Α7 Β7 經濟部中央橾準局員工消费合作社印装 五、發明説明（1 ) 本發明係有關一可以滴劑形式使用之無菌液眼用製劑 ，特別是用作人造淚液而來治療“乾眼症”之製劑，Μ及 係有翻裂備此種凝膠裂劑的方法。 使用水性製劑來替代自然淚液Μ及來治療“乾眼症” ，係行之有年。此種水性製劑，譬如，包含有以聚乙烯酵 (PVOH)，聚乙烯吡咯嗣（PVP)，缕維素衍生物或葡聚糖為 主的造膜物質。有關此方面的一覽可參見譬如Sucker, Fuchs和Speiser在1978年所著的“製蕖技術”。此等，一 般而言，係只含一捶流醱或液體柑的条統。典型的是，一 其它成份的水溶液。當有難溶於水或不溶於水的成份存在 時，它們係Μ撤細形式固髏*懸浮於水柑中。 在半合成製劑*譬如是那些以纖維素衍生物或葡聚糖 爲主的製劑，由於此等物質，難Μ獲得不存在有不溶成份 ，而使製備倍感困難。因此*必須用非常高成本方式，從 此等製劑，去製備出不會導致由機槭作用所造成的眼剌撖 的溶液。再者，因它們只能用褀雜方式，或根本無法去過 濂或除去菌類，故此等製劑是非常難Μ除菌的。且它們亦 無法在不損及其品質下，進行高溫高壓殺菌。绻雒素衍生 物是無法，在不造成不可逆黏度改變下，進行高溫高壓殺 菌。葡聚耱的製劑在高溫高®殺S下，會部份被分解。 且，聚乙烯醇只能在，其係為非常純的水解形式下， 被加熱殺菌。此係因*否則的話，PVOH成份會被解聚化。 由於PVOHM及PVP僅能提供柑當低的稠化效果，故必須使 用相當高量的此等成份來提供合適的黏性。此會導致眼用 (請先閱讀背面之注項再填寫本頁) 本紙張尺度適用中國囷家標準（CNS ) A4規格（210X297公釐） 4 瞠4386 0 2 經濟部中央橾準局員工消費合作社印装 A7 B7 五、發明説明（2 ) 製劑内此等成份高用量，譬如，在PV0H的情況*含多於10 ϋ：的董。 在 DE 34 40 352和 DE 43 03 8UM 及 US 5,252,318專 利茱中已揭示有，聚丙烯酸和其衍生物，諸如Carbopol 940(可購自Β· F. Goodrich公司）的使用作無菌液滴性眼 用製劑。在公告日係爲本發明優先權日之後的US 5,441, 732專利案中，已有揭示兩特定膠睡成份的組合，其一是 熱膠凝，而另一則M PH值的改變來膠凝。各種不同的缕維 素衍生物，被以熱反應性凝膠聚合物來描逑*而聚丙烯酸 鹽，特別是交聯之聚丙烯酸鹽，被提及到，其聚合物膠凝 係依PH值而定。此時，凝膠的形成，顯然係準備只有在眼 內，藉著藥劑施與，而導致pH值的變化，始發生。椐稱* 此等聚合物混合劑係要與能溶解多種活性劑的有機性油類 併用。而維生素A並未被提及。 就順依性*非刺橄性，販售期限等而論，用作造膜製 劑或潤滑製劑的眼用製劑，必須採極高的檫準才行。尤其 是，當眼用製劑必須長期使用*餐如，治療w乾眼症”的 一般性情況。甚至，在暫時性剌激，如眼内的灼熱感等相 當不適感時，任何長時間的治療，均會馇成傷害。在此類 眼用製劑的施用時，若有視力異常，模糊或其它急性剌激 副作用，均是無法接受的。 在“乾眼症”的治療中。使用通篑以维生素A的棕櫊 酸鹽形式的維生素A，是被認定有效的。因此 ，K Carbopo1 為主的凝穋滴液製劑己有販售（在本發明優先權曰之後） 本紙诙尺度適用中國國家標準（CNS ) Λ4規格（2]0X297公楚） t— n n^i n^i I- (請先閱讀背面之注意事項再填寫本頁) 訂 5 02 A7 B7 經濟部中央揉準局員工消費合作社印製 五、發明説明（3 ) 。此製劑除了其它一般晋知成份外，更含有維生素A的棕棚 酸鹽。此等單相凝膠具有一連鏞水液相，但不含其它任何 疏水性第二液柑。此等製劑，當雒生素A成份量含超過40¾ 時，販售期限係約一年。經测試顯示，在此等製劑中，每 超過半年，維生素A含置會減少20¾左右，是K，在超過40 Z的劑量，在一年後仍存在有保証的最低含量。 自然淚液亦包含有由三睃甘油酯和磷脂所組成的脂肪 成分。亦有人«試（WO 94/05298)使用三酸甘油酯於合成 淚液中。惟必須在乳化劑添加時，才有可能。在局部施用 到眼中時，整個製劑係呈乳狀液的形式。此造成的不利之 處是，在眼内自然淚液的合宜殘留量會遭乳化劑所破壊。 本發明的重要目的係提供一具有改善的販售期限的眼 用製劑，特別是凝膠製劑。尤其是> 當它含有聲如是維生 素A及其衍生物等敏感性物質時，更係如此。 本發明的另一重要目的係，特別在當為提昇其販售期 時限而製備時，提供一不會造成急性剌激之製劑。 本發明的再一重要目的係提供一製劑，其係使在長時 期間，一再地使用製劑成為可能；和/或在各次施用後， 在眼内久留而又不會引起不相容性、或缺乏順依性、或刺 激眼性等成爲可能。 本發明係基於各種不同令人訝異的發現。 在一方面，令人訝異的是，當裂劑係以具一水性液相 和一疏水液相的二成分糸統形式呈現時，在用於“乾眼症 w的人造淚液和製劑中，雒生素A和其衍生物，待别是維 (請先閱讀背面之注意事項再填寫本頁) 裝. 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公竣） 經濟部中央椟準局員工消費合作杜印繁 Α7 Β7 A'發明説明（4 ) 生素A的棕櫊酸酯的柑當快速的分解，將可急遽地減少。 待別是，K其中提供有呈非常徹細掖滴形式的疏水性液油 相的連續性水相的製劑尤佳。此事實很難加Μ解釋。最有 可能的是，氧和/或光係造成维生素Α分解的明鍵，而對 於此二者，到底製劑係包含一或兩分開液柑，應不致造成 任何實質不同。或許有人更會預期到《在疏水相中的維生 素A成分的溶液中*其對氧和/或光更具高敏感性。 可能的話，抗氧化劑，特別是維生素E和其衍生物， 尤其是維生素ε乙酸酯的併用，可對此等製劑造成影谨。 在任何情形下，在本發明製劑中，維生素Α最好係與此等 抗氧化劑一齊使用。 另一方面*本發明的另一令人訝異的發現是，它使得 非常接近自然淚液的組成之具有水性和液狀疏水性相的製 劑製備成為可能。尤其是，具有對應的三酸甘油醏内容， 而郤不需同時使用乳化劑。因依本發明*此棰製劑係呈凝 膠滴掖製劑形式，故此係可能的。相較於無任何凝膠基質 的製劑，在本發明凝膠製劑中三酸甘油醋係可在非常長的 貯存期間，Μ呈非常撤細液滴形式提供*而在甚至無任何 乳化劑存在下，液滴在凝膠中呈相當穩定狀。製備此等無 菌狀的製劑係可在無困難下爲之，且製劑係不具剌激性| 故柑當地理想。 包含凝膠製劑的本發明製劑*具有幾乎與自然淚液完 全一樣的折射率。它們在眼内可提供長期效果。 本發明製劑顯示出可對水性眼凝镙，提供較小的表面 本紙張尺度適用中國國家標準（CNS ) A4規格（2!〇x297公釐） -I ---τ----裝---- -- (請先閩讀背面之注意事項再填窝本頁) 7 經濟部中央標準局員工消費合作杜印製 A7 __B7五、發明説明（5 ) 張力，故可在角膜上有良好的分佈。同時，在油相中溶解 或懸浮的任何活性劑，可更均勻地分佈。欲置於角膜上的 客體，諸如皤形眼鏡或眼科裝置的前鏡的潤濕性可改善。 長期硏究顯示，本發明製劑在市售的5克多箔管包裝 中，恃別安定。此不但在溫帶氣候（1YC, 45¾相對濕度） 的情況下係如此，在地中海/亞熱帶氣候（26^C, 60¾相對 濕度），甚至是非常熱且潮濕的氣候（31°C, 70¾柑對濕度） 下，亦幾乎顯示不出，在維生素A含量（若提供時），pH值 ，滲透壓，黏度和外觀方面，有任何改變。 基本上，此等眼科學上可被接受的有機油類係可適用 於本發明兩相製劑的液體疏水性成分，尤其是凝膠體，可 在乳化劑不存在下，以液滴狀均散在水相中。為脂肪酸衍 生物所形成的例子，諸如有脂肪酸酯，三酸甘油酯和肽酸 酯。三酸甘油酯是目前較佳者，特別是大都或全部由Ce-C13脂肪酸所形成的同質性或混合三睃甘油酯。尤其是， 在“德國藥典”（DAB) 10 (1993)內所定義的中鋪三賅甘 油酯為較佳。此等三酸甘油酯的酸成分係至少95X正辛酸 和正癸酸的混合物；其餘係由較短的脂肪酸所構成。 此等中鐽三酸甘油酯係從椰子（cocos nucifera L.) 的内胚乳的乾固部份油半合成製備得。其方式係將得自内 胚乳的椰子油水解，分皤所得的脂肪酸，爾後捋酸再醋化 Ο 此等中鏈三酸甘油酯係已被用作化妝品的基本物質* 用作醫藥品的佐劑和載体，以及用於某些食品等。惟，有 I. - -- I Hi I - - - I. r I- « ^^^1 --if I --5J (請先聞讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS > A4規格（210X297公釐） A7 B7 五、發明説明（6 ) 關其在眼用製劑的此等使用的潛力和限制的瞭解，則甚少 ，縱使中鏈三酸甘油脂有許多已知的有益特性。 本發明裂劑，尤其是以凝膠為主，具有在水相中作為 凝膠形成劑之典型含量係在0 · 1至3重量X之間，特別是約 為0.2重量％聚丙烯睃的製劑，典型地含有0.5至10重量;ί， 特別是約1重量S：的此等中鍵三酸甘油酯。 本發明凝醪製劑最好具有，在pH值為6至8之間時，約 2000至6000m帕範圍的黏度。 本發明製劑最好含有保存劑，特別是諸如森特亞醢胺 (centrimid),氣化苯甲烴銨或柳汞等。更佳的是，此等凝 穋製劑含至少一等張劑，而Μ山梨醇為待別適合。 維生素Α成分，尤其是維生素Α的棕柵酸酯，其特别佳 的含量係在每克發明製劑500國際單位的级距上。維生素A 成份，較佳的是以少量之至少一抗氧劑來安定化，其中以 維生素E和維生素E乙酸酯為待別有利。 經濟部中央梂準局員工消費合作社印裝 n- J- I —J ,n I n , 装―— II —訂 (請先閲讀背面之注意事項再填寫本頁) 本發明無菌製劑，特別是凝膠的製備，係Μ多步驟來 進行。在製備凝穋中*無菌聚丙烯酸懸浮液最好是由DE 4 3 03 818所掲示的步驟來獲得。亦即，利用在約12〇°C，1 巴過壓，歴時20分鐘的高歴高溫殺菌。同時，製備含有保 存劑和等張劑，最好是森特亞醢肢和山梨酵的水溶液。使 用気作為加壓空氣，或更簡單地使用加壓空氣，利用無菌 過濾，將此等水溶液加至高溫高壓殺菌的聚丙烯酸懸浮液 。接箸，藉著無菌氫氧化納溶液的加入來小心翼翼地進行 中和，Μ起始凝膠的形成。一旦中和完成後，在形成的凝 本紙浪尺度適用中國國家標隼（CNS ) A4規格（210X297公釐） 1194386 02 ; ' Α7 Β7 經濟部中央椋準局負工消費合作衽印策 五、發明説明（7 ) 膠中，就不再有自由鹸存在。疏水性液體成分，即最好是 中鍵三酸甘油酯，接著在無菌狀態下，被弄進到無菌凝膠 内。保持攪拌直至整阃均質化達成。在本發明勻散液中， 如此得到的油滴大小最大係約100 W π，因而，此與未添加 強乳化劑的習知乳化液所得的那一種不同。 無菌凝膠於是可依習知方式加以調製。 苔則，活性劑，特別是如維生素A的棕櫊酸酯，可加 入如此形成的無菌凝膠，使雒生素A成分及較小量的最好 亦存在的抗氧化劑*被溶到中性油中，然後再進行無菌過 濾。其次，無菌油溶液被攪拌而進入凝膠。 當製劑無凝膠時，則使用對等的程序進行*譬如製備 成一滴液。 依据本發明使用的凝膠形成劑最好是*分子量約爲3 至5百萬範圍的聚丙烯酸。特別是諸如Car bopol聚合酸商 品，如可購自B. F. Goodrich公司的Carbopol 980 NF為 較佳。在此製劑中，濃度約為0.2重量2。 凝膠形成所需的中和可依晋知方式，使用無菌稀氫氧 化鈉溶液來進行，而其中Μ 1N的氫氧化鈉溶液爲特別有利 。不過，其它無機鹼或鹼金靥碳酸鹽，或諸如胺等的有機 鹼，特別是三乙基胺和二異丙基胺也可使用。 如此所得的凝膠的黏度在20°C時係2000至6000®帕範圍 〇 依本發明通常所用的保存劑，諸如森特亞瞌胺，氯化 苯甲烴銨或柳汞等，可使用習知的濃度，亦即，用森持亞 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（21〇><297公釐） 10 經濟部中央樣準局員工消費合作社印製 A7 B7 五、發明説明（8 ) 醯胺時，為約0.01重量2。等張劑，譬如，多官能酵*如 甘S醇，葡聚醇，甘油*丙二醇或特別佳的山梨醇等，亦 可以習知濃度使用。就山梨醇而言，約4.85¾重量S；的濃度 為較佳。 本發明將進一步以兩齒實施例來加以說明。 瞄例1 將懸浮在約375公斤的水中的2000公斤聚丙烯酸< Carbopol 980 ΝΠ的均質懸浮液，一次注入通過孔洞大小 約為25至40 μ n的绻雒除去過雒器，而進入處理裝置。然 後在121。(：和1巴過壓下高壓高溫殺菌20分鐘，爾後再冷部 至室溫，並使用去菌空氣濾器提供大氣壓。 同時，在合適的器皿內放進964公斤的水》而在攬拌 下*先将森特亞醯胺溶解，次將48.510公斤溶解到水中。 此溶液再利用具有0.2w 孔洞大小的蒸氣殺菌濾膜*加到 己高壓高溫殺菌的聚丙烯酸懸浮液中，且以氣氣作為加塑 氣體。接著，裝置被抽氣一次或多次以破除可能形成的泡 沫。 其次，在攪拌和無菌狀態下，將0.S32公斤的氫氧化 鈉溶進約20公斤的水中。氫氧化納係利用，通經蒸氣殺菌 瀘膜而的過濾，而被加至森特亞豳胺/山梨醇/聚丙烯醇 懸浮液中。接著，再將剩餘量的水加入。利用均質化器加 工所形成的凝膠。 其後，中鍵三酸甘油01再通經具有0. 2 w a孔洞大小的 殺菌濾器，加到無菌凝謬，接著攢拌直至達到完全的均質 本紙蒗尺度適用中國國家榡隼（CNS ) A4規格（210 X 297公釐） (请先閲讀背面之注意事項再填寫本頁) 装 -、Tr 11 經濟部中央楼準为員工消費合作杜印策 A7 B7五、發明説明（9 ) 化。测定所形成凝繆的pH，其值在20° C下應為6到8。本發 明製劑的滲透壓是在260至320 hOsb/Ks的範圍。Μ此方式 形成的凝膠在無菌狀態下*被充入到5克的多箔管中。 簸例2 將0.6克的雒生素Α的棕櫊酸酯和0.03克的維生素Ε乙 酸酯溶到9.37克中性油中（Myritol 318)。令溶液通過 0.22 wm的濾器而過濾，使其無菌。 將10克的中性油溶液加入到依範例1所製備的990克的 凝膠，並使用翼攪拌器而使其進入到凝膠中。經過20分鐘 的規拌，所得產物被充入到10克多箔管。此凝膠係對應於 在超出20；ϊ時，每克製劑中，500國際單位雒生素A的含量 0 ί·Η齡例 依範例1裂備Carbopol凝膠，惟其中並不加入中鍵三酸 甘油酯。 hh » Sf. Μ 如範例2，比較例的凝膠被供Μ對應含量的維生素Α的 棕櫊睃酯。 無三酸甘油酯成分的維生素A製劑的樣品，一齊和依 範例2的對應樣品，在橒準條件下被貯存。經歷整整六個 月的貯存期後，在無三酸甘油酯成分的比較樣品的維生素 A的含量下降了 207·的量。而依範例2的樣品，在測量準確 度内，雄生素A的含量被發現保持不變。 n^— ^^^1 —^n m ^^^^1 n^v I ^^^1 —Εϋ ^^^1 ^^^1 m ¾i (請先閲讀背面之注意事項再填寫本頁) 本紙张尺度適用中國國家標隼（CNS ) A4規格（210XZ97公釐） 12Α7 Β7 Printed by the Consumer Cooperatives of the Central Bureau of Quasi-Economic Bureau of the Ministry of Economic Affairs 5. Description of the invention (1) The present invention relates to a sterile liquid ophthalmic preparation that can be used in the form of drops, especially as an artificial tear to treat "dry eye disease" ", And M is a method for preparing this gel cleaving agent. The use of aqueous preparations to replace natural tears M and to treat "dry eye disease" has been around for many years. Such an aqueous preparation contains, for example, a film-forming substance mainly composed of polyvinyl enzyme (PVOH), polyvinylpyrrolidine (PVP), a vitamine derivative or dextran. An overview of this can be found in, for example, Sucker, Fuchs and Speiser's 蕖 Technology of 蕖, 1978. These, in general, are systems containing only a single stream or liquid tangerine. Typically, it is an aqueous solution of other ingredients. When water-insoluble or water-insoluble ingredients are present, they are in a finely divided form and suspended in water orange. In semi-synthetic preparations * such as those mainly composed of cellulose derivatives or dextran, due to these materials, it is difficult to obtain the absence of insoluble ingredients, making the preparation more difficult. It is therefore necessary to use very costly methods from these preparations to prepare solutions that do not cause eye strain caused by organic maple action. Furthermore, because they can only be doped, or can't be ridden or removed fungus at all, these preparations are very difficult to sterilize. And they can not be sterilized at high temperature and pressure without compromising their quality. It is impossible to carry out sterilization by high temperature and high pressure without causing irreversible viscosity change. The preparation of glucosinolate is partially decomposed at high temperature and high performance. Moreover, polyvinyl alcohol can only be sterilized by heating in a very pure hydrolyzed form. This is because otherwise, the PVOH component would be depolymerized. Since PVOHM and PVP can only provide a low-density effect, it is necessary to use a relatively high amount of these ingredients to provide suitable viscosity. This will cause eye use (please read the note on the back before filling out this page) This paper size applies the Chinese Family Standard (CNS) A4 specification (210X297 mm) 4 瞠 4386 0 2 Employee Consumer Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs Printed A7 B7 V. Description of the invention (2) The high amount of these ingredients in the preparation, for example, in the case of PV0H * contains more than 10%: Dong. It is disclosed in DE 34 40 352 and DE 43 03 8UM and US 5,252,318 that polyacrylic acid and its derivatives, such as Carbopol 940 (available from B.F. Goodrich), are used for sterile ophthalmic drops. preparation. In the US 5,441,732 patent with the publication date being the priority date of the present invention, a combination of two specific gel sleeping ingredients has been disclosed, one of which is thermal gelation, and the other is a change in M PH value to gel. Various derivatives of streptavidin are described as heat-reactive gel polymers * while polyacrylates, especially cross-linked polyacrylates, are mentioned, and their polymer gelling systems are based on pH It depends. At this time, it is obvious that the formation of the gel only occurs in the eye, and the pH change occurs due to the administration of the drug. Name * These polymer blends are used in combination with organic oils that dissolve a variety of active agents. Vitamin A was not mentioned. Ophthalmic preparations used as film-forming or lubricating preparations must comply with extremely high standards in terms of compliance, non-stinging properties, and sales period. In particular, when the ophthalmic preparations must be used for a long period of time, such as the general case of "dry eye treatment". Even when the temporary irritation, such as a burning sensation in the eye, is quite uncomfortable, any long-term treatment Can cause harm. In the application of such ophthalmic preparations, if there is abnormal vision, blurry or other acute irritant side effects, it is unacceptable. In the treatment of "dry eye disease". Vitamin A in the form of palmitate of vitamin A is considered to be effective. Therefore, K Carbopo1-based condensate drop preparations have been sold (after the priority of the present invention) The paper standard is applicable to Chinese national standards (CNS) Λ4 specification (2) 0X297 Gongchu t— nn ^ in ^ i I- (Please read the precautions on the back before filling in this page) Order 5 02 A7 B7 Printed by the Employee Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 5. Description of the invention (3). In addition to other commonly known ingredients, this preparation also contains palmitate salt of vitamin A. These single-phase gels have a continuous aqueous liquid phase, but do not contain any other hydrophobic properties. Liquid orange. These preparations, when When the content of the element A exceeds 40¾, the sales period is about one year. Tests have shown that in these preparations, the vitamin A content will be reduced by about 20¾ every more than half a year, which is K, at a dose of more than 40Z There is still a guaranteed minimum content after one year. Natural tears also contain fatty components consisting of triglycerides and phospholipids. It has also been «try (WO 94/05298) to use triglycerides in synthetic tears It is only possible when the emulsifier is added. When topically applied to the eye, the entire formulation is in the form of an emulsion. This has the disadvantage that the appropriate residual amount of natural tears in the eye is emulsified. It is an important object of the present invention to provide an ophthalmic preparation, especially a gel preparation, with an improved shelf life. In particular, when it contains sensitive substances such as vitamin A and its derivatives, This is more so. Another important object of the present invention is to provide a preparation that does not cause acute irritation, especially when it is prepared to increase the time limit of its sales period. Another important object of the present invention is to provide a preparation, It makes it possible to use the formulation repeatedly over a long period of time; and / or after each application, it stays in the eye for a long time without causing incompatibility, or lack of compliance, or irritation of the eye. Possibly. The present invention is based on various surprising findings. On the one hand, it is surprising that when the lysing agent is presented in a two-component system with an aqueous liquid phase and a hydrophobic liquid phase, In artificial tears and preparations used for "dry eye disease", Biotin A and its derivatives are to be kept intact (please read the precautions on the back before filling this page). Standard (CNS) A4 specification (210X297 completed) Consumption cooperation between employees of the Central Bureau of Commerce, Ministry of Economic Affairs, Du Yinfan A7, B7, A 'Invention Description (4) The palmitate of biotin A will be decomposed quickly, and it will be urgent. To reduce. In particular, the formulation in which K is provided with a continuous aqueous phase of a hydrophobic liquid-oil phase in the form of very fine droplets is particularly preferred. It is difficult to explain this fact. It is most likely that the oxygen and / or light system caused the bright bonds of vitamin A to break down, and for both, the base formulation should contain one or two separate liquid oranges that should not cause any substantial difference. Perhaps someone would have expected that "a solution of the vitamin A component in the hydrophobic phase * would be more sensitive to oxygen and / or light. Where possible, the combined use of antioxidants, especially vitamin E and its derivatives, especially vitamin ε acetate, can affect these formulations. In any case, in the preparation of the present invention, vitamin A is preferably used together with these antioxidants. On the other hand * another surprising finding of the present invention is that it makes it possible to prepare formulations with aqueous and liquid hydrophobic phases very close to the composition of natural tears. In particular, it has the corresponding triglyceride content without the need to use an emulsifier at the same time. This is possible because the tincture preparation is in the form of a gel drop tincture according to the present invention. Compared to formulations without any gel matrix, the triglycerides in the gel formulations of the present invention can be provided in the form of very finely divided droplets during very long storage periods * without the presence of any emulsifiers. The droplets are quite stable in the gel. The preparation of these bacteria-free formulations can be done without difficulty, and the formulations are not irritating | so the local ideal. Formulations of the invention containing gel formulations * have almost the same refractive index as natural tears. They provide long-term results in the eyes. The preparation of the present invention is shown to be capable of condensing water-based eyes and providing a smaller surface. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2.0 × 297 mm) -I --- τ ---- pack- --(Please read the precautions on the back before filling in this page) 7 Consumption cooperation by employees of the Central Standards Bureau of the Ministry of Economic Affairs, printed A7 __B7 V. Description of the invention (5) Tension, so it can be good on the cornea distributed. At the same time, any active agent dissolved or suspended in the oil phase can be more evenly distributed. The wettability of the object to be placed on the cornea, such as the front lens of an eyeglass or an ophthalmic device, can be improved. Long-term investigations have shown that the formulation of the present invention is stable in a commercially available 5-gram multi-foil tube package. This is not only the case in temperate climates (1YC, 45¾ relative humidity), in the Mediterranean / subtropical climate (26 ^ C, 60¾ relative humidity), or even very hot and humid climates (31 ° C, 70¾ orange to humidity) ), It shows almost no changes in vitamin A content (if provided), pH, osmotic pressure, viscosity and appearance. Basically, these ophthalmically acceptable organic oils are suitable for the liquid hydrophobic component of the two-phase preparation of the present invention, especially the gel, which can be dispersed in the form of droplets in the absence of an emulsifier. In the water phase. Examples of fatty acid derivatives include fatty acid esters, triglycerides and peptidic acid esters. Triglycerides are currently preferred, especially homogeneous or mixed triglycerides formed mostly or entirely of Ce-C13 fatty acids. In particular, mesotrimethylene glycol as defined in the "German Pharmacopoeia" (DAB) 10 (1993) is preferred. The acid content of these triglycerides is at least 95X a mixture of n-octanoic acid and n-decanoic acid; the rest are composed of shorter fatty acids. These triglycerides are semi-synthesized from the dried solid part of the endosperm of coconut (cocos nucifera L.). The method is to hydrolyze coconut oil derived from endosperm, tiller the fatty acid obtained, and then re-acetate the acid. These medium-chain triglycerides have been used as basic substances in cosmetics * Agents and carriers, as well as certain foods. However, there are I.--I Hi I---I. r I- «^^^ 1 --if I --5J (Please read the precautions on the back before filling this page) This paper size is applicable to China National standard (CNS > A4 specification (210X297 mm) A7 B7 V. Description of invention (6) Little is known about the potential and limitations of these uses in ophthalmic preparations, even though medium chain triglycerides There are many known beneficial properties. The cleavage agent of the present invention, especially a gel, has a typical content as a gel-forming agent in the aqueous phase, which is between 0.1 and 3 by weight X, especially about 0.2% by weight preparation of polypropylene hydrazone, typically containing 0.5 to 10% by weight; especially, about 1% by weight of S: these medium-bond triglycerides. The coagulant preparation of the present invention preferably has a pH value of 6 Viscosity in the range of about 2000 to 6000 mPa between 8 and 8. The preparation of the present invention preferably contains a preservative, especially such as centrimid, vaporized benzyl ammonium, or salicylate. Yes, these coagulated preparations contain at least one isotonic agent, and M sorbitol is a suitable alternative. Vitamin A ingredients, especially vitamin A palmitic acid Its particularly good content is at the level of 500 international units per gram of the invention. The vitamin A component is preferably stabilized with a small amount of at least one antioxidant, among which vitamin E and vitamin E acetate For the benefit of others, printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs n- J- I —J, n I n, installed — — II — order (please read the precautions on the back before filling this page) The present invention is sterile The preparation of the preparation, especially the gel, is carried out in multiple steps. In the preparation of the gelatin, the sterile polyacrylic acid suspension is preferably obtained by the steps shown in DE 4 3 03 818. That is, using about 12 〇 ° C, 1 bar overpressure, high-temperature high-temperature sterilization for 20 minutes. At the same time, prepare an aqueous solution containing preservatives and isotonic agents, preferably Centennial limbs and sorbic acid. Use radon as pressurized air Or more simply use pressurized air and use sterile filtration to add this aqueous solution to a high temperature and high pressure sterilized polyacrylic acid suspension. Then, carefully neutralize by adding a sterile sodium hydroxide solution, starting from Gel formation begins. Once in After completion, the national standard (CNS) A4 specification (210X297 mm) 1194386 02; 'Α7 Β7 Central Government Bureau of Ministry of Economic Affairs, Ministry of Economic Affairs, Ministry of Economic Affairs and Consumer Consumption Co-operation, Printing Policy, and Invention Description (7 ) In the gel, there is no more free tincture. The hydrophobic liquid component, that is, the middle bond triglyceride is best, and then in a sterile state, into the sterile gel. Keep stirring until the whole is homogenized Achieved. In the homogeneous liquid of the present invention, the size of the oil droplets thus obtained is about 100 W π at the maximum, and therefore, this is different from the conventional emulsion obtained without adding a strong emulsifier. The sterile gel can then be prepared in a conventional manner. Moss, active agents, especially palmitic acid esters such as vitamin A, can be added to the sterile gel so formed, so that the biotin A component and a small amount of the best antioxidant that is also present * are dissolved to neutrality Oil and then sterile filtered. Second, the sterile oil solution is stirred into the gel. When the formulation is gel-free, it is performed using a peer-to-peer procedure, for example, as a drop. The gel former used in accordance with the present invention is preferably a polyacrylic acid having a molecular weight in the range of about 3 to 5 million. In particular, commercial products such as Car bopol polymeric acids, such as Carbopol 980 NF, commercially available from B. F. Goodrich, are preferred. In this formulation, the concentration is about 0.2% by weight. The neutralization required for gel formation can be performed in a known manner using a sterile dilute sodium hydroxide solution, of which M 1N sodium hydroxide solution is particularly advantageous. However, other inorganic bases or alkali metal carbonates, or organic bases such as amines, especially triethylamine and diisopropylamine, can also be used. The viscosity of the gel thus obtained is in the range of 2000 to 6000® Pa at 20 ° C. According to the preservatives commonly used in the present invention, such as Centramide, benzalkonium chloride or salicylate, etc. Known concentration, that is, use Moriichi (please read the notes on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (21〇 > < 297mm) 10 Ministry of Economic Affairs Printing of A7 B7 by the Consumer Cooperatives of the Central Bureau of Prototype and V. 5. Description of the Invention (8) In the case of amidine, it is about 0.01 weight2. Isotonic agents, such as polyfunctional enzymes * such as glycerol, dextran, glycerol * propylene glycol, or particularly preferred sorbitol, can also be used at known concentrations. In the case of sorbitol, a concentration of about 4.85 ¾ weight S; is preferred. The invention will be further described with a two-tooth embodiment. Example 1 A 2000 kg polyacrylic acid < Carbopol 980 ΝΠ homogeneous suspension suspended in about 375 kg of water was once injected into a processing device through a plutonium having a hole size of about 25 to 40 μn, and entered the processing device. . Then at 121. (: Sterilize with high pressure and high temperature for 20 minutes at 1 bar overpressure, then cool down to room temperature, and use a sterilizing air filter to provide atmospheric pressure. At the same time, put 964 kg of water in a suitable container "and mix under * Dissolve Centramide first, and then dissolve 48.510 kg in water. This solution is then re-used with a steam sterilization filter with a pore size of 0.2w. As a plasticizing gas. Next, the device is evacuated one or more times to remove possible foam. Secondly, under stirring and aseptic conditions, 0.38 kg of sodium hydroxide is dissolved into about 20 kg of water. Hydroxide The nano-system is filtered by passing through a steam sterilization membrane and added to the Centramide / Sorbitol / Polyalcohol suspension. Then, the remaining amount of water is added. The homogenizer is used to process the plant. After that, the medium bond triglycerol 01 was passed through a sterilizing filter with a hole size of 0.2 wa, added to the sterile gel, and then mixed until it reached a completely homogeneous paper. (CNS) A4 Grid (210 X 297 mm) (Please read the precautions on the back before filling out this page) Installation, Tr 11 The Central Building of the Ministry of Economy must cooperate with employee consumption Du Yince A7 B7 V. Invention Description (9). Measurement The pH of the formed gel should be 6 to 8 at 20 ° C. The osmotic pressure of the preparation of the present invention is in the range of 260 to 320 hOsb / Ks. The gel formed in this way is aseptically * Fill it into a 5 g multi-foil tube. Example 2 Dissolve 0.6 g of biotin A palmitate and 0.03 g of vitamin E acetate in 9.37 g of neutral oil (Myritol 318). Let The solution was filtered through a 0.22 wm filter to make it sterile. 10 g of a neutral oil solution was added to the 990 g of the gel prepared according to Example 1, and it was introduced into the gel using a wing stirrer. After 20 minutes of mixing, the resulting product is filled into a 10-gram multi-foil tube. This gel corresponds to a content of 500 international units of biotin A per gram of preparation when it exceeds 20; The carbopol gel was prepared according to Example 1, but the middle bond triglyceride was not added. Hh »Sf. Μ As in Example 2, the gel of the comparative example Provides palmitoyl esters of vitamin A with corresponding content of M. Samples of vitamin A preparations without triglyceride components are stored together with the corresponding samples according to Example 2 under standard conditions. After six full months of storage After that period, the vitamin A content of the triglyceride-free comparison sample decreased by 207 ·. According to the sample of Example 2, the content of androgen A was found to remain unchanged within the measurement accuracy. N ^ — ^^^ 1 — ^ nm ^^^^ 1 n ^ v I ^^^ 1 —Εϋ ^^^ 1 ^^^ 1 m ¾i (Please read the precautions on the back before filling this page) This paper size Applicable to Chinese National Standard (CNS) A4 (210XZ97 mm) 12