JP6872188B2 - Fatty acid composition and its production method, and skin external preparations, quasi-drugs and cosmetics containing the fatty acid composition. - Google Patents
Fatty acid composition and its production method, and skin external preparations, quasi-drugs and cosmetics containing the fatty acid composition. Download PDFInfo
- Publication number
- JP6872188B2 JP6872188B2 JP2017034097A JP2017034097A JP6872188B2 JP 6872188 B2 JP6872188 B2 JP 6872188B2 JP 2017034097 A JP2017034097 A JP 2017034097A JP 2017034097 A JP2017034097 A JP 2017034097A JP 6872188 B2 JP6872188 B2 JP 6872188B2
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- JP
- Japan
- Prior art keywords
- acid
- lipase
- fatty acid
- triglyceride
- palmitoleic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
Description
本発明は、新規な脂肪酸組成物およびその製造方法に関し、さらには、該脂肪酸組成物を含有する皮膚外用剤、医薬部外品および化粧品に関する。 The present invention relates to a novel fatty acid composition and a method for producing the same, and further to skin external preparations, quasi-drugs and cosmetics containing the fatty acid composition.
アトピー性皮膚炎は、日本皮膚科学会ガイドラインによると、表皮、なかでも角層の異常に起因する皮膚の乾燥とバリアー機能異常という皮膚の生理学的異常を伴い、多彩な非特異的刺激反応および特異的アレルギー反応が関与して生じる、慢性に経過する炎症と掻痒をその病態とする湿疹・皮膚炎群の一疾患であるとされる。特に先進国では罹患率が高く、子供の15〜30%、成人の5%が罹患しているといわれる。 According to the guidelines of the Japanese Society of Dermatitis, atopic dermatitis is accompanied by various non-specific irritant reactions and peculiarities, accompanied by skin dryness and barrier dysfunction caused by abnormalities in the epidermis, especially the stratum corneum. It is said to be a disease of the eczema / dermatitis group whose pathological condition is chronic inflammation and pruritus caused by an allergic reaction. Especially in developed countries, the prevalence is high, and it is said that 15 to 30% of children and 5% of adults are affected.
アトピー性皮膚炎は、アトピー素因(家族歴、アレルギー疾患の既往歴、IgE抗体を産生しやすい性質等)、表皮常在細菌叢のバランスの乱れ、栄養的要因(高リノール酸食用油やそれを素材とする食品等)、環境的要因(塵埃、ストレス、不規則な生活等)等の複合的な要因によって発症する。
近年、黄色ブドウ球菌がアトピー性皮膚炎患者の皮膚で高頻度で検出されること、アトピー性皮膚炎患者の炎症部で黄色ブドウ球菌が劇的に増加することが報告され(非特許文献1、2)、表皮の黄色ブドウ球菌(Staphylococcus aureus)の異常増殖がアトピー性皮膚炎の増悪化の原因となっている可能性が示唆されている。これは、黄色ブドウ球菌が生産するプロテインA、δトキシン、V8プロテアーゼなどが炎症の増悪化に関与しているためとされている。
Atopic dermatitis is a predisposition to atopy (family history, history of allergic diseases, prone to produce IgE antibodies, etc.), imbalance of indigenous bacterial flora of the epidermis, and nutritional factors (high linoleic acid edible oil and it). It is caused by multiple factors such as foods used as raw materials) and environmental factors (dust, stress, irregular life, etc.).
In recent years, it has been reported that Staphylococcus aureus is frequently detected in the skin of patients with atopic dermatitis, and that Staphylococcus aureus increases dramatically in the inflamed area of patients with atopic dermatitis (Non-Patent Document 1, Non-Patent Document 1, 2) It has been suggested that the overgrowth of Staphylococcus aureus in the epidermis may be the cause of the exacerbation of atopic dermatitis. It is said that this is because proteins A, delta toxin, V8 protease and the like produced by Staphylococcus aureus are involved in the exacerbation of inflammation.
それゆえ、アトピー性皮膚炎患者に対し、ムピロシン、フシジン酸等の外用、ジクロキサシリン、セファレキシン、エリスロマイシン等の内服等、抗生物質による治療も行われている。
しかしながら、上記のような抗生物質は、皮膚の常在細菌であり、黄色ブドウ球菌(Staphylococcus aureus)の増殖を阻害し、黄色ブドウ球菌(Staphylococcus aureus)の分泌物による炎症の憎悪に対し抑制作用を示す表皮ブドウ球菌(Staphylococcus epidermidis)までも殺菌してしまい、表皮常在細菌叢のバランスの乱れが改善されない可能性が高い。
Therefore, patients with atopic dermatitis are also treated with antibiotics such as external use of mupirocin, fusidic acid, etc., and oral administration of dicloxacillin, cephalexin, erythromycin, etc.
However, antibiotics such as those mentioned above are indigenous bacteria on the skin, inhibit the growth of Staphylococcus aureus, and suppress the exacerbation of inflammation caused by the secretions of Staphylococcus aureus. Even the indicated Staphylococcus epidermidis is sterilized, and it is highly possible that the imbalance of the indigenous flora of the epidermis will not be improved.
一方、アトピー性皮膚炎患者の皮脂中におけるサピエン酸((Z)−6−ヘキサデセン酸)の含有量が、健常者に比べて1/10程度に減少していることが報告され(非特許文献3)、サピエン酸の異性体であり、食経験もあるパルミトレイン酸((Z)−9−ヘキサデセン酸)が、黄色ブドウ球菌に対して抗菌活性を有することが報告される(特許文献1)に至って、パルミトレイン酸の皮膚外用剤における利用が検討されてきた。
しかし、食経験があり、安全性が確認されている植物油等で、パルミトレイン酸を多く含有するものは少なく、シーベリー(Hippophae rhamnoides)という植物の果肉に40質量%程度含有されているものの、シーベリーは栽培地域が限定されており、パルミトレイン酸の実用的な供給源として適するとはいえない。
また、シーベリーの果肉油をはじめ、植物油等には、例えばリノール酸、リノレイン酸等、二重結合を2個以上有し、酸化安定性のよくない多価不飽和脂肪酸(二重結合を2個以上有する不飽和脂肪酸)が相当量含有されるため、植物油から得られた脂肪酸組成物については、酸化安定性に問題があり、皮膚外用剤等に利用するには好ましくない。
On the other hand, it has been reported that the content of sapienic acid ((Z) -6-hexadecenoic acid) in the sebum of patients with atopic dermatitis is reduced to about 1/10 of that of healthy subjects (Non-Patent Documents). 3) It has been reported that palmitoleic acid ((Z) -9-hexadecenoic acid), which is an isomer of sapienic acid and has eating experience, has antibacterial activity against Staphylococcus aureus (Patent Document 1). Therefore, the use of palmitoleic acid in external skin preparations has been studied.
However, few vegetable oils that have been eaten and have been confirmed to be safe contain a large amount of palmitoleic acid, and although the pulp of a plant called seaberry (Hippophae rhamnoides) contains about 40% by mass, seaberry is The cultivation area is limited, and it cannot be said that it is suitable as a practical source of palmitoleic acid.
In addition, vegetable oils such as seaberry fruit oil have two or more double bonds such as linoleic acid and linoleic acid, and polyunsaturated fatty acids with poor oxidative stability (two double bonds). Since the above unsaturated fatty acid) is contained in a considerable amount, the fatty acid composition obtained from vegetable oil has a problem in oxidative stability and is not preferable for use as an external preparation for skin.
さらに、病院の集中治療室(ICU)などで働く労働者で、手洗いやアルコール消毒を繰り返す者では、41.2%〜52.9%において、手に黄色ブドウ球菌が検出されることが報告されている(非特許文献4、5)。
それゆえ、食品工場等の労働者や、家庭で家事に従事する者で、頻繁に手洗いや消毒を繰り返し、手荒れ等の肌荒れが見られる者の皮膚では、同様に黄色ブドウ球菌が増殖している可能性が示唆される。
従って、アトピー性皮膚炎の症状の悪化を防止し、または症状を改善するためのみならず、皮膚の洗浄、消毒に起因する肌荒れの予防または改善のためにも、黄色ブドウ球菌の異常な増殖を防止または抑制し、表皮常在菌叢のバランスを正常な状態に維持、改善する必要性は高い。
Furthermore, it has been reported that Staphylococcus aureus is detected in the hands in 41.2% to 52.9% of workers who work in the intensive care unit (ICU) of hospitals and who repeatedly wash their hands and disinfect with alcohol. (Non-Patent Documents 4 and 5).
Therefore, Staphylococcus aureus grows on the skin of workers in food factories and those who engage in household chores and who frequently wash and disinfect their hands and have rough skin such as rough hands. Possibility is suggested.
Therefore, the abnormal growth of Staphylococcus aureus is not only to prevent the exacerbation of the symptoms of atopic dermatitis or to improve the symptoms, but also to prevent or improve the rough skin caused by cleaning and disinfecting the skin. There is a strong need to prevent or suppress and maintain and improve the balance of indigenous epidermal flora.
そこで、本発明は、パルミトレイン酸を高含有量で含有し、黄色ブドウ球菌(Staphylococcus aureus)を抑制し、表皮ブドウ球菌を抑制しない選択的抗菌剤、つまり表皮常在細菌叢のバランスを保つ抗菌剤として有用な、脂肪酸組成物を提供することを目的とした。 Therefore, the present invention is a selective antibacterial agent containing a high content of palmitoleic acid, suppressing Staphylococcus aureus, and not suppressing Staphylococcus epidermidis, that is, an antibacterial agent that maintains the balance of the indigenous bacterial flora of the epidermis. It is an object of the present invention to provide a fatty acid composition useful as a staphylococcus aureus.
本発明者らは、上記課題を解決すべく鋭意検討した結果、sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂より、リパーゼによりsn−1位およびsn−3位の脂肪酸を遊離させ、次いで遊離させた脂肪酸を回収することにより、パルミトレイン酸を55モル%以上含有する脂肪酸組成物を得ることに成功し、本発明を完成するに至った。 As a result of diligent studies to solve the above problems, the present inventors have determined that the sn-1 position and the sn-3 position are higher than those of fats and oils containing a triglyceride having palmitoleic acid at the sn-1 position and the sn-3 position by lipase. By liberating the fatty acid and then recovering the liberated fatty acid, a fatty acid composition containing 55 mol% or more of palmitoleic acid was successfully obtained, and the present invention was completed.
すなわち、本発明は以下に関する。
[1]パルミトレイン酸を55モル%以上含有する、脂肪酸組成物。
[2]パルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)が、モル比にて2.4以上である、[1]に記載の組成物。
[3]パルミトレイン酸とオレイン酸との含有量比(パルミトレイン酸/オレイン酸)が、モル比にて3以上である、[1]に記載の組成物。
[4]多価不飽和脂肪酸を実質的に含有しない、[1]〜[3]のいずれかに記載の組成物。
[5][1]〜[4]のいずれかに記載の組成物を含有する、黄色ブドウ球菌(Staphylococcus aureus)に対する選択的抗菌剤。
[6][1]〜[4]のいずれかに記載の組成物を含有する、皮膚外用剤。
[7][1]〜[4]のいずれかに記載の組成物を含有する、医薬部外品。
[8][1]〜[4]のいずれかに記載の組成物を含有する、化粧品。
[9](1)sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂より、リパーゼによりsn−1位およびsn−3位の脂肪酸を遊離させる工程、および(2)前記工程で遊離させた脂肪酸を回収する工程を含む、パルミトレイン酸を55モル%以上含有する脂肪酸組成物の製造方法。
[10]sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂が、トリグリセリド全体におけるパルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)より、sn−1位およびsn−3位におけるパルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)の方が大きい油脂である、[9]に記載の製造方法。
[11]sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂が、サッカロマイセス セレビシエ(Saccharomyces cerevisiae)により生産された油脂である、[9]または[10]に記載の製造方法。
[12]サッカロマイセス セレビシエ(Saccharomyces cerevisiae)が、ジアシルグリセロールアシルトランスフェラーゼのN末端欠失遺伝子を過剰発現している形質転換株である、[11]に記載の製造方法。
[13]リパーゼが、トリグリセリドのsn−1位およびsn−3位の脂肪酸を優先的に遊離させるリパーゼである、[9]〜[12]のいずれかに記載の製造方法。
[14]トリグリセリドのsn−1位およびsn−3位の脂肪酸を優先的に遊離させるリパーゼが、シュードザイマ(Pseudozyma)属に属する微生物由来のリパーゼまたはアルカリゲネス(Alcaligenes)属に属する微生物由来のリパーゼである、[13]に記載の製造方法。
[15]シュードザイマ(Pseudozyma)属に属する微生物由来のリパーゼによりsn−1位およびsn−3位の脂肪酸を遊離させる工程が、過剰量のエタノールの存在下に行われる、[14]に記載の製造方法。
[16]リパーゼが、トリグリセリドのsn−1位およびsn−3位の脂肪酸を特異的に遊離させるリパーゼである、[9]〜[12]のいずれかに記載の製造方法。
[17]トリグリセリドのsn−1位およびsn−3位の脂肪酸を特異的に遊離させるリパーゼが、クモノスカビ(Rhizopus)属に属する微生物由来のリパーゼである、[16]に記載の製造方法。
[18]リパーゼが、オレイン酸よりもパルミトレイン酸を優先的に遊離させるリパーゼである、[9]〜[12]のいずれかに記載の製造方法。
[19]オレイン酸よりもパルミトレイン酸を優先的に遊離させるリパーゼが、カンジダ(Candida)属に属する微生物由来のリパーゼである、[18]に記載の製造方法。
That is, the present invention relates to the following.
[1] A fatty acid composition containing 55 mol% or more of palmitoleic acid.
[2] The composition according to [1], wherein the content ratio of palmitoleic acid to oleic acid (palmitoleic acid / oleic acid) is 2.4 or more in terms of molar ratio.
[3] The composition according to [1], wherein the content ratio of palmitoleic acid to oleic acid (palmitoleic acid / oleic acid) is 3 or more in terms of molar ratio.
[4] The composition according to any one of [1] to [3], which does not substantially contain polyunsaturated fatty acids.
[5] A selective antibacterial agent against Staphylococcus aureus, which comprises the composition according to any one of [1] to [4].
[6] An external preparation for skin containing the composition according to any one of [1] to [4].
[7] A quasi-drug containing the composition according to any one of [1] to [4].
[8] A cosmetic product containing the composition according to any one of [1] to [4].
[9] (1) A step of liberating the fatty acids at the sn-1 and sn-3 positions with lipase from a fat and oil containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions, and (2) the above. A method for producing a fatty acid composition containing 55 mol% or more of palmitoleic acid, which comprises a step of recovering the fatty acid liberated in the step.
[10] Oils and fats containing triglycerides having palmitoleic acid at the sn-1 and sn-3 positions are at the sn-1 position and sn-1 position and based on the content ratio of palmitoleic acid and oleic acid (palmitoleic acid / oleic acid) in the total triglyceride. The production method according to [9], wherein the oil / fat has a larger content ratio of palmitoleic acid to oleic acid (palmitoleic acid / oleic acid) at the sn-3 position.
[11] The production method according to [9] or [10], wherein the fat or oil containing a triglyceride having palmitoleic acid at the sn-1 position and the sn-3 position is a fat or oil produced by Saccharomyces cerevisiae. ..
[12] The production method according to [11], wherein Saccharomyces cerevisiae is a transformant overexpressing the N-terminal deletion gene of diaccharomyces acyltransferase.
[13] The production method according to any one of [9] to [12], wherein the lipase is a lipase that preferentially releases the fatty acids at the sn-1 and sn-3 positions of triglyceride.
[14] The lipase that preferentially releases the fatty acids at the sn-1 and sn-3 positions of triglyceride is a lipase derived from a microorganism belonging to the genus Pseudozyma or a lipase derived from a microorganism belonging to the genus Alcaligenes. , [13].
[15] The production according to [14], wherein the step of liberating the fatty acids at the sn-1 and sn-3 positions with a lipase derived from a microorganism belonging to the genus Pseudozyma is carried out in the presence of an excess amount of ethanol. Method.
[16] The production method according to any one of [9] to [12], wherein the lipase is a lipase that specifically liberates the fatty acids at the sn-1 and sn-3 positions of triglyceride.
[17] The production method according to [16], wherein the lipase that specifically liberates the fatty acids at the sn-1 and sn-3 positions of triglyceride is a lipase derived from a microorganism belonging to the genus Rhizopus.
[18] The production method according to any one of [9] to [12], wherein the lipase is a lipase that preferentially releases palmitoleic acid over oleic acid.
[19] The production method according to [18], wherein the lipase that preferentially releases palmitoleic acid over oleic acid is a lipase derived from a microorganism belonging to the genus Candida.
本発明により、黄色ブドウ球菌(Staphylococcus aureus)に対し、選択的な抗菌活性を有するパルミトレイン酸を、従来にない高濃度で含有する脂肪酸組成物を得ることができる。
本発明の脂肪酸組成物は、黄色ブドウ球菌(Staphylococcus aureus)の生育を抑制し、表皮ブドウ球菌の生育を抑制しない選択的抗菌剤、つまり表皮常在細菌叢のバランスを保つ抗菌剤として、特にアトピー性皮膚炎の症状の悪化を防止し、またはアトピー性皮膚炎の症状を改善するための皮膚外用剤、医薬部外品または化粧品として、好適に利用され得る。
また、本発明の脂肪酸組成物は、アトピー性皮膚炎のみならず、家事や職務上の皮膚の洗浄、消毒等により生じる手荒れ等の肌荒れを予防または改善するための皮膚外用剤、医薬部外品または化粧品としても、好適に利用され得る。
INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain a fatty acid composition containing palmitoleic acid having selective antibacterial activity against Staphylococcus aureus at an unprecedented high concentration.
The fatty acid composition of the present invention is a selective antibacterial agent that suppresses the growth of Staphylococcus aureus and does not suppress the growth of epidermal staphylococci, that is, an antibacterial agent that maintains the balance of the indigenous bacterial flora of the epidermis, particularly atopy. It can be suitably used as an external preparation for skin, a non-pharmaceutical product, or a cosmetic for preventing exacerbation of the symptoms of staphylococcus aureus or ameliorating the symptoms of atopic dermatitis.
In addition, the fatty acid composition of the present invention is an external preparation for skin, a quasi-drug for preventing or ameliorating not only atopic dermatitis but also rough skin such as rough hands caused by cleaning and disinfecting the skin during housework and work. Alternatively, it can be suitably used as a cosmetic product.
本発明は、パルミトレイン酸を、組成物の全量に対し55モル%以上含有する脂肪酸組成物(以下、本明細書において「本発明の脂肪酸組成物」ともいう)を提供する。 The present invention provides a fatty acid composition containing palmitoleic acid in an amount of 55 mol% or more based on the total amount of the composition (hereinafter, also referred to as “fatty acid composition of the present invention” in the present specification).
本発明の脂肪酸組成物に含有されるパルミトレイン酸は、9位に二重結合を1個有する炭素数16の不飽和脂肪酸((Z)−9−ヘキサデセン酸))である。
本発明の脂肪酸組成物は、パルミトレイン酸を組成物の全量に対し、好ましくは58モル%以上含有し、より好ましくは60モル%以上含有する。
また、後述するリパーゼを用いた製造方法における効率等を考慮すると、本発明の脂肪酸組成物におけるパルミトレイン酸の含有量は、通常70モル%以下である。
The palmitoleic acid contained in the fatty acid composition of the present invention is an unsaturated fatty acid having 16 carbon atoms ((Z) -9-hexadecenoic acid) having one double bond at the 9-position.
The fatty acid composition of the present invention contains palmitoleic acid in an amount of preferably 58 mol% or more, more preferably 60 mol% or more, based on the total amount of the composition.
Further, considering the efficiency of the production method using lipase described later, the content of palmitoleic acid in the fatty acid composition of the present invention is usually 70 mol% or less.
本発明の脂肪酸組成物は、パルミトレイン酸の他に、炭素数10〜20程度の飽和または不飽和脂肪酸を含有していてもよいが、黄色ブドウ球菌(Staphylococcus aureus)に対する選択的抗菌活性の観点からは、オレイン酸がパルミトレイン酸の抗菌活性に抑制的に作用することから、オレイン酸((Z)−9−オクタデセン酸)の含有量が少ない方が望ましく、パルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)が、モル比にて2.4以上であることが好ましく、3以上であることがより好ましい。
さらに、本発明の脂肪酸組成物は、酸素に対して不安定であり、皮膚外用剤等として製剤化する際に、安定性等品質に悪影響を及ぼすおそれのあるリノール酸((9Z,12Z)−9,12−オクタデカジエン酸)、α−リノレン酸(9Z,12Z,15Z)−9,12,15−オクタデカトリエン酸)、γ−リノレン酸(6Z,9Z,12Z)−6,9,12−オクタデカトリエン酸)等の多価不飽和脂肪酸を実質的に含有しないことが好ましい。
ここで、「多価不飽和脂肪酸を実質的に含有しない」とは、上記多価不飽和脂肪酸の通常の分析方法、たとえばガスクロマトグラフィーによる定量方法等により、上記多価不法脂肪酸が検出されない、すなわち検出限界(0.1モル%)以下であることをいう。
The fatty acid composition of the present invention may contain saturated or unsaturated fatty acids having about 10 to 20 carbon atoms in addition to palmitoleic acid, but from the viewpoint of selective antibacterial activity against Staphylococcus aureus. Since oleic acid acts suppressively on the antibacterial activity of palmitoleic acid, it is desirable that the content of oleic acid ((Z) -9-octadecenoic acid) is small, and the content ratio of palmitoleic acid to oleic acid ( Palmitoleic acid / oleic acid) is preferably 2.4 or more in terms of molar ratio, and more preferably 3 or more.
Furthermore, the fatty acid composition of the present invention is unstable to oxygen and may adversely affect quality such as stability when formulated as an external preparation for skin or the like ((9Z, 12Z)-. 9,12-Octadecadienoic acid), α-linolenic acid (9Z, 12Z, 15Z) -9,12,15-octadecatrine acid), γ-linolenic acid (6Z, 9Z, 12Z) -6,9, It is preferable that it does not substantially contain polyunsaturated fatty acids such as 12-octadecatrienoic acid).
Here, "substantially free of polyunsaturated fatty acids" means that the polyunsaturated fatty acids are not detected by the usual analysis method of the polyunsaturated fatty acids, for example, a quantification method by gas chromatography or the like. That is, it means that it is below the detection limit (0.1 mol%).
本発明の脂肪酸組成物は、上記の通り、融点が−1℃であるパルミトレイン酸を55モル%以上含有し、長鎖の飽和脂肪酸の含有量が少ないことから、通常20℃で液状を呈する。 As described above, the fatty acid composition of the present invention contains 55 mol% or more of palmitoleic acid having a melting point of -1 ° C. and has a low content of long-chain saturated fatty acids, so that it usually exhibits a liquid state at 20 ° C.
本発明の脂肪酸組成物は、sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂より、リパーゼによりsn−1位およびsn−3位の脂肪酸を遊離させ、遊離した脂肪酸を回収することにより、好適に得ることができる。また、前記の油脂は、トリグリセリド全体におけるパルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)より、sn−1位およびsn−3位におけるパルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)の方が大きい油脂であることがより好ましい。 In the fatty acid composition of the present invention, the fatty acids at the sn-1 and sn-3 positions are liberated by lipase from the fat and oil containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions, and the liberated fatty acids are released. By collecting it, it can be preferably obtained. Further, in the above fats and oils, the content ratio of palmitoleic acid and oleic acid at the sn-1 position and the sn-3 position (palmitoleic acid) is higher than the content ratio of palmitoleic acid and oleic acid in the whole triglyceride (palmitoleic acid / oleic acid). / Oleic acid) is more preferable.
上記したトリグリセリドを含有する油脂としては、植物や、酵母等の微生物等から得られる油脂であって、食経験のある油脂であることが好ましく、サッカロマイセス セレビシエ(Saccharomyces cerevisiae)により生産された油脂であることがより好ましい。
サッカロマイセス セレビシエ(Saccharomyces cerevisiae)としては、脂質生産能の高い形質転換株を用いることが好ましい。かかる形質転換株としては、特開2015−146778号公報に記載されているようなジアシルグリセロールアシルトランスフェラーゼ(DGAT)のN末端欠失遺伝子を過剰発現している形質転換株であって、sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドの含有量の高い脂質を生産する能力を有するものを、好ましく用いることができる。さらには、DGATのN末端欠失遺伝子をサッカロマイセス セレビシエ(Saccharomyces cerevisiae)のDGATの遺伝子(DGA1)破壊株で過剰発現させた形質転換株がより好ましい。特に、N末端の29残基を欠失したDGATを、DGA1遺伝子破壊株等の細胞内のヒストンアセチルトランスフェラーゼをコードするESA1遺伝子の機能を低下させたサッカロマイセス セレビシエ(Saccharomyces cerevisiae)で過剰発現させた形質転換株が好ましく用いられる。
なお、上記DGATのN末端欠失遺伝子を過剰発現している形質転換株等の作成、培養等は、神坂ら(Appl. Microbiol. Biotechnol. 99 201-210 (2015))、特開2015−146778号公報等に記載された方法に従って行うことができる。
The fats and oils containing the above-mentioned triglyceride are fats and oils obtained from plants, microorganisms such as yeast, and the like, and are preferably fats and oils having eating experience, and are fats and oils produced by Saccharomyces cerevisiae. Is more preferable.
As Saccharomyces cerevisiae, it is preferable to use a transformant having a high lipid-producing ability. Such a transformant is a transformant overexpressing the N-terminal deletion gene of diacylglycerol acyltransferase (DGAT) as described in JP-A-2015-146778, sn-1. Those having an ability to produce a lipid having a high content of triglyceride having palmitoleic acid at the position and the sn-3 position can be preferably used. Furthermore, a transformant in which the N-terminal deletion gene of DGAT is overexpressed with a Saccharomyces cerevisiae DGAT gene (DGA1) disrupted strain is more preferable. In particular, a trait in which DGAT lacking 29 residues at the N-terminal was overexpressed with Saccharomyces cerevisiae, which reduced the function of the ESA1 gene encoding histone acetyltransferase in cells such as a DGA1 gene disruption strain. Convertible strains are preferably used.
For the preparation, culture, etc. of transformants, etc. that overexpress the N-terminal deletion gene of DGAT, Kamisaka et al. (Appl. Microbiol. Biotechnol. 99 201-210 (2015)), JP-A-2015-146778. It can be carried out according to the method described in the publication.
本発明の脂肪酸組成物を得るためには、リパーゼとして、トリグリセリドのsn−1位およびsn−3位の脂肪酸を優先的に遊離させるリパーゼ、またはトリグリセリドのsn−1位およびsn−3位の脂肪酸を特異的に遊離させるリパーゼを用いることが好ましい。
トリグリセリドのsn−1位およびsn−3位の脂肪酸を優先的に遊離させるリパーゼとしては、シュードザイマ アンタークティカ(Pseudozyma antarctica)等、シュードザイマ(Pseudozyma)属に属する微生物、アルカリゲネス(Alcaligenes)属に属する微生物、シュードモナス(Psudomonas)属に属する微生物およびバークホルデリア(Burkholderia)属に属する微生物等に由来するリパーゼが、好ましいものとして挙げられ、なかでも、シュードザイマ(Pseudozyma)属に属する微生物由来のリパーゼおよびアルカリゲネス(Alcaligenes)属に属する微生物由来のリパーゼがより好ましい。
トリグリセリドのsn−1位およびsn−3位の脂肪酸を特異的に遊離させるリパーゼとしては、リゾプス ジャポニクス(Rhizopus japonicus)やリゾプス オリゼ(Rhizopus oryzae)等のクモノスカビ(Rhizopus)属に属する微生物、リゾムコール ミヘイ(Rhizomucor miehei)等のリゾムコール(Rhizomucor)属に属する微生物、サーモミセス ラヌギノサス(Thermomyces lanuginosus)等のサーモミセス(Thermomyces)属に属する微生物等に由来するリパーゼ、および膵臓リパーゼが、好ましいものとして挙げられる。なかでも、クモノスカビ(Rhizopus)属に属する微生物由来のリパーゼがより好ましい。
In order to obtain the fatty acid composition of the present invention, the lipase is a lipase that preferentially releases the fatty acids at the sn-1 and sn-3 positions of the triglyceride, or the fatty acids at the sn-1 and sn-3 positions of the triglyceride. It is preferable to use a lipase that specifically liberates.
Lipases that preferentially release the sn-1 and sn-3 fatty acids of triglycerides include microorganisms belonging to the genus Pseudozyma and microorganisms belonging to the genus Alcaligenes, such as Pseudozyma antarctica. , Lipases derived from microorganisms belonging to the genus Psudomonas and microorganisms belonging to the genus Burkholderia, etc. are preferred, and among them, lipases derived from microorganisms belonging to the genus Pseudozyma and Alcaligenes ( Lipases derived from microorganisms belonging to the genus Alcaligenes) are more preferred.
Lipases that specifically release the sn-1 and sn-3 fatty acids of triglycerides include Rhizopus oryzae, a microorganism belonging to the genus Rhizopus, such as Rhizopus japonicus and Rhizopus oryzae. Preferred are lipases derived from microorganisms belonging to the genus Rhizomucor such as Rhizomucor miehei), microorganisms belonging to the genus Thermomyces such as Thermomyces lanuginosus, and pancreatic lipases. Of these, lipases derived from microorganisms belonging to the genus Rhizopus are more preferable.
また、本発明においては、オレイン酸よりもパルミトレイン酸を優先的に遊離させるリパーゼを用いることもできる。
かかるリパーゼとしては、カンジダ ルゴサ(Candida rugosa)等のカンジダ(Candida)属に属する微生物、ゲオトリクム カンディダム(Geotrichum candidum)等のゲオトリクム(Geotrichum)属に属する微生物等に由来するリパーゼが、好ましいものとして挙げられ、カンジダ(Candida)属に属する微生物由来のリパーゼがより好ましい。
Further, in the present invention, a lipase that preferentially liberates palmitoleic acid over oleic acid can also be used.
As such lipase, a lipase derived from a microorganism belonging to the genus Candida such as Candida rugosa, a microorganism belonging to the genus Geotrichum such as Geotrichum candidum, and the like are preferable. , Lipases derived from microorganisms belonging to the genus Candida are more preferred.
上記したリパーゼは、遊離型のリパーゼであってもよく、樹脂等の担体に結合させたり、マイクロカプセルまたはリポソームに内包させたりして、固定化されたものであってもよい。
本発明においては、各社より提供されている市販のリパーゼを用いることができる。
The above-mentioned lipase may be a free lipase, or may be immobilized by binding to a carrier such as a resin or encapsulating it in microcapsules or liposomes.
In the present invention, commercially available lipases provided by each company can be used.
sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂より、リパーゼによりsn−1位およびsn−3位の脂肪酸を遊離させる反応は、使用するリパーゼの種類により、反応条件を適宜設定して行うことができる。
リパーゼの添加量としては、基質であるトリグリセリド100質量部に対し、通常0.01質量部〜10質量部であり、好ましくは0.03質量部〜1.5質量部である。遊離型の酵素の場合は、水系での反応であり、トリグリセリドに対して添加する水の量は、好ましくは0.01質量%から99質量%、より好ましくは5質量%から95質量%である。固定化酵素の場合は、水を添加しても、しなくてもよい。
酵素反応は、必要に応じて水、ヘキサン等の溶媒を用い、通常5℃〜60℃、好ましくは20℃〜40℃、pH=3〜9、好ましくはpH=5〜7にて、通常0.5時間〜18時間行わせる。反応時間が長くなると、sn−1位からsn−3位のすべてにおいて脂肪酸の遊離が進行したり、アシル基転移が生じたりするため、反応時間は2時間〜3時間程度とすることが好ましい。リパーゼによる加水分解反応を停止させるには、加熱による失活、エタノールやメタノールなどの短鎖アルコールによる失活、静置や遠心分離による油水分離等を行うことが好ましい。固定化酵素の場合は、静置や濾過により固定化酵素を除くだけでよい。未反応のトリグリセリドは、反応液に水酸化カリウム等のアルカリ剤を加え、遊離脂肪酸を鹸化して水層に移行させた後、n−ヘキサン等の非極性有機溶媒により抽出する等して、除去することができる。
なお、リパーゼとして、シュードザイマ(Pseudozyma)属に属する微生物由来のリパーゼを用いる場合、基質であるトリグリセリド100質量部に対し、500質量部くらいの過剰量のエタノールの存在下に反応させると、前記リパーゼが、sn−1位およびsn−3位に対してほぼ特異的に作用するため、好ましい。かかる場合には、sn−1位およびsn−3位の脂肪酸は、エチルエステルとして遊離するため、通常の方法により鹸化した後、遊離脂肪酸を回収する。
The reaction for liberating the fatty acids at the sn-1 and sn-3 positions with lipase from fats and oils containing triglyceride having palmitoleic acid at the sn-1 and sn-3 positions depends on the type of lipase used. It can be set as appropriate.
The amount of lipase added is usually 0.01 parts by mass to 10 parts by mass, preferably 0.03 parts by mass to 1.5 parts by mass, based on 100 parts by mass of the substrate triglyceride. In the case of the free enzyme, it is a reaction in an aqueous system, and the amount of water added to the triglyceride is preferably 0.01% by mass to 99% by mass, more preferably 5% by mass to 95% by mass. .. In the case of immobilized enzymes, water may or may not be added.
The enzymatic reaction is usually 0 ° C. to 60 ° C., preferably 20 ° C. to 40 ° C., pH = 3 to 9, preferably pH = 5 to 7, using a solvent such as water or hexane as necessary. . Let it run for 5 to 18 hours. When the reaction time is long, the release of fatty acids proceeds at all of the sn-1 position to the sn-3 position and the acyl group transfer occurs. Therefore, the reaction time is preferably about 2 hours to 3 hours. In order to stop the hydrolysis reaction by lipase, it is preferable to inactivate by heating, inactivate by short-chain alcohol such as ethanol or methanol, and separate oil and water by standing or centrifuging. In the case of an immobilized enzyme, it is only necessary to remove the immobilized enzyme by standing or filtering. Unreacted triglyceride is removed by adding an alkaline agent such as potassium hydroxide to the reaction solution, saponifying the free fatty acid and transferring it to the aqueous layer, and then extracting it with a non-polar organic solvent such as n-hexane. can do.
When a lipase derived from a microorganism belonging to the genus Pseudozyma is used as the lipase, 100 parts by mass of triglyceride, which is a substrate, is reacted in the presence of an excess amount of ethanol of about 500 parts by mass, and the lipase is released. , Sn-1 position and sn-3 position are preferable because they act almost specifically. In such a case, since the fatty acids at the sn-1 and sn-3 positions are liberated as ethyl esters, the free fatty acids are recovered after saponification by a usual method.
上記リパーゼにより遊離された脂肪酸は、(1)シリカゲルカラム等によるカラムクロマトグラフィーによる分離、(2)反応液に水酸化カリウム等のアルカリ剤を加えて、遊離脂肪酸を鹸化して水層に移行させた後、n−ヘキサン等の低極性有機溶媒による抽出等により未反応のトリグリセリドを除去し、水層に塩酸等の酸を添加して酸性とした後、n−ヘキサン等の低極性有機溶媒で抽出し、溶媒を蒸発させて除去する方法、(3)油水分離等により水を除去した後、蒸留により遊離脂肪酸を回収する方法等、通常の方法により回収することができる。 The fatty acid liberated by the lipase is (1) separated by column chromatography using a silica gel column or the like, and (2) an alkaline agent such as potassium hydroxide is added to the reaction solution to sacrifice the free fatty acid and transfer it to the aqueous layer. After that, unreacted triglyceride is removed by extraction with a low-polar organic solvent such as n-hexane, and an acid such as hydrochloric acid is added to the aqueous layer to make it acidic, and then with a low-polar organic solvent such as n-hexane. It can be recovered by a usual method such as a method of extracting and removing the solvent by evaporating, (3) a method of removing water by oil-water separation or the like, and then recovering a free fatty acid by distillation.
本発明の脂肪酸組成物は、黄色ブドウ球菌(Staphylococcus aureus)に対して選択的抗菌活性を有するパルミトレイン酸の含有量が高く(脂肪酸組成物の全量に対し55モル%以上)、パルミトレイン酸の前記選択的抗菌活性を阻害するオレイン酸の含有量が低いため、アトピー性皮膚炎の増悪化に関与する黄色ブドウ球菌(Staphylococcus aureus)の生育を抑制するが、健常な皮膚の常在細菌である表皮ブドウ球菌(Staphylococcus epidermidis)の生育は抑制せず、表皮ブドウ球菌(Staphylococcus epidermidis)を減少させるおそれが少ない。
従って、本発明の脂肪酸組成物は、黄色ブドウ球菌(Staphylococcus aureus)に対する選択的抗菌剤として有用であり、皮膚の常在細菌叢を健常な状態に維持し、または改善して、アトピー性皮膚炎の症状の悪化を防止し、またはアトピー性皮膚炎の症状を改善する上で有効な皮膚外用剤、医薬部外品、化粧品等として、あるいは、家事や職務上の皮膚の洗浄、消毒等により生じる肌荒れを予防または改善する上で有効な皮膚外用剤、医薬部外品、化粧品等として、好ましく利用することができる。
The fatty acid composition of the present invention has a high content of palmitoreic acid having selective antibacterial activity against Staphylococcus aureus (55 mol% or more based on the total amount of the fatty acid composition), and the selection of palmitoreic acid. The low content of oleic acid, which inhibits antibacterial activity, suppresses the growth of Staphylococcus aureus, which is involved in the exacerbation of atopic dermatitis, but is a resident bacterium of healthy skin, Staphylococcus epidermidis. It does not suppress the growth of Staphylococcus epidermidis and is less likely to reduce Staphylococcus epidermidis.
Therefore, the fatty acid composition of the present invention is useful as a selective antibacterial agent against Staphylococcus aureus, and maintains or improves the resident bacterial flora of the skin in a healthy state, resulting in atopic dermatitis. It is caused by skin external preparations, non-medicinal products, cosmetics, etc. that are effective in preventing the worsening of the symptoms of atopic dermatitis or improving the symptoms of atopic dermatitis, or by cleaning or disinfecting the skin during domestic or professional work. It can be preferably used as an external preparation for skin, a non-medicinal product, a cosmetic product, etc., which is effective in preventing or improving rough skin.
よって、本発明は、本発明の脂肪酸組成物を含有する、黄色ブドウ球菌(Staphylococcus aureus)に対する選択的抗菌剤(以下、本明細書において、「本発明の抗菌剤」とも称する)を提供する。
本発明の抗菌剤は、本発明の脂肪酸組成物に、必要に応じて、製剤の分野で用いられる一般的な添加剤を加えて、製剤の分野で周知の製剤化手段、たとえば第十七改正日本薬局方製剤総則[3]製剤各条に記載された方法等により、調製することができ、油状;懸濁液状、乳液状等の液状;ゲル状、ペースト状、クリーム状等の半固形状;粉末状、顆粒状、タブレット状、カプセル状等の固形状等の形態とすることができる。
本発明の目的には、本発明の抗菌剤は、皮膚に外用され得る形態とすることが好ましい。
Therefore, the present invention provides a selective antibacterial agent against Staphylococcus aureus containing the fatty acid composition of the present invention (hereinafter, also referred to as “antibacterial agent of the present invention” in the present specification).
The antibacterial agent of the present invention is prepared by adding a general additive used in the field of formulation to the fatty acid composition of the present invention, if necessary, and a formulation means known in the field of formulation, for example, the 17th revision. General rules for pharmaceutical products of the Japanese Pharmacy [3] Formulations It can be prepared by the methods described in each article, and can be prepared as oily; liquid such as suspension or milky; semi-solid such as gel, paste or cream. It can be in the form of a solid such as powder, granule, tablet, capsule or the like.
For the purposes of the present invention, the antibacterial agent of the present invention is preferably in a form that can be applied externally to the skin.
上記添加剤としては、賦形剤、結合剤、崩壊剤、滑沢剤、被覆剤、基剤、溶剤、乳化剤、分散剤、懸濁化剤、安定化剤、粘稠剤、pH調整剤、抗酸化剤、防腐剤、保存剤、矯味剤、甘味剤、香料、着色剤等が挙げられる。 Examples of the above additives include excipients, binders, disintegrants, lubricants, coating agents, bases, solvents, emulsifiers, dispersants, suspending agents, stabilizers, thickeners, pH adjusters, etc. Examples thereof include antioxidants, preservatives, preservatives, flavoring agents, sweeteners, flavors, coloring agents and the like.
賦形剤としては、無水ケイ酸、ケイ酸カルシウム、ケイ酸アルミン酸マグネシウム、デンプン(トウモロコシデンプン、バレイショデンプン、コムギデンプン等)、糖類(ブドウ糖、乳糖、白糖等)、糖アルコール(ソルビトール、マルチトール、マンニトール等)が挙げられる。 Excipients include silicon dioxide, calcium silicate, magnesium silicate aluminate, starch (corn starch, potato starch, wheat starch, etc.), sugars (dextrose, lactose, sucrose, etc.), sugar alcohols (sorbitol, martitol, etc.). , Mannitol, etc.).
結合剤としては、ゼラチン、カゼインナトリウム、デンプン(ヒドロキシプロピルスターチ、アルファー化デンプン、部分アルファー化デンプン等)、セルロースおよびその誘導体(結晶セルロース、ヒドロキシプロピルセルロース、カルボキシメチルセルロース等)等が挙げられる。 Examples of the binder include gelatin, sodium caseinate, starch (hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, etc.), cellulose and its derivatives (crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, etc.) and the like.
崩壊剤としては、ポビドン、クロスポビドン、セルロースおよびその誘導体(結晶セルロース、メチルセルロース等)等が挙げられる。 Examples of the disintegrant include povidone, crospovidone, cellulose and its derivatives (crystalline cellulose, methyl cellulose, etc.).
滑沢剤としては、タルク、合成ケイ酸アルミニウム、ケイ酸マグネシウム、ステアリン酸カルシウム、ステアリン酸マグネシウム等が挙げられる。 Examples of the lubricant include talc, synthetic aluminum silicate, magnesium silicate, calcium stearate, magnesium stearate and the like.
被覆剤としては、メタクリル酸共重合体(メタクリル酸・アクリル酸エチル共重合体等)、メタクリレート共重合体(アクリル酸エチル・メタクリル酸メチル共重合体、アクリル酸エチル・メタクリル酸メチル・メタクリル酸塩化トリメチルアンモニウムエチル共重合体等)等が挙げられる。 Examples of the coating agent include a methacrylic acid copolymer (methacrylic acid / ethyl acrylate copolymer, etc.), a methacrylate copolymer (ethyl acrylate / methyl methacrylate copolymer, ethyl acrylate / methyl methacrylate / chloride methacrylate, etc.). (Trimethylammonium ethyl copolymer, etc.) and the like.
基剤としては、炭化水素(流動パラフィン等)、ポリエチレングリコール(マクロゴール400、マクロゴール1500等)等が挙げられる。 Examples of the base include hydrocarbons (liquid paraffin and the like), polyethylene glycol (macrogol 400, macrogol 1500 and the like) and the like.
溶剤としては、精製水、一価アルコール(エタノール等)、多価アルコール(プロピレングリコール、グリセリン等)等が挙げられる。 Examples of the solvent include purified water, monohydric alcohol (ethanol, etc.), polyhydric alcohol (propylene glycol, glycerin, etc.) and the like.
乳化剤としては、非イオン性界面活性剤(ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ショ糖脂肪酸エステル等)、陰イオン性界面活性剤(アルキル硫酸ナトリウム、N−アシルグルタミン酸塩等)、精製大豆レシチン等が挙げられる。 Examples of the emulsifier include nonionic surfactants (sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, etc.), anionic surfactants (sodium alkyl sulfate, N-acylglutamate, etc.). ), Purified soybean lecithin and the like.
分散剤としては、アラビアゴム、アルギン酸プロピレングリコール、非イオン性界面活性剤(ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール等)、陰イオン性界面活性剤(アルキル硫酸ナトリウム等)等が挙げられる。 Dispersants include gum arabic, propylene glycol alginate, nonionic surfactants (polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol, etc.), anionic surfactants (polyoxyethylene polyoxypropylene glycol, etc.) Alkyl sulfate sodium, etc.) and the like.
懸濁化剤としては、アルギン酸ナトリウム、非イオン性界面活性剤(ポリオキシエチレンラウリルエーテル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、プロピレングリコール脂肪酸エステル等)等が挙げられる。 Examples of the suspending agent include sodium alginate, nonionic surfactants (polyoxyethylene lauryl ether, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, propylene glycol fatty acid ester, etc.) and the like.
安定化剤としては、アジピン酸、エチレンジアミン四酢酸塩(カルシウム二ナトリウム塩、二ナトリウム塩等)、α−シクロデキストリン、β−シクロデキストリン等が挙げられる。 Examples of the stabilizer include adipic acid, ethylenediaminetetraacetic acid salt (calcium disodium salt, disodium salt, etc.), α-cyclodextrin, β-cyclodextrin and the like.
粘稠剤としては、水溶性高分子(ポリアクリル酸ナトリウム、カルボキシビニルポリマー等)、多糖類(アルギン酸ナトリウム、キサンタンガム、トラガント等)等が挙げられる。 Examples of the thickener include water-soluble polymers (sodium polyacrylate, carboxyvinyl polymer, etc.), polysaccharides (sodium alginate, xanthan gum, tragant, etc.) and the like.
pH調整剤としては、塩酸、リン酸、酢酸、クエン酸、乳酸、水酸化ナトリウム、リン酸水素ナトリウム等が挙げられる。 Examples of the pH adjuster include hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid, sodium hydroxide, sodium hydrogen phosphate and the like.
抗酸化剤としては、ジブチルヒドロキシトルエン(BHT)、ブチルヒドロキシアニソール(BHA)、dl−α−トコフェロール、エリソルビン酸、没食子酸プロピル等が挙げられる。 Examples of the antioxidant include dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), dl-α-tocopherol, erythorbic acid, propyl gallate and the like.
防腐剤としては、安息香酸ナトリウム、ソルビン酸、ソルビン酸カリウム、デヒドロ酢酸、デヒドロ酢酸ナトリウム、パラオキシ安息香酸エステル(パラオキシ安息香酸メチル等)等が挙げられる。
また、保存剤としては、安息香酸、安息香酸ナトリウム、ソルビトール、パラオキシ安息香酸エステル(パラオキシ安息香酸メチル等)、プロピレングリコール等が挙げられる。
Examples of the preservative include sodium benzoate, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate, paraoxybenzoic acid ester (methyl paraoxybenzoate, etc.) and the like.
Examples of the preservative include benzoic acid, sodium benzoate, sorbitol, paraoxybenzoic acid ester (methyl paraoxybenzoate, etc.), propylene glycol and the like.
矯味剤としては、アスコルビン酸、エリスリトール、5’−グアニル酸二ナトリウム、クエン酸、L−グルタミン酸ナトリウム、酒石酸、DL−リンゴ酸等が挙げられる。
また、甘味剤としては、アスパルテーム、カンゾウエキス、サッカリン等が挙げられる。
Examples of the flavoring agent include ascorbic acid, erythritol, disodium 5'-guanylate, citric acid, monosodium L-glutamate, tartaric acid, DL-malic acid and the like.
Examples of the sweetener include aspartame, licorice extract, saccharin and the like.
香料としては、オレンジエッセンス、l−メントール、d−ボルネオール、バニリン、リナロール等が挙げられる。 Examples of the fragrance include orange essence, l-menthol, d-borneol, vanillin, linalool and the like.
着色剤としては、タール色素(食用赤色2号、食用青色1号、食用黄色4号等)、無機顔料(ベンガラ、黄色三二酸化鉄、酸化チタン等)、天然色素(アナトー色素、ウコン色素、カロテノイド等)等が挙げられる。 Coloring agents include tar pigments (edible red No. 2, edible blue No. 1, edible yellow No. 4, etc.), inorganic pigments (bengala, yellow iron sesquioxide, titanium oxide, etc.), natural pigments (anato pigments, corn pigments, carotenoids, etc.) Etc.) etc.
上記した添加剤は、必要に応じて、1種または2種以上を用いることができる。 As the above-mentioned additives, one kind or two or more kinds can be used as needed.
本発明の抗菌剤における、本発明の脂肪酸組成物の含有量としては、本発明の抗菌剤の全量に対するパルミトレイン酸の含有量として、通常0.001質量%〜10質量%であり、0.005質量%〜5質量%であることが好ましい。 The content of the fatty acid composition of the present invention in the antibacterial agent of the present invention is usually 0.001% by mass to 10% by mass, 0.005% by mass, as the content of palmitoleic acid with respect to the total amount of the antibacterial agent of the present invention. It is preferably mass% to 5% by mass.
本発明の抗菌剤の適用量は、本発明の抗菌剤が適用される対象(以下、本明細書において「適用対象」ともいう)の種別、性別、年齢、皮膚の状態、本発明の抗菌剤の剤形、適用経路等により適宜決定されるが、適用対象がヒト成人であり、外用により適用する場合、パルミトレイン酸の適用量として、1回あたり通常0.02μg/cm2〜200μg/cm2であり、好ましくは、0.1μg/cm2〜100μg/cm2である。
上記の量は、1日に1回〜数回、適用することができる。
本発明の抗菌剤の適用期間は、適用対象において観察される皮膚の状態(皮膚常在細菌叢のバランスの状態)等により適宜決定されるが、通常1日間〜30日間であり、好ましくは3日間〜15日間である。
なお、本発明の抗菌剤は、安全性の確認された酵母等の脂質より得られるパルミトレイン酸を有効成分とするため安全性が高く、連続した適用に適する。
The applicable amount of the antibacterial agent of the present invention is the type, gender, age, skin condition, and antibacterial agent of the present invention of the subject to which the antibacterial agent of the present invention is applied (hereinafter, also referred to as “applicable subject” in the present specification). dosage form, is appropriately determined by the application route and the like, application target is a human adult, when applied by external application as an application amount of palmitoleic acid, per normal 0.02μg / cm 2 ~200μg / cm 2 by weight, preferably, 0.1μg / cm 2 ~100μg / cm 2.
The above amount can be applied once to several times a day.
The application period of the antibacterial agent of the present invention is appropriately determined depending on the skin condition (state of balance of the skin indigenous bacterial flora) observed in the application target, but is usually 1 to 30 days, preferably 3 days. 1 to 15 days.
Since the antibacterial agent of the present invention contains palmitoleic acid obtained from a lipid such as yeast whose safety has been confirmed as an active ingredient, it is highly safe and suitable for continuous application.
本発明の抗菌剤の適用対象となる動物(以下、本明細書において「対象動物」ともいう)としては、哺乳動物(ヒト、サル、マウス、ラット、モルモット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ウマ、ロバ、ブタ、ヒツジ等)等が挙げられる。なお、本発明の抗菌剤をヒト以外の対象動物に適用する場合、本発明の抗菌剤の適用量は、対象動物の種類、性別、体重、皮膚の状態等に応じて適宜設定すればよい。 The animals to which the antibacterial agent of the present invention is applied (hereinafter, also referred to as “target animals” in the present specification) include mammals (humans, monkeys, mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, and cows). , Horses, donkeys, pigs, sheep, etc.). When the antibacterial agent of the present invention is applied to a target animal other than human, the application amount of the antibacterial agent of the present invention may be appropriately set according to the type, sex, body weight, skin condition, etc. of the target animal.
本発明の抗菌剤は、皮膚常在細菌叢のバランスの乱れを正常な状態に改善し、または皮膚常在細菌叢のバランスを正常な状態に維持して、アトピー性皮膚炎の症状の悪化の防止、またはアトピー性皮膚炎の症状の改善に有効であり、アトピー性皮膚炎患者またはアトピー性皮膚炎の症状を呈する動物に対し、好適に適用することができる。
また、本発明の抗菌剤は、アトピー性皮膚炎患者のみならず、家事や職務上、皮膚の洗浄、消毒等を行う頻度が高く、手荒れ等、肌荒れ症状を呈するおそれのある者または肌荒れ症状を呈する者においても、肌荒れ症状を予防しまたは改善するために好適に適用され得る。
The antibacterial agent of the present invention improves the imbalance of the resident skin flora to a normal state, or maintains the balance of the resident skin flora to a normal state, and exacerbates the symptoms of atopic dermatitis. It is effective in preventing or improving the symptoms of atopic dermatitis, and can be suitably applied to patients with atopic dermatitis or animals exhibiting symptoms of atopic dermatitis.
In addition, the antibacterial agent of the present invention frequently cleans and disinfects the skin not only for patients with atopic dermatitis but also for household work and duties, and may cause rough skin symptoms such as rough hands or rough skin symptoms. It can also be suitably applied to those who present it to prevent or ameliorate rough skin symptoms.
本発明はまた、本発明の脂肪酸組成物を含有する皮膚外用剤(以下、本明細書において「本発明の皮膚外用剤」ともいう)を提供する。
ここで、「皮膚外用剤」とは、皮膚の病変部位に外用にて適用される医薬品をいうが、皮膚を通して有効成分を循環血流に送達させることを目的とした経皮吸収型製剤も含まれる。
本発明の皮膚外用剤は、本発明の脂肪酸組成物に、必要に応じて、皮膚外用剤の製造に際して用いられる一般的な添加剤を加えて、外用散剤等の外用固形剤;リニメント剤、ローション剤(液剤、乳濁液剤、懸濁液剤等)等の外用液剤;外用エアゾール剤、ポンプスプレー剤等のスプレー剤;油脂性軟膏剤、水溶性軟膏剤等の軟膏剤;水中油型または油中水型のクリーム剤;水性ゲル剤、油性ゲル剤等のゲル剤;テープ剤、パップ剤等の貼付剤等の剤形で提供することができる。
本発明の皮膚外用剤は、一般的な皮膚外用剤の製造方法、たとえば、第十七改正日本薬局方製剤総則[3]製剤各条の「11.皮膚などに適用する製剤」の項に記載された方法に従って、製造することができる。
The present invention also provides a skin external preparation containing the fatty acid composition of the present invention (hereinafter, also referred to as “the skin external preparation of the present invention” in the present specification).
Here, the "external skin preparation" refers to a drug applied externally to a lesion site of the skin, but also includes a transdermal preparation for the purpose of delivering the active ingredient to the circulating bloodstream through the skin. Is done.
The skin external preparation of the present invention is an external solid preparation such as an external powder; a liniment agent, a lotion, by adding a general additive used in the production of the skin external preparation to the fatty acid composition of the present invention, if necessary. Topical solutions such as agents (liquids, emulsions, suspensions, etc.); sprays such as external aerosols and pump sprays; ointments such as oily ointments and water-soluble ointments; oil-in-water or in oil It can be provided in the form of a water-type cream agent; a gel agent such as an aqueous gel agent or an oil-based gel agent; a patch agent such as a tape agent or a poultice agent.
The external preparation for skin of the present invention is described in a general method for producing an external preparation for skin, for example, in the section of "11. Preparation for skin, etc." It can be manufactured according to the method described.
本発明の皮膚外用剤には、上記した賦形剤、結合剤、崩壊剤、滑沢剤、基剤、溶剤、乳化剤、分散剤、懸濁化剤、安定化剤、粘稠剤、pH調整剤、抗酸化剤、防腐剤、保存剤、香料、着色剤等の1種または2種以上を用いることができる。 The external preparation for skin of the present invention includes the above-mentioned excipients, binders, disintegrants, lubricants, bases, solvents, emulsifiers, dispersants, suspending agents, stabilizers, thickeners, and pH adjustments. One or more kinds of agents, antioxidants, preservatives, preservatives, fragrances, colorants and the like can be used.
また、本発明の皮膚外用剤には、本発明の特徴を損なわない範囲で、イブプロフェンピコナール、スプロフェン、ブフェキサマク、ベンダザック、ウフェナマート、グリチルレチン酸等の非ステロイド性抗炎症薬;酪酸クロベタゾン等の副腎皮質ステロイド;フシジン酸ナトリウム、ムピロシン等の抗生物質;タクロリムス水和物等の免疫調整外用薬等を含有させることができる。 In addition, the external preparation for skin of the present invention includes non-steroidal anti-inflammatory drugs such as ibuprofen piconal, suprofen, bufexamac, bendazac, ufenamate, and glycyrrhetinic acid; Cortical steroids; antibiotics such as sodium fusidate and mupirocin; immunomodulatory external preparations such as tacrolimus hydrate can be contained.
本発明の皮膚外用剤における、本発明の脂肪酸組成物の含有量は、本発明の抗菌剤について上記した含有量と同様である。 The content of the fatty acid composition of the present invention in the external preparation for skin of the present invention is the same as the above-mentioned content of the antibacterial agent of the present invention.
本発明の皮膚外用剤は、アトピー性皮膚炎患者またはアトピー性皮膚炎の症状を呈する動物に対し、炎症の悪化の防止または症状の改善のために、好適に適用することができる。
また、本発明の皮膚外用剤は、皮膚の洗浄、消毒等に起因する手荒れ等、肌荒れ症状を呈するおそれのある者または肌荒れ症状を呈する者においても、肌荒れ症状を予防しまたは改善するために、好適に適用することができる。
本発明の皮膚外用剤の1日あたりの適用量および適用期間は、本発明の皮膚外用剤の適用対象の種別、性別、年齢、皮膚症状の程度、本発明の皮膚外用剤の剤形等により適宜決定される。たとえば、ヒト成人の場合、パルミトレイン酸の適用量として、本発明の抗菌剤について上述した適用量と同程度の量となるように適用することができ、本発明の抗菌剤について上記した回数及び期間にて適用することができる。
The external preparation for skin of the present invention can be suitably applied to patients with atopic dermatitis or animals presenting with symptoms of atopic dermatitis in order to prevent exacerbation of inflammation or improve the symptoms.
In addition, the external preparation for skin of the present invention may cause rough skin symptoms such as rough hands caused by washing and disinfecting the skin, or even those who have rough skin symptoms in order to prevent or improve the rough skin symptoms. It can be preferably applied.
The daily application amount and application period of the skin external preparation of the present invention depends on the type, gender, age, degree of skin symptoms, dosage form of the skin external preparation of the present invention, and the like. It will be decided as appropriate. For example, in the case of a human adult, the amount of palmitoleic acid applied can be adjusted to the same amount as the above-mentioned application amount of the antibacterial agent of the present invention, and the above-mentioned number of times and period of the antibacterial agent of the present invention can be applied. It can be applied at.
さらに本発明は、本発明の脂肪酸組成物を含有する医薬部外品、特に皮膚外用医薬部外品(以下、本明細書において「本発明の医薬部外品」ともいう)または化粧品(以下、本明細書において「本発明の化粧品」ともいう)を提供する。
ここで、「医薬部外品」とは、医薬品よりは人体等に対する効果が緩和であるが、何らかの改善効果を有するものをいい、特に皮膚に外用される医薬部外品を「皮膚外用医薬部外品」という。いわゆる薬用化粧品は、皮膚外用医薬部外品に含まれる。
また、「化粧品」とは、身体を清潔にしたり、見た目を美しくしたりする目的で、皮膚等に適用されるもので、作用の緩和なものをいう。
本発明の医薬部外品または化粧品は、上記した本発明の皮膚外用剤に準じて製造することができ、化粧水、美容液、乳液、クリーム、洗顔料、パック、身体用洗浄料等の形態で提供され得る。
Furthermore, the present invention further relates to a quasi-drug containing the fatty acid composition of the present invention, particularly a quasi-drug for skin external use (hereinafter, also referred to as “quasi-drug of the present invention” in the present specification) or a cosmetic product (hereinafter, referred to as “quasi-drug”). Also referred to herein as "cosmetics of the present invention").
Here, the term "quasi-drug" refers to a product that has a milder effect on the human body than a drug but has some improvement effect, and in particular, a quasi-drug that is applied externally to the skin is referred to as a "quasi-drug for skin". It is called "quasi-drug". So-called medicated cosmetics are included in quasi-drugs for external use on the skin.
In addition, "cosmetics" are applied to the skin and the like for the purpose of cleansing the body and beautifying the appearance, and are those having a mild action.
The quasi-drug or cosmetic of the present invention can be produced according to the above-mentioned external preparation for skin of the present invention, and is in the form of a lotion, beauty essence, milky lotion, cream, facial cleanser, facial mask, body cleanser, etc. Can be provided at.
本発明の医薬部外品または化粧品には、本発明の特徴を損なわない範囲で、多価アルコール(グリセリン、1,3−ブチレングリコール、ジプロピレングリコール等)、アミノ酸またはその塩(アラニン、セリン、プロリン、DL−ピロリドンカルボン酸ナトリウム等)、タンパク質(ホエイ、水溶性コラーゲン、加水分解エラスチン等)、核酸(デオキシリボ核酸ナトリウム等)、ムコ多糖(コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム等)、ヘパリン類似物質、植物抽出物(アシタバ抽出物、キュウリ抽出物、シラカバ抽出物等)等の保湿剤;アズレン類(アズレン、グアイアズレン、グアイアズレンスルホン酸エチル、グアイアズレンスルホン酸ナトリウム等)、アラントインおよびその誘導体(アラントイン、アスコルビン酸アラントイン、アラントイングリチルレチン酸等)、ビタミン((アスコルビル/トコフェリル)リン酸カリウム、パンテノール等)、植物抽出物(カミツレ抽出物、カンゾウ抽出物、キダチアロエ抽出物等)、グリチルリチン酸およびその塩(グリチルリチン酸、グリチルリチン酸アンモニウム、グリチルリチン酸二カリウム等)、グリチルレチン酸およびその誘導体(グリチルレチン酸、グリチルレチン酸グリセリル、グリチルレチン酸ピリドキシン、サクシニルグリチルレチン酸二ナトリウム等)等の抗炎症・肌荒れ防止剤等を含有させることができる。 The pharmaceutical non-medicinal product or cosmetic product of the present invention includes polyhydric alcohols (glycerin, 1,3-butylene glycol, dipropylene glycol, etc.), amino acids or salts thereof (alanine, serine, etc.) as long as the characteristics of the present invention are not impaired. Proline, DL-sodium pyrrolidone carboxylate, etc.), protein (whey, water-soluble collagen, hydrolyzed elastin, etc.), nucleic acid (sodium deoxyribonucleic acid, etc.), mucopolysaccharide (sodium chondroitin sulfate, sodium hyaluronate, etc.), heparin-like substance, Moisturizers such as plant extracts (Ashitaba extract, cucumber extract, white birch extract, etc.); azulene (azulene, guaiazulene, ethyl guaiazulene sulfonate, sodium guaiazulene sulfonate, etc.), allantin and its derivatives (alantin, ascorbic acid, etc.) Allantin, allantinglycyrrhetinic acid, etc.), vitamins ((ascorbyl / tocopheryl) potassium phosphate, pantenol, etc.), plant extracts (chamomile extract, kanzo extract, kidachialoe extract, etc.), glycyrrhizinic acid and its salts (glycyrrhizinic acid) , Ammonium glycyrrhetinate, dipotassium glycyrrhizinate, etc.), glycyrrhetinic acid and its derivatives (glycyrrhetinic acid, glyceryl glycyrrhetinate, pyridoxin glycyrrhetinate, disodium succinylglycyrrhetinate, etc.) it can.
本発明の医薬部外品または化粧品における本発明の脂肪酸組成物の含有量は、本発明の皮膚外用剤に準じて適宜決定することができるが、パルミトレイン酸の1日あたりの適用量が、本発明の抗菌剤について上記した1日あたりの適用量となるように、本発明の脂肪酸組成物が適用されるように設定されることが好ましい。 The content of the fatty acid composition of the present invention in the quasi-drug or cosmetic of the present invention can be appropriately determined according to the external preparation for skin of the present invention, but the daily application amount of palmitoleic acid is the present invention. It is preferable that the fatty acid composition of the present invention is applied so that the amount of the antibacterial agent of the present invention applied per day is as described above.
本発明の医薬部外品または化粧品は、アトピー性皮膚炎患者の皮膚の状態の悪化を防止し、またはアトピー性皮膚炎患者の皮膚の状態を改善するために、あるいは、手荒れ等、肌荒れ症状を呈するおそれのある者または肌荒れ症状を呈する者において、肌荒れ症状を予防しまたは改善するために、好適に用いることができる。
また、本発明の医薬部外品または化粧品は、主としてヒトの皮膚、特にアトピー素因を有するヒト、または、特に皮膚の洗浄、消毒等に起因する肌荒れ症状を呈するヒトの皮膚の常在細菌叢のバランスを、正常な状態に維持するために好適に用いられる。
特に、本発明の医薬部外品または化粧品は、安全性の確認された酵母等の脂質より得られるパルミトレイン酸を有効成分として含有するため安全性が高く、日常的な皮膚の手入れを目的として、長期間にわたり連続して適用することができる。
The non-medicinal product or cosmetic product of the present invention is used to prevent deterioration of the skin condition of atopic dermatitis patients, or to improve the skin condition of atopic dermatitis patients, or to cause rough skin symptoms such as rough hands. It can be suitably used for preventing or ameliorating the rough skin symptom in a person who may exhibit the rough skin symptom or a person who presents the rough skin symptom.
In addition, the quasi-drug or cosmetic product of the present invention is mainly composed of the indigenous bacterial flora of human skin, particularly human skin having an atopic predisposition, or human skin exhibiting rough skin symptoms due to washing, disinfection, etc. of the skin. It is preferably used to maintain the balance in a normal state.
In particular, the quasi-drug or cosmetic product of the present invention is highly safe because it contains palmitoleic acid obtained from a lipid such as yeast whose safety has been confirmed as an active ingredient, and is intended for daily skin care. It can be applied continuously over a long period of time.
さらに、本発明は、上記した本発明の脂肪酸組成物の製造方法(以下、本明細書において「本発明の製造方法」とも称する)を提供する。
本発明の製造方法は、(1)sn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂より、リパーゼによりsn−1位およびsn−3位の脂肪酸を遊離させる工程、および(2)前記工程で遊離させた脂肪酸を回収する工程を含む。
Furthermore, the present invention provides the above-mentioned method for producing a fatty acid composition of the present invention (hereinafter, also referred to as "the method for producing the present invention" in the present specification).
The production method of the present invention comprises (1) a step of liberating the fatty acids at the sn-1 and sn-3 positions with lipase from a fat and oil containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions. (2) The step of recovering the fatty acid liberated in the step is included.
本発明において用い得るsn−1位およびsn−3位にパルミトレイン酸を有するトリグリセリドを含有する油脂、ならびにリパーゼの種類等、本発明において、sn−1位およびsn−3位の脂肪酸を遊離させるための酵素反応の条件、遊離させた脂肪酸の回収方法等については、本発明の脂肪酸組成物に関して上述した通りである。 In order to release the fatty acids at the sn-1 and sn-3 positions in the present invention, such as fats and oils containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions that can be used in the present invention, and the type of lipase. The conditions for the enzymatic reaction, the method for recovering the liberated fatty acid, and the like are as described above for the fatty acid composition of the present invention.
本発明の製造方法における各工程においては、本発明の特徴を損なわない範囲で、適宜必要に応じて、再結晶、各種クロマトグラフィー等の精製手段、ろ過、遠心分離等の固液分離手段等を用いることができる。 In each step of the production method of the present invention, purification means such as recrystallization and various chromatographys, solid-liquid separation means such as filtration and centrifugation may be used as appropriate as necessary without impairing the characteristics of the present invention. Can be used.
さらに本発明について、実施例により詳細に説明する。 Further, the present invention will be described in detail with reference to Examples.
[参考例1]精製酵母トリグリセリドの調製
神坂ら(特開2015−146778号公報)に記載された方法により、サッカロマイセス セレビシエ(Saccharomyces cerevisiae)の形質転換体により生産された油脂を回収した。前記油脂(5g)中に残存する溶媒をエバポレーターで除去し、脱溶媒後の油脂3.57gを、n−ヘキサン:酢酸エチル=98:2(容量比)で平衡化したシリカゲルクロマトグラフィー(2.6cm×26cm)に負荷して、前記溶媒40mL×15本、およびヘキサン:酢酸エチル=95:5(容量比)40mL×15本で溶出させた。トリアシルグリセリドを含むフラクションNo.15〜25の画分を回収し、エバポレーターで溶媒を除去し、参考例1の精製酵母トリグリセリド2.74gを得た。
[Reference Example 1] Preparation of purified yeast triglyceride The fats and oils produced by the transformant of Saccharomyces cerevisiae were recovered by the method described in Kansaka et al. (Japanese Patent Laid-Open No. 2015-146778). The solvent remaining in the fat (5 g) was removed by an evaporator, and 3.57 g of the desolvated fat was equilibrated with n-hexane: ethyl acetate = 98: 2 (volume ratio) in silica gel chromatography (2. 6 cm × 26 cm) was loaded and eluted with 40 mL × 15 of the solvent and 40 mL × 15 of hexane: ethyl acetate = 95: 5 (volume ratio). Fraction No. containing triacylglyceride. Fractions 15 to 25 were collected and the solvent was removed with an evaporator to obtain 2.74 g of the purified yeast triglyceride of Reference Example 1.
参考例1の精製酵母トリグリセリドについて、sn−1,3位およびsn−2位の脂肪酸組成を、下記の通り、Y. Watanabeらの方法(J. Oleo Sci., 64, 1193 (2015))に従って測定した。
参考例1の精製酵母トリグリセリド100mgに、エタノール1gおよびシュードザイマ アンタークティカ(Pseudozyma antarctica)由来の固定化リパーゼ(「ノボザイム(Novozyme)435)」(ノボザイムズ(Novozumes)社))0.044gを加え、30℃で往復振とうさせながら3時間反応させ、ろ過して上清を回収した。次いで、エバポレーターで溶媒を除去し、全量を、n−ヘキサン:ジエチルエーテル=8:2(容量比)で平衡化したセプ−パックシリカ(Sep-Pack silica)カートリッジ(「WAT051900」(ウォーターズ(Waters)社))に負荷し、前記溶媒30mLにより、脂肪酸エチルエステルおよびジグリセリドを溶出させて除去した。次に、ジエチルエーテル10mLでsn−2位にアシル基を一つ有するモノグリセリド(sn−2モノグリセリド)を溶出させ、ロータリーエバポレーターで溶媒を除去した。
For the purified yeast triglyceride of Reference Example 1, the fatty acid composition at the sn-1,3 and sn-2 positions was adjusted according to the method of Y. Watanabe et al. (J. Oleo Sci., 64, 1193 (2015)) as follows. It was measured.
To 100 mg of purified yeast triglyceride of Reference Example 1, 1 g of ethanol and 0.044 g of immobilized lipase derived from Pseudozyma antarctica (“Novozyme 435” (Novozumes)) were added, and 30 The reaction was carried out at ° C. with reciprocating shaking for 3 hours, and the supernatant was collected by filtration. The solvent was then removed with an evaporator and the total amount was equilibrated with n-hexane: diethyl ether = 8: 2 (volume ratio) Sep-Pack silica cartridge (“WAT051900” (Waters). The company)) was loaded, and the fatty acid ethyl ester and diglyceride were eluted and removed with 30 mL of the solvent. Next, 10 mL of diethyl ether was used to elute a monoglyceride having one acyl group at the sn-2 position (sn-2 monoglyceride), and the solvent was removed with a rotary evaporator.
メタノール3mLに、参考例1のトリグリセリドおよび前記由来のsn−2モノグリセリド各5μL、および28質量%のナトリウムメトキシドのメタノール溶液を添加し、75℃で15分間加熱して、脂肪酸のメチルエステル化を行った。放冷後、n−ヘキサン0.5mLを添加混合し、次いで水3mLを添加混合して、脂肪酸メチルエステルをn−ヘキサンにて抽出し、n−ヘキサン層を回収した。
回収したn−ヘキサン層を、キャピラリーガスクロマトグラフ(「Agilent 6890N」(アジレントテクノロジー(Agilent Technologies)社)にて下記の条件下に分析し、脂肪酸の定量を行った。
To 3 mL of methanol, 5 μL each of the triglyceride of Reference Example 1 and the sn-2 monoglyceride derived from the above, and a methanol solution of 28% by mass of sodium methoxide were added, and heated at 75 ° C. for 15 minutes to methyl esterify the fatty acid. went. After allowing to cool, 0.5 mL of n-hexane was added and mixed, then 3 mL of water was added and mixed, and the fatty acid methyl ester was extracted with n-hexane to recover the n-hexane layer.
The recovered n-hexane layer was analyzed by a capillary gas chromatograph (“Agilent 6890N” (Agilent Technologies) under the following conditions, and fatty acids were quantified.
<分析条件>
キャピラリーカラム:DB−23(0.25mm×30m)(アジレントテクノロジー(Agilent Technologies)社)
注入口温度:245℃
注入量:3μL
検出器:水素炎イオン化型検出器(FID)(250℃)
カラム温度:
(1)150℃で0.5分間保持
(2)150℃〜170℃;4℃/分にて昇温
(3)170℃〜195℃;5℃/分にて昇温
(4)195℃〜215℃;10℃/分にて昇温
(5)215℃で11分間保持
<Analysis conditions>
Capillary column: DB-23 (0.25 mm x 30 m) (Agilent Technologies)
Injection port temperature: 245 ° C
Injection volume: 3 μL
Detector: Hydrogen flame ionization detector (FID) (250 ° C)
Column temperature:
(1) Hold at 150 ° C for 0.5 minutes (2) 150 ° C to 170 ° C; raise temperature at 4 ° C / min (3) 170 ° C to 195 ° C; raise temperature at 5 ° C / min (4) 195 ° C ~ 215 ° C; temperature rise at 10 ° C / min (5) Hold at 215 ° C for 11 minutes
参考例1の精製酵母トリグリセリド(sn−1,2,3位の全脂肪酸の組成)およびsn−2モノグリセリドの脂肪酸組成(モル%)から、sn−1,3位の脂肪酸組成(モル%)を算出した。その結果を表1に示した。 From the purified yeast triglyceride (composition of all fatty acids at positions sn-1, 2, and 3) and the fatty acid composition of sn-2 monoglyceride (mol%) of Reference Example 1, the fatty acid composition at positions sn-1, 3 (mol%) is obtained. Calculated. The results are shown in Table 1.
表1に示されるように、サッカロマイセス セレビシエ(Saccharomyces cerevisiae)の形質転換体由来の参考例1の精製酵母トリグリセリドには、従来の植物油脂等に比べてパルミトレイン酸が多く含まれることが認められた。一方、酸化安定性が悪く、製剤安定性の観点から好ましくない多価不飽和脂肪酸がほとんど含まれないことが認められた。
また、表1に示されるように、参考例1の精製酵母トリグリセリドでは、トリグリセリド全体における脂肪酸組成(sn−1,2,3位の全脂肪酸組成)に比べて、sn−1,3位におけるパルミトレイン酸含有量が多く、sn−1,3位におけるオレイン酸含有量が少ない、すなわちパルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)が高いことが分かる。
つまり、参考例1の精製酵母トリグリセリドは、パルミトレイン酸を20モル%以上含むが、リノール酸を10モル%程度含むシーベリー油や、リノール酸とリノレイン酸をそれぞれ2モル%〜3モル%ずつ含むマカダミアナッツ油に比べて、本発明の脂肪酸組成物を製造するための出発原料として有用である。
As shown in Table 1, it was found that the purified yeast triglyceride of Reference Example 1 derived from the transformant of Saccharomyces cerevisiae contained a large amount of palmitoleic acid as compared with conventional vegetable oils and fats. On the other hand, it was found that the oxidative stability was poor and that polyunsaturated fatty acids, which were unfavorable from the viewpoint of pharmaceutical stability, were hardly contained.
Further, as shown in Table 1, in the purified yeast triglyceride of Reference Example 1, palmitoleic acid at the sn-1,3 position is compared with the fatty acid composition of the entire triglyceride (total fatty acid composition at the sn-1, 2, and 3 positions). It can be seen that the acid content is high and the oleic acid content at the sn-1 and 3 positions is low, that is, the content ratio of palmitoleic acid to oleic acid (palmitoleic acid / oleic acid) is high.
That is, the purified yeast triglyceride of Reference Example 1 contains 20 mol% or more of palmitoleic acid, but seaberry oil containing about 10 mol% of linoleic acid, and macadamia containing 2 mol% to 3 mol% of linoleic acid and 3 mol% of linoleic acid, respectively. Compared to nut oil, it is useful as a starting material for producing the fatty acid composition of the present invention.
[実施例1]シュードザイマ アンタークティカ(Pseudozyma antarctica)由来の固定化リパーゼを用いた脂肪酸組成物の調製
参考例1の精製酵母トリグリセリド200mgに、エタノール2gおよび上記ノボザイム(Novozyme)435(ノボザイムズ(Novozumes)社)0.088gを加え、30℃で往復振とうさせながら2.5時間反応させ、ろ過して上清を回収した。次いで、エバポレーターで溶媒を除去し、半量ずつ、n−ヘキサン:ジエチルエーテル=8:2(容量比)で平衡化したセプ−パックシリカ(Sep-Pack silica)カートリッジ(「WAT051900」(ウォーターズ(Waters)社))に負荷し、前記溶媒10mLで脂肪酸エチルエステルを溶出させた。さらに、前記溶媒30mLにより、ジグリセリドを溶出させて除去した。次に、ジエチルエーテル10mLでsn−2モノグリセリドを溶出させ、エバポレーターで溶媒を除去した。
2回分のカラム分画により得られた脂肪酸エチルエステルを混合し、脱溶媒後(推定130mg)、エタノール3gおよび5M水酸化ナトリウム0.2gを加え、60℃で15分間加熱し、鹸化した。次いで、室温まで冷却して水4mLを添加し、酸性になるまで2M塩酸を添加した後、n−ヘキサン3mLで2回抽出した。ヘキサン層を回収してエバポレーターで溶媒を除去し、遊離脂肪酸を回収した(実施例1の脂肪酸組成物)。
一方、2回分のカラム分画により得られたsn−2モノグリセリドを混合し、脱溶媒後(推定50mg)、エタノール3g、水0.1mLおよび5M水酸化ナトリウム0.1gを加え、60℃で15分間加熱し、鹸化した。次いで、室温まで冷却して水4mLを添加し、酸性になるまで2M塩酸を添加した後、n−ヘキサン3mLで2回抽出した。ヘキサン層を回収してエバポレーターで溶媒を除去し、遊離脂肪酸を回収し、比較例1の脂肪酸組成物とした。
また、ノボザイム(Novozume)435を用いた上記の反応を一昼夜行わせると、トリグリセリドのsn−1,2,3位の脂肪酸がすべてエチルエステルに変換されるため、一昼夜反応させて得られる遊離脂肪酸の組成は、出発物質として用いた参考例1の精製酵母トリグリセリドにおける脂肪酸組成と同様であると考えることができる。そこで、比較のため、次のように、一昼夜反応させた場合の脂肪酸組成物を調製した。
参考例1の精製酵母トリグリセリド200mgに、エタノール2gおよび上記ノボザイム(Novozyme)435(ノボザイムズ(Novozumes)社)0.088gを加え、30℃で往復振とうさせながら24時間反応させ、ろ過して上清を回収し、エバポレーターで溶媒を除去した。次に、得られたエチルエステル(約200mg)に、エタノール6gおよび5M水酸化ナトリウム0.4gを加え、60℃で15分間加熱し、鹸化した。次いで、室温まで冷却して水10mLを添加し、酸性になるまで2M塩酸を添加した後、n−ヘキサン10mLで2回抽出した。ヘキサン層を回収してエバポレーターで溶媒を除去し、遊離脂肪酸を回収した(24時間反応生成物)。
[Example 1] Preparation of fatty acid composition using immobilized lipase derived from Pseudozyma antarctica To 200 mg of purified yeast triglyceride of Reference Example 1, 2 g of ethanol and Novozyme 435 (Novozumes) The company) added 0.088 g, reacted at 30 ° C. with reciprocating shaking for 2.5 hours, and filtered to collect the supernatant. Then, the solvent was removed with an evaporator, and half by half, equilibrated with n-hexane: diethyl ether = 8: 2 (volume ratio), Sep-Pack silica cartridge ("WAT051900" (Waters). The company)) was loaded, and the fatty acid ethyl ester was eluted with 10 mL of the solvent. Further, the diglyceride was eluted and removed with 30 mL of the solvent. Next, sn-2 monoglyceride was eluted with 10 mL of diethyl ether, and the solvent was removed with an evaporator.
The fatty acid ethyl ester obtained by two column fractions was mixed, desolvated (estimated 130 mg), 3 g of ethanol and 0.2 g of 5M sodium hydroxide were added, and the mixture was heated at 60 ° C. for 15 minutes for saponification. Then, the mixture was cooled to room temperature, 4 mL of water was added, 2M hydrochloric acid was added until it became acidic, and then the mixture was extracted twice with 3 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and the free fatty acid was recovered (fatty acid composition of Example 1).
On the other hand, the sn-2 monoglyceride obtained by two column fractions was mixed, and after desolvation (estimated 50 mg), 3 g of ethanol, 0.1 mL of water and 0.1 g of 5M sodium hydroxide were added, and 15 at 60 ° C. It was heated for minutes and saponified. Then, the mixture was cooled to room temperature, 4 mL of water was added, 2M hydrochloric acid was added until it became acidic, and then the mixture was extracted twice with 3 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and the free fatty acid was recovered to obtain the fatty acid composition of Comparative Example 1.
Further, when the above reaction using Novozume 435 is carried out all day and night, all the fatty acids at the sn-1, 2, and 3 positions of triglyceride are converted into ethyl esters, so that the free fatty acids obtained by the reaction all day and night can be obtained. The composition can be considered to be similar to the fatty acid composition in the purified yeast triglyceride of Reference Example 1 used as a starting material. Therefore, for comparison, a fatty acid composition was prepared as follows when the reaction was carried out day and night.
To 200 mg of the purified yeast triglyceride of Reference Example 1, 2 g of ethanol and 0.088 g of the above Novozyme 435 (Novozumes) were added, reacted at 30 ° C. with reciprocating shaking for 24 hours, filtered and the supernatant was obtained. Was recovered and the solvent was removed with an evaporator. Next, 6 g of ethanol and 0.4 g of 5M sodium hydroxide were added to the obtained ethyl ester (about 200 mg), and the mixture was heated at 60 ° C. for 15 minutes for saponification. Then, the mixture was cooled to room temperature, 10 mL of water was added, 2M hydrochloric acid was added until it became acidic, and then the mixture was extracted twice with 10 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and free fatty acids were recovered (24-hour reaction product).
[実施例2]リゾプス ジャポニクス(Rhizopus japonicus)由来のリパーゼを用いた脂肪酸組成物の調製
参考例1の精製酵母トリグリセリド200mgに、水1.8mLおよびリゾプス ジャポニクス(Rhizopus japonicus)由来のリパーゼ(「リリパーゼA−10D」(ナガセケムテックス株式会社))(25mg/mL)0.053mLを加え、35℃にて350rpmで撹拌しながら2.5時間反応させた後、エタノール10mLを添加して反応を停止させ、50mM水酸化カリウムで遊離脂肪酸を滴定することにより、加水分解率を求めた。
次に、滴定後の溶液に水10mLと5M水酸化カリウム1mLを添加し、n−ヘキサン15mLで3回抽出して、未反応のトリグリセリドを除去した。次いで、水層に2M塩酸を酸性になるまで添加し、n−ヘキサン15mLで2回抽出した。ヘキサン層を回収してエバポレーターで溶媒を除去し、遊離脂肪酸を回収した(実施例2の脂肪酸組成物)。
また、比較のため、次のように、上記リパーゼによる反応を一昼夜行わせて脂肪酸組成物を調製した。
参考例1の精製酵母トリグリセリド200mgに、水1.53mLおよびリリパーゼA−10D(ナガセケムテックス株式会社)(25mg/mL)0.27mLを加え、35℃にて350rpmで撹拌しながら24時間反応させた後、上記と同様の操作を行い、遊離脂肪酸を回収した(24時間反応生成物)。
[Example 2] Preparation of fatty acid composition using lipase derived from Rhizopus japonicus To 200 mg of purified yeast triglyceride of Reference Example 1, 1.8 mL of water and lipase derived from Rhizopus japonicus (“Lipase A”). -10D ”(Nagase Chemtex Co., Ltd.)) (25 mg / mL) 0.053 mL was added, and the reaction was carried out at 35 ° C. at 350 rpm for 2.5 hours, and then 10 mL of ethanol was added to stop the reaction. , The hydrolysis rate was determined by titrating the free fatty acid with 50 mM potassium hydroxide.
Next, 10 mL of water and 1 mL of 5M potassium hydroxide were added to the solution after titration, and extraction was performed 3 times with 15 mL of n-hexane to remove unreacted triglyceride. Then, 2M hydrochloric acid was added to the aqueous layer until it became acidic, and the mixture was extracted twice with 15 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and the free fatty acid was recovered (fatty acid composition of Example 2).
Further, for comparison, a fatty acid composition was prepared by carrying out the reaction with the above lipase all day and night as follows.
To 200 mg of purified yeast triglyceride of Reference Example 1, 1.53 mL of water and 0.27 mL of Lilipase A-10D (Nagasechemtex Co., Ltd.) (25 mg / mL) were added, and the mixture was reacted at 35 ° C. for 24 hours with stirring at 350 rpm. After that, the same operation as above was carried out to recover the free fatty acid (24-hour reaction product).
[実施例3]カンジダ ルゴサ(Candida rugosa)由来のリパーゼを用いた脂肪酸組成物の調製
参考例1の精製酵母トリグリセリド100mgに、水0.9mLおよびカンジダ ルゴサ(Candida rugosa)由来のリパーゼ(「リパーゼOF」(名糖産業株式会社))(10mg/mL)0.011mLを加え、35℃にて350rpmで撹拌しながら2.5時間反応させた後、エタノール10mLを添加して反応を停止させ、50mM水酸化カリウムで遊離脂肪酸を滴定することにより、加水分解率を求めた。
次に、滴定後の溶液に水10mLと5M水酸化カリウム1mLを添加し、n−ヘキサン15mLで3回抽出して、未反応のトリグリセリドを除去した。次いで、水層に2M塩酸を酸性になるまで添加し、n−ヘキサン15mLで2回抽出した。ヘキサン層を回収してエバポレーターで溶媒を除去し、遊離脂肪酸を回収した(実施例3の脂肪酸組成物)。
また、比較のため、次のように、上記リパーゼによる反応を一昼夜行わせて脂肪酸組成物を調製した。
参考例1の精製酵母トリグリセリド100mgに、水0.84mLおよびリパーゼOF(名糖産業株式会社)(10mg/mL)0.06mLを加え、35℃にて350rpmで撹拌しながら24時間反応させた後、上記と同様の操作を行い、遊離脂肪酸を回収した(24時間反応生成物)。
[Example 3] Preparation of fatty acid composition using lipase derived from Candida rugosa To 100 mg of purified yeast triglyceride of Reference Example 1, 0.9 mL of water and lipase derived from Candida rugosa (“Lipase OF”) (Meishu Sangyo Co., Ltd.)) (10 mg / mL) 0.011 mL was added and reacted at 35 ° C. at 350 rpm for 2.5 hours, then 10 mL of ethanol was added to stop the reaction, and 50 mM. The hydrolysis rate was determined by titrating free fatty acids with potassium hydroxide.
Next, 10 mL of water and 1 mL of 5M potassium hydroxide were added to the solution after titration, and extraction was performed 3 times with 15 mL of n-hexane to remove unreacted triglyceride. Then, 2M hydrochloric acid was added to the aqueous layer until it became acidic, and the mixture was extracted twice with 15 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and the free fatty acid was recovered (fatty acid composition of Example 3).
Further, for comparison, a fatty acid composition was prepared by carrying out the reaction with the above lipase all day and night as follows.
To 100 mg of purified yeast triglyceride of Reference Example 1, 0.84 mL of water and 0.06 mL of Lipase OF (Meito Sangyo Co., Ltd.) (10 mg / mL) were added, and the mixture was reacted at 35 ° C. at 350 rpm for 24 hours. , The same operation as above was carried out to recover free fatty acids (24-hour reaction product).
[実施例4]アルカリゲネス(Alcaligenes)属に属する微生物由来のリパーゼを用いた脂肪酸組成物の調製
参考例1の精製酵母トリグリセリド200mgに、水1.97mLおよびアルカリゲネス(Alcaligenes)属に属する微生物由来のリパーゼ(「リパーゼQLM」(名糖産業株式会社))(50mg/mL)0.03mLを加え、35℃にて350rpmで撹拌しながら2.5時間反応させた後、エタノール10mLを添加して反応を停止させ、50mM水酸化カリウムで遊離脂肪酸を滴定することにより、加水分解率を求めた。
次に、滴定後の溶液に水10mLと5M水酸化カリウム1mLを添加し、n−ヘキサン15mLで3回抽出して、未反応のトリグリセリドを除去した。次いで、水層に2M塩酸を酸性になるまで添加し、n−ヘキサン15mLで2回抽出した。ヘキサン層を回収してエバポレーターで溶媒を除去し、遊離脂肪酸を回収した(実施例4の脂肪酸組成物)。
また、比較のため、次のように、上記リパーゼによる反応を一昼夜行わせて脂肪酸組成物を調製した。
参考例1の精製酵母トリグリセリド100mgに、水0.6mLおよびリパーゼQLM(名糖産業株式会社)(50mg/mL)0.4mLを加え、35℃にて350rpmで撹拌しながら24時間反応させた後、上記と同様の操作を行い、遊離脂肪酸を回収した(24時間反応生成物)。
[Example 4] Preparation of fatty acid composition using lipase derived from a microorganism belonging to the genus Alcaligenes To 200 mg of purified yeast triglyceride of Reference Example 1, 1.97 mL of water and lipase derived from a microorganism belonging to the genus Alcaligenes ("Lipase QLM" (Meishu Sangyo Co., Ltd.)) (50 mg / mL) 0.03 mL was added, and the reaction was carried out at 35 ° C. at 350 rpm for 2.5 hours, and then 10 mL of ethanol was added to carry out the reaction. The hydrolysis rate was determined by stopping and titrating the free fatty acid with 50 mM potassium hydroxide.
Next, 10 mL of water and 1 mL of 5M potassium hydroxide were added to the solution after titration, and extraction was performed 3 times with 15 mL of n-hexane to remove unreacted triglyceride. Then, 2M hydrochloric acid was added to the aqueous layer until it became acidic, and the mixture was extracted twice with 15 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and the free fatty acid was recovered (fatty acid composition of Example 4).
In addition, for comparison, a fatty acid composition was prepared by carrying out the reaction with the above lipase all day and night as follows.
To 100 mg of purified yeast triglyceride of Reference Example 1, 0.6 mL of water and 0.4 mL of Lipase QLM (Meito Sangyo Co., Ltd.) (50 mg / mL) were added, and the mixture was reacted at 35 ° C. at 350 rpm for 24 hours. , The same operation as above was carried out to recover free fatty acids (24-hour reaction product).
[比較例2]鹸化による脂肪酸組成物の調製
参考例1の精製酵母トリグリセリド50mgに、エタノール3g、水0.1mLおよび5M水酸化ナトリウム0.1gを加え、60℃で15分間加熱して鹸化した。次いで室温まで冷却し、水4mLを添加して、酸性になるまで2M塩酸を添加し、n−ヘキサン3mLで2回抽出した。ヘキサン層を回収し、エバポレーターで溶媒を除去して遊離脂肪酸を回収し、比較例2の脂肪酸組成物とした。
[Comparative Example 2] Preparation of fatty acid composition by saponification To 50 mg of purified yeast triglyceride of Reference Example 1, 3 g of ethanol, 0.1 mL of water and 0.1 g of 5M sodium hydroxide were added and saponified by heating at 60 ° C. for 15 minutes. .. Then, the mixture was cooled to room temperature, 4 mL of water was added, 2 M hydrochloric acid was added until it became acidic, and the mixture was extracted twice with 3 mL of n-hexane. The hexane layer was recovered, the solvent was removed by an evaporator, and free fatty acids were recovered to obtain a fatty acid composition of Comparative Example 2.
[試験例1]脂肪酸組成の分析
実施例1〜4の各脂肪酸組成物および、各実施例で比較のために24時間反応させて得られた脂肪酸組成物(24時間反応生成物)について、脂肪酸組成の分析を行った。
メタノール3mLに、上記各試料5μLおよび14質量%の三フッ化ホウ素メタノール錯体のメタノール溶液を添加し、75℃で15分間加熱して、脂肪酸のメチルエステル化を行った。放冷後、n−ヘキサン0.5mLを添加混合し、次いで水3mLを添加混合して、脂肪酸メチルエステルをn−ヘキサンにて抽出し、n−ヘキサン層を回収した。
回収したn−ヘキサン層を、上記参考例1の精製酵母トリグリセリドの脂肪酸組成の分析と同様の条件下、キャピラリーガスクロマトグラフ(「Agilent 6890N」(アジレントテクノロジー(Agilent Technologies)社)にて分析し、脂肪酸の定量を行った。
脂肪酸組成の分析結果を表2に示した。
[Test Example 1] Analysis of fatty acid composition The fatty acids of each of the fatty acid compositions of Examples 1 to 4 and the fatty acid composition (24-hour reaction product) obtained by reacting each of the examples for 24 hours for comparison. The composition was analyzed.
To 3 mL of methanol, 5 μL of each of the above samples and a methanol solution of 14% by mass of boron trifluoride methanol complex were added, and the mixture was heated at 75 ° C. for 15 minutes to perform methyl esterification of fatty acids. After allowing to cool, 0.5 mL of n-hexane was added and mixed, then 3 mL of water was added and mixed, and the fatty acid methyl ester was extracted with n-hexane to recover the n-hexane layer.
The recovered n-hexane layer was analyzed by a capillary gas chromatograph (“Agilent 6890N” (Agilent Technologies)) under the same conditions as the analysis of the fatty acid composition of the purified yeast triglyceride of Reference Example 1 above, and the fatty acids were analyzed. Was quantified.
The analysis results of the fatty acid composition are shown in Table 2.
実施例2〜4の脂肪酸組成物の調製時における加水分解率を、表3に示した。なお、実施例1の脂肪酸組成物の調製時(シュードザイマ アンタークティカ(Pseudozyma antarctica)由来の固定化リパーゼを用いた場合)には、滴定により加水分解率を求めることができなかったため、文献値から推定される加水分解率を記載した。 The hydrolysis rate at the time of preparation of the fatty acid compositions of Examples 2 to 4 is shown in Table 3. At the time of preparation of the fatty acid composition of Example 1 (when an immobilized lipase derived from Pseudozyma antarctica was used), the hydrolysis rate could not be determined by titration, so that the hydrolysis rate could not be determined from the literature values. The estimated hydrolysis rate is described.
表2に示されるように、実施例1の脂肪酸組成物において、参考例1の精製酵母トリグリセリドに比べ、パルミトレイン酸含有量が向上し、かつオレイン酸含有量が低下し、パルミトレイン酸とオレイン酸との含有量比(パルミトレイン酸/オレイン酸)がモル比にて1.62から3.52に上昇したことが認められた。また、実施例1の脂肪酸組成物の脂肪酸組成は、参考例1の精製酵母トリグリセリドのsn−1,3位の脂肪酸組成に近く、過剰量のエタノールの存在下に、シュードザイマ アンタークティカ(Pseudozyma antarctica)由来の固定化リパーゼにより、トリグリセリドのsn−1,3位に結合したパルミトレイン酸が優先的に遊離されることが確認された。
また、表3に示されるように、実施例1の脂肪酸組成物の調製において、2.5時間反応後における加水分解率は約67%と推定される。すなわち、シュードザイマ アンタークティカ(Pseudozyma antarctica)由来の固定化リパーゼを用いる方法は、生成された脂肪酸エチルエステルを鹸化する工程を要するものの、収率が高い方法であることが示唆された。
As shown in Table 2, in the fatty acid composition of Example 1, the palmitoleic acid content was improved and the oleic acid content was decreased as compared with the purified yeast triglyceride of Reference Example 1, and palmitoleic acid and oleic acid were added. It was observed that the content ratio (palmitoleic acid / oleic acid) of was increased from 1.62 to 3.52 in terms of molar ratio. Further, the fatty acid composition of the fatty acid composition of Example 1 is close to the fatty acid composition of the sn-1,3 position of the purified yeast triglyceride of Reference Example 1, and in the presence of an excess amount of ethanol, Pseudozyma antarctica. It was confirmed that the immobilized lipase derived from) preferentially releases palmitoleic acid bound to the sn-1,3 position of triglyceride.
Further, as shown in Table 3, in the preparation of the fatty acid composition of Example 1, the hydrolysis rate after the reaction for 2.5 hours is estimated to be about 67%. That is, it was suggested that the method using the immobilized lipase derived from Pseudozyma antarctica requires a step of saponifying the produced fatty acid ethyl ester, but the yield is high.
実施例2の脂肪酸組成物は、トリグリセリドのsn−1,3位に特異的に作用するリゾプス ジャポニクス(Rhizopus japonicus)由来のリパーゼにより得られたため、表2に示されるように、実施例1の脂肪酸組成物よりもパルミトレイン酸含有量が高く、かつオレイン酸含有量が低く、パルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)についても、モル比にて3.99と高い値が認められた。
しかしながら、表3に示されるように、実施例2の脂肪酸組成物の調製において、2.5時間反応後の加水分解率はやや低く、収率がやや低い傾向が認められた。これは、リゾプス ジャポニクス(Rhizopus japonicus)由来のリパーゼによる反応においては、加水分解とエステル化反応の双方が起こり、トリアシルグリセロール、ジアシルグリセロール、モノアシルグリセロールおよび遊離脂肪酸が、一定の比率にて平衡になる傾向があるためである。
また、リゾプス ジャポニクス(Rhizopus japonicus)由来のリパーゼはsn−1,3位に特異的であるものの、反応時間が長くなると、ジグリセリドまたはモノグリセリドのsn−2位とsn−1位またはsn−3位の間で非酵素的なアシル基転移が生じ、sn−2位の脂肪酸がゆっくりと遊離されるため、24時間反応させた後のパルミトレイン酸とオレイン酸の含有量比(パルミトレイン酸/オレイン酸)は、2.5時間反応後に比べて低下した。
Since the fatty acid composition of Example 2 was obtained by a lipase derived from Rhizopus japonicus, which specifically acts on the sn-1,3 position of triglyceride, the fatty acid of Example 1 is shown in Table 2. The palmitoleic acid content is higher and the oleic acid content is lower than the composition, and the content ratio of palmitoleic acid to oleic acid (palmitoleic acid / oleic acid) is also as high as 3.99 in terms of molar ratio. Was done.
However, as shown in Table 3, in the preparation of the fatty acid composition of Example 2, the hydrolysis rate after the 2.5-hour reaction tended to be slightly low, and the yield tended to be slightly low. This is because in the reaction with lipase derived from Rhizopus japonicus, both hydrolysis and esterification reaction occur, and triacylglycerol, diacylglycerol, monoacylglycerol and free fatty acid are balanced at a constant ratio. This is because it tends to be.
In addition, although lipase derived from Rhizopus japonicus is specific for sn-1,3 position, when the reaction time is long, diglyceride or monoglyceride at sn-2 position and sn-1 position or sn-3 position. Since a non-enzymatic acyl group transfer occurs between them and the fatty acid at the sn-2 position is slowly released, the content ratio of palmitereic acid to oleic acid (palmitoleic acid / oleic acid) after the reaction for 24 hours is , It decreased as compared with after the reaction for 2.5 hours.
実施例3の脂肪酸組成物は、トリグリセリドのsn−1,2,3位に均等に作用するが、オレイン酸よりもパルミトレイン酸に対し良好に作用するカンジダ ルゴサ(Candida rugosa)由来のリパーゼを用いて調製され、前記リパーゼが飽和脂肪酸には作用しにくいことから、表2において、他の実施例の組成物に比べて高いパルミトレイン酸含有量を示した。
また、表3より、実施例3の調製の際に、反応時間を24時間とした場合には、トリグリセリドの加水分解はほぼ完全に進行することが認められた。
The fatty acid composition of Example 3 uses a lipase derived from Candida rugosa, which acts equally on the sn-1, 2, and 3 positions of triglyceride, but acts better on palmitoleic acid than on oleic acid. Since the prepared lipase does not easily act on saturated fatty acids, Table 2 shows a high palmitoleic acid content as compared with the compositions of other examples.
Further, from Table 3, it was confirmed that when the reaction time was 24 hours in the preparation of Example 3, the hydrolysis of triglyceride proceeded almost completely.
実施例4の脂肪酸組成物は、トリグリセリドのsn−1,2,3位に均等に作用し、またはsn−1,3位に対して優先的に作用するものの、脂肪酸特異性を示さないアルカリゲネス(Alcaligenes)属に属する微生物由来のリパーゼを用いて調製されたため、表2に示されるように、パルミトレイン酸含有量は参考例1の精製酵母トリグリセリドよりもやや向上するものの、その程度は、実施例1〜3の脂肪酸組成物のそれぞれに比べてやや低いものであった。
なお、表3より、実施例4の脂肪酸組成物の調製の際に、反応時間を24時間とした場合には、トリグリセリドの加水分解はほぼ完全に進行することが認められた。
The fatty acid composition of Example 4 acts equally on the sn-1,2,3 positions of the triglyceride, or preferentially acts on the sn-1,3 positions, but does not exhibit fatty acid specificity. Since it was prepared using a lipase derived from a microorganism belonging to the genus Alcaligenes), as shown in Table 2, the palmitoleic acid content is slightly higher than that of the purified yeast triglyceride of Reference Example 1, but the degree is slightly higher than that of Example 1. It was slightly lower than each of the fatty acid compositions of ~ 3.
From Table 3, it was confirmed that when the reaction time was 24 hours in the preparation of the fatty acid composition of Example 4, the hydrolysis of triglyceride proceeded almost completely.
[試験例2]抗菌活性の評価
実施例1〜4の各脂肪酸組成物および、各実施例で比較のために24時間反応させて得られた脂肪酸組成物(24時間反応生成物)、ならびに比較例1、2の各脂肪酸組成物について、日本化学療法学会標準法である微量液体希釈法に従って最小発育阻止濃度(minimum inhibitory concentration,MIC)を測定し、抗菌活性を評価した。
(1)試験菌株懸濁液
Staphylococcus aureus NBRC13276株およびStaphylococcus epidermidis NBRC100911株をそれぞれN.B.培地(0.5質量%鰹肉エキス(和光純薬工業株式会社)、1質量%ポリペプトン(日本製薬株式会社)、0.5質量%塩化ナトリウム、pH=7.0)3mLに1白金耳植菌し、振とうしながら37℃で一晩前々培養した。この前々培養液を、植菌量が20質量%となるように、新しいN.B.培地4mLに植菌し、振とうしながら37℃で3時間前培養した。660nmにおける濁度(OD660)の測定値から、OD660=1における生菌数が6.4×108コロニーフォーミングユニット(colony forming unit,cfu)/mLとして生菌数を算定し、この前培養液を、2.0×104cfu/mLとなるように、N.B.培地(pH=6.0)で希釈して、試験菌株懸濁液を調製した。
(2)供試試料
実施例1〜4の各脂肪酸組成物および、各実施例で比較のために24時間反応させて得られた脂肪酸組成物(24時間反応生成物)、ならびに比較例1、2の各脂肪酸組成物を、それぞれ10,000μg/mLとなるようにジメチルスルホキシド(DMSO)に溶解し、各供試試料とした。
また、対照として、試薬のパルミトレイン酸およびオレイン酸(東京化成工業株式会社)についても、同様に抗菌活性を評価した。
(3)MICの測定
試験菌株懸濁液(2.0×104cfu/mL)234μLを96穴丸底マイクロプレートの2列目に分注し、3〜11列目には130μLずつ分注した。次いで、供試試料(10,000μg/mL)26μLをマイクロプレートの2列目に添加し、ピペッティングにより十分懸濁し、10倍に希釈した。次に、この懸濁液130μLをマイクロプレートの3列目に添加して懸濁し、順次2倍ずつ段階的に希釈した。
マイクロプレートを37℃にて2日間静置して培養した後、試験菌株の生育を、培養液の濁度または沈殿した菌体の有無を目視により確認して判定し、試験菌株の生育が見られなくなる供試試料の最小濃度を、MICとした。
[Test Example 2] Evaluation of antibacterial activity Each of the fatty acid compositions of Examples 1 to 4 and the fatty acid composition (24-hour reaction product) obtained by reacting each Example for 24 hours for comparison, and comparison. For each of the fatty acid compositions of Examples 1 and 2, the minimum inhibitory concentration (MIC) was measured according to the trace liquid dilution method which is the standard method of the Japan Society of Chemotherapy, and the antibacterial activity was evaluated.
(1) Test strain suspension
Staphylococcus aureus NBRC13276 strain and Staphylococcus epidermidis NBRC100911 strain were respectively N. B. Medium (0.5 mass% eel meat extract (Wako Pure Chemical Industries, Ltd.), 1 mass% polypeptone (Nihon Pharmaceutical Co., Ltd.), 0.5 mass% sodium chloride, pH = 7.0) 1 loopful in 3 mL The fungus was cultured at 37 ° C. overnight with shaking. In this pre-pre-culture solution, a new N. was added so that the inoculation amount was 20% by mass. B. The cells were inoculated into 4 mL of the medium and pre-cultured at 37 ° C. for 3 hours with shaking. From measurements of turbidity (OD 660) at 660 nm, OD 660 = number of living bacteria 6.4 × 10 8 colony forming units in 1 (colony forming unit, cfu) / calculated the number of viable bacteria as mL, this prior The culture solution was adjusted to 2.0 × 10 4 cfu / mL by N. B. A test strain suspension was prepared by diluting with medium (pH = 6.0).
(2) Test Samples Each fatty acid composition of Examples 1 to 4, a fatty acid composition (24-hour reaction product) obtained by reacting each Example for 24 hours for comparison, and Comparative Example 1, Each fatty acid composition of No. 2 was dissolved in dimethyl sulfoxide (DMSO) so as to be 10,000 μg / mL, respectively, and used as each test sample.
As a control, the reagents palmitoleic acid and oleic acid (Tokyo Chemical Industry Co., Ltd.) were also evaluated for antibacterial activity in the same manner.
(3) Measurement of MIC 234 μL of the test strain suspension (2.0 × 10 4 cfu / mL) was dispensed into the second row of the 96-well round-bottomed microplate, and 130 μL was dispensed into the third to eleventh rows. did. Then, 26 μL of the test sample (10,000 μg / mL) was added to the second row of the microplate, sufficiently suspended by pipetting, and diluted 10-fold. Next, 130 μL of this suspension was added to the third row of the microplate and suspended, and the suspension was sequentially diluted 2-fold in steps.
After culturing the microplate at 37 ° C. for 2 days, the growth of the test strain was judged by visually confirming the turbidity of the culture solution or the presence or absence of precipitated cells, and the growth of the test strain was observed. The minimum concentration of the test sample that could not be used was defined as MIC.
抗菌活性の評価結果を、表4に示した。 The evaluation results of antibacterial activity are shown in Table 4.
表4に示されるように、パルミトレイン酸は、低濃度でStaphylococcus aureus NBRC13276株の生育を選択的に抑制したが、オレイン酸は、Staphylococcus aureus NBRC13276株に対して有効な抗菌活性を示さなかった。
パルミトレイン酸含有量が高く、オレイン酸含有量が低く、参考例1の精製酵母トリグリセリドに比べてパルミトレイン酸とオレイン酸との含有量比(パルミトレイン酸/オレイン酸)が向上した実施例1〜3の脂肪酸組成物については、Staphylococcus aureus NBRC13276株に対し良好な抗菌活性が認められた。一方、皮膚の常在細菌であるStaphylococcus epidermidis NBRC100911株の生育には影響を与えないことが認められた。
これに対し、sn−2モノグリセリド由来で、オレイン酸含有量の高い比較例1の脂肪酸組成物は、Staphylococcus aureus NBRC13276株に対して抗菌活性を示さず、参考例1の精製トリグリセリドの鹸化物で、パルミトレイン酸およびオレイン酸を含む比較例2の脂肪酸組成物では、各実施例の脂肪酸組成物に比べて抗菌活性の低下が認められ、オレイン酸の存在により、パルミトレイン酸のStaphylococcus aureus NBRC13276株に対する抗菌活性が阻害されることが示唆された。
また、他の実施例に比べて、パルミトレイン酸含有量がやや低い実施例4の脂肪酸組成物についても、他の実施例に比べれば低いものの、Staphylococcus aureus NBRC13276株に対する選択的な抗菌活性が認められた。
トリグリセリドの加水分解がほぼ完全に進行した実施例1、3、4の24時間反応生成組成物は、パルミトレイン酸含有量およびオレイン酸含有量が比較例2の脂肪酸組成物と同程度であり、表4に示されるように、Staphylococcus aureus NBRC13276株に対する抗菌活性は認められなかった。
As shown in Table 4, palmitoleic acid selectively suppressed the growth of Staphylococcus aureus NBRC13276 strain at low concentrations, but oleic acid did not show effective antibacterial activity against Staphylococcus aureus NBRC13276 strain.
In Examples 1 to 3, the palmitoleic acid content was high, the oleic acid content was low, and the content ratio of palmitoleic acid to oleic acid (palmitoleic acid / oleic acid) was improved as compared with the purified yeast triglyceride of Reference Example 1. As for the fatty acid composition, good antibacterial activity was observed against Staphylococcus aureus NBRC13276 strain. On the other hand, it was found that it did not affect the growth of Staphylococcus epidermidis NBRC100911 strain, which is a resident bacterium of the skin.
On the other hand, the fatty acid composition of Comparative Example 1 derived from sn-2 monoglyceride and having a high oleic acid content did not show antibacterial activity against Staphylococcus aureus NBRC13276 strain, and was a saponified product of the purified triglyceride of Reference Example 1. In the fatty acid composition of Comparative Example 2 containing palmitoleic acid and oleic acid, a decrease in antibacterial activity was observed as compared with the fatty acid composition of each example, and the presence of oleic acid caused the antibacterial activity of palmitoleic acid against the Staphylococcus aureus NBRC13276 strain. Was suggested to be inhibited.
In addition, the fatty acid composition of Example 4, which has a slightly lower palmitoleic acid content than the other examples, also showed selective antibacterial activity against the Staphylococcus aureus NBRC13276 strain, although it was lower than the other examples. It was.
The 24-hour reaction-producing compositions of Examples 1, 3 and 4 in which the hydrolysis of triglyceride proceeded almost completely had palmitoleic acid content and oleic acid content similar to those of the fatty acid composition of Comparative Example 2, and the table shows. As shown in 4, no antibacterial activity was observed against Staphylococcus aureus NBRC13276 strain.
[試験例3]皮膚外用剤における脂肪酸組成物の有効量について、共培養法による検討
(1)試験菌
N.B.寒天培地(0.1質量%鰹肉エキス(和光純薬工業株式会社)、1質量%ポリペプトン(日本製薬株式会社)、7.5質量%塩化ナトリウム、2質量%寒天、pH=6.0)の同一プレートに、Staphylococcus aureus NBRC13276株およびStaphylococcus epidermidis NBRC100911株を、それぞれ3,000cfu/cm2となるように塗布した。
(2)試料
皮膚外用剤のモデルとして、N.B.液体培地(0.5質量%鰹肉エキス、1質量%ポリペプトン、0.5質量%塩化ナトリウム、0.4質量%増粘剤(グアーガム)、pH=6.0)に、実施例1の脂肪酸組成物を0.5質量%となるように懸濁し、次いで0.001質量%となるまで、順次2倍ずつ段階的に希釈した。
なお、実施例1の脂肪酸組成物を添加しないものを対照(control)とした。
(3)脂肪酸組成物の有効量の算出
上記の試料および対照を2mg/cm2となるように、上記2種の試験菌を塗布したN.B.寒天培地に塗布した。37℃で2日間培養後、生育した細菌を綿棒で回収して7.5質量%食塩水に懸濁し、適宜希釈後、卵黄添加マンニット食塩寒天培地(アズワン株式会社)に塗布した。37℃で1日間培養後、生育したコロニーの形状および色ならびに卵黄反応陽性か陰性かにより、Staphylococcus aureus NBRC13276株とStaphylococcus epidermidis NBRC100911株を判別した。
(3)結果
上記の検討結果を図1に示した。皮膚外用剤のモデルである試料中における実施例1の脂肪酸組成物の含有量が0.0313質量%以上で、Staphylococcus aureus NBRC13276株の生育が完全に抑制され、Staphylococcus epidermidis NBRC100911株のみが生育することが認められた。
0.0313質量%の脂肪酸組成物を含む皮膚外用剤モデル試料を2mg/cm2となるように皮膚に塗布した場合、皮膚における脂肪酸組成物の塗布量は0.625μg/cm2であり、パルミトレイン酸の塗布量は、0.37μg/cm2となる。
従って、本発明の皮膚外用剤を適用する場合、パルミトレイン酸の適用量として、0.37μg/cm2で黄色ブドウ球菌の生育を抑制し得る可能性が示唆された。
[Test Example 3] Examination of effective amount of fatty acid composition in external preparation for skin by co-culture method (1) Test bacteria N. B. Agar medium (0.1% by mass staphylococcus extract (Wako Pure Chemical Industries, Ltd.), 1% by mass polypeptone (Nippon Pharmaceutical Co., Ltd.), 7.5% by mass sodium chloride, 2% by mass agar, pH = 6.0) Staphylococcus aureus NBRC13276 strain and Staphylococcus epidermidis NBRC100911 strain were each applied to the same plate at 3,000 cfu / cm 2.
(2) Sample As a model of external preparation for skin, N.I. B. The fatty acid of Example 1 in a liquid medium (0.5% by mass eel meat extract, 1% by mass polypeptone, 0.5% by mass sodium chloride, 0.4% by mass thickener (guar gum), pH = 6.0). The composition was suspended to 0.5% by weight and then diluted 2-fold in steps until 0.001% by weight.
The one to which the fatty acid composition of Example 1 was not added was used as a control.
(3) Calculation of Effective Amount of Fatty Acid Composition The above two kinds of test bacteria were applied to the above sample and control so as to be 2 mg / cm 2. B. It was applied to an agar medium. After culturing at 37 ° C. for 2 days, the grown bacteria were collected with a cotton swab, suspended in 7.5% by mass saline solution, diluted appropriately, and then applied to egg yolk-added mannitol salt agar medium (AS ONE Corporation). After culturing at 37 ° C. for 1 day, Staphylococcus aureus NBRC13276 strain and Staphylococcus epidermidis NBRC100911 strain were discriminated based on the shape and color of the grown colonies and whether the yolk reaction was positive or negative.
(3) Results The results of the above examination are shown in FIG. When the content of the fatty acid composition of Example 1 in the sample which is a model of the external preparation for skin is 0.0313% by mass or more, the growth of Staphylococcus aureus NBRC13276 strain is completely suppressed, and only Staphylococcus epidermidis NBRC100911 strain grows. Was recognized.
If the external preparation for skin model specimen containing 0.0313 wt% of the fatty acid composition was applied to the skin so that 2 mg / cm 2, the coating amount of the fatty acid composition in the skin is 0.625 [mu] g / cm 2, palmitoleic The amount of acid applied is 0.37 μg / cm 2 .
Therefore, it was suggested that when the external preparation for skin of the present invention is applied, the growth of Staphylococcus aureus can be suppressed at an applied amount of palmitoleic acid of 0.37 μg / cm 2.
以上詳述したように、本発明により、黄色ブドウ球菌(Staphylococcus aureus)に対し、選択的な抗菌活性を有するパルミトレイン酸を、従来にない高濃度で含有する脂肪酸組成物を得ることができる。
本発明の脂肪酸組成物は、黄色ブドウ球菌(Staphylococcus aureus)に対する選択的抗菌剤として、特にアトピー性皮膚炎の症状の悪化の防止またはアトピー性皮膚炎の症状の改善に有効な皮膚外用剤、医薬部外品または化粧品として、利用することができる。
さらに本発明の脂肪酸組成物は、黄色ブドウ球菌(Staphylococcus aureus)の検出が報告されている皮膚の洗浄、消毒等に起因する肌荒れの予防または改善に有効な皮膚外用剤、医薬部外品または化粧品として、利用することができる。
As described in detail above, according to the present invention, it is possible to obtain a fatty acid composition containing palmitoleic acid having selective antibacterial activity against Staphylococcus aureus at an unprecedented high concentration.
The fatty acid composition of the present invention is used as a selective antibacterial agent against Staphylococcus aureus, and is particularly effective as an external preparation for skin or a drug for preventing exacerbation of atopic dermatitis symptoms or ameliorating atopic dermatitis symptoms. It can be used as an external product or cosmetic.
Further, the fatty acid composition of the present invention is an external preparation for skin, a quasi-drug or a cosmetic product effective for preventing or improving rough skin caused by washing or disinfecting the skin for which detection of Staphylococcus aureus has been reported. Can be used as.
Claims (10)
リパーゼが、トリグリセリドのsn−1位およびsn−3位の脂肪酸を優先的に遊離させるリパーゼである、製造方法。 (1) A step of liberating the fatty acids at the sn-1 and sn-3 positions with lipase from a fat and oil containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions, and (2) a step of liberating the fatty acids at the sn-3 position. A method for producing a fatty acid composition containing 55 mol% or more of palmitoleic acid, which comprises a step of recovering the fatty acid.
Lipase, a lipase liberating preferentially the sn-1 position and sn-3 position of fatty acid triglycerides, manufacturing methods.
リパーゼが、トリグリセリドのsn−1位およびsn−3位の脂肪酸を特異的に遊離させるリパーゼである、製造方法。 (1) A step of liberating the fatty acids at the sn-1 and sn-3 positions with lipase from a fat and oil containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions, and (2) a step of liberating the fatty acids at the sn-3 position. A method for producing a fatty acid composition containing 55 mol% or more of palmitoleic acid, which comprises a step of recovering the fatty acid.
Lipase, a lipase that specifically release the sn-1 position and sn-3 position of fatty acid triglycerides, manufacturing methods.
リパーゼが、オレイン酸よりもパルミトレイン酸を優先的に遊離させるリパーゼである、製造方法。 (1) A step of liberating the fatty acids at the sn-1 and sn-3 positions with lipase from a fat and oil containing a triglyceride having palmitoleic acid at the sn-1 and sn-3 positions, and (2) a step of liberating the fatty acids at the sn-3 position. A method for producing a fatty acid composition containing 55 mol% or more of palmitoleic acid, which comprises a step of recovering the fatty acid.
Lipase, a lipase palmitoleic acid is liberated preferentially than oleic acid, manufacturing methods.
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