200908991 九、發明說明： 【發明所屬之技術領域】 本發明係關於梔子素（genipin)使用做為人體或動物皮 膚標記染料之新用途。本發明更進一步提供一種人體或動 物皮膚標記組成物，其包括梔子素為標記染料，及醫藥上 可接受之載劑或稀釋劑。 【先前技術】 梔子素（genipin)為去羥梔子苷（genip〇side)之水解產 物，存在茜草科植物槐子樹（Gardenia ㈨ 的果實中。在生物醫學方面’目前已知梔子素具有：⑴做 為生物交聯劑，應用於人工器官製造上交聯去細胞生物組 織，亦用於交聯血紅素製備交聯行人工代血；⑺促進胰細 胞分泌騰島素，預期可應用於治療第二型糖尿病患者；⑺ 能促進納離子從肝細胞到毛細膽管之輸送，而促進膽汁分 泌作用；及⑷對天竺鼠離體小腸有抗乙醯膽素作用，抗毒 扁豆驗（PU〇carpine)作用，抗組織胺作用抗⑽_作 用，與抑制胃醋酸扭動症狀等功效。振子素本身為無色， 但是在自發性與胺基酸反應後會形成藍色色素因此已有 研究報告指出’梔子素由於其顏色持久度及靈敏度較優， 200908991 故可用於取代節三酮（ninhydrin)做為指致分析伽啊_ 中之呈色劑。(參見’例如’李s.w·等人，心咖 Acta 2003, 480, 261-21 A.) 扼子果實所含之色素已之可用於做為天然染料和食用 色素’其中由黃料果實直接取得之黃振子色素（㈤‘ Yellow)經過酵素處理後，便得梔子藍色素。 栀子藍色素中的主要成份即為梔子素，此藍色色素為一般 已用於做為食品藍色著色劑之可食用色素，且在東亞或東 南亞已廣泛使用於食物染色。 患者（尤其指癌症患者）在進行定期檢驗及/或放射治 療期間’必需使用塗料標記出欲進行檢驗及，或放射治療之 區域或部位’目前各醫療院所普遍使用—般市售之油性標 °己筆，例如習知的馬克筆或奇異筆來進行標定。 然而，習知的油性標記筆在身體上所做的記號，容易 在患者洗澡或擦拭時被去除或淡化，而造成辨識上的困 難’因此常為使標記能較長時間保留在身體上，往往必需 忍受無法清潔身體的不便，在夏日I熱的氣溫下尤其是一 項困擾。於是’本案發明人遂創先提出將梔子素應用於人 體或動物皮膚標s己上。經本發明之實驗證明，以梔子素作 為染料調配成的標記組成物，能在身體皮膚上保留一段較 長的％間，且不因清洗或擦栻而被除掉，極具有產業利用 200908991 性，遂而完成本發明 【發明内容】 本發明目的及優點將部分描述於下，或可由描述中顯 而易見。 ’‘ 本發明目的為提供—種栀子素（genipin)使用做為人體 Γ :動物皮膚標記染料之新用冑。於本文中所記載之“皮膚 :5己，並不限定於醫療方面，亦可指為使染料能較長期 ”留在皮膚上之用㊣。例如’可應用於彩妝、動物標記及 其他人體或動物辨識方面。 本發明另—Β α & 的為，提供一種用於人體或動物皮膚之 記組成物，I句人 、3梔子素為標記染料，及醫藥上可接受 :劑或稀釋劑。其他於具體態樣，本發明之標記組成物 =步包含額外的染料，以助於初期標示。於-項項具 體態樣，用於本發明 笔 E 己、且成物之稀釋劑為油性溶劑。於 另—項具體態樣，用 性溶劑。 、本發明標記組成物之稀釋劑為酒精 本發明的其他特性將力下^ — — 例顴容祛㈣/曰 下面洋細揭示具體貫施 m察後k得顯而易見。 200908991 【實施方式】 本發明將詳細描述特殊的具體實施例 例：由發明解釋提供，並非意欲用以限制本發明:、在：明 的範圍及精神内，本發明左 个赞明存在傾向於包括這些及其他變更 及變動。200908991 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the use of genipin as a new dye for human or animal skin marking dyes. The invention still further provides a human or animal skin marking composition comprising scorpionin as a labeling dye, and a pharmaceutically acceptable carrier or diluent. [Prior Art] Genipin is a hydrolysate of genip〇side, which is present in the fruit of the genus Rubenaceae (Gardenia (Nine). In biomedical science] scorpionin is currently known. It has: (1) as a biological cross-linking agent, it is applied to artificial organ production to cross-link decellularized biological tissues, and is also used for cross-linking heme to prepare cross-linked artificial blood; (7) promoting pancreatic cell secretion of tamsin, expected to be applied For the treatment of patients with type 2 diabetes; (7) can promote the transport of nano ions from the liver cells to the capillary bile duct, and promote the secretion of bile; and (4) the anti-acetylcholine effect on the isolated small intestine of the guinea pig, anti-virus lentils test (PU〇 Carpine), antihistamine action (10) _ effect, and inhibition of gastric acid writhing symptoms. Vibrin itself is colorless, but will form a blue pigment after spontaneous reaction with amino acid, so research reports have pointed out Because of its long-lasting color and sensitivity, 200908991 can be used to replace ninhydrin as a coloring agent for analysis. (See 'Li'. w·等人,心咖Acta 2003, 480, 261-21 A.) The pigment contained in the fruit of the hazelnut has been used as a natural dye and food color, which is obtained directly from the yellow fruit ((5) 'Yellow' is treated with enzymes to obtain gardenia blue pigment. The main ingredient in gardenia blue pigment is gardenia, which is an edible pigment that has been generally used as a food blue colorant. It has been widely used in food dyeing in East Asia or Southeast Asia. Patients (especially cancer patients) during the period of regular testing and / or radiation therapy, 'must use the paint to mark the area or site to be tested and or radiation treatment' Medical institutions generally use the oil-based standard pens that are commercially available, such as conventional markers or singular pens for calibration. However, the marks made on the body by the conventional oil-based marker pens are easy to bathe in patients or It is removed or faded when wiping, which causes difficulty in identification. Therefore, it is often necessary to keep the mark on the body for a long time, and it is often necessary to endure the inconvenience of being unable to clean the body. In particular, Wen is particularly troubled. So the inventor of the present invention proposed to apply scorpion scorpion to the human or animal skin label. The experiment of the present invention proves that the labeling composition prepared by using scorpion sin as a dye It can be retained on the skin of the body for a long period of time, and is not removed by washing or rubbing. It has the industrial use of 200,908,991, and the present invention has been completed. [Invention] The object and advantages of the present invention will be partially described. As below, or can be clearly seen from the description. '' The purpose of the present invention is to provide a new use of genipin as a human enamel: animal skin marking dye. "Skin: 5" It is not limited to medical treatment. It can also be used to keep the dye on the skin for a longer period of time. For example, it can be applied to make-up, animal marking and other human or animal identification. In the present invention, Βα & is provided as a composition for human or animal skin, I sentence, 3 scorpion is a marker dye, and pharmaceutically acceptable: agent or diluent. In other embodiments, the marker composition of the present invention = step contains additional dye to aid in initial labeling. In the case of the item, the diluent used in the present invention is an oily solvent. In another case, use a solvent. The diluent of the labeling composition of the present invention is alcohol. The other characteristics of the present invention will be the result of the force ^ — 祛 四 四 四 四 四 四 四 四 四 四 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰The present invention will be described in detail with reference to the particular embodiments of the present invention, which are not intended to limit the scope of the invention. These and other changes and changes.
Γ V 實施例i•料素溶液於皮膚上之呈色及掉色試驗 以腕酒精溶解hllg梔子素成為10%振子素溶 液。取梔子素溶液稀釋成終濃度為7%、5%、2%及， 各自200U1;亦取市售雄獅墨水2〇〇1^做為控制組。以… 沾取各濃度並塗抹在手背上。於指定時間拍攝糖子素於皮 膚上之呈色情形，並且以及比對振子素溶液及市售墨水於 皮膚上之存在情形。結果示於圖1。 由第一圖之拍照記錄顯示，振子素溶液塗抹於皮膚上 後12小時，即逐漸顯現出藍色，並且經過長達實驗期之第 十-天’減在皮膚上保留其可辨識之色度。反之，市售 雄獅墨水耗本身即具有顏色，但是在塗抹於皮膚上後第3 天’其原本的顏色已消退至幾乎無法辨識其標記位置，並 且在第4天便已完全消逝。 200908991 實2· 振子素配製成油性與酒精性標記組成物 之體表著色性試驗 首先利用60%酒精配置成1〇%梔子素溶液。秤取1克梔 子素（Wako,產品編號：078-03021 )加入9ml之60%酒精， 至於3rc恆溫水槽中反應約1〇分鐘’待梔子素粉末溶解即 可，配好之溶液需避光冷藏。將所得之1〇%梔子素溶液，以 酒4“生墨水（雄獅，成分一染料、樹脂、溶劑），或油性墨 X (雄獅，成分—染料、樹脂、溶劑）依下表所示稀釋， 而配製成不㈤濃度之標記組絲，所得標記組成物之最終 /辰度分別為〇%、1%、2%、5%及1〇%。 6 0 %酒精 (ml) 墨水（m 1) 總體積~' 4. 5 ml 4. 5 ml 10 ml ~~~~~ 9 ml 10 ml ~~ g 4. 5 ml 5 ml 10 ml s g 1.8 ml 8 ml 10 ml ~~~~~~ g 0. 9 ml 9 ml 卜10 ml 10 ml 10 ml 〜Γ V Example i• Coloring and fading test of the solution of the phytochemical on the skin The hllg scorpion was dissolved in the wrist alcohol to become a 10% vibrin solution. The hazelnut solution was diluted to a final concentration of 7%, 5%, 2% and 200 U1 each; and the commercially available male lion ink 2〇〇1^ was also used as a control group. Dip each concentration and apply it on the back of the hand. The coloration of glycosides on the skin was taken at the specified time, and the presence of the vibrin solution and commercially available ink on the skin was observed. The results are shown in Figure 1. The photo record of the first figure shows that the vibrin solution gradually appeared blue after 12 hours of application on the skin, and retained its recognizable color on the skin after the tenth day of the experimental period. . On the contrary, the commercially available lion's ink consumption itself has a color, but on the third day after being applied to the skin, its original color has faded to almost no recognition of its marked position, and it has completely disappeared on the fourth day. 200908991 实2· Muscles are formulated into oily and alcoholic marker compositions. Body surface colorability test First, use 60% alcohol to prepare a 1%% scorpion solution. Weigh 1 gram of scorpion (Wako, product number: 078-03021) and add 9ml of 60% alcohol. As for the reaction in the 3rc constant temperature water tank for about 1 minute, the scorpion powder can be dissolved. Light refrigerated. The obtained 1%% scorpion solution, with wine 4 "raw ink (lion, ingredient-dye, resin, solvent), or oily ink X (lion, ingredient - dye, resin, solvent) according to the following table Dilution is shown, and the labeled silk of the concentration of (5) is prepared, and the final/length of the obtained labeled composition is 〇%, 1%, 2%, 5% and 1%, respectively. 60% alcohol (ml) ink (m 1) total volume ~' 4. 5 ml 4. 5 ml 10 ml ~~~~~ 9 ml 10 ml ~~ g 4. 5 ml 5 ml 10 ml sg 1.8 ml 8 ml 10 ml ~~~~~ ~ g 0. 9 ml 9 ml Bu 10 ml 10 ml 10 ml ~
將調配完成 每天正常洗澡， 之標記組成物以毛細管點在皮膚上， 〈-is 並於固定時間地點照相，將收集到之相片 200908991 進行分析，以評估酒精性或油性標記組成物於皮膚上之附 著程度及掉色現象。 結果： 如圖2所示’經過試驗後發現’油性標記組成物利用 毛細管點於皮膚上會呈現擴散現象，酒精性標記組成物則 無此現象。結果，油性標記組成物約擴散至原半徑的3倍。 在持久性方面，則是以油性標記組成物為較佳，即便是濃 度低如2%之標記組成物’在經過14天之後，仍然清晰可 見。 而圖係將每天收集到的相片利用影像軟體分析，其中 亦以市售標記筆（奇異筆）染料為比較組。由圖2所示之 數值圖表發現，不論是本發明之標記組成物，或是—般市 售奇異筆墨水，皆隨著時間增加而顏色會慢慢褪掉，但是 本發明標記組成物之掉色情況較輕微，於第14天時仍有原 來約40%之顏色附著在身體表面上。 實施例3.本發明標記組成物（油性）於塗抹後在不 同時間沖洗之掉色試驗 如實施例1所述，配製得最終濃度為1〇%之（油性） 標記組成物。於受測自願者洗澡前4、6、8、1 〇小护將 調配完成之標記組成物塗繪於其皮膚上，並於固定時間地 10 200908991 點照相。將於各時間點收集収相片以影像軟體進行分 析’以評估染料於皮膚上之附著程度及掉色現象，亦可: 併觀察與評估本發明標記組成物對於皮膚之刺激性，及是 會否造成過敏現象。 結果： 如第四圖所示，本發明標記組成物塗抹於皮膚後1〇小 w ’始進仃洗澡之掉色情形最輕微，I色效果亦最佳。即 便是相同濃度之標記組成物，隨著試劑停留於皮膚的時間 越短，也間接影響到後續的呈色時間。 無意受限於任何理論，梔子素已知為一種天然交聯 記’故推測其經塗覆於皮膚上後，會與表皮或真皮中之J 白質產生交聯作用’而有利於其穩定存在皮膚上。故，由 於本發明標記組成物塗抹於皮膚上後，需時間與皮膚反 應’ s反應效果尚未完成時便經過清潔劑沖洗，會將染料 之色素沖散’ π降低存在皮膚表面上之色素含量，遂造成 呈色效果不佳。因此’本發明標記組成物塗抹後，應至少 半天後才可洗澡’以便維持其標記效果。X，振子素原本 為無色’當與皮膚之蛋白質組成胺基酸結合後即顯現出藍 色（參見’實施例1所示之結果），因此為使能立即在皮膚 上顯示出標記位置’可於本發明皮膚標記組成物中，添加 額外的習知㈣’再藉由梔子素之作用，而使標記能更長 200908991 期穩定存在皮膚上。 綜合以上之實驗結果，以振子素（genipin)做為人體或 動物皮膚標記之染料’可達到優於習知或市售標記染料的 皮膚持久性，且經過沖洗後10天，仍可看到原本之標記位 置。再者，因為梔子藍色素本身即為一種安全的食用色素， 而且梔子素已知為一種無毒性天然交聯劑，故本發明之標 記組成物使用在皮膚上，亦具有不產生過敏及/或刺激性的 〇 優點。 12 200908991 【圖式簡單說明】 、弟一圖為顯示梔子素溶液"〇%、7%、5%、2%與1%)， 以及市售雄獅黑匕「 甲土水（作為控制組），在塗覆至於皮膚上（以 t i ρ點在皮膚、仏 )後，於所指定時間點（第0 M、2、2.5、 12 小時、1、9、q λ 〇 、5'6、7、8、9、10、11 及 12 天） 之呈色程度及掉色現 ].、、'月 園片由左至右為S牌（雄獅 墨水）、10%' 7%、5%、2%及爾子素溶液。 ^二圖為顯示本發明酒精性及油性標記組成物，在塗覆 至於皮膚上（以毛細管點在皮膚上）I，於所指定時間點 ^ 3 1 Q及14天）之附著程度及掉色現象的照片。 弟二圖係將每天收韋㊆丨沾士 木i的相片利用影像軟體分析，以數 值續·製得之圖表。A為以油性俨 由性軚C組成物進行試驗所得之結 果B為以，酉精性標記組成物進行試驗所得之結果。The preparation will be completed every day, and the labeled composition will be spotted on the skin with a capillary, <-is and photographed at a fixed time, and the collected photo 200908991 will be analyzed to evaluate the composition of the alcoholic or oily marker on the skin. Degree of adhesion and discoloration. RESULTS: As shown in Fig. 2, it was found that the oily marker composition exhibited a diffusion phenomenon on the skin by using capillary spots, and the alcoholic marker composition did not. As a result, the oily marker composition diffused to about 3 times the original radius. In terms of durability, it is preferred to use an oil-based marking composition, and even a labeled composition having a low concentration of 2% is clearly visible after 14 days. The pictures collected by the map are analyzed by image software, and the commercially available marker pen (singular pen) dye is also used as a comparison group. It is found from the numerical graph shown in Fig. 2 that whether the marking composition of the present invention or the commercially available singular pen ink is gradually faded with time, the color of the marking composition of the present invention is faded. The situation is mild, and on the 14th day, about 40% of the original color is attached to the body surface. Example 3. Color drop test of the marking composition (oily) of the present invention after rinsing at different times As described in Example 1, an (oily) marking composition having a final concentration of 1% was prepared. 4, 6, 8, and 1 〇 护 前 前 洗澡 洗澡 洗澡 洗澡 洗澡 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 受 标记 受 受 标记 标记 标记 标记Photographs will be collected at various time points for analysis by image software to assess the adhesion and fading of the dye on the skin. It is also possible to: observe and evaluate the irritation of the labeling composition of the present invention on the skin, and whether it will cause Allergies. Results: As shown in the fourth figure, the marking composition of the present invention was applied to the skin 1 〇 small w 。 始 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃 仃Even the labeling composition of the same concentration, as the reagent stays in the skin for a shorter period of time, indirectly affects the subsequent coloring time. Without intending to be bound by any theory, scorpion is known as a natural cross-linking, so it is speculated that after it is applied to the skin, it will cross-link with the white matter in the epidermis or dermis, which is conducive to its stable existence. On the skin. Therefore, since the marking composition of the present invention is applied to the skin, it takes time to react with the skin. When the effect of the reaction is not completed, it is washed by the detergent, and the dye of the dye is dispersed to reduce the amount of pigment present on the surface of the skin.遂 Causes poor color rendering. Therefore, the coating composition of the present invention should be bathed at least half a day after application to maintain its marking effect. X, the vibrin is originally colorless, and when it is combined with the protein-constituting amino acid of the skin, it appears blue (see the results shown in 'Example 1), so that the mark position can be immediately displayed on the skin. In the skin marker composition of the present invention, an additional conventional (four)' is added to further stabilize the presence of the marker on the skin by the action of scorpion. Based on the above experimental results, genipin (the dye labeled as human or animal skin) can achieve skin durability superior to conventional or commercially available marking dyes, and can still be seen 10 days after rinsing. Marked position. Furthermore, since scorpion blue pigment itself is a safe food coloring matter, and scorpion scorpion is known as a non-toxic natural cross-linking agent, the marking composition of the present invention is used on the skin and has no allergies and / or irritating 〇 advantages. 12 200908991 [Simplified illustration], the younger one shows the scorpion solution "〇%, 7%, 5%, 2% and 1%), and the commercially available lion black 匕 "A soil water (as control Group), after application to the skin (with ti ρ point on the skin, 仏), at the specified time point (0 M, 2, 2.5, 12 hours, 1, 9 , q λ 〇, 5'6, 7, 8, 9, 10, 11 and 12 days) The degree of coloration and color drop is now].,, 'Yueyuan is from left to right for S brand (lion ink), 10% '7%, 5%, 2% erion solution. ^ Figure 2 shows the alcoholic and oily marker composition of the present invention, applied to the skin (with capillary points on the skin) I at the specified time point ^ 3 1 Q and 14 Photograph of the degree of adhesion and fading of the day. The second picture of the dynasty is to use the image software analysis of the photos of the 丨 丨 丨 丨 木 每天 , , , 利用 利用 利用 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表 图表The result B obtained by the test of the composition is the result of the test conducted on the composition of the sputum.
弟四圖列示本發明擇#纟B 谁从 成物塗抹於皮膚後10小時始 進仃洗滞’之後於所指定時間 5,, ^ 间點（弟0、6及10天）颧疚 到的之附著程度及掉色現象。 八彡说务、 【主要元件符號說明】 13The four figures show the invention. #纟B Who started the sputum stagnation 10 hours after the application was applied to the skin, and then at the specified time 5, ^ (point 0, 6 and 10 days) The degree of adhesion and fading. Gossip, [Major component symbol description] 13