TWI313597B

TWI313597B - Compositions for transmucosal administration containing coeneyme q as the ingrediet

Info

Publication number: TWI313597B
Application number: TW91114681A
Authority: TW
Inventors: Kenji Fujii; Kawabe Taizo; Kazunori Hosoe
Original assignee: Kaneka Corp
Priority date: 2002-05-01
Filing date: 2002-07-02
Publication date: 2009-08-21

Description

A7 1313597 五、發明說明（ί ) [技術領域] 本發明係關於一種以輔酶Q爲有效成分之黏膜投予用組成物。 [背景技術] 輔酶Q係一種廣泛分布從細菌到哺乳動物等活體之必需成分。輔酶Q除了在活體內反覆進行氧化還原以發揮其作爲電子傳遞系之傳遞成分功能外，還原型輔酶Q亦爲一種抗氧化物質。以人類爲首之多種動物或魚或鳥，係以輔酶Q之側鏈具有10個重覆構造之輔酶Q!◦爲主成分，且已知活體中通常有40〜90%左右之輔酶Q1()是以還原型存在。輔酶Q因係活體內可生物合成者故不能列入維他命類，但實際上被認爲和維他命相同。又人類中輔酶Q1G之生物合成隨年齢增加其能力會下降並且活體內之含量減少，故被提倡應有以某種形式補給之必要性。輔酶Qi。中氧化型輔酶Q!。被作爲充血性心功能衰竭藥用於醫藥用途，此外，醫藥用途以外其與維他命一樣使用爲營養劑、營養補助劑，或對過敏性疾病之有效性、運動能力增加等廣泛領域之有效性亦已被報導。且，因對癡呆症等與腦有關之疾病的有效性亦被報導，故被預想爲對於高齢者很有用的物質。輔酶Q1G之有用性很高且已使用動物進行安全性試驗，用大鼠以每日1.2g/kg之高投予量連續投予52週亦被認爲完全沒有毒性，已被證明爲一種高安全性之化合物（J. ____3_._ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 爹訂---------^ 1313597 A7 B7 五、發明說明（> )A7 1313597 V. [Description of the Invention] [Technical Field] The present invention relates to a composition for administration of a mucous membrane having coenzyme Q as an active ingredient. [Background Art] Coenzyme Q is a necessary component for widely distributing living organisms such as bacteria and mammals. Coenzyme Q is also an antioxidant substance in addition to its redox effect in vivo to exert its function as a transport component of the electron transport system. A variety of animals or fish or birds, including humans, have a coenzyme Q!◦ with 10 repetitive structures in the side chain of Coenzyme Q, and it is known that there are usually 40 to 90% of coenzyme Q1 in living organisms ( ) exists in a reduced form. Coenzyme Q cannot be listed as a vitamin because it is biosynthesized in vivo, but it is actually considered to be the same as vitamins. In addition, the biosynthesis of coenzyme Q1G in humans decreases with the increase of its ability and decreases in vivo, so it is advocated that it should be replenished in some form. Coenzyme Qi. Medium oxidized coenzyme Q!. It is used as a congestive heart failure medicine for medical purposes. In addition to its use in medicine, it is used as a nutrient or nutrient supplement in addition to vitamins, or it is effective in a wide range of areas such as the effectiveness of allergic diseases and increased exercise capacity. Has been reported. Furthermore, since the effectiveness of brain-related diseases such as dementia has also been reported, it is expected to be a substance that is useful for sorghum. Coenzyme Q1G is highly useful and has been tested for safety in animals. Continuous administration of rats at a daily dose of 1.2 g/kg for 52 weeks is considered to be completely non-toxic and has been shown to be a high Safety Compound (J. ____3_._ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ------ ---^ 1313597 A7 B7 V. Description of the invention (> )

Agric. Food Chem. 1999 Vol. 47p3756-3763)。但，糸至□投予以外之投予途徑則只有皮膚用劑被實際使用，對經口攝取有困難之重症疾病患者或是高齡者、幼兒，要投予在事實上是有困難的。又，對容易變成過敏患者的患部之腸管、鼻、耳等局部，經口投予無法得到足夠之輔酶Q濃度’ 是以現實上無法有效利用輔酶Q。發明之要旨本發明之目的爲提供一種製劑，該製劑以輔酶Q爲有效成分，且對經口攝取有困難之患者或是老人容易使用’ 或對於無法得到足夠濃度之局部可有效供給輔酶Q。本發明者等爲解決上述課題進行硏究結果，發現藉利用黏膜吸收可使輔酶Q被吸收至活體內。並且發現，該輔酶Q製劑因使用含有還原型輔酶Q之組成物，與僅含有氧化型輔酶Q之組成物比較，明顯可得到高血中濃度。又’ 亦發現藉利用黏膜吸收，可有效將輔酶Q送達至局部。即，本發明爲一種以下式（1) (請先閱讀背面之注意事項再填寫本頁)Agric. Food Chem. 1999 Vol. 47p3756-3763). However, it is only in the case that the dermatological agent is actually used, and it is difficult to administer a severely ill patient or an elderly person or a child who has difficulty in taking it by mouth. Further, in the case of the intestines, the nose, the ear, etc., which are likely to become allergic patients, it is impossible to obtain sufficient coenzyme Q concentration by oral administration. Disclosure of the Invention An object of the present invention is to provide a preparation which is Coenzyme Q as an active ingredient and which is easy to use for a patient who is suffering from oral ingestion or an elderly person, or which is effective for supplying Coenzyme Q to a portion where a sufficient concentration cannot be obtained. In order to solve the above problems, the inventors of the present invention have found that coenzyme Q can be absorbed into a living body by utilizing mucosal absorption. Further, it was found that the coenzyme Q preparation was significantly higher in blood concentration than the composition containing only the oxidized coenzyme Q by using a composition containing reduced coenzyme Q. Also, it has been found that by using mucous membrane absorption, coenzyme Q can be effectively delivered to the local area. That is, the present invention is a following formula (1) (please read the notes on the back and then fill out this page)

I ϋ 一3’ I 1— a— 1· n «I I 〇I ϋ a 3' I 1 — a — 1· n «I I 〇

'CH2-C=C-CH2-)-H η k ch3 ⑴ (式中’ n表示1〜12之整數)所表示之氧化型輔酶Q，及/或下式(2) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1313597 五、發明說明（ 0H CH3〇>v^k/CH3 (2) CH;0' CH3 -ch;-c=c-ch2·'CH2-C=C-CH2-)-H η k ch3 (1) (wherein 'n represents an integer from 1 to 12) is represented by the oxidized coenzyme Q, and/or the following formula (2) Standard (CNS) A4 specification (210 X 297 mm) 1313597 V. Description of invention (0H CH3〇>v^k/CH3 (2) CH; 0' CH3 -ch;-c=c-ch2·

OH k (式中，n表示1〜12之整數)所表示之還原型輔酶Q爲有效成分之黏膜投予用組成物，爲一種組成物全量中前述氧化型輔酶Q及還原型輔酶Q合計比例爲〇.0001〜99重量％之黏膜投予用組成物。該組成物可作爲適用於人者，亦可作爲適用於動物者。動物比如有狗、貓等寵物或賽馬等牛、馬、豬、羊、大鼠、家鼠等家畜、鳥等。本發明中，「黏膜投予用組成物」係指具有用以透過黏膜吸收至體內所製造之形態之組成物。本發明中’ 「黏膜」指腸、鼻腔黏膜、口腔黏膜、耳內黏膜、***黏膜等又，本發明亦爲一種將上述黏膜投予用組成物應用於人或動物黏膜所構成之將輔酶Q送達活體內的方法。又’ 本發明亦爲一種將上述黏膜投予用組成物應用於患病的人或動物黏膜所構成之疾病治療方法。應用時之條件依組成物之形態，可使用通常已知之條件，比如爲栓劑時，以每日1次使用含有輔酶Q之栓劑較佳。此情形下輔酶Q之含量以30mg以上，100mg以下爲較佳，更佳爲50mg以上， 100mg以下。爲點眼劑或點鼻劑時，以每日2〜3次次使用含有輔酶Q之點眼劑或點鼻劑較佳。此情形下，輔酶Q之含量以0.01重量％以上，10重量％以下爲較佳，更佳爲本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁)OH k (wherein, n represents an integer of 1 to 12), wherein the reduced coenzyme Q is an active ingredient of a composition for mucosal administration, and the total ratio of the oxidized coenzyme Q and the reduced coenzyme Q in a total amount of the composition is It is a composition for administration of a mucous membrane of 0.001 to 99% by weight. The composition can be applied to humans as well as to animals. Animals include dogs, cats and other pets or horses, horses, pigs, sheep, rats, house mice and other livestock and birds. In the present invention, the "mucosal administration composition" means a composition having a form which is absorbed into the body through the mucosa. In the present invention, the term "mucosa" refers to the intestinal mucosa, the oral mucosa, the oral mucosa, the intra-oral mucosa, the vaginal mucosa, and the like. The present invention also provides a coenzyme Q which is composed of the above-mentioned mucosal administration composition applied to human or animal mucosa. The method of delivery to the living body. Further, the present invention is also a method for treating a disease comprising the above-mentioned composition for administration of a mucous membrane applied to a diseased human or animal mucosa. The conditions at the time of application may be those conventionally known depending on the form of the composition. For example, when a suppository is used, it is preferred to use a suppository containing Coenzyme Q once a day. In this case, the content of the coenzyme Q is preferably 30 mg or more and 100 mg or less, more preferably 50 mg or more and 100 mg or less. In the case of an eye drop or a nasal spray, it is preferred to use an eye drop or a nasal spray containing Coenzyme Q 2 to 3 times a day. In this case, the content of the coenzyme Q is preferably 0.01% by weight or more and 10% by weight or less, more preferably the Chinese National Standard (CNS) A4 specification (210 X 297 mm) for the paper scale (please read the back side first) Please fill out this page again)

A7 1313597 ____B7 _ 五、發明說明（屮） 0.1重量％以上，3重量％以下。發明之詳細揭示以下詳述本發明。上式（1)所表示之化合物爲氧化型輔酶Q，上式(2)所表示者爲還原型輔酶Q。氧化型輔酶Q及還原型輔酶Q之取得方法不特別限定，比如，可採用合成、發酵、天然物萃取等先前周知的方法得到輔酶Q之後，藉色層分析法濃縮沖提液中之氧化型輔酶Q區或還原型輔酶Q區的方法等。此情形下欲得到還原型輔酶Q時，依需要對上述輔酶Q亦可添加硼氫化鈉、連二亞硫酸鈉等一般性還原劑，並以常法使上述輔酶Q中所含之氧化型輔酶Q還原成還原型輔酶Q後，以色層分析法進行濃縮。又，亦可使用以上述還原劑對既有之高純度輔酶Q作用之方法。本發明中可使用之氧化型輔酶Q及還原型輔酶Q如前述式（1)及式(2)中所示，可使用側鏈之重覆單位(式中η)爲 ^12個者，其中又以重覆單位爲10個者，即氧化型輔酶 Q10及還原型輔酶Q1Q爲特別較佳可使用者。本發明之組成物中輔酶Q之含量，可依用途、劑型等適當決定，但組成物全量中氧化型輔酶Q及還原型輔酶Q 合計所占比例之下限爲(僅含還原型輔酶Q時，爲組成物全量中還原型輔酶Q所占之比例)爲0.0001重量％，上限爲 99重量％。較佳値之下限爲0.005重量％，較佳値之上限 ______6___ 本紙張尺度適用中國國家標準（CNS)A4i格（210 X 297公愛^ (請先閲讀背面之注意事項再填寫本頁) 訂---------線_ 1313597 a7 B7 j-------------— 五、發明說明（ζ) 爲50重量％。更佳値之下限爲0·01重量％，更佳値之上限爲30重量％。又’本發明之組成物同時含有氧化型輔酶Q及還原型輔酶Q二者時，氧化型輔酶Q及還原型輔酶Q合計量中還原型輔fe Q之比例以超過20重量％較佳。更佳爲40重量 %以上。上述比例之上限只要爲100重量％以下即可，以不滿100重量％爲較佳，98重量％以下更佳。本發明之黏膜投予用組成物依其投予路徑可製劑化爲栓劑、***栓劑、點鼻劑、點耳劑、口腔黏膜貼附劑、牙膏、錠劑、點滴劑、***劑、口腔內溶解劑等形態。各該等製劑可倂用通常使用之製劑添加物，用先前已知之方法藉製劑化製造。製劑爲栓劑時之製劑添加物，比如有依索卡卡歐(花王社製）、午依貼布索耳(依魯司社製）、撒波塞耳(喀貼佛謝社製）、法馬索耳（日本油脂社製）、馬沙耶士塔納利姆(修司社製）、奴巴η合(漢客耳社製）、SB基劑(太陽油脂社製)等半合成硬化油類，可可脂、掠欄脂、棕欄核油、椰子油、精觀椰子油、豬脂等天然油脂類，羊毛脂、還原含水羊毛脂等蠘類，凡士林、角黨燦、角黨:院、液體石蠟等烴類，月桂醇、鯨蠟醇、硬脂醇等高級醇類，硬脂酸丁酯、丙二酸二月桂酯等脂肪酸酯類，三油精、三硬脂酸甘油酯等甘油中長鏈殘酸酯類，甘油乙醯基乙酸酯等甘油取代竣酸酯類、馬可洛構(maCr〇g〇1)、鯨蠟基馬可洛構等聚乙二醇及宜衍生物等。、尺度適用中國國家標準（cns)a!^~^y〇"x 2977公愛)--------- f請先閱讀背面之注意事項再填寫本頁}A7 1313597 ____B7 _ V. Description of the invention (屮) 0.1% by weight or more and 3% by weight or less. DETAILED DESCRIPTION OF THE INVENTION The present invention is described in detail below. The compound represented by the above formula (1) is an oxidized coenzyme Q, and the above formula (2) represents a reduced coenzyme Q. The method for obtaining the oxidized coenzyme Q and the reduced coenzyme Q is not particularly limited. For example, after the coenzyme Q is obtained by a conventionally known method such as synthesis, fermentation, or natural extract, the oxidized form in the extract is concentrated by chromatography. A method of a coenzyme Q region or a reduced coenzyme Q region. In this case, in order to obtain reduced coenzyme Q, a general reducing agent such as sodium borohydride or sodium dithionite may be added to the above coenzyme Q as needed, and the oxidized coenzyme Q contained in the above coenzyme Q may be reduced by a usual method. After the reduced coenzyme Q is formed, it is concentrated by chromatography. Further, a method of applying the above-mentioned reducing agent to the existing high-purity coenzyme Q can also be used. As shown in the above formulas (1) and (2), the oxidized coenzyme Q and the reduced coenzyme Q which can be used in the present invention can be used as a repeating unit of the side chain (where η) is ^12, wherein Further, it is particularly preferable that the oxidized coenzyme Q10 and the reduced coenzyme Q1Q are used in a repeating unit of 10. The content of the coenzyme Q in the composition of the present invention can be appropriately determined depending on the use, the dosage form, etc., but the lower limit of the proportion of the total amount of the oxidized coenzyme Q and the reduced coenzyme Q in the total amount of the composition is (only when the reduced coenzyme Q is contained, The proportion of the reduced coenzyme Q in the total amount of the composition was 0.0001% by weight, and the upper limit was 99% by weight. The lower limit of the preferred crucible is 0.005 wt%, preferably the upper limit of the crucible ______6___ This paper scale applies to the Chinese National Standard (CNS) A4i grid (210 X 297 public love ^ (please read the back note before filling this page) --------- Line _ 1313597 a7 B7 j------------- — V. Description of the invention (ζ) is 50% by weight. The lower limit of the better 値 is 0·01 The upper limit of the weight %, more preferably, is 30% by weight. Further, when the composition of the present invention contains both the oxidized coenzyme Q and the reduced coenzyme Q, the oxidized coenzyme Q and the reduced coenzyme Q total amount are reduced. The ratio of fe Q is preferably more than 20% by weight, more preferably 40% by weight or more, and the upper limit of the above ratio may be 100% by weight or less, preferably less than 100% by weight, more preferably 98% by weight or less. The mucosal administration composition of the invention can be formulated into a suppository, a vaginal suppository, a nasal spray, an ear locus, an oral mucosa patch, a toothpaste, a lozenge, a drip, a buccal agent, or an oral cavity according to the route of administration thereof. Forms such as a solubilizing agent, etc. Each of these preparations may be prepared by a conventionally known method by using a preparation additive which is usually used. Manufactured as a suppository preparation, such as Isocacao (made by Kaosha), Nobuntsu (made by Essex), Sapossel (made by Kasei Co., Ltd.) Semi-synthetic hardening such as Famasol (manufactured by Nippon Oil & Fats Co., Ltd.), Masai Tanalim (manufactured by Shusei Co., Ltd.), Nuba η (manufactured by Hankee), and SB base (made by Sun Oil Co., Ltd.) Oils, cocoa butter, grazing fat, palm oil, coconut oil, refined coconut oil, pig fat and other natural oils, lanolin, reduced water-containing lanolin and other mites, Vaseline, Jiao Dangcan, Jiaofang: Hydrocarbons such as hospitals and liquid paraffin, higher alcohols such as lauryl alcohol, cetyl alcohol and stearyl alcohol, fatty acid esters such as butyl stearate and dilauryl malonate, triolein and glyceryl tristearate Long-chain residual acid esters such as glycerol, glycerol-substituted phthalic acid esters such as glyceryl acetoxyacetate, glycerol (maCr〇g〇1), cetyl Marcolin and other polyethylene glycols Suitable derivatives, etc., scale applicable to Chinese national standards (cns) a!^~^y〇"x 2977 public love)--------- f Please read the notes on the back and fill out this page }

A7 1313597 ____ B7_________ 五、發明說明（t) 又，製劑爲點鼻劑時之製劑添加物’比如有生理食鹽水，作爲緩衝劑之乳酸鹽系緩衝劑、醋酸鹽系緩衝劑、磷酸鹽系緩衝劑等，做爲殺菌防腐劑之對羥基苯甲酸酯、丙二醇、苄乙銨、烷基二甲基苄基氯化銨、山梨酸或其鹽，氯丁醇等，作爲增稠劑之聚乙烯醇、聚乙烯基咯酮、葡聚糖、藻酸金屬鹽、蔗糖、明膠、甲基纖維素、透明質酸金屬鹽等，作爲粉末投予用基劑之結晶纖維素、0C-纖維素、交聯化羧基甲基纖維素鈉、羥基丙基纖維素、β-環狀糊精、二甲基-β-環狀糊精、乳糖等。又，本發明之組成物中可含有適用於其各自形態及目的之吸收促進劑。本發明之黏膜投予用組成物可使用爲醫藥。此情形下治療之疾病比如有痔瘡、潰瘍性大腸炎、克隆氏病 (Crohn’s disease)、心疾病、腦疾病、腦梗塞、糖尿病、糖尿病性網膜症、心肌梗塞、過敏性鼻炎、花粉症、結膜炎、齒肉炎、齒槽膿漏等。此情形下亦可含有輔酶Q以外之其他藥用成分。如本發明之栓劑可含有痔瘡、潰瘍性大腸炎、克隆氏病等腸疾病通常使用之藥劑，或者解熱鎭痛藥、營養補助劑等以全身爲對象之物質。如本發明之點鼻劑可含有過敏性鼻炎或花粉症通常使用之藥劑。如本發明之牙膏可含有齒肉炎或齒槽膿漏通常使用之藥用成分等成分。 _____8_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂---------線j A7 1313597 _________B7____ 五、發明說明（7 ) 本發明之黏膜投予用組成物亦可用於營養補給。此情形下亦可含有輔酶Q以外之其他營養補助成分。上述營養補助成分比如有維他命類、生藥萃取物、藥草萃取物、多酚類、蜂膠等。用以實施發明之最佳形態以下舉實施例及製劑例對本發明作更詳細說明，但本發明不限定於該等實施例。 (實施例1)。 (1) 檢體試料1之調製將氧化型輔酶Q1Glg於50°c水浴上使熔解後，添加馬可洛構lOOO(PEGlOOO)使成爲10ml。將其於5(TC下均質的熔融混合，於室溫使固化得到直徑約5mm之圓柱狀栓劑。 (2) 檢體試料2之調製將還原型輔酶Q1()lg(含有5%之氧化型輔酶Q1Q於5〇 °C水浴上使熔解後，同樣添加已溶解之馬可洛構 1000(PEG1000)使成爲l〇ml。將其於50°C下均質的熔融混合，於室溫使固化得到栓劑。栓劑中還原型輔酶Q1Q之比例爲輔酶Q1()全量之95%，且調製時沒有觀察到氧化。 (3) 經黏膜吸收試驗使用檢體試料1及2作爲試驗試料。試驗以禁食1晚之雄性威士達(Wistar)品系大鼠(體重250〜300g)進行。將檢體試料1或檢體試料2以lg/kg之比例分別***大鼠的直腸。***之後，隨時間採血並定量血漿中之輔酶Q1Q量。 __________9 __ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)A7 1313597 ____ B7_________ V. INSTRUCTION DESCRIPTION (t) In addition, the preparation is a preparation for the preparation of a nasal spray, such as a physiological saline solution, a lactate buffer as a buffer, an acetate buffer, and a phosphate buffer. Agent, etc., as a bactericidal preservative, parabens, propylene glycol, benzethonium chloride, alkyl dimethyl benzyl ammonium chloride, sorbic acid or its salts, chlorobutanol, etc., as a thickener Vinyl alcohol, polyvinyl ketone, dextran, metal alginate, sucrose, gelatin, methyl cellulose, hyaluronic acid metal salt, etc., as a powder for the administration of crystalline cellulose, 0C-cellulose , cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, β-cyclodextrin, dimethyl-β-cyclodextrin, lactose and the like. Further, the composition of the present invention may contain an absorption enhancer suitable for its respective form and purpose. The composition for administration of a mucosa of the present invention can be used as a medicine. The diseases treated in this case include acne, ulcerative colitis, Crohn's disease, heart disease, brain disease, cerebral infarction, diabetes, diabetic retinopathy, myocardial infarction, allergic rhinitis, hay fever, conjunctivitis. , dentitis, alveolar pus and so on. In this case, other medicinal ingredients other than Coenzyme Q may also be contained. The suppository of the present invention may contain a drug which is usually used for intestinal diseases such as acne, ulcerative colitis, and Crohn's disease, or a substance which is mainly used for the whole body such as an antipyretic analgesic or a nutritional supplement. The nasal spray according to the present invention may contain an agent commonly used for allergic rhinitis or hay fever. The toothpaste according to the present invention may contain a component such as a medicinal component which is usually used for tetanitis or alveolar pyorrhea. _____8_ This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Order --------- Line j A7 1313597 _________B7____ V. Disclosure of the Invention (7) The composition for administration of a mucous membrane of the present invention can also be used for nutritional supplementation. In this case, other nutritional supplements other than Coenzyme Q may also be included. The above nutritional supplements include, for example, vitamins, crude drug extracts, herb extracts, polyphenols, propolis, and the like. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below with reference to examples and examples, but the invention is not limited to the examples. (Example 1). (1) Preparation of sample sample 1 After the oxidized coenzyme Q1Glg was melted on a 50 ° C water bath, Marcolo 100 (PEG 100) was added to make 10 ml. The mixture was homogenized and melted at 5 (TC), and solidified at room temperature to obtain a cylindrical suppository having a diameter of about 5 mm. (2) Modification of sample sample 2 Reduced coenzyme Q1 () lg (containing 5% of oxidized form) After coenzyme Q1Q was melted on a 5 ° C water bath, the dissolved Marcolin 1000 (PEG 1000) was also added to make l〇ml, which was homogeneously melt-mixed at 50 ° C and solidified at room temperature. Suppository. The ratio of reduced coenzyme Q1Q in the suppository was 95% of the total amount of coenzyme Q1(), and no oxidation was observed during the preparation. (3) Samples 1 and 2 were used as test samples in the mucosal absorption test. One-night male Wistar strain rats (body weight: 250 to 300 g) were inserted into the rat rectum at a ratio of lg/kg, respectively. After the insertion, blood was collected over time. And quantify the amount of coenzyme Q1Q in plasma. __________9 __ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

表1 1313597 μ B7 五、發明說明（方）血漿中之輔酶Qw量表示於表1。各値爲n=10之平均値土標準偏差。時間血漿中輔酶Qio量㈣如）含氧化型輔酶Qio 含還原型輔酶Q10 之栓劑之栓劑 0 12.88±1.94 13.79±1.34 (100) · (1〇〇) 1 11.67+2.33 14.86±1.89 (91) _ (108) 2 18.51±4.56 17.68+3.55 (144*) 028) 4 15.96±3.61 21.55±4.61 (124) _ (156*) 8 15.63±3.30 37.61±4.88 (121) _ (272***) 12 14.75±2.99 46.11±6.09 (115) (334***) 24 11.37±1.87 28.64±5.50 (88) (207***) *p<0.05，**p<0_01，***p<0.〇〇l， Student-t test 如上，可知將輔酶Q1q製成栓劑實施經黏膜投予’可使血漿中之輔酶Q1Q量增加。該結果表示難溶且唯有經口攝取方法之輔酶Qio，即使在經口攝取有困難時，仍可藉經黏膜投予來供給。更令人驚訝的是，含95%還原型輔酶 Qio之輔酶Qio製成之栓劑，相較於含100%還原型輔酶Qi〇者，可增加較多血漿中之輔酶Q1()量，判斷對於活體之輔酶Q1。補給更加良好。 (實施例2)黏膜移行性試驗與實施例1同樣，製作含還原型及氧化型輔酶Q10之栓劑。用本栓劑對大鼠大腸黏膜之輔酶Qiq移行性進行評本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -1!!1 訂·! 線，表2 1313597 A7 __B7 五、發明說明（Ό 價。試驗方法與實施例1相同，使用雄性威士達(wistar)品系大鼠’將檢體試料1或檢體試料2以lg/kg之比例*** 大鼠的直腸。隨時間採取大鼠之直腸，充分洗淨後，以高效能液相層析法定量直腸組織中之輔酶Q1Q量。直腸組織中之輔酶Q1Q量表示於表2。各値爲n=5之平均値：t標準偏差。時間直腸Φ之輔酶Ql〇量(pg/g) 宫氧化型輔g| Q1() 含還原型輔酶Q1〇之栓劑之栓劑 0 〇.88±〇.21 0.73+0.15 (100) (100) 2 1.22±〇.3l 1.78±0.56 (138) (2431) 4 1.41±〇.48 2.37±0.62 (_ (3252) 8 1.29+0.32 2.19±0.53 (147) (3002) 24 1.07±0.31 1.64 土 0.41 (122) (2241) (請先閱讀背面之注意事項再填寫本頁)Table 1 1313597 μ B7 V. Description of the invention (Parts) The amount of coenzyme Qw in plasma is shown in Table 1. Each 値 is the average bauxite standard deviation of n=10. Time amount of coenzyme Qio in plasma (4), for example, suppository containing oxidized coenzyme Qio suppository containing reduced coenzyme Q10 0 12.88±1.94 13.79±1.34 (100) · (1〇〇) 1 11.67+2.33 14.86±1.89 (91) _ (108) 2 18.51±4.56 17.68+3.55 (144*) 028) 4 15.96±3.61 21.55±4.61 (124) _ (156*) 8 15.63±3.30 37.61±4.88 (121) _ (272***) 12 14.75 ±2.99 46.11±6.09 (115) (334***) 24 11.37±1.87 28.64±5.50 (88) (207***) *p<0.05,**p<0_01,***p<0.〇〇 l, Student-t test As above, it can be seen that the administration of coenzyme Q1q as a suppository for mucosal administration can increase the amount of coenzyme Q1Q in plasma. This result indicates that the coenzyme Qio which is insoluble and only the oral ingestion method can be supplied by mucosal administration even when it is difficult to orally ingest. Even more surprisingly, the suppository made of the coenzyme Qio containing 95% reduced coenzyme Qio can increase the amount of coenzyme Q1() in the plasma compared with the 100% reduced coenzyme Qii. Coenzyme Q1 in vivo. The supply is even better. (Example 2) Mucosal migration test A suppository containing reduced-type and oxidized coenzyme Q10 was produced in the same manner as in Example 1. Use this suppository to evaluate the migration of coenzyme Qiq in rat colonic mucosa. The paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -1! !1 订·! Line, Table 2 1313597 A7 __B7 V. Description of invention (price. Test method is the same as in Example 1, using male Wistar strain rat 'sample 1 or sample 2 The rectum of the rat was inserted at a ratio of lg/kg. The rectum of the rat was taken over time, and after washing, the amount of coenzyme Q1Q in the rectal tissue was quantified by high performance liquid chromatography. The amount of coenzyme Q1Q in the rectal tissue was expressed. In Table 2. Each 値 is the average n of t=5: t standard deviation. Time rectal Φ coenzyme Ql 〇 quantity (pg / g) uterine oxidized auxiliary g | Q1 () suppository containing reduced coenzyme Q1 栓 suppository 0 〇.88±〇.21 0.73+0.15 (100) (100) 2 1.22±〇.3l 1.78±0.56 (138) (2431) 4 1.41±〇.48 2.37±0.62 (_ (3252) 8 1.29+0.32 2.19±0.53 (147) (3002) 24 1.07±0.31 1.64 Earth 0.41 (122) (2241) (Please read the notes on the back and fill out this page)

1 ρ<0·05，2 ρ<〇·〇1， Student-t test 如上，可知將輔酶Q1G製成栓劑實施經黏膜投予，可 2 使直腸黏膜中之輔酶Q1()量增加。該結果顯示可對黏膜有效供給輔酶Qw。更令人驚課的是，含95%還原型輔酶Q1〇之輔酶Q1Q製成之栓劑，相較於含100%還原型輔酶Q1〇者，可增加較多黏膜中之輔酶Q1()量，判斷對於活體之輔酶 Q1C•補給更加良好。 (調製例1)栓劑本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公f ) 1313597 A7 _____ _B7 五、發明說明（|: c) 輔酶Q10 l.Og 馬可洛構全量100g 惟’輔酶Q!。爲還原型:氧化型之比爲98:2。 (調製例2)點眼劑輔酶Q1() o.lg 甘油 l.Og 丙二醇 l.Og 聚山梨酸酯80 1.5g 磷酸二氫鈉 o.lg 烷基二甲基苄基氯化銨 0_005g 蒸館水全量lOOmL 惟，輔酶Q1G還原型:氧化型之比爲98:2。產業上之可利用性本發明之組成物係由以上之構成所形成，對輔酶Q在經口以外之全身補給及局部黏膜之蓄積效果良好，對於老人或重症患者之健康照顧、及大腸疾病、過敏疾病等於局部黏膜發生之疾病可發揮良好的效果。1 ρ<0·05,2 ρ<〇·〇1, Student-t test As described above, it can be seen that coenzyme Q1G is administered as a suppository for mucosal administration, and the amount of coenzyme Q1() in the rectal mucosa can be increased. This result shows that coenzyme Qw can be efficiently supplied to the mucosa. What is even more shocking is that the suppository made of coenzyme Q1Q containing 95% reduced coenzyme Q1〇 can increase the amount of coenzyme Q1() in more mucosa than that of 100% reduced coenzyme Q1. It is judged that the coenzyme Q1C• replenishment for living organisms is better. (Preparation Example 1) Suppository The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public f) 1313597 A7 _____ _B7 V. Description of invention (|: c) Coenzyme Q10 l.Og Marco Polo total amount 100g 'Coenzyme Q!. For the reduced type: the oxidation type ratio is 98:2. (Preparation Example 2) Eyedrop Coenzyme Q1() o.lg Glycerol 1.Og Propylene glycol l.Og Polysorbate 80 1.5g Sodium dihydrogen phosphate o.lg Alkyl dimethyl benzyl ammonium chloride 0_005g Steaming hall The total amount of water is 100 mL, but the ratio of the coenzyme Q1G reduction type to the oxidation type is 98:2. INDUSTRIAL APPLICABILITY The composition of the present invention is formed by the above constitution, and has a good effect on the accumulation of coenzyme Q in the systemic supplement and local mucosa other than oral administration, health care for the elderly or critically ill patients, and colorectal diseases, Allergic diseases are equal to the disease caused by local mucosa and can exert good effects.

_________12 本紙張尺度適用中國國家標準（CNS)A4規格（210^ 297公釐"T (請先閱讀背面之注意事項再填寫本頁)_________12 This paper size applies to the Chinese National Standard (CNS) A4 specification (210^297 mm"T (please read the notes on the back and fill out this page)

Claims

13 f 3597 I - J _ n 第91114681號專利申請案，申請專利範圍替換本 •2008.3 1.一種黏膜投予用組成物，其特徵在於:係以下式(2)13 f 3597 I - J _ n Patent Application No. 91114681, Replacing the Patent Application Range • 2008.3 1. A composition for mucous membrane administration, which is characterized by the following formula (2)

(2) (式中，η表示1〜12之整數)所表示之還原型輔酶Q作爲有效成分，且組成物全量中該還原型輔酶Q比例爲 0.0001 〜99 重量％。 2. —種黏膜投予用組成物，其特徵在於：含有下式(2)(2) (In the formula, η represents an integer of 1 to 12), the reduced coenzyme Q is an effective component, and the ratio of the reduced coenzyme Q in the total amount of the composition is 0.0001 to 99% by weight. 2. A composition for administration of a mucous membrane characterized by: containing the following formula (2)

(式中，η表示1〜12之整數)所表示之還原型輔酶Q，以及下式（1)(wherein, η represents an integer of 1 to 12), the reduced coenzyme Q, and the following formula (1)

(式中，η表示1〜12之整數)所表示之氧化型輔酶Q ; 且組成物全量中該氧化型輔酶Q與還原型輔酶Q合計比例 13 1313597 爲0.0001〜99重量％ ; 且還原型輔酶Q與氧化型輔酶Q之合計量中還原型輔酶Q 的比例超過20重量％。 . 3. 如申請專利範圍第1項之黏膜投予用組成物，其中 . 式(2)所表示之還原型輔酶Q爲式中η爲10之還原型輔酶 QlO。 4. 如申請專利範圍第2項之黏膜投予用組成物，其中式（1)所表示之氧化型輔酶Q爲式中η爲10之氧化型輔酶 Q1〇，而式(2)所表示之還原型輔酶Q爲式中η爲10之還原型輔酶Qio。 5. 如申請專利範圍第1項至4項中任一項之黏膜投予用組成物，其係爲栓劑、點鼻劑、點耳劑、點眼劑、口腔黏膜貼附劑、錠劑、點滴劑、***劑、口腔內溶解劑、陰道栓劑或牙膏。 6. 如申請專利範圍第1至4項中任一項之黏膜投予用組成物，其係作爲醫藥用。 Φ 7. 如申請專利範圍第6項之黏膜投予用組成物，其係用於治療心疾病、腦疾病、腦梗塞、糖尿病、糖尿病性網膜症、心肌梗塞、過敏性鼻炎、花粉症、結膜炎、齒肉炎 ’ 或齒槽膿漏。 · 8. 如申請專利範圍第7項之黏膜投予用組成物，其進一步包含心疾病、腦疾病、腦梗塞、糖尿病、糖尿病性網膜症、心肌梗塞、過敏性鼻炎、花粉症、結膜炎、齒肉炎或齒槽膿漏之治療藥。 14 1313597 9.如申請專利範圍第1至4項中任一項之黏膜投予用組成物，其係用於營養補給。 1〇_如申請專利範圍第9項之黏膜投予用組成物，其進一步包含輔酶Q以外之營養補助成分。 11.如申請專利範圍第1至4項中任一項之黏膜投予用組成物，其係應用於人。 I2·如申請專利範圍第1至4項中任一項之黏膜投予用組成物，其係應用於動物。 13.如申請專利範圍第12項之黏膜投予用組成物，其係應用於狗及/或貓。 H.如申請專利範圍第12項之黏膜投予用組成物，其係應用於賽馬。(wherein, η represents an integer of from 1 to 12), and the total amount of the oxidized coenzyme Q and the reduced coenzyme Q is from 0.0001 to 99% by weight; and the reduced coenzyme The ratio of reduced coenzyme Q in the total amount of Q to oxidized coenzyme Q exceeds 20% by weight. 3. The composition for mucosal administration according to item 1 of the patent application, wherein the reduced coenzyme Q represented by the formula (2) is a reduced coenzyme Q10 having a η of 10 in the formula. 4. The composition for mucosal administration according to item 2 of the patent application, wherein the oxidized coenzyme Q represented by the formula (1) is an oxidized coenzyme Q1〇 having a η of 10 in the formula, and represented by the formula (2) The reduced coenzyme Q is a reduced coenzyme Qio having a η of 10 in the formula. 5. The composition for mucosal administration according to any one of claims 1 to 4, which is a suppository, a nasal spray, an ear locus, an eye drop, an oral mucosa patch, a lozenge, A drip, a buccal, an oral solution, a vaginal suppository or a toothpaste. 6. The composition for mucosal administration according to any one of claims 1 to 4, which is for use as a medicine. Φ 7. The composition for mucosal administration according to item 6 of the patent application is for treating heart disease, brain disease, cerebral infarction, diabetes, diabetic retinopathy, myocardial infarction, allergic rhinitis, hay fever, conjunctivitis , dentitis' or alveolar pyorrhea. · 8. The composition for mucosal administration according to item 7 of the patent application further includes heart disease, brain disease, cerebral infarction, diabetes, diabetic retinopathy, myocardial infarction, allergic rhinitis, hay fever, conjunctivitis, teeth A therapeutic drug for gingivitis or alveolar pyorrhea. 14 1313597 9. The composition for mucosal administration according to any one of claims 1 to 4, which is for use in nutritional supplementation. 1〇_ The composition for mucosal administration according to item 9 of the patent application, which further comprises a nutritional supplement other than Coenzyme Q. The composition for mucosal administration according to any one of claims 1 to 4, which is applied to a human. I2. The composition for mucosal administration according to any one of claims 1 to 4, which is applied to an animal. 13. The composition for mucosal administration according to claim 12, which is applied to dogs and/or cats. H. The composition for mucosal administration according to claim 12 of the patent application, which is applied to horse racing.

1515