolenic acid (DGLA) is present in the form of glyceride, phospholipid, glycolipid, alkyl ester, or free fatty acid. . 前記グリセライドが、トリグリセライド、ジグリセライド又はモノグリセライドである、請求項10に記載の組成物又は飲食物。   11. The composition or food or drink according to claim 10, wherein the glyceride is triglyceride, diglyceride or monoglyceride. 前記グリセライドが、トリグリセライド及び/又はジグリセライドである、請求項11に記載の組成物又は飲食物。   12. The composition or food or drink according to claim 11, wherein the glyceride is triglyceride and / or diglyceride. 丸剤、錠剤又はカプセル剤の形態である、請求項1〜12のいずれか1項に記載の組成物又は飲食物。   The composition or food or drink according to any one of claims 1 to 12, which is in the form of a pill, tablet or capsule. 皮膚疾患の予防又は治療のためのジホモ−γ−リノレン酸(DGLA)の使用。   Use of dihomo-γ-linolenic acid (DGLA) for prevention or treatment of skin diseases.
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JP2005036235A JP5546087B2 (en) 2005-02-14 2005-02-14 Oral treatment or prevention agent for skin diseases
US11/884,199 US9006287B2 (en) 2005-02-14 2006-02-10 Composition comprising dihomo-γ-linolenic acid (DGLA) as active ingredient
CA2599112A CA2599112C (en) 2005-02-14 2006-02-10 Composition comprising dihomo-.gamma.-linolenic acid (dgla) as the active ingredient
EP19183855.6A EP3581178B1 (en) 2005-02-14 2006-02-10 Composition containing dihomo-(gamma)-linolenic acid (dgla) as active ingredient
EP06713928.7A EP1852114B1 (en) 2005-02-14 2006-02-10 Composition containing dihomo-y-linolenic acid (dgla) as active ingredient
PCT/JP2006/302787 WO2006085687A1 (en) 2005-02-14 2006-02-10 Composition containing dihomo-ϝ-linolenic acid (dgla) as the active ingredient
CN2012100164426A CN102600174A (en) 2005-02-14 2006-02-14 Composition comprising dihomo-.gamma-linolenic acid (dgla) as the active ingredient
CN 200610003112 CN101019853B (en) 2005-02-14 2006-02-14 Composition containing dihomo-gamma-linolenic acid (DGLA) as the active ingredient
US14/644,231 US9943495B2 (en) 2005-02-14 2015-03-11 Composition containing dihomo-γ-linolenic acid (DGLA) as the active ingredient
US15/911,806 US10342773B2 (en) 2005-02-14 2018-03-05 Composition containing dihomo-γ-linolenic acid (DGLA) as the active ingredient

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US9006287B2 (en) 2005-02-14 2015-04-14 Suntory Holdings Limited Composition comprising dihomo-γ-linolenic acid (DGLA) as active ingredient
US9820484B2 (en) 2013-12-04 2017-11-21 Nippon Suisan Kaisha, Ltd. Dihomo-γ-linolenic acid-containing microbial oil and dihomo-γ-linolenic acid-containing microbial biomass
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