JP2016130265A - Agent for inhibiting maillard reaction in living body or ages production inhibitor - Google Patents
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Abstract
Description
本発明は、生体内で起こるメイラード反応を抑制する組成物、または、アドバンスド・グリケーション・エンド・プロダクツ（Advanced Glycation End Products：ＡＧＥｓ）の生成や蓄積を抑制する組成物に関する。特に、皮膚褐変化や肌透明度低下、糖尿病性の白内障、血管障害または腎機能障害を抑制または改善する内服または外用剤組成物に関する。 The present invention relates to a composition that suppresses the Maillard reaction that occurs in a living body, or a composition that suppresses the generation and accumulation of Advanced Glycation End Products (AGEs). In particular, the present invention relates to an internal preparation or an external preparation composition for suppressing or improving skin browning, skin transparency reduction, diabetic cataract, vascular disorder or renal dysfunction.
ブドウ糖などの還元糖は、タンパク質またはアミノ酸との間で糖化反応（メイラード反応）が起り、糖化産物が生成することは食品等の褐変現象として古くからよく知られているものである。生体内でも、特に糖尿病などで高血糖状態が続いたり、加齢により分解反応が進行し難くなると、タンパク質またはアミノ酸の糖化反応が起こり、糖化産物の生成に傾くため、タンパク質の機能が損なわれたり、糖化産物が蓄積したりすることがある。 Reducing sugars such as glucose undergo a saccharification reaction (Maillard reaction) with proteins or amino acids, and the production of saccharified products has long been well known as a browning phenomenon in foods and the like. Even in the living body, especially when hyperglycemia continues due to diabetes, etc., or when the degradation reaction is difficult to progress due to aging, the glycation reaction of protein or amino acid occurs, and the production of glycation products tends to occur. Saccharification products may accumulate.
このメイラード反応による糖化産物は最終的に終末糖化産物（Advanced Glycation End Products：以下、ＡＧＥｓと略称することもある）となる。ＡＧＥｓの生成は不可逆反応であるが、生成したＡＧＥｓは代謝によって体外へ排出される。しかし、加齢等により代謝速度が遅くなると、生体内の各組織にさらに蓄積されやすくなってくる（以上、例えば、特許文献１〜２参照）。 The saccharification product by this Maillard reaction finally becomes an advanced glycation end product (hereinafter sometimes abbreviated as AGEs). The generation of AGEs is an irreversible reaction, but the generated AGEs are excreted from the body by metabolism. However, when the metabolic rate is slowed down due to aging or the like, it is more likely to accumulate in each tissue in the living body (see, for example, Patent Documents 1 and 2).
ＡＧＥｓが生体内の各組織に蓄積したり、その受容体と結合したりすると、種々の症状が引き起こされる。例えば、皮膚では肌の褐変化や肌のくすみの一因になり、高血糖状態では白内障、血管障害、腎機能障害が原因となる。従って、ＡＧＥｓの生成を予防または抑制することは極めて重要である（例えば、特許文献１〜２参照）。 When AGEs accumulate in each tissue in the living body or bind to its receptor, various symptoms are caused. For example, skin contributes to browning of the skin and skin dullness, and in a hyperglycemic state, cataracts, vascular disorders, and renal dysfunction are the cause. Therefore, it is extremely important to prevent or suppress the generation of AGEs (see, for example, Patent Documents 1 and 2).
これまでに、食品のメイラード反応を抑制する安全な物質として種々の天然成分が探索されてきた（例えば、特許文献２の「従来の技術」参照）。また、皮膚におけるＡＧＥｓ生成抑制成分として、種々の植物抽出成分が探索されてきている（例えば、特許文献３参照）。 So far, various natural ingredients have been searched for as safe substances that suppress the Maillard reaction of food (see, for example, “Prior Art” in Patent Document 2). In addition, various plant extract components have been searched for as components for inhibiting the generation of AGEs in the skin (see, for example, Patent Document 3).
一方、ジクロロ酢酸ジイソプロピルアミン（Diisopropylamine dichloroacetate：以下、ＤＡＤＡと略称することもある）は、皮膚組織賦活作用による皮膚老化防止効果（特許文献４参照）や、肝機能改善作用（例えば、非特許文献１参照）、抗疲労作用（特許文献５参照）を有することが知られている。さらに、ＤＡＤＡは皮膚血行促進剤または細胞賦活剤として市販の化粧品に配合されており（例えば、特許文献６参照）、慢性肝疾患における肝機能の改善の効能を有する医薬品として供されてきている（例えば、非特許文献２参照）。 On the other hand, diisopropylamine dichloroacetate (hereinafter sometimes abbreviated as DADA) is a skin aging preventive effect (see Patent Document 4) due to a skin tissue activating action, or a liver function improving action (for example, Non-Patent Document 1). And an anti-fatigue action (see Patent Document 5). Furthermore, DADA is blended in commercially available cosmetics as a skin blood circulation promoter or cell activator (see, for example, Patent Document 6), and has been provided as a pharmaceutical product having the effect of improving liver function in chronic liver disease ( For example, refer nonpatent literature 2).
また、抗プラスミン剤であるトラネキサム酸は、１）抗出血作用、２）抗アレルギー作用、３）抗炎症作用、等が知られている医薬である（例えば、非特許文献２参照）。さらに、トラネキサム酸は消炎剤として化粧品にも配合されており（例えば、特許文献７参照）、内服のトラネキサム酸含有組成物は、しみ（肝斑に限る）に対する効能を有する一般用医薬品として供されてきている（例えば、非特許文献３参照）。 In addition, tranexamic acid, which is an antiplasmin agent, is a pharmaceutical known to have 1) anti-bleeding action, 2) anti-allergic action, 3) anti-inflammatory action, and the like (see, for example, Non-Patent Document 2). Furthermore, tranexamic acid is also incorporated into cosmetics as an anti-inflammatory agent (see, for example, Patent Document 7), and the internal tranexamic acid-containing composition is provided as an over-the-counter medicine having an effect on stains (limited to melasma). (For example, see Non-Patent Document 3).
しかし、ＤＡＤＡもトラネキサム酸も、メイラード反応抑制作用、ひいては、皮膚褐変化、肌透明度低下、糖尿病性白内障、糖尿病性血管障害または糖尿病性腎機能障害の予防または抑制作用は知られておらず示唆もない。さらに、ＤＡＤＡとトラネキサム酸の配合について報告された文献は一つも見当たらない。 However, neither DADA nor tranexamic acid has known or suggested the Maillard reaction inhibitory action, and therefore the prevention or suppression action of skin browning, skin transparency reduction, diabetic cataract, diabetic vascular disorder or diabetic renal dysfunction Absent. In addition, there is no literature reported on the combination of DADA and tranexamic acid.
本発明は、内服しても外用であっても安全で、かつ優れた生体内メイラード反応抑制剤組成物またはＡＧＥｓ生成抑制剤を提供することを課題とする。 An object of the present invention is to provide an in-vivo Maillard reaction inhibitor composition or an AGEs production inhibitor that is safe whether it is used internally or externally.
本発明者らは、上記課題を解決するために長年にわたり研究を重ねた結果、ＤＡＤＡとトラネキサム酸とを併用することにより、生体内メイラード反応が抑制され、その結果としてＡＧＥｓの生成が抑制されることを見出した。 As a result of repeated researches over many years in order to solve the above-mentioned problems, the present inventors combined the use of DADA and tranexamic acid to suppress the in vivo Maillard reaction and, as a result, the generation of AGEs. I found out.
上記知見に基づき、ＤＡＤＡとトラネキサム酸を含有する組成物が、生体内メイラード反応またはＡＧＥｓ生成および蓄積に起因する、皮膚褐変化、肌透明度低下、さらには、高血糖による障害である糖尿病性白内障、血管障害または腎機能障害の有効な予防又は改善剤となることを見出し、本発明を完成させた。 Based on the above findings, the composition containing DADA and tranexamic acid is diabetic cataract, which is a skin browning change, skin transparency reduction, and hyperglycemia caused by in vivo Maillard reaction or AGEs generation and accumulation, The present invention has been completed by finding that it is an effective preventive or ameliorating agent for vascular disorders or renal dysfunction.
すなわち、本発明は、
（１）トラネキサム酸とジクロロ酢酸ジイソプロピルアミンを含有することを特徴とする、医薬または化粧料組成物であり、好適には、
（２）トラネキサム酸とジクロロ酢酸ジイソプロピルアミンを含有することを特徴とする、生体内のメイラード反応抑制剤組成物、
（３）トラネキサム酸とジクロロ酢酸ジイソプロピルアミンを含有することを特徴とする、アドバンスド・グリケーション・エンド・プロダクツの生成抑制剤組成物、
（４）トラネキサム酸とジクロロ酢酸ジイソプロピルアミンを含有することを特徴とする、皮膚褐変化または肌の透明度低下抑制剤組成物、
（５）トラネキサム酸とジクロロ酢酸ジイソプロピルアミンを含有することを特徴とする、高血糖による障害の予防または治療剤組成物、
（６）高血糖による障害が、糖尿病性白内障、血管障害または腎機能障害である、請求項５に記載の予防または治療剤組成物、または、
（７）投与経路が外用または内服である上記（１）〜（５）のいずれか１項に記載の組成物である。
That is, the present invention
(1) A pharmaceutical or cosmetic composition characterized by containing tranexamic acid and dichloroacetic acid diisopropylamine,
(2) An in-vivo Maillard reaction inhibitor composition comprising tranexamic acid and dichloroacetic acid diisopropylamine,
(3) A composition for inhibiting the formation of advanced glycation end products, comprising tranexamic acid and diisopropylamine dichloroacetate,
(4) A skin browning change or skin transparency lowering inhibitor composition comprising tranexamic acid and dichloroacetic acid diisopropylamine,
(5) A composition for preventing or treating a disorder caused by hyperglycemia, comprising tranexamic acid and diisopropylamine dichloroacetate,
(6) The preventive or therapeutic agent composition according to claim 5, wherein the disorder due to hyperglycemia is diabetic cataract, vascular disorder or renal dysfunction, or
(7) The composition according to any one of (1) to (5), wherein the route of administration is external or internal use.
本発明の、生体内メイラード反応またはアドバンスド・グリケーション・エンド・プロダクツ（ＡＧＥｓ）の生成抑制剤は、皮膚褐変化、肌透明度低下、糖尿病性白内障、糖尿病性血管障害または腎機能障害を予防または改善することができ、しかも極めて安全であり、かつ経口投与でも外用でも有効なため有用である。 In vivo Maillard reaction or advanced glycation end products (AGEs) inhibitors of the present invention prevent or improve skin browning, skin transparency, diabetic cataract, diabetic vascular disorder or renal dysfunction It is useful because it is extremely safe and effective for oral administration and external use.
本発明におけるジクロロ酢酸ジイソプロピルアミン（ＤＡＤＡ：Diisopropylamine dichloroacetate）は日本薬局方外医薬品規格２００２に収載されており、トラネキサム酸は第１５改正日本薬局方に収載されているため、いずれも容易に入手できる。 Diisopropylamine dichloroacetate (DADA) in the present invention is listed in the Japanese Pharmacopoeia Standard 2002, and tranexamic acid is listed in the 15th revised Japanese Pharmacopoeia, so both are readily available.
本発明の組成物は、医薬品、医薬部外品または化粧料として使用される。本発明の投与経路は、経口的および経皮的のいずれの投与形態であってもよい。 The composition of the present invention is used as a pharmaceutical, a quasi drug or a cosmetic. The administration route of the present invention may be either oral or transdermal administration form.
本発明の剤形は特に限定されないが、皮膚に適用される外用剤の場合は、例えば、ローション、乳液等の液剤、クリーム、ゲル、または軟膏等の半固形製剤、あるいは、テープ、パッチ、パップ等の貼付剤が挙げられる。また、経口投与の場合には、例えば、錠剤、カプセル剤、液剤等が挙げられる。 The dosage form of the present invention is not particularly limited. In the case of an external preparation applied to the skin, for example, a liquid preparation such as lotion and emulsion, a semi-solid preparation such as cream, gel or ointment, or a tape, patch or patch. And the like. Moreover, in the case of oral administration, a tablet, a capsule, a liquid agent etc. are mentioned, for example.
本発明の組成物が内服剤の場合、ＤＡＤＡおよびトラネキサム酸の投与量としては、いずれも好適には、１日当たり０．１〜２０００ｍｇ、より好適には１〜１０００ｍｇであり、それらを１〜３回に分けて服用する。 When the composition of the present invention is an internal preparation, the dose of DADA and tranexamic acid is preferably 0.1 to 2000 mg, more preferably 1 to 1000 mg per day, Take in divided doses.
また、本発明の組成物が外用剤の場合、ＤＡＤＡおよびトラネキサム酸の配合量としては、いずれも好適には製剤全体の総量を基準として０．０１〜５０ｗ／ｖ％、より好適には０．１〜２０ｗ／ｖ％であり、それらを１〜３回に分けて塗布する。 Moreover, when the composition of this invention is an external preparation, as compounding quantity of DADA and tranexamic acid, all are suitably 0.01-50 w / v% on the basis of the total amount of the whole preparation, More preferably, it is 0.8. 1 to 20 w / v%, and apply them in 1 to 3 times.
本発明の、生体内メイラード反応抑制剤、または、アドバンスト・グリケーション・エンド・プロダクツ（ＡＧＥｓ）生成抑制剤は、本発明の効果を損なわない限り、ＤＡＤＡおよびトラネキサム酸に加えて、他の薬効成分である美白剤、抗炎症剤、抗酸化剤、各種糖尿病治療薬を配合することができる。また、製剤用の成分として基剤、香料、防腐剤、保存剤、保湿剤、界面活性剤、潤沢剤、賦形剤、ｐＨ調節剤、矯味剤、香料等、一般に許容されている医薬または化粧品添加剤成分を併せて配合することができる。 In vivo Maillard reaction inhibitor or advanced glycation end products (AGEs) production inhibitor of the present invention is not limited to DADA and tranexamic acid, as long as the effects of the present invention are not impaired. Whitening agents, anti-inflammatory agents, antioxidants, and various antidiabetic agents can be added. In addition, bases, fragrances, preservatives, preservatives, moisturizers, surfactants, lubricants, excipients, pH regulators, flavoring agents, fragrances, etc., which are generally accepted as pharmaceutical ingredients, are used as pharmaceutical ingredients. Additive components can be blended together.
本発明を医薬品、医薬部外品または化粧料として用いるための製剤は、第１５改正日本薬局方製剤総則に記載の方法や、通常用いられている公知の化粧料の製造方法に準じて製造することができる。 Preparations for using the present invention as pharmaceuticals, quasi-drugs or cosmetics are manufactured according to the methods described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations and commonly used methods for manufacturing cosmetics. be able to.
以下、本発明について実施例を挙げてより詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.
＜製剤例１＞ローション
（Ａ）ＤＡＤＡ１０ｇ、トラネキサム酸１５ｇ、クエン酸ナトリウム０．１ｇ、ピロリドンカルボン酸１ｇ、１，３−ブチレングリコール５ｇを混合し、精製水で全量を１００ｇとした。
（Ｂ）ＰＯＥ（３０）ＰＯＰ（６）デシルテトラデシル０．６ｇ、防腐剤適量、エタノール１０ｇを混合した。
（Ａ）と（Ｂ）を５０℃で加温溶解し、(B)を(A)に攪拌しながら可溶化した。攪拌しながら冷却し、３０℃で攪拌を止め、放置した。
<Formulation example 1> Lotion (A) DADA 10 g, tranexamic acid 15 g, sodium citrate 0.1 g, pyrrolidone carboxylic acid 1 g, 1,3-butylene glycol 5 g were mixed, and the total amount was adjusted to 100 g with purified water.
(B) POE (30) POP (6) Decyltetradecyl 0.6 g, an appropriate amount of preservative, and 10 g of ethanol were mixed.
(A) and (B) were dissolved by heating at 50 ° C., and (B) was solubilized with stirring in (A). The mixture was cooled with stirring, the stirring was stopped at 30 ° C., and the mixture was allowed to stand.
＜製剤例２＞乳液
（Ａ）ＤＡＤＡ１０ｇ、トラネキサム酸１５ｇ、ニコムルス４１を２ｇ、スクワラン１０ｇ、防腐剤適量を混合し、精製水で全量を１００ｇとした。
（Ｂ）カルボキシビニルポリマー０．１ｇ、キサンタンガム０．２ｇ、精製水１０ｇを混合した。
（Ｃ）トリエタノールアミン０．１ｇ、１，３−ブチレングリコール５ｇ、精製水４．９ｇを混合した。
（Ｄ）ヒアルロン酸ナトリウム２ｇ、精製水３ｇを混合した。
（Ａ）を８０℃で加温し、均一に混合した。（Ｂ）〜（Ｄ）は常温で溶解した。（Ａ）を攪拌しながら（Ｂ）と（Ｃ）を加えた。攪拌しながら冷却し、５０℃以下で（Ｄ）を加え、３５〜３０℃で攪拌を止め、放置した。
<Formulation example 2> Emulsion (A) DADA 10 g, tranexamic acid 15 g, Nicolulus 41 2 g, squalane 10 g, and preservative appropriate amount were mixed, and the total amount was 100 g with purified water.
(B) 0.1 g of carboxyvinyl polymer, 0.2 g of xanthan gum and 10 g of purified water were mixed.
(C) Triethanolamine 0.1 g, 1,3-butylene glycol 5 g, and purified water 4.9 g were mixed.
(D) 2 g of sodium hyaluronate and 3 g of purified water were mixed.
(A) was heated at 80 ° C. and mixed uniformly. (B) to (D) were dissolved at room temperature. (B) and (C) were added while stirring (A). The mixture was cooled with stirring, (D) was added at 50 ° C. or lower, and stirring was stopped at 35 to 30 ° C. and left standing.
＜製剤例３＞液剤
ＤＡＤＡ２５ｇ、トラネキサム酸１５ｇ、果糖ブドウ糖液糖１００ｇ、ｐＨ調整剤適量を混合し、精製水で全量１０００ｇの液剤を調製した。
<Formulation Example 3> Liquid agent DDA 25 g, tranexamic acid 15 g, fructose glucose liquid sugar 100 g, and a pH adjuster appropriate amount were mixed, and a total amount of 1000 g liquid was prepared with purified water.
＜製剤例４＞錠剤
ＤＡＤＡ２５ｇ、トラネキサム酸１５ｇ、乳糖 ３５０ｇ、結晶セルロース適量を投入・混合し、結合剤としてヒドロキシプロピルセルロースを噴霧し造粒顆粒を調製した。造粒顆粒４９．５ｇにステアリン酸マグネシウム０．５ｇを混合・打錠して裸錠を調製した。
<Formulation Example 4> Tablets DADA 25 g, tranexamic acid 15 g, lactose 350 g, and appropriate amounts of crystalline cellulose were added and mixed, and hydroxypropylcellulose was sprayed as a binder to prepare granulated granules. A granulated granule (49.5 g) was mixed with 0.5 g of magnesium stearate and tableted to prepare a bare tablet.
＜製剤例５＞散剤
ＤＡＤＡ２５ｇ、トラネキサム酸１５ｇ、乳糖３５０ｇ、結晶セルロース適量を投入・混合し、結合剤としてヒドロキシプロピルセルロースを噴霧し散剤を調製した。
<Formulation Example 5> Powder A 25 mg DADA, 15 g tranexamic acid, 350 g lactose, and appropriate amounts of crystalline cellulose were added and mixed, and hydroxypropylcellulose was sprayed as a binder to prepare a powder.
＜試験例１＞蛍光性ＡＧＥｓ生成阻害活性試験
（被験薬）
ＤＡＤＡおよびトラネキサム酸はいずれも第一三共製のものを使用した。
<Test Example 1> Fluorescence AGEs production inhibitory activity test (test drug)
Both DADA and tranexamic acid were manufactured by Daiichi Sankyo.
（サンプル溶液の調製）
ＤＡＤＡとトラネキサム酸の合剤は、１／１５Mリン酸緩衝液（ｐＨ７．２）を用いて、それぞれの成分が所定の濃度となるように希釈を行い、サンプル溶液とした。
(Preparation of sample solution)
A mixture of DADA and tranexamic acid was diluted with a 1/15 M phosphate buffer (pH 7.2) so that each component had a predetermined concentration to obtain a sample solution.
（アルブミン溶液の調製）
ヒト血清アルブミン（シグマアルドリッチ社製）を１／１５Mリン酸緩衝液（ｐＨ７．２）を用いて、２４ｍｇ／ｍＬとなるように調製した。
(Preparation of albumin solution)
Human serum albumin (manufactured by Sigma-Aldrich) was prepared to be 24 mg / mL using 1/15 M phosphate buffer (pH 7.2).
（グルコース溶液の調製）
グルコース（和光純薬社製）を１／１５Mリン酸緩衝液（ｐＨ７．２）を用いて、０．６Ｍとなるように調製した。
(Preparation of glucose solution)
Glucose (manufactured by Wako Pure Chemical Industries, Ltd.) was prepared using a 1/15 M phosphate buffer (pH 7.2) so as to have a concentration of 0.6M.
（被験溶液の調製）
１．５ｍＬチューブ中で、サンプル溶液群１５０μＬ、グルコース溶液１５０μＬ、アルブミン溶液１５０μＬを混合し、６０℃で４０時間保持して試験液を得た。次に、該試験液に３７０ｎｍの励起光を照射し、生じる４４０ｎｍの蛍光を測定した。この測定で得られた結果を測定値Ａとする。
(Preparation of test solution)
In a 1.5 mL tube, a sample solution group of 150 μL, a glucose solution of 150 μL, and an albumin solution of 150 μL were mixed and held at 60 ° C. for 40 hours to obtain a test solution. Next, the test solution was irradiated with 370 nm excitation light, and the resulting fluorescence at 440 nm was measured. The result obtained by this measurement is defined as a measurement value A.
（ｂｌａｎｋの調製）
被験溶液ｂｌａｎｋの調製は以下のように行った。１．５ｍＬチューブ中でサンプル溶液群１５０μＬ、グルコース溶液１５０μＬを混合し、６０℃で４０時間保持した後、アルブミン溶液１５０μＬを混合して試験液を得た。該試験液に３７０ｎｍの励起光を照射し、生じる４４０ｎｍの蛍光を測定した。この測定で得られた結果を測定値Ｂとする。
蛍光性ＡＤＥｓの生成量を下記の式によりえられる蛍光量として算出した。
ＡＧＥｓ生成量（蛍光量）＝測定値Ａ―測定値Ｂ
(Preparation of blank)
The test solution blank was prepared as follows. A sample solution group of 150 μL and a glucose solution of 150 μL were mixed in a 1.5 mL tube and held at 60 ° C. for 40 hours, and then an albumin solution of 150 μL was mixed to obtain a test solution. The test solution was irradiated with 370 nm excitation light, and the resulting fluorescence at 440 nm was measured. The result obtained by this measurement is defined as a measurement value B.
The amount of fluorescent ADEs produced was calculated as the amount of fluorescence obtained by the following formula.
AGE generation amount (fluorescence amount) = measured value A−measured value B
（試験結果）
被験薬を含有しない（対照）におけるＡＧＥｓ値に対する、ＤＡＤＡ（１０ｍｇ／ｍＬ）およびトラネキサム酸（０．１ｍｇ／ｍＬ）の合剤でのＡＧＥｓ値の結果を図１に示す。なお、各値はN＝６の平均値である。いずれもＡＧＥｓ生成抑制作用の知られていないＤＡＤＡとトラネキサム酸を併用すると、図１に示すように顕著なＡＧＥｓの生成抑制効果が発現することが判明した。
(Test results)
FIG. 1 shows the results of AGEs in the combination of DADA (10 mg / mL) and tranexamic acid (0.1 mg / mL) versus AGEs in the test drug-free (control). Each value is an average value of N = 6. In both cases, it was found that when DADA and tranexamic acid, which are not known to inhibit AGEs production, are used in combination, a remarkable AGEs production inhibitory effect appears as shown in FIG.
本発明の組成物は、皮膚褐変化、肌透明度低下、糖尿病性白内障、糖尿病性血管障害または腎機能障害を予防または改善することができ、しかも、安全であり、かつ経口投与でも外用でも有効なため、極めて有用である。さらに経口投与であっても外用してもよく、医薬品、医薬部外品または化粧料として利用可能である。 The composition of the present invention can prevent or ameliorate skin browning, decreased skin transparency, diabetic cataract, diabetic vascular disorder or renal dysfunction, and is safe and effective for oral administration and external use. Therefore, it is extremely useful. Furthermore, it may be orally administered or applied externally, and can be used as a pharmaceutical, a quasi-drug or a cosmetic.
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| JP5969787B2 (en) | 2016-08-17 |
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