201043265 r· 六、發明說明： ^【發明所屬之技術領域】 _、本發明是關於一種口腔用I且成物，該組成物具有清涼 感，且含有有機酸，保存性優越。 【先前技術】 *近年來，人們對於外表修飾的關心提高。其中包含口 六而有種種口腔用組成物的開發。對這些口腔用組成物 ❹所期待的功用已知是防止口臭及口中濕潤效果等。 作為口腔用組成物者，可舉例如洗口劑、 f膏、含嗽劑或口中喷霧劑等。其中，關於洗口劑、含嗽 =、牙膏，因為有攜帶不便、使用場所受限制等的缺點， 因而有即時性效果而不挑選使用場所且少量可顯現充分效 果的製劑，例如，口中噴霧劑等的使用價值正在昇高。 一般而言，口腔用組成物在以賦與清涼感或 目的下’通常是配合清涼成分的薄荷腦或其類似成分^ 〇二，使薄荷腦發揮其本來有的清涼感或清爽感，通常需要 、弋的濃度，例如在少量使用時，必需要調製成0.4重量％ 以上的水溶液，以往為了溶解薄荷腦之目的，將乙醇等的 低級醇添加到該組成物，並採取使用做為溶解助劑而組人 聚氧乙烯（polyoxyethy 1 ene，P0E)硬化藏麻仔油^ =二 子性界面活性劑的手段。 $離 ，一方面，本發明人等先前發現藉由有機酸而有口中 =禦素（万-defensin)促進作用（專利文獻υ。汐〜御~ 疋具有抗菌活性的肽（peptide)，有報告指出能抑制:= 322082 3 201043265 就可期待除了會有對 中細菌相的改善，更 感染。因此，促進冷〜防禦素的分泌， 鱗齒或牙周病的預防之外，尚可有口 進一步會有改善舌苔的效果。 物去到：前作為含有高用量的有機酸的口腔用組成 物者，揭不有洗口劑（專利文獻2)。但是，如要以 揮如上述的薄荷腦的清涼感或預防二 現==要…絮素分泌促進效果的顯 現貝1有機酉夂也需要以高濃度配合。但是， 薄荷腦雙方都加一定量以上時，則薄荷腦的溶解性= 好’溶解助劑的聚氧乙埽硬化萬麻仔油等的非離子性界面 活性劑也受到有機酸的影響而有分解的傾向，其結果 薄荷腦的溶解性降低而析出的顧慮。 * I此，如料有更高的彻價值，使薄荷腦及有機 H的紋之㈣_物，尤其是心量而可顯現充分 效果的組成物（例如口中喷霧劑用組成物）之開發。 [專利文獻1]國際公開恥2005/027893 [專利文獻2]曰本專利特開平7_ι31 【發明内容】 [發明要解決的課題] 本發明之目的是，要完成具有附加價值的上述口腔用 組成物’财便難高，以少料可顯現充分效果的組成 物（例如口中噴霧肋成物）。具體而言是要提供—種安定 的腔用，、且成物，在含有薄荷腦及有機酸的口腔用组成物 中，對於做為溶解助劑而㈣的非離子性界面活性劑的安 322082 4 201043265 定性不會有影響，而有清涼感及預防口腔内各種疾患的效 果。 [解決課題的手段] 本發明人等，為解決上述課題而精心檢討，發現：由 配合揮發性清涼成分、以及有機酸及/或有機酸之鹽，再配 合低級醇及非離子性界面活性劑，則可抑制非離子性界面 活性劑的分解，提高其保存安定性。具體而言，對薄荷腦 等的揮發性清涼成分，加入乙醇等低級醇及聚氧乙烯硬化 〇 蓖麻仔油等非離子性界面活性劑的水溶液所成的口腔用組 成物中，配合具有占-防禦素促進作用的檸檬酸等的有機酸 及/或有機酸鹽時，藉由將其配合量設在特定的範圍内，則 可抑制溶解助劑的非離子性界面活性劑的分解，而提高其 保存安定性。在這個組成物中，除了預防口臭的效果及口 中的濕潤效果外，還有口腔的抗菌作用等，可期待由於口 腔的免疫活性的提高而改善口腔環境的效果。本發明是基 0 於這些知識一再檢討而完成的。 本發明提供下列的組成物。 1. 一種口腔用組成物，係含有0. 2重量％以上的揮發性清涼 成分（A)，及1重量％以上的有機酸（B)。 2. 前述1所記載的口腔用組成物，其再含有低級醇（C)及非 離子性界面活性劑（D)。 3. 前述1或2所記載的口腔用組成物，其中，成分（A)是薄 荷腦（mentol)。 4. 前述1至3中任一項所記載的口腔用組成物，其中，成 5 322082 201043265 分（B)的碳數是C4至C8所成的有機酸。 5.前述2至4中任一項所記載的口腔用組成物，其中，成 分（C)是碳數C2至C6所成的低級醇。 6·前述2至5中任一項所記載的口腔用組成物，其中，成 分（D)是氧化乙烯的附加莫耳數在4〇以上的聚氧乙烯硬化 萬麻仔油。 7. 前述2所記載的口腔用組成物，係含有下列成分（A)至 (D): (A) 0.4重量％以上的薄荷腦 (B) 1重量％以上的C4至C8所成的有機酸 (C) 1〇重量％以上的（^至邙所成的低級醇 (D) 0.1重量％以上的氧化乙烯的附加莫耳數在4〇以上的 t氧乙烯硬化蓖麻仔油。 8. 則述2至7中任一項所記載的口腔用組成物，其中，成 刀（C)為乙醇。 ^刖述1至8中任一項所記載的口腔用組成物，其中，成 分（B)為由富馬酸、蘋果酸、檸檬酸、抗壞血酸及酒石酸所 選的1種或2種以上及其鹽的混合物。 10.前述9所記載的口腔用組成物，其中，成分（B)為檸檬 酸及檸檬酸鹽的混合物。 U·☆前述10所記載的口腔用組成物，其中，成分（B)是相對 於檸^篆酸1重量部，檸檬酸鹽為01至7重量部的混合物。 述10所記載的口腔用組成物，其中，成分（β)是由檸 檬酸12至95%及檸檬酸鹽88至5%的重量配合比率所成。 322082 6 201043265 13. 前述2至12中任一項所記載的口腔用組成物，係含有 ' 做為成分（E)的3價醇。 14. 前述13項所記載的口腔用組成物，其中，成分（E)是甘 油。 15. 前述1至14中任一項所記載的口腔用組成物，該前述 口腔用組成物為口中喷霧用。 16. 前述1至15中任一項所記載的口腔用組成物，該組成 物不含防腐劑。 f% i 17.前述1至16中任一項所記載的口腔用組成物，該組成 物具有/3-防禦素分泌促進作用。 18. 前述1至16中任一項所記載的口腔用組成物，該組成 物具有預防口臭效果。 19. 前述18所記載的口腔用組成物，其中，口臭係起因於 口腔内的含硫氣體。 20. 前述19所記載的口腔用組成物，其中，含硫氣體為揮 Q 發性含硫化合物。 21. 前述1至16中任一項所記載的口腔用組成物，該組成 物具有齲齒關連細菌降低作用。 22. 前述21所記載的口腔用組成物，其中，齲齒關連細菌 為鏈球菌（Streptococcus)及/或乳酸桿菌。 23. 前述22所記載的口腔用組成物，其中，鏈球菌屬為轉 糖鏈球菌群（mutans streptococci)。 24. —種含有揮發性清涼成分與有機酸的組成物，該組成物 含有用以使該揮發性清涼成分安定之低級醇及非離子性界 7 322082 201043265 面活性劑。 25. 前述24的組成物，該组成物含有0. 4重量％以上的揮發 性清涼成分與1重量％以上的有機酸，並添加有10重量％ 以上的低級醇與0. 1%重量％以上的非離子性界面活性劑。 26. —種揮發性清涼成分的安定化方法，其特徵為係在配合 揮發性清涼成分與有機酸的組成物中，添加低級醇及非離 子性界面活性劑。 27. 前述26的安定化法，係在配合0. 4重量％以上的揮發性 清涼成分與1重量％以上的有機酸的組成物中，添加1 〇重 量％以上的低級醇及0.1重量％以上的非離子性界面活性 劑。 [發明的效果] 本發明的口腔用組成物，雖含有有機酸，而薄荷腦沒 有因低級醇及非離子性界面活性劑而減弱其溶解性，結 果，可提供安定的含有上述成分的口腔用組成物。具體而 言，在以特定比率的乙醇與聚氧乙烯硬化蓖麻仔油溶解薄 荷腦的組成物中，藉由含有特定比率的有機酸，則可以提 供安定的口腔用組成物。特別是在本發明的組成物中，即 使含有高濃度的有機酸（例如檸檬酸），但藉由使其共含其 鹽的技術，本發明人等發現如此更能抑制聚氧乙烯硬化蓖 麻仔油的分解之事實，不需要使用苯甲酸等的保存劑，而 可呈現足夠的保存安全性。如此，可提供一種口腔用組成 物，係由於使用該組成物而能保持薄荷腦的清涼感，並在 口腔内發揮人/3-防禦素分泌促進作用等的有用作用，可以 8 322082 201043265 保持口腔内的健康。 ^ 【實施方式】 [實施發明的最佳形態] 本發明的口腔用組成物是含有（A)揮發性清涼劑與（B) , 有機酸，再含（C)低級醇與（D)非離子性界面活性劑，含適 宜的（E)3價醇。由於含該（A)至（E)成分，在口腔清涼劑中 除了有預防口臭及保濕效果之外，也可得到有機酸的yS-防禦素促進作用。 0 本發明的口腔用組成物所使用的上述成分，除了在本 說明中有特別的記載之外，並不限定其分子量、異構物、 配糖物、水合物或鹽等。 在本發明中，上述（A)的揮發性清涼成分並不限定源自 天然物或合成品、其鹽、含有這些成分等的形狀，又，這 些可以單獨使用1種，或可組合2種以上使用。理想的是 薄荷腦，其中尤以1-薄荷醇為理想。 'Q 在本發明的口腔用組成物中，上述（A)成分是組成物總 量的0. 2重量％以上，以0. 4至10重量％為佳，更佳是0. 5 至2重量％。尤其是單次的喷霧中，要有充分的清涼感及預 防口臭作用，則在0.4重量％以上，尤其是在0.5至2重量 %的範園為理想。 在本發明中，做為上述（B)成分而使用的有機酸者，期 望碳數在4至8所成的有機酸。其例期望是富馬酸、蘋果 酸、檸檬酸、抗壞血酸、乳酸、乙酸、己二酸（adipic acid)、 酒石酸、肉桂酸、麩胺酸及琥珀酸，而較理想的是富馬酸、 9 322082 201043265 蘋果酸、摔檬酸、抗壞血酸及酒石酸，更理想的是摔樣酸。 在本發明中的上述⑻成分可以單獨使用1#，也可以㈣ 組合2種以上而使用。 又，本發明中的（B)成分，可以是上述有機酸與該有機 I之鹽的組合’組合使㈣，⑼成分的非離子性界面活性 劑的保存安定性可㈣會提昇很大。有機酸㈣只要在藥 學上或Κσσ衛生上可容許的上述有機酸之鹽即可，其中， 尤其是以可能經π性利用的納鹽或鉀鹽為理想。八 本發明的口腔用組成物中，上述⑻成分是組成物總量 ^重«以上，以i至30重量％為佳，較佳是2至2〇重 置％ ’更佳是3至15重量％ ’特別佳是5至13%。 上述⑻成分中的有機酸與有機酸鹽的配合比，相對於 :機酸！重量份’有機酸鹽是以〇.⑴重量份為理想： ^想的是相對於有機酸1重量份，有機酸鹽是0.2至5 里：’更理想的是相對於有機酸1重量份 〇·6至4. 5重量份。 疋 ，此’做為⑻成分為使用檸檬酸與檸檬酸鹽之組合 二=_1^是相當於檸檬酸咖重 想的疋15至85%，更理想的是Π至70重量％。 簟互tr)成分中的有機酸與有機酸鹽的配合比也可以 4 6 ίΐΓ广對於有機酸1莫耳’有機酸鹽是。.此至 二==較理想的是相對於有機酸丨莫耳，有機 有莫耳’更理想的是相對於有機酸1莫耳， 有機酸鹽是0.35至3莫耳的配合比。 今 322082 201043265 在本發明中，做為上述（c)成分而使用的低級醇是指直 鏈或分支鏈的碳數2至6的醇，只要在此範圍而在藥學上 或食品衛生上可容許的醇即可而無特別的限制。其中較理 想的是由碳數2至4所選擇的醇，具體上是以乙醇為理想。 本發明之口腔用組成物中，上述（C)成分期望是組成物 之總量的10重量％以上，而以10至50重量％為佳，較佳是 10至30重量％，更佳是15至25重量％。 加之，上述（C)成分，由薄荷腦所代表的揮發性清涼成 〇 分的溶解性方面而言，需要有10重量％以上，但如在3 0重 量％以上時，從揮發性及刺激性方面而言在嗜好上並不是所 希望的。又，如後述的實施例所示，在這樣的濃度中，會 降低有機酸的溶解性，而不能完成本案的處方。 在本發明中，做為上述（D)成分而使用的非離子性界面 活性劑者，可列舉：蔗糖脂肪酸酯、麥芽糖（maltose)脂肪 酸酯、乳糖脂肪酸酯等糖脂肪酸酯，麥芽糖醇（maltitol) Q 脂肪酸酯、乳糖醇脂肪酸酯等的糖醇脂肪酸酯，聚氧乙烯 山梨糖醇單月桂酸酯、聚氧乙烯山梨糖醇單硬脂酸酯等的 聚氧乙烯山梨糖醇脂肪酸酯，聚氧乙烯硬化蓖麻仔油等的 聚氧乙烯脂肪酸酯，月桂酸單或二乙醇醯胺、肉豆蔻酸單 或二乙醇醯胺等的脂肪酸二乙醇醯胺，山梨糖醇脂肪酸 酯、聚氧乙烯高級醇醚、聚氧乙烯聚氧丙烯共聚物、聚氧 乙烯聚氧丙烯脂肪酸酯等。其中以聚氧乙烯硬化蓖麻仔油 為理想，較理想的是附加氧乙烯在40以上，更理想的是附 加6 0的物料。 11 322082 201043265 本發，的口腔用紅成物中，上述⑻成分是組成物總量 的〇. 1重里％以上，理想的是〇.工至1〇重量％，較理想的是 1至5重量％，更理想的是2至5重量％，特別理想的是2 至3重量％。 在本發明中’在上述做為（E)成分使用的3價醇，可舉 例如甘油。以甘油所代表的3價醇，在低溫下預防薄荷腦 或檸檬酸的析出上有用。 3價醇的配合量是1至20重量％，理想的是5至15重 量％’更理想的是5至1〇重量％。 本發明的口腔用組成物是一種水溶液，可以由（A)與（B) 成刀所成也可以由上述（A)至（D)成分所成，也可以又含 有適宜ΐ的（E)。又，可配合在食品衛生上或藥學上可容許 的擔體’再視需要也可以適宜配合添加物等的其他成分。 再者，本發明的口腔用組成物也可以含有做為（F)成分 的玻尿酸（hyaluronicacid)或普魯藍多醣（Pulluian)也可 以。玻尿酸特別是以平均分子量50000以下的低分子的破 尿酸為理想，使用上述的低分子玻尿酸時或普魯藍多醣 時，因黏性不高，以口腔清涼劑的形態使用時，不會發生 各器的阻塞，可不挑選容器而適合使用於噴霧製劑。在本 發明中，由於含有該成分，表現有機酸的石_防禦素促進作 用’同時兼具有阻礙因酸引起的牙齒琺瑯質溶解之作用， 對於做為維持健康的口腔内環境的口腔保養製品上特別有 用。 低分子玻尿酸的配合量期望是〇. 01至10重量％，理神、 322082 12 201043265 是0.1至5重量％。普魯藍多_ 壬曰。/诚相θ n s q 的配合量期望是〇. 〇1至5 重量％，理想的是〇· 05至3重| 曰。/ K ’更理想的是0. 1至1重 量％。 作為本發明的口腔用組成Ί X物所含的各成分的重量配合 比’將組成物中的（A)成分含量當做ι時，⑻成分為i至 40的範圍為理想，更理想的是2至2〇，特別理想的是4至 15的範圍。 以上述範圍的濃度將組成物中的（A)成分及（B)成分配 〇 合時，（C)成分是相對於（A)成分的重量配合量1的5至80’ 理想的是10至60的範圍，（D)成分是相對於（A)成分的重 量配合量1的1至20，理想的是在2至1〇的範圍。 (E)成分的重量配合比則並無特別限定，視其形態而對 (A)成分的配合量1，可在1至20的範圍適宜地選擇。同 樣，對（F)成分也對（A)成分重量配合量1，在〇. 1至20之 範圍可適宜選擇。 ◎ 本發明的口腔用組成物之特徵是以少量的使用量而可 期待有充分的效果。在這裏所稱的少量是指1次使用置在 0.001至10ml，理想的是0.01至5ml，更理想的疋02 至2ml的範圍，只要是適於少量使用的形態’就沒有特別 的限定。 做為本發明的口腔用組成物之適合形態者’可舉例示 口中喷霧劑，口中噴霧劑是在口腔内將液狀的本發明組成 物當喷霧使用。本發明所稱的口中喷霧用組成物’就是本 發明的口腔用組成物的水溶液，適合以液態在口腔喷霧而 322082 13 201043265 能得到效果的組成物。這裏所稱的喷霧，對液滴大小、量、 速度等並無特別限制，直接、間接產生都可以。又並不需 要是完全的霧狀，也可以以噴射狀使用。 將本發明的組成物做為口中喷霧劑使用時，由於薄荷 與有機酸的併用，可期待顯著的唾液分泌促進效果，所以 特別適合做為口腔濕潤劑使用。口腔濕潤劑是對唾液分泌 不全的口腔乾燥症（dry mouth)的症狀改善特別有用。口腔 乾燥症的主要症狀，可列舉如：口乾、舌頭刺痛、在意口 臭、味覺不正常，容易患蛀牙或牙周病等。本發明的組成 物可促進唾液的分泌，同時因配合特定的有機酸而會促進 /3 -防禦素的分泌，可期待特別對姓牙齒、牙周病、口中細 菌相、口内發炎、口臭或舌苔等的改善或治療有效果。再 者，對該組成物加低分子玻尿酸等時，也可期待能防止因 酸而引起的牙齒琺瑯質溶解。 又，在本發明中，含硫氣體是指含有硫的氣體，可舉 例如硫化氫、曱硫醇、硫化碳、二硫化碳、二乙基硫醚、 二甲基二硫等的揮發性含硫化合物的存在，其中尤以被認 為是口臭的原因的氣體可舉例如硫化氫、甲硫醇、二甲基 二硫等。 又，本發明中，鑛齒關連細菌是指鏈球菌、乳酸桿菌 等。又，齲齒關連細菌，特別是被認為以鏈球菌為代表性， 其中尤以轉糖鏈球菌為其代表。 又，在本發明中，可再配合各種添加劑，例如甘味料、 色素（染料、顏料）、香味料、防腐劑、殺菌劑（抗菌劑）、 14 322082 201043265 增黏劑、抗氧化劑、金屬封鎖劑、防臭劑、pH調整劑等。 * 作為甘味料者，包含例如葡萄糖、半乳糖、蔗糖、或 木糖醇等的天然糖，糖精、阿斯巴甜（Aspartame)等的合成 甘味料等，其中尤以使用如木糖醇的低齲齒性的甘味料為 理想，但不限定所記載的成分。 又，本發明的另一個特徵係期望不摻配如防腐劑等的 成分。本發明品藉由配合成分的薄荷腦、乙醇及高濃度的 有機酸，即使不摻配防腐劑或殺菌劑（抗菌劑）也能夠得到 〇 充分的長期安定性。尤其是，在不摻配一般所使用的苯曱 酸鈉等的防腐劑而能充分適用於長期保存的同時，可減少 不需要的食品添加物的配合。因此，本發明品含在口腔内 後，並不需要特別吐出，在身體内可攝取該溶液。 本發明的口腔用組成物，少量就可以顯現目的之效 果。例如，雖是為了適用於做為口中喷霧製劑等而發明的， 但由於能使其成為其他形態，也可以將其形態做為其他的 Q 口腔保養製品（口腔用製品）的形態而使用。 本發明的口腔用組成物做為口腔保養製品（口腔用製 品）的形態時，其形態並無特別的限制。其一例可舉示牙膏 劑、洗口劑、口腔凝膠劑、漱口劑等。 本發明的口中喷霧用組成物，只要是在口腔内將本發 明的組成物喷霧使用，對其適用方法並無特別的限制，但 為了要將依上述（B)成分的人yS-防禦素產生促進作用能有 效地表現出來，例如，將上述（B)成分以每日在口腔内適用 相當於1 mg以上，理想是5至500Omg，更理想的是5至30Omg 15 322082 201043265 之量分成1至10次（通常2至30mg/次程度）。又，本發明 的口腔用組成物，為了要使由於上述（B)成分之人防禦 素產生促進作用能有效地表現出來，在口腔内使用後，例 如，期望在口腔内滞留約1秒鐘以上為理想。 作為本口腔用組成物保存的容器者，並無特別的限 制，但以聚對苯二曱酸二乙酯（polyethylene terephthalate)或玻璃為理想。例如，聚丙烯或聚乙稀製 的容器時，由於摻配成分有被吸附的現象，所以不適於做 為本組成物的容器。又，並不經常接觸的部分，例如蓋等， 其材質則並無特別的限定，也可以用上述的聚丙烯或聚乙 烯製造。 [實施例] 以下，列舉試驗例及實施例說明本發明，但本發明並 不受這些實施例的限定。 實施例1 含薄荷腦與有機酸的組成物的溶解性變化 為了要檢討在含有薄荷腦的口中清涼劑中，配合有機 酸的合適性之目的下，檢討乙醇及聚氧乙烯硬化蓖麻仔油 的配合量對有機酸的溶解性的影響。於是，調製如表1所 示的處方，檢討滿足充分的溶解性的條件。 16 322082 201043265 ^ [表 1] 重量％(w/w) 薄荷腦 1 擰檬酸 7 Ρ0Ε硬化蓖麻仔油6 0 * 1至5 乙醇 5至40 甘油 10 甘味料 適量 香料 適量 精製水 其餘 合計 100 *聚氧乙烯硬化蓖麻仔油60* 所得結果示於第1圖。由此結果表示，在配合有機酸 時，聚氧乙烯硬化蓖麻仔油的配合量在2重量％以上的範 圍，表現有充分的有機酸之溶解性。又，乙醇量在25重量 %以下的範圍時，表示可以調製安定的製劑。相較之下，在 將乙醇配合成上述範圍以上時，檸檬酸之外，薄荷腦的溶 解性明顯地減弱，明顯地不適合做為製劑。又，在低濃度 薄何腦的莖（0. 2重置％)下進行同樣的試驗時’各成分的量 對聚氧乙烯硬化蓖麻仔油的溶解性沒有影響。 試驗例2 有機酸摻配口腔用組成物的保存安定性的檢討 檢討在含有機酸的口腔組成物中聚氧乙烯硬化蓖麻仔 油的分解舉動。所用的處方示於表2。 17 322082 201043265 [表2] 重量％(w/w) 比較例1 比較例2 薄荷腦 0· 5 0. 5 檸檬酸 3 5 P0E硬化蓖麻仔油60 3 3 乙醇 15 15 甘油 10 10 甘味料 適量 適量 香料 適量 適量 精製水 其餘 其餘 合計 100 100 處方的調製方法 在加溫到8 0 °C以上的精製水中加檸檬酸、甘油、甘味 料並攪拌溶解後，冷卻至室溫。再將溶解在乙醇的香味料、 薄荷腦、Ρ0Ε硬化蓖麻仔油緩緩加入而完成處方。又，在 以下的試驗例中，如無特別記載，都是用本調製方法而調 製者。 將如上述調製的口中喷霧用組成物（比較例1、2)分別 加入到3 Om 1的透明玻璃管瓶中，以螺旋蓋加蓋。將這些管 瓶保管在40、60、80°C的恆溫槽中，每隔數日測定聚氧乙 烯硬化萬麻仔油含量，評估組成物的保存安定性。 聚氧乙烯硬化蓖麻仔油的含量是使用液體層析分析 18 322082 201043265 法，以通常所知的方法測定。 * 所得比較例1及2的結果中，將比較例2的結果表示 於第2圖。在剛調製妤時，薄荷腦等的溶解性都可滿足要 求，但經保存後，聚氧乙烯硬化蓖麻仔油隨時間而分解， , 可看到薄荷腦析出而產生白色混濁。又，其分解是顯示與 溫度有關。再者，在40°C下保存時，也顯示有聚氧乙烯硬 化蓖麻仔油的分解，表示在口腔用組成物含有有機酸時， 組成物明顯地成為不安定。又，在比較例1中也是有同樣 ^ 的結果。 試驗3 有機酸摻配口腔用組成物的保存安定性檢討2 檸檬酸、檸檬酸鈉的混合比率的變化對保存安定性變化之 影響（聚氧乙烯硬化蓖麻仔油含有量變化） 如表3所示以含有檸檬酸與檸檬酸鹽的處方調製的供 試驗液（實施例1至3)，以試驗例2所記載的方法調製後， 在80°C條件下保存，評估其安定性。又，聚氧乙烯硬化蓖 q 麻仔油量的測定，是用與上述同樣的方法測定。 19 322082 201043265 [表3] 重量％(w/w) 實施例1 實施例2 實施例3 薄荷腦 0. 5 0.5 0. 5 --- 檸檬酸酐 4. 3 3.7 3. 1 檸檬酸三鈉二水合物 1.1 2 2. 9 甘油 5 5 5 Ρ0Ε硬化蓖麻仔油fin 3 3 3 乙醇 15 15 15 甘味料 適量 適量 適量 香料 適量 適量 適量 精製水 其餘 其餘 其餘 合計 ---------- 100 100 100 其結果，如第3圖所記載，在80°C的苛刻條件下，藉 由組合擰檬酸與檸檬酸鹽，呈現聚氧乙烯硬化蓖麻仔油的 分解顯著地被抑制。由此表示，在含有有機酸的口中清涼 劑中’由於有機酸與其鹽的適當組合’可抑制聚氧乙烯硬 化蓖麻仔油的分解。 試驗例4有機酸摻配口中喷霧用組成物的保存安定性檢 討3 其次，以確認上述試驗例3的保存安定性是否會隨溫 度而變化之目的下，脾本 ^ 將以表4的處方調製的供試驗液，在 4 0、6 0、8 0 C的條件下伴在，ja 卜保存砰估其安定性。又，聚氧乙 322082 20 201043265 烯硬化蓖麻仔油量的測定，是用與上述同樣的方法測定。 [表4] 重量％(w/w) 實施例4 薄荷腦 0. 5 檸檬酸 2. 5 檸檬酸三鈉二水合物 3. 8 甘油 5 Ρ0Ε硬化蓖麻仔油6 0 3 乙醇 15 甘味料 適量 香料 適量 精製水 其餘 合計 100 其結果，如第4圖所示，在實施例4中，在任一溫度 保存下，聚氧乙烯硬化蓖麻仔油幾乎都沒有分解，表示是 安定的處方。 試驗例5 有機酸摻配口中喷霧用組成物的保存安定性 根據上述試驗例3至4的結果，再另外設定檸檬酸與 檸檬酸鹽的配合量如表5而調製供試驗液，在40°C的條件 下保存，評估其安定性。實施例3的供試驗液也一併做為 陽性對照而供試驗。聚氧乙稀硬化蓖麻仔油量的測定，是 用與上述同樣的方法測定。 21 322082 201043265 [表5]201043265 r· VI. Description of the invention: ^ [Technical field to which the invention pertains] _ The present invention relates to an oral I composition, which has a cooling sensation and contains an organic acid, and has excellent preservative properties. [Prior Art] * In recent years, people's interest in appearance modification has increased. It includes the development of various oral compositions. The functions expected for these oral compositions are known to prevent bad breath and moisturizing effects in the mouth. Examples of the composition for the oral cavity include a mouthwash, a f cream, an expectorant or an oral spray. Among them, the mouthwash, the enamel-containing, and the toothpaste have shortcomings such as being inconvenient to carry and limited in use, and therefore have an immediate effect, and do not select a place to be used, and a small amount of a formulation which exhibits sufficient effects, for example, a spray in the mouth, etc. The value of use is rising. In general, the oral composition is required to impart a refreshing sensation or purpose, usually a menthol or a similar component of a cooling ingredient, so that the menthol exerts its original refreshing feeling or refreshing feeling, and is usually required. When the concentration of hydrazine is used in a small amount, for example, it is necessary to prepare an aqueous solution of 0.4% by weight or more. Conventionally, a lower alcohol such as ethanol is added to the composition for the purpose of dissolving menthol, and it is used as a dissolution aid. The group of people polyoxyethy 1 (ene, P0E) hardened Tibetan acacia oil ^ = two sub-surfactant means. On the one hand, the inventors of the present invention have previously found that the use of an organic acid to promote the effect of phenanthrene-defence (the patent document υ.汐~御~疋 has an antibacterial activity of a peptide, has been reported It is pointed out that it can suppress: = 322082 3 201043265 It can be expected that there will be improvement in the bacterial phase and infection. Therefore, in addition to promoting the secretion of cold-defensin, prevention of scaly teeth or periodontal disease, there is still a further There is an effect of improving the tongue coating. The object goes to: before, as an oral composition containing a high amount of organic acid, there is no mouthwash (Patent Document 2). However, if you want to use the menthol as described above The sense of cooling or prevention is two == To be... The effect of the promotion of flocculating secretion is also required. The organic sputum also needs to be mixed at a high concentration. However, when both menthols are added in a certain amount or more, the solubility of menthol = good' The nonionic surfactant such as polyoxyethylene oxime hardening of the dissolution aid is also decomposed by the influence of the organic acid, and as a result, the solubility of the menthol is lowered and the precipitation is considered. If there is a higher The development of a composition (for example, a composition for a spray in the mouth) which exhibits a sufficient effect, such as a menthol and an organic H. (Patent Document 1) International Public Shame 2005/ 027893 [Patent Document 2] Japanese Patent Laid-Open No. Hei 7_ι31 [Description of the Invention] [Problem to be Solved by the Invention] The object of the present invention is to complete the above-mentioned oral composition having added value, which is difficult to be high, and is less likely to be used. A composition that exhibits sufficient effects (for example, a spray rib in the mouth). Specifically, it is intended to provide a stable cavity, and a substance, in an oral composition containing menthol and an organic acid, (4) The non-ionic surfactant of the (4) non-ionic surfactant is not affected by the qualitative properties, but has a cooling sensation and the effect of preventing various diseases in the oral cavity. [Means for Solving the Problem] The present inventors have solved the above After careful review of the subject, it was found that the non-ionic interface can be suppressed by blending volatile cooling components, salts of organic acids and/or organic acids, and lower alcohols and nonionic surfactants. The decomposition of the active agent improves the storage stability. Specifically, an aqueous solution of a non-ionic surfactant such as a lower alcohol such as ethanol or a polyoxyethylene hardened ramie oil is added to a volatile cooling component such as menthol. When an organic acid and/or an organic acid salt such as citric acid which has a defensin-promoting action is blended in the composition for oral cavity formation, the amount of the compounding agent can be suppressed in a specific range. The decomposition of the nonionic surfactant improves the preservation stability. In addition to the effect of preventing bad breath and the moisturizing effect in the mouth, the composition also has an antibacterial effect on the oral cavity, and can be expected to be immunologically active due to the oral cavity. The improvement of the oral environment is improved. The present invention is based on the repeated review of this knowledge. The present invention provides the following compositions. 1. An oral composition comprising 0.2% by weight or more of a volatile cooling component (A) and 1% by weight or more of an organic acid (B). 2. The oral composition according to the above 1, which further comprises a lower alcohol (C) and a nonionic surfactant (D). 3. The oral composition according to the above 1 or 2, wherein the component (A) is a mentol. 4. The oral composition according to any one of the above 1 to 3, wherein the carbon number of 5 322082 201043265 (B) is an organic acid formed by C4 to C8. The composition for oral cavity according to any one of the items 2 to 4, wherein the component (C) is a lower alcohol having a carbon number of C2 to C6. The oral composition according to any one of the items 2 to 5, wherein the component (D) is a polyoxyethylene hardened kenaf oil having an additional number of moles of ethylene oxide of 4 Å or more. 7. The oral composition according to the above 2, comprising the following components (A) to (D): (A) 0.4% by weight or more of menthol (B) 1% by weight or more of C4 to C8 organic acid (C) 1% by weight or more of the lower alcohol (D) of 0.1% by weight or more of ethylene oxide, and the addition of oxyethylene hardened ramie oil having a molar number of 4 Å or more. The composition for oral cavity according to any one of the items 1 to 8, wherein the component (B) is an oral composition according to any one of the items 1 to 8. A mixture of one or more selected from the group consisting of fumaric acid, malic acid, citric acid, ascorbic acid, and tartaric acid, and a mixture thereof. The oral composition according to the above 9, wherein the component (B) is a lemon. The composition for oral cavity according to the above 10, wherein the component (B) is a mixture of 1 part by weight to the citrate and 1 to 7 parts by weight of the citrate. The oral composition according to 10, wherein the component (β) is formed by a weight ratio of 12 to 95% of citric acid and 88 to 5% of citrate. The oral composition according to any one of the above-mentioned items, wherein the composition for oral cavity of the above-mentioned item (E) is a trivalent alcohol. The component (E) is glycerin. The oral composition according to any one of the above 1 to 14, wherein the oral composition is sprayed in the mouth. The oral composition which does not contain a preservative. The composition of the oral cavity of any one of the above 1 to 16 which has a /3-defensin secretion promoting action. The composition for oral cavity according to any one of the above aspects of the present invention, wherein the oral odor is caused by a sulfur-containing gas in the oral cavity. The composition for oral cavity according to the above-mentioned item, wherein the sulfur-containing gas is a sulfur-containing sulfur-containing compound. The composition for oral cavity according to any one of the above 1 to 16, which has a reduction in caries-related bacteria 22. The oral composition according to the above 21, wherein The dental caries-related bacteria are Streptococcus and/or Lactobacillus. The oral composition according to the above 22, wherein the Streptococcus is a mutans streptococci. a composition of a cooling component and an organic acid, the composition comprising a lower alcohol for calming the volatile cooling component and a nonionic boundary agent. The composition of the above 24, the composition containing 0 And a nonionic surfactant of 0.1% by weight or more and 10% by weight or more of the lower alcohol and 0.1% by weight or more of the nonionic surfactant. 26. A method for stabilizing a volatile cooling component, characterized in that a lower alcohol and a nonionic surfactant are added to a composition comprising a volatile cooling component and an organic acid. 27. The stabilization method of the above-mentioned 26, wherein a composition of 0.4% by weight or more of the volatile cooling component and 1% by weight or more of the organic acid is added to the lower alcohol of 1% by weight or more and 0.1% by weight or more. A nonionic surfactant. [Effects of the Invention] The oral composition of the present invention contains an organic acid, and menthol is not weakened by a lower alcohol and a nonionic surfactant, and as a result, a stable oral cavity containing the above components can be provided. Composition. Specifically, a composition for dissolving a thin lotus brain in a specific ratio of ethanol and polyoxyethylene hardened ramie oil can provide a stable oral composition by containing a specific ratio of an organic acid. In particular, in the composition of the present invention, even if a high concentration of an organic acid (for example, citric acid) is contained, the inventors have found that the polyoxyethylene hardened ramie is more inhibited by the technique of co-containing the salt thereof. The fact that the oil is decomposed does not require the use of a preservative such as benzoic acid, but exhibits sufficient preservation safety. In this way, it is possible to provide a composition for oral cavity, which can maintain the refreshing sensation of menthol by using the composition, and can exert a useful effect such as a human/3-deficiency secretion promoting action in the oral cavity, and can maintain the oral cavity in 8 322082 201043265. Health inside. [Embodiment] [Best Mode for Carrying Out the Invention] The oral composition of the present invention contains (A) a volatile cooling agent and (B), an organic acid, and further contains (C) a lower alcohol and (D) a nonionic a surfactant, containing a suitable (E) trivalent alcohol. By containing the components (A) to (E), in addition to preventing bad breath and moisturizing effect in the oral freshener, the yS-defensin promoting action of the organic acid can also be obtained. The above-mentioned components used in the oral composition of the present invention are not limited to the molecular weight, the isomer, the glycoside, the hydrate or the salt, etc., unless otherwise specified in the description. In the present invention, the volatile cooling component of the above (A) is not limited to a shape derived from a natural product or a synthetic product, a salt thereof, or a component thereof, and these may be used alone or in combination of two or more. use. Ideally, menthol, especially 1-menthol, is ideal. 5至2重量。 The weight of the composition of the present invention is preferably 0. 2 to 10% by weight, more preferably 0.5 to 2 weight %. In particular, in a single spray, it is desirable to have a sufficient cooling feeling and prevent bad breath, and it is preferably 0.4% by weight or more, especially 0.5 to 2% by weight. In the present invention, as the organic acid used as the component (B), an organic acid having a carbon number of 4 to 8 is desired. Examples thereof are fumaric acid, malic acid, citric acid, ascorbic acid, lactic acid, acetic acid, adipic acid, tartaric acid, cinnamic acid, glutamic acid, and succinic acid, and more preferably fumaric acid, 9 322082 201043265 Malic acid, citric acid, ascorbic acid and tartaric acid, more ideally, acid. The component (8) in the present invention may be used singly or in combination of two or more. Further, the component (B) in the present invention may be a combination of the above-mentioned organic acid and a salt of the organic I, and (4), and the storage stability of the nonionic surfactant of the component (9) may be greatly improved. The organic acid (4) may be any salt of the above organic acid which is pharmaceutically acceptable or hysteretically acceptable, and among them, a sodium salt or a potassium salt which may be utilized by π is preferable. In the oral composition of the invention, the component (8) is a total amount of the composition of the above, preferably from i to 30% by weight, preferably from 2 to 2%, and more preferably from 3 to 15% by weight. % 'extra good is 5 to 13%. The compounding ratio of the organic acid to the organic acid salt in the above component (8) is relative to: organic acid! The parts by weight of the 'organic acid salt are preferably y. (1) parts by weight: ^ It is considered that the organic acid salt is 0.2 to 5 liters relative to 1 part by weight of the organic acid: 'more desirably 1 part by weight relative to the organic acid 〇 6重量份。 5 parts by weight.疋 , this as the component (8) is a combination of citric acid and citrate. Two = 1 ^ is equivalent to 15 to 85% of citric acid, more preferably 70% by weight. The compounding ratio of the organic acid to the organic acid salt in the component of the cross-tr) can also be as broad as possible for the organic acid 1 molar organic acid salt. Preferably, the ratio of the organic acid salt is from 0.35 to 3 moles with respect to the organic acid 1 mole, and the organic acid salt is more preferred than the organic acid oxime. 322082 201043265 In the present invention, the lower alcohol used as the component (c) above refers to an alcohol having 2 to 6 carbon atoms in a straight chain or a branched chain, and is pharmaceutically or foodly acceptable as long as it is within this range. The alcohol can be used without particular limitation. Among them, an alcohol selected from 2 to 4 carbon atoms is preferable, and ethanol is preferable. In the oral composition of the present invention, the component (C) is desirably 10% by weight or more based on the total amount of the composition, more preferably 10 to 50% by weight, still more preferably 10 to 30% by weight, still more preferably 15%. Up to 25% by weight. In addition, the component (C) is required to have a solubility of 10% by weight or more in terms of solubility in the volatility and coolness represented by menthol, but is more volatile and irritating when it is 30% by weight or more. In terms of hobbies, it is not desirable. Further, as shown in the examples described later, in such a concentration, the solubility of the organic acid is lowered, and the prescription of the present invention cannot be completed. In the present invention, examples of the nonionic surfactant used as the component (D) include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters, and maltose. Alcoholic acid esters such as maltitol Q fatty acid esters, lactitol fatty acid esters, polyoxyethylene sorbates such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monostearate A polyoxyethylene fatty acid ester such as a sugar alcohol fatty acid ester, a polyoxyethylene hardened ramie oil, a fatty acid diethanol amide such as lauric acid mono or diethanol decylamine, myristic acid mono or diethanol decylamine, and Yamanashi Sugar alcohol fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene polyoxypropylene fatty acid ester, and the like. Among them, polyoxyethylene hardened ramie oil is ideal, and it is desirable that the additional oxyethylene is 40 or more, and more preferably 60%. 11 322082 201043265 In the oral red form of the present invention, the above component (8) is the total amount of the composition. 1% by weight or more, preferably 〇. work to 1% by weight, preferably 1 to 5 parts by weight. %, more desirably 2 to 5% by weight, particularly desirably 2 to 3% by weight. In the present invention, the trivalent alcohol used as the component (E) is exemplified by glycerin. A trivalent alcohol represented by glycerin is useful for preventing precipitation of menthol or citric acid at a low temperature. The compounding amount of the trivalent alcohol is from 1 to 20% by weight, desirably from 5 to 15% by weight, and more desirably from 5 to 1% by weight. The oral composition of the present invention is an aqueous solution which may be formed by (A) and (B) or may be formed of the above components (A) to (D), or may contain (E) which is suitable for hydrazine. Further, it may be blended in a food hygiene or a pharmaceutically acceptable carrier. Other components such as additives may be appropriately blended as needed. Further, the oral composition of the present invention may contain a hyaluronic acid or a pullulian as the component (F). Hyaluronic acid is preferably a low molecular weight uric acid having an average molecular weight of 50,000 or less. When the above-mentioned low molecular weight hyaluronic acid or pullulan polysaccharide is used, since it is not sticky, it is not used in the form of an oral cooling agent. The blockage of the device can be applied to the spray formulation without selecting a container. In the present invention, since the component contains a stone-defensin promoting action of an organic acid, it also has an effect of inhibiting the dissolution of tooth enamel caused by acid, and is used as an oral care product for maintaining a healthy oral environment. Particularly useful. The blending amount of the low molecular weight hyaluronic acid is desirably 0.1 to 10% by weight, and 321082 12 201043265 is 0.1 to 5% by weight. Plu Lando _ 壬曰. The amount of the θ n s q is expected to be 〇. 〇1 to 5 wt%, ideally 〇· 05 to 3 wt | 曰. More preferably, it is from 0.1 to 1% by weight. The weight ratio of each component contained in the composition for oral cavity of the present invention is 'when the content of the component (A) in the composition is ι, the component (8) is preferably in the range of i to 40, and more preferably 2 Up to 2 inches, particularly ideally in the range of 4 to 15. When the component (A) and the component (B) in the composition are blended and blended at a concentration in the above range, the component (C) is 5 to 80' of the weight compounding amount 1 of the component (A), and preferably 10 to 10 In the range of 60, the component (D) is 1 to 20, preferably 2 to 1 Torr, based on the weight of the component (A). The weight ratio of the component (E) is not particularly limited, and the compounding amount 1 of the component (A) can be appropriately selected in the range of 1 to 20 depending on the form. Similarly, the component (F) is also blended in an amount of 1 for the component (A), and can be suitably selected in the range of from 1 to 20. The characteristics of the oral composition of the present invention are expected to have sufficient effects in a small amount of use. The small amount referred to herein means that it is placed in a range of 0.001 to 10 ml, preferably 0.01 to 5 ml, more preferably in the range of 疋02 to 2 ml, and is not particularly limited as long as it is suitable for a small amount. As a suitable form of the oral composition of the present invention, an oral spray can be exemplified, and the oral spray is used by spraying the liquid composition of the present invention in the oral cavity. The composition for in-oral spray referred to in the present invention is an aqueous solution of the oral composition of the present invention, and is suitable for a composition which can be effectively sprayed in a liquid state at 322082 13 201043265. The spray referred to herein is not particularly limited in terms of droplet size, amount, speed, and the like, and may be directly or indirectly produced. It does not need to be completely foggy, but it can also be used in the form of a spray. When the composition of the present invention is used as an oral spray, a synergistic effect of saliva secretion can be expected due to the combination of peppermint and an organic acid, and therefore it is particularly suitable for use as a mouth moisturizer. Oral humectants are particularly useful for the improvement of symptoms of dry mouth with incomplete saliva secretion. The main symptoms of oral dryness include, for example, dry mouth, tingling tongue, deodorant smell, abnormal taste, and prone to tooth decay or periodontal disease. The composition of the present invention can promote the secretion of saliva, and at the same time promotes the secretion of /3 - defensin by blending with a specific organic acid, and can be expected especially for the tooth, periodontal disease, oral bacterial phase, intraoral inflammation, bad breath or tongue coating. Improvement or treatment is effective. Further, when low molecular hyaluronic acid or the like is added to the composition, it is expected to prevent dissolution of tooth enamel due to acid. Further, in the present invention, the sulfur-containing gas means a sulfur-containing gas, and examples thereof include volatile sulfur compounds such as hydrogen sulfide, sulfonium thiol, carbon sulfide, carbon disulfide, diethyl sulfide, and dimethyl disulfide. The gas which is considered to be a cause of bad breath, for example, may be hydrogen sulfide, methyl mercaptan, dimethyl disulfide or the like. Further, in the present invention, the mineral-toothed bacteria means Streptococcus, Lactobacillus or the like. In addition, caries-related bacteria, in particular, are considered to be representative of streptococcus, among which S. mutans is particularly representative. Further, in the present invention, various additives such as sweeteners, pigments (dyes, pigments), flavoring agents, preservatives, bactericides (antibacterial agents), 14 322082 201043265 tackifiers, antioxidants, metal blocking agents may be further blended. , deodorant, pH adjuster, etc. * As a sweetener, it contains natural sugars such as glucose, galactose, sucrose, or xylitol, synthetic sweeteners such as saccharin, aspartame, etc., among which low is used, such as xylitol. A dental caries sweetener is preferred, but the components described are not limited. Further, another feature of the present invention is that it is not necessary to incorporate a component such as a preservative. According to the present invention, menthol, ethanol, and a high concentration of an organic acid can be used to obtain sufficient long-term stability even without a preservative or a bactericide (antibacterial agent). In particular, it can be sufficiently applied to long-term storage without preserving a preservative such as sodium benzoate which is generally used, and can reduce the blending of unnecessary food additives. Therefore, after the product of the present invention is contained in the oral cavity, it is not necessary to be spit out, and the solution can be taken up in the body. The oral composition of the present invention can exhibit the intended effect in a small amount. For example, the invention has been invented for use as a spray preparation for oral administration, and the like. However, it can be used in the form of another Q oral care product (oral product). When the oral composition of the present invention is in the form of an oral care product (oral product), the form thereof is not particularly limited. Examples thereof include a toothpaste, a mouthwash, an oral gel, a mouthwash, and the like. The composition for intraoral spray of the present invention is not particularly limited as long as the composition of the present invention is sprayed in the oral cavity, but the method of applying the composition of the above (B) is yS-defense. The stimulating action can be effectively expressed. For example, the above component (B) is divided into daily doses of 1 mg or more, desirably 5 to 500 mg, more preferably 5 to 30 mg 15 322082 201043265. 1 to 10 times (usually 2 to 30 mg/time). Further, the oral composition of the present invention can be effectively expressed in order to promote the defensin promoting action of the component (B). After use in the oral cavity, for example, it is desirable to remain in the oral cavity for about 1 second or longer. Ideal. The container to be stored in the oral composition is not particularly limited, but polyethylene terephthalate or glass is preferred. For example, in the case of a polypropylene or a polyethylene container, since the blending component is adsorbed, it is not suitable as a container of the composition. Further, the material which is not frequently contacted, such as a lid, etc., is not particularly limited in its material, and may be made of the above-mentioned polypropylene or polyethylene. [Examples] Hereinafter, the present invention will be described by way of Test Examples and Examples, but the present invention is not limited by these Examples. Example 1 Change in solubility of a composition containing menthol and an organic acid In order to review the suitability of an organic acid in a mouth-cooling agent containing menthol, the ethanol and polyoxyethylene hardened ramie oil were reviewed. The effect of the amount of compounding on the solubility of organic acids. Then, the prescriptions shown in Table 1 were prepared, and the conditions for satisfying sufficient solubility were examined. 16 322082 201043265 ^ [Table 1] Weight% (w/w) Menthol 1 citric acid 7 Ρ 0 Ε Hardened ramie oil 6 0 * 1 to 5 Ethanol 5 to 40 Glycerin 10 Glycol flavors Appropriate amount of spices Refined water remaining total 100 * Polyoxyethylene hardened ramie oil 60* The results obtained are shown in Figure 1. As a result, when the organic acid is blended, the blending amount of the polyoxyethylene hardened ramie oil is in the range of 2% by weight or more, and the solubility of the organic acid is sufficiently exhibited. Further, when the amount of ethanol is in the range of 25% by weight or less, it means that a stable preparation can be prepared. In contrast, when ethanol is blended into the above range, the solubility of menthol is significantly weakened in addition to citric acid, and it is clearly unsuitable as a preparation. Further, when the same test was carried out under the stem of a low concentration thin brain (0.2% by weight), the amount of each component had no effect on the solubility of the polyoxyethylene hardened castor oil. Test Example 2 Review of preservation stability of organic acid blended oral composition The decomposition behavior of polyoxyethylene hardened castor oil in an oral composition containing organic acid was examined. The prescriptions used are shown in Table 2. 17 322082 201043265 [Table 2] Weight % (w/w) Comparative Example 1 Comparative Example 2 Menthol 0. 5 0. 5 Citric acid 3 5 P0E hardened ramie oil 60 3 3 Ethanol 15 15 Glycerin 10 10 Sweetener Appropriate amount of spices, appropriate amount of refined water, and the rest of the total 100 100 prescription preparation method Add citric acid, glycerin, and sweetener to the purified water heated to 80 ° C or higher, stir and dissolve, and then cool to room temperature. Then, the fragrance dissolved in ethanol, menthol, Ε0Ε hardened ramie oil is slowly added to complete the prescription. Further, in the following test examples, unless otherwise specified, the modulation method was used. The in-oral spray composition (Comparative Examples 1 and 2) prepared as described above was separately added to a 3 Om 1 clear glass vial and capped with a screw cap. The vials were stored in a thermostat at 40, 60, and 80 ° C, and the content of the polyoxyethylene hardened Wanma oil was measured every few days to evaluate the preservation stability of the composition. The content of polyoxyethylene hardened ramie oil is determined by a method known in the art using liquid chromatography analysis 18 322082 201043265. * Among the results of Comparative Examples 1 and 2, the results of Comparative Example 2 are shown in Fig. 2. The solubility of menthol and the like can be satisfied when the sputum is just prepared, but after storage, the polyoxyethylene hardened ramie oil is decomposed over time, and it can be seen that menthol is precipitated to cause white turbidity. Again, its decomposition is related to temperature. Further, when stored at 40 ° C, decomposition of polyoxyethylene hardened ramie oil was also observed, indicating that the composition was significantly unstable when the oral composition contained an organic acid. Further, in Comparative Example 1, the same result was obtained. Test 3 Preservation stability of organic acid blended oral composition 2 Effect of change in mixing ratio of citric acid and sodium citrate on preservation stability (change in polyoxyethylene hardened ramie oil content) The test solution (Examples 1 to 3) prepared by the formulation containing citric acid and citrate was prepared by the method described in Test Example 2, and then stored at 80 ° C to evaluate the stability. Further, the measurement of the amount of polyoxyethylene hardened 蓖 q acacia oil was measured by the same method as above. 19 322082 201043265 [Table 3] wt% (w/w) Example 1 Example 2 Example 3 menthol 0. 5 0.5 0. 5 --- citric anhydride 4. 3 3.7 3. 1 Trisodium citrate dihydrate 1.1 2 2. 9 Glycerin 5 5 5 Ρ0Ε Hardened ramie oil fin 3 3 3 Ethanol 15 15 15 Sweeteners Appropriate amount of appropriate amount of spices Right amount Appropriate amount of refined water Total rest of the rest---------- 100 As a result, as shown in Fig. 3, decomposition of polyoxyethylene hardened castor oil was remarkably suppressed by combining citric acid and citrate under severe conditions of 80 °C. From this, it is shown that the decomposition of the polyoxyethylene hardened ramie oil can be suppressed in the mouth-cooling agent containing an organic acid by the appropriate combination of the organic acid and its salt. Test Example 4 Preservation stability evaluation of the composition for spraying in the organic acid blending port 3 Next, in order to confirm whether or not the storage stability of the above Test Example 3 changes with temperature, the spleen will be prescribed in Table 4. The prepared test solution is accompanied by the conditions of 40, 60, and 80 C, and the stability of the test solution is estimated. Further, the amount of polyoxyethylene 322082 20 201043265 olefin-hardened ramie oil was measured by the same method as above. [Table 4] Weight % (w/w) Example 4 Menthol 0. 5 Citric acid 2. 5 Trisodium citrate dihydrate 3. 8 Glycerin 5 Ρ 0 Ε Hardened ramie oil 6 0 3 Ethanol 15 Glycol As a result, as shown in Fig. 4, in Example 4, the polyoxyethylene hardened ramie oil was hardly decomposed at any temperature, indicating that it was a stable prescription. Test Example 5 Preservation stability of the composition for spraying in the organic acid blending port According to the results of the above Test Examples 3 to 4, the compounding amount of citric acid and citrate was additionally set as shown in Table 5 to prepare a test solution, at 40 Store under °C conditions and evaluate its stability. The test solution of Example 3 was also used as a positive control for the test. The amount of polyoxyethylene hardened ramie oil was measured by the same method as above. 21 322082 201043265 [Table 5]
其結果，如第 -圖所示，在實施例3、5、6中，类 = 安:性:實際上。，討長期間保 、 廣;凡採用在40C程度的加速試驗 安定'I月成物’由在此條件下所示的成分保 =的2酸推配Μ —防禦素分 進作用。表Π It實際確認^防禦素的分糾 表6表不供試驗的組成物的處方。 322082 22 201043265 [表6] 重量％(w/w) 實施例7 實施例8 薄何腦 0. 5 0. 5 獰檬酸酐 4 3. 7 擰檬酸三鈉二水合物 6. 1 3. 5 甘油 5 5 P0E硬化蓖麻仔油6 0 3 3 乙醇 15 15 甘味料 適量 適量 香料 適量 適量 精製水 其餘 其餘 合計 100 100 試驗是在安靜下實施。對健康的成年人3名，將上述 的製劑壓喷4次分量（約0. 13g)在口腔内喷霧後，在口腔 内保持1分鐘後，回收唾液。又，為了確認其變化之目的 下，採取在測定前的安靜下的唾液。採取的唾液的人石-防禦素2(hBD2)量，是使用「商品名：-defensin 2，Human, ELISA Kit(Phoenix Pharmaceuticals 公司製）」，遵照所 附的說明書做測定。 其結果，如第6圖所示，在本發明所完成的製劑中， 對前值（pre)，喷霧後（post)可明顯確認/3-防禦素的分泌 促進效果。又，關於清涼感及口臭，也是可得到充分的使 23 322082 201043265 用感的組成物。 本’且成物疋做為噴霧用而製劑的組成物，與漱口水等 其他的口腔保養製品相比，一次的使用適用量極為少量: 雖然如此，可確認有效果，因此可認為是與以往的口中清 凉劑不同的新製劑。 根據下述的表7至9所示的組成，使用試驗例2所記 ώ :周製方法’ 5周製實施例9至11的σ腔用組成物。本組 成物是特料合於做為口中儒使用者。 ㈣例9 σ中噴霧用組成物 [表7] 〜--—--- ~~——-~~~-__ 重量％(w/w) 乙醇 ~--—____ 20 檸檬酸 ^——-- -—~~---- 2 二水合物 —--- ,2 ---~~-____ 1 硬化蓖麻仔油60 —-- 2 甘油 _ 一------ 5 -一- 適量 香料 -—-— -*—1 適量 水 __ ------ 其餘 合計 一 — 100 實施例10 口中喷霧用組成物 322082 24 201043265As a result, as shown in the first figure, in the examples 3, 5, and 6, the class = safety: sex: actually. In the long period of time, the test is carried out; the accelerated test at the 40C level is used to stabilize the 'I month's product' and the two acids are used as the ingredients shown under this condition. Table Π It actually confirms the division of the defensin Table 6 shows the prescription of the composition for the test. 322082 22 201043265 [Table 6] Weight % (w/w) Example 7 Example 8 Thin He Brain 0. 5 0. 5 Citric anhydride 4 3. 7 Trisodium citrate dihydrate 6. 1 3. 5 Glycerin 5 5 P0E Hardened ramie oil 6 0 3 3 Ethanol 15 15 Sweeteners Appropriate amount of spices Appropriate amount of refined water The rest of the total 100 100 The test was carried out under quiet conditions. For 3 healthy adults, the above-mentioned preparation was sprayed 4 times (about 0.13 g) in the oral cavity, and after holding in the oral cavity for 1 minute, saliva was recovered. Further, in order to confirm the change, saliva under quiet before measurement was taken. The amount of the human stone-defensin 2 (hBD2) of the saliva was measured using the "trade name: -defensin 2, Human, ELISA Kit (manufactured by Phoenix Pharmaceuticals)", and the measurement was carried out in accordance with the attached instructions. As a result, as shown in Fig. 6, in the preparation completed by the present invention, the secretion promoting effect of /3-deficiency was clearly confirmed for the pre-value (pre) and post-spray (post). In addition, as for the sense of coolness and bad breath, it is also possible to obtain a composition that is sufficient for 23 322082 201043265. This composition is used as a composition for spraying, and it is used in a small amount compared with other oral care products such as mouthwashes. However, it can be confirmed that it is effective. Different new preparations for the freshener in the mouth. According to the compositions shown in Tables 7 to 9 below, the composition for the sigma chamber of Examples 9 to 11 was prepared by the method of Test Example 2: Weekly Method '5 weeks. This group of products is specially designed as a user in the mouth. (4) Example 9 Composition for sigma spray [Table 7] ~------ ~~——-~~~-__ Weight% (w/w) Ethanol~---____ 20 Citric acid ^——- - -~~~---- 2 Dihydrate---- , 2 ---~~-____ 1 Hardened ramie oil 60 —- 2 Glycerin _ I ------ 5 -1 Appropriate amount of spices-----*-1 The right amount of water__ ------ The rest of the total one - 100 Example 10 The composition of the spray in the mouth 322082 24 201043265
[表8] 重量％(w/w) 乙醇 25 檸檬酸 5 檸檬酸鈉二水合物 2 L-薄荷腦 0. 5 聚氧乙烯硬化蓖麻仔油60 3 低分子玻尿酸 0. 25 甘油 10 甘味料 適量 香料 適量 精製水 其餘 合計 100 實施例11 口中喷霧用組成物 25 322082 201043265 [表9] 重量％(w/w) 乙醇 15 檸檬酸 4 檸檬酸鈉二水合物 3 L-薄荷腦 0. 5 聚氧乙稀硬化蓖麻仔油6 0 2. 5 玻尿酸 0. 2 甘油 10 甘味料 適量 香料 適量 精製水 其餘 合計 100 實施例12 口中喷霧用組成物 26 322082 201043265 ❹ [表 10] 重量％(w/w) 乙醇 15 檸檬酸 3 檸檬酸鈉二水合物 6 L-薄荷腦 0. 5 聚氧乙烯硬化蓖麻仔油60 2. 5 普魯藍多糖 0. 2 甘油 10 甘味料 適量 香料 適量 精製水 其餘 合計 100 27 322082 201043265 實施例14 口中喷霧用組成物 [表 11 ] 重量％(w/w) 乙醇 20 檸檬酸 4 檸檬酸鈉二水合物 7 L-薄荷腦 0. 5 聚氧乙烯硬化蓖麻仔油60 3 普魯藍多糖 0. 1 玻尿酸 0. 1 甘油 12 甘味料 適量 香料 適量 精製水 其餘 合計 100 試驗例7 口中喷霧用組成物的評估試驗 調製本發明製劑的口中喷霧用組成物，評估其對口臭 的抑制效果為目的，以健康正常成年人為對象，做為主評 估項目而測定口臭氣體，及做為副評估項目而測定口腔内 細菌數。 (口中喷霧試驗液） 將薄荷腦0. 5%、檸檬酸2. 8%及檸檬酸鈉6. 4°/。配合， 其他摻配適量的甘油、聚氧乙稀硬化蓖麻仔油、乙醇、甘 28 322082 201043265 味料、香料，而製作本發明製劑的口中喷霧試驗液。 1 (試驗液的給藥方法） 對健康正常成年人12名（年齡·· 41±2.4歲），將試驗 液每次4壓喷（約0. 15g)，1日5次、噴霧給藥3週。各試 驗液在給藥後保持在口腔内1分鐘。 1曰的給藥時間是，第1次在早餐後，之後每隔2至3 小時給藥共計5次。 (測定項目、測定樣本採取及測定） ° (1) 口臭氣體 測定樣本採取時期：給藥開始前，及給藥開始1、2、 3週後。 採取及測定方法：測定裝置是使用口臭測定器 breathtron(Yoshida公司，型式BT-814)，遵照該裝置的 使用方法採取口臭氣體，測定揮發性含硫化合物的濃度。 (2) 口腔内細菌數（齲齒、牙周病關連菌） q 測定樣本採取時期：給藥開始前（pre)及給藥開始3週 後（post)。 採取及測定方法：測定裝置是使用BML公司製齒科檢 查服務的唾液採取工具箱，遵照該裝置的使用方法回收咀 嚼刺激唾液，測定乳酸桿菌（LB菌）及轉糖鏈球菌的菌數。 轉糖鏈球菌的測定是對供驗者9人實施。 (結果） 將口臭的結果示於第7圖，將口腔内細菌數的結果中 的乳酸桿菌的結果表示於第8圖，轉糖鏈球菌的結果表示 29 322082 201043265 於第9圖。圖中所示是供試驗者全員的結果平均值。 口臭氣體的試驗中，由於使用本申請案的口中喷霧用 組成物，而觀察到口臭原因的揮發性含硫化合物的濃度隨 時間的經過而減少。 口腔内細菌數的試驗中，也由於使用本申請案的口中 喷霧用組成物，而觀察到口腔内的鑛齒、牙周病的原因菌 的減少。 【圖式簡單說明】 第1圖表示在試驗例1中，乙醇及聚氧乙烯硬化蓖麻 仔油的配合量對有機酸的溶解性的影響。 第2圖表示在試驗例2中，含5%的有機酸的組成物中， 聚氧乙烯硬化蓖麻仔油的安定性隨時間變化的情形。 第3圖表示在試驗例3中，在檸檬酸、檸檬酸鈉的混 合組成物中，聚氧乙烯硬化蓖麻仔油的安定性隨時間變化 的情形。 第4圖表示在試驗例4中，在檸檬酸、檸檬酸鈉的混 合組成物中，在不同保存溫度下的聚氧乙烯硬化蓖麻仔油 的安定性隨時間變化的情形。 第5圖表示在試驗例5中，口中喷霧用組成物的保存 安定性。 第6圖表示在試驗例6中，口中喷霧用組成物對yS-防禦素2的分泌促進作用。 第7圖表示在試驗例7中，本申請案的口中喷霧對口 臭氣體之抑制效果。圖中，「VSC」表示揮發性含硫化合物 30 322082 201043265 (volatile sulfur compounds)的濃度。 第8圖表示在試驗例7中，本申請案的口中喷霧對乳 酸桿菌（LB菌）的抑制作用。圖中「CFU」表示菌落形成單 位（colony-forming unit) ° 第9圖表示在試驗例7中，本申請案的口中噴霧對轉 糖鏈球菌的抑制效果。圖中「CFU」表示菌落形成單位 (colony-forming unit) 〇 【主要元件符號說明】 〇 . 〇 31 322082[Table 8] wt% (w/w) Ethanol 25 Citric acid 5 Sodium citrate dihydrate 2 L-menthol 0. 5 Polyoxyethylene hardened ramie oil 60 3 Low molecular weight hyaluronic acid 0. 25 Glycerin 10 Glycyrrhizin Appropriate amount of flavoring amount of refined water remaining total 100 Example 11 Oral spray composition 25 322082 201043265 [Table 9] Weight % (w / w) Ethanol 15 Citric acid 4 Sodium citrate dihydrate 3 L - menthol 0. 5 Polyoxyethylene hardened ramie oil 6 0 2. 5 hyaluronic acid 0.2 glycerin 10 sweetener appropriate amount of spices appropriate amount of refined water remaining total 100 Example 12 Oral spray composition 26 322082 201043265 ❹ [Table 10] Weight% ( w/w) Ethanol 15 Citric acid 3 Sodium citrate dihydrate 6 L-Menthol 0. 5 Polyoxyethylene hardened ramie oil 60 2. 5 Pullulan polysaccharide 0. 2 Glycerin 10 Sweeteners Water remaining total 100 27 322082 201043265 Example 14 Oral spray composition [Table 11] Weight % (w / w) Ethanol 20 Citric acid 4 Sodium citrate dihydrate 7 L - menthol 0. 5 Polyoxyethylene hardening Ramie oil 60 3 Blue polysaccharide 0.1 chlorouric acid 0. 1 glycerin 12 sweetener appropriate amount of flavor appropriate amount of refined water remaining total 100 Test Example 7 Evaluation of the composition for spray in the mouth The composition of the spray in the mouth of the preparation of the present invention was prepared to evaluate the bad breath. For the purpose of suppressing the effect, the healthy and normal adults are used as the main evaluation item to measure the bad breath gas, and the number of bacteria in the oral cavity is measured as a secondary evaluation item. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. In combination, an appropriate amount of glycerin, polyoxyethylene hardened ramie oil, ethanol, glycerin 28 322082 201043265 flavoring materials, spices, and the preparation of the oral spray test solution of the preparation of the present invention. 1 (Method of administration of test solution) For 12 healthy adults (age 41±2.4 years old), test solution is sprayed 4 times (about 0.15g), 5 times a day, spray 3 week. Each test solution was kept in the oral cavity for 1 minute after administration. The administration time of 1 是 is the first time after breakfast, and then every 5 to 3 hours after administration for a total of 5 times. (Measurement items, measurement sample take and measurement) ° (1) Bad breath gas Measurement sample take-up period: before the start of administration, and after 1, 2, and 3 weeks from the start of administration. Adoption and measurement method: The measurement device was a breath odor meter (Yoshida Co., Ltd., model BT-814), and a bad breath gas was taken in accordance with the method of using the device to measure the concentration of the volatile sulfur-containing compound. (2) Number of bacteria in the mouth (caries, periodontal disease related bacteria) q The sample taking period is measured: before the start of administration (pre) and after 3 weeks from the start of administration (post). Adoption and measurement method: The measurement device is a saliva-using kit using the dental examination service of BML, and the chewing stimulation saliva is recovered in accordance with the method of use of the device, and the number of bacteria of Lactobacillus (LB bacteria) and S. subtilis is measured. The determination of S. suis was performed on 9 subjects. (Results) The results of the bad breath are shown in Fig. 7, and the results of the Lactobacillus in the results of the number of bacteria in the oral cavity are shown in Fig. 8, and the results of the S. subtilis are shown in Fig. 9 of 29 322082 201043265. The figure shows the average of the results for all the testers. In the test of the bad breath gas, the concentration of the volatile sulfur-containing compound which causes the bad breath was observed to decrease with the passage of time by using the composition for oral spray application of the present application. In the test for the number of bacteria in the oral cavity, the use of the composition for oral spray in the present application also observed a decrease in the cause of the mineral tooth and periodontal disease in the oral cavity. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the influence of the blending amount of ethanol and polyoxyethylene hardened castor oil on the solubility of an organic acid in Test Example 1. Fig. 2 is a view showing the case where the stability of the polyoxyethylene hardened ramie oil was changed with time in the composition containing 5% of the organic acid in Test Example 2. Fig. 3 is a view showing the case where the stability of the polyoxyethylene hardened ramie oil was changed with time in the mixed composition of citric acid and sodium citrate in Test Example 3. Fig. 4 is a view showing the case where the stability of the polyoxyethylene hardened ramie oil at different storage temperatures was changed with time in the mixed composition of citric acid and sodium citrate in Test Example 4. Fig. 5 is a view showing the storage stability of the composition for spray in the mouth in Test Example 5. Fig. 6 is a view showing the secretion promoting action of the composition for intraoral spray on yS-defensin 2 in Test Example 6. Fig. 7 is a view showing the inhibitory effect of the spray in the mouth of the present application on the bad breath gas in Test Example 7. In the figure, "VSC" indicates the concentration of volatile sulfur compounds 30 322082 201043265 (volatile sulfur compounds). Fig. 8 is a view showing the inhibitory action of the oral spray of the present application on Lactobacillus (LB bacteria) in Test Example 7. In the figure, "CFU" indicates a colony-forming unit. Fig. 9 is a view showing the inhibitory effect of the spray in the mouth of the present application on S. mutans in Test Example 7. In the figure, "CFU" means a colony-forming unit 〇 [Description of main component symbols] 〇 . 〇 31 322082