491712 A7 _____B7 _ 五、發明說明（ί ) 本發明關於一種如包括作爲一種活性成份之環孢菌素 的軟膠囊製劑。更精確地說，本發明關於一種軟膠囊製劑， 其包括一種於包含特定成形劑之明膠囊殼內之穩定的環孢 菌素組成物，以及其製備方法。 環孢菌素是一種特殊的大分子（分子量1 2 0 2 · 6 4) 環肽化合物，其由1 1個胺基酸所組成，其具有廣泛有效 之藥理活性範圍，特別是免疫抑制活性和抗炎活性。因此， 環孢菌素已被使用在抑制活體於組織和器官移植時，所導 致之先天免疫反應，例如心臟、肺臟、肝臟、腎臟、胰臟、 骨髓、皮膚和角膜之移植，以及特別是外來組織和器官之 移植。此外，環孢菌素可以有效抑制血液疾病如貧血；不 同的自體免疫病如全身性紅斑狼瘡、自發性吸收障礙徵候 群等；以及炎性疾病如關節炎、類風溼病等。環孢菌素可 以有效治療原蟲病如瘧疾、血吸蟲病等，以及此外，最近 其亦被使用在化學療法。 環孢菌素具有高度親脂肪性和疏水性。因此，環孢菌 素缺少可溶於水的特性，及此外其可溶於有機溶劑如甲 醇、乙醇、丙酮、乙醚、氯仿及相同性質之溶劑。由於環 孢菌素具有上述之低水溶性的性質，當環孢菌素以口服的 方式施藥時，其生物可用度相當低且可因每一個別患者之 狀況而受到極度影響。由上所述，其很難保持有效治療濃 度。而且，環孢菌素可能顯示出値得注意之副作用如毒腎 性。因此，環孢菌素由於其低水溶性，而很難製備成口服 施藥之製劑，由上所述，數目眾多的硏究報告已經被引導 3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)491712 A7 _____B7 _ V. Description of the Invention (ί) The present invention relates to a soft capsule preparation such as that comprising cyclosporin as an active ingredient. More specifically, the present invention relates to a soft capsule preparation including a stable cyclosporin composition in a capsule shell containing a specific forming agent, and a method for preparing the same. Cyclosporine is a special macromolecule (molecular weight 1 2 0 2 · 6 4) cyclic peptide compound, which is composed of 11 amino acids, which has a wide range of effective pharmacological activities, especially immunosuppressive activity and Anti-inflammatory activity. Therefore, cyclosporin has been used to inhibit the innate immune response caused by living tissue and organ transplantation, such as heart, lung, liver, kidney, pancreas, bone marrow, skin and corneal transplantation, and especially foreign Tissue and organ transplants. In addition, cyclosporin can effectively inhibit blood diseases such as anemia; different autoimmune diseases such as systemic lupus erythematosus and spontaneous malabsorption syndromes; and inflammatory diseases such as arthritis and rheumatism. Cyclosporine is effective in treating protozoal diseases such as malaria and schistosomiasis, and more recently, it has also been used in chemotherapy. Cyclosporine is highly lipophilic and hydrophobic. Therefore, cyclosporin lacks water-soluble properties, and in addition, it is soluble in organic solvents such as methanol, ethanol, acetone, ether, chloroform, and solvents of the same nature. Because cyclosporin has the aforementioned low water-solubility properties, when cyclosporin is administered orally, its bioavailability is quite low and can be extremely affected by the condition of each individual patient. From the above, it is difficult to maintain an effective therapeutic concentration. Furthermore, cyclosporin may show noticeable side effects such as toxic and renal properties. Therefore, cyclosporin is difficult to prepare for oral administration due to its low water solubility. From the above, a large number of research reports have been guided. 3 The paper standard is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the notes on the back before filling this page)
I 訂-l·---- 線丨t 491712 A7 _ B7___ 五、發明說明（，） 至如何發現一種適合作爲有效口服施與之環孢菌素製劑， 該製劑能提供合適的統一劑量及適當的生物可用度。 在先前技術中，適合口服施與之缺少水溶性的環孢菌 素製劑，通常已經被以一種先濃縮的乳劑形式製備。 一種典型的方法是使用於一九八三年六月十四日所發表之 美國專利案號4，3 8 8，3 0 7所教導之組合物。該專 利揭示一種使用乙醇之環孢菌素液體配方。根據該美國專 利說明書所揭示的方法，環孢菌素與一種由作爲一共同表 面活性劑之乙醇所組成之載體；作爲植物油之橄欖油；一 種天然植物油三甘油脂之轉酯化產物；及一種作爲表面活 性劑之聚烯屬烴基多元醇結合，以形成該液體配方。 然而，該產生之液體配方以一種水性稀釋藥施與時，其使 患者適合此施藥方式及於口服施藥時提供一統一劑量將變 得非常困難。 爲了減輕在口服施藥前，於水中稀釋環孢菌素液體組 成物之不便，一種以一先濃縮之乳劑形式之液體組成物已 經被製成一種軟膠囊製劑，目前該軟膠囊可自商業上如散 德依蒙（S andimmune )(註冊商標）獲得。在該案中，由 於環孢菌素溶解度之需要，該環孢菌素軟膠囊因而包含乙 醇。然而，既然乙醇即使在常溫下亦具揮發性，因而其可 滲透該膠囊之明膠殼，欲防止乙醇在儲存和供銷期間從軟 膠囊製劑中揮發，該軟膠囊製劑可被包裝在一特殊包裝材 料內，例如，一種鋁一鋁發泡包裝。 最近發展一種在儲存期間具有穩定性’及進一步提供實質 4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公t ) (請先閱讀背面之注意事項再填寫本頁) _· »* 訂---------線-- 491712 A7 _____Β7___ 五、發明說明（々） 地不會改變其生物可用度，和在個別患者間之差異性的環 孢菌素製劑已成爲可能，因而可統一地維持該環孢菌素之 生物效果。一種以此目的而發展的製劑，其揭示於韓國公 開專利公告案號9 3 - 1 1 3，該製劑已用散德依蒙尼歐 熱（Sandimmun Neoral )之註冊商標商品化。然而，既然該 製劑亦使用乙醇，因此在該先前包含乙醇之製劑，於儲存 的穩定度及乙醇成份的改變上可能有一些缺點。 由上所述，本案發明者已經硏究在不同的表面活性 劑、油成份、共同表面活性劑等眾多組合中，發現一種具 有穩定及提供高度生物可用度之環孢菌素組成物，以及在 藥物動力學性質的觀點下，該環孢菌素組成物具有比其它 先前的環孢菌素製劑，於個別患者間之血液等級具有較低 的差異性。因此，我們已經鑑定出一種特定之環孢菌素組 成物，其包括如下所定義的組成份，並且其能滿足上述之 需求及能由本發明完成。 因此，本發明的一項觀點爲提供一種適合製成軟膠囊 配方之組成物，其包括作爲一種活性成份之環孢菌素；一 種親水性成份聚乙二醇或一種非親水性成份丙烯碳酸酯或 其混合物，一種如下所定義之油成份；及一種表面活性劑。 本發明更進一步之觀點爲提供一種軟膠囊製劑，其包 括一種包含作爲一種活性成份之環孢菌素組成物；一種親 水性成份聚乙二醇或一種非親水性成份丙烯碳酸酯或其混 合物，作爲一種油成份之一種脂肪酸和伯醇的酯化化合物 之混合物，中等鏈脂肪酸三甘油脂（如果需要的話）和脂 5 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) ·* 訂l·-------線—應 491712 A7 __B7_ 五、發明說明（4r ) 肪酸單酸甘油脂；及一種具有H L B (親水親油平衡）値 8至1 7之表面活性劑。 本發明另外更進一步的觀點爲提供一種用來製備如上 述定義之軟明膠囊製劑之方法。 即使本發明.此處所描述的內容，特別是關於軟明膠 囊，但可以了解的是，本發明涵蓋的範圍包括該組成物本 身可作爲如一種飮料溶液，例如，散德依蒙尼歐熱 (Sandimmun Neoral )，或是其它統一劑量形式。 在一項觀點下，本發明關於一種包含環孢菌素之膠 囊，該膠囊具有高度儲存穩定性，在一段時間後，組成物 不會有太大變化，且可增進生物可用度，其包括一種包含 作爲一種活性成份之環孢菌素組成物；作爲第二成份之一 種親水性成份聚乙二醇或一種非親水性成份丙烯碳酸酯或 其混合物，一種如下所定義之油成份；及一種表面活性劑。 欲將該包含環孢菌素之組成物製成軟膠囊製劑時，須 使用一種明膠殼。然而，當軟膠囊以一般包含作爲成形劑 之甘油的膠囊殼所製成時，該軟膠囊製劑有一些缺點，由 於甘油之流入物在進入乳劑時，在該先濃縮之乳劑的乳化 狀態因而可能改變，因此，使該環孢菌素之溶解度明顯降 低而導致環孢菌素自乳劑中沉澱。 由上所述，本發明較佳之一種明膠殼是使用一種丙二 醇及聚乙二醇之混合物作爲軟膠囊殼之成形劑，而不是甘 油，其可解決關於甘油之流入物的問題。 然而，根據本發明當該包含丙二醇及聚乙二醇之膠囊 6 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) 訂-卜-------線」 491712 A7 ___B7 _ 五、發明說明（< ) 殼帶藉由一種傳統地使用冷卻圓筒之水冷卻法製備而成 時，該膠囊殼帶不容易從圓筒中移除。該膠囊殼帶從冷卻 圓筒移除的可移動性，可藉由使該冷卻圓筒過冷而得到改· 善，可藉一冷卻水連續循環以降低該帶之溫度至攝氏1 7 度。然而，被冷卻到低溫之膠囊殼帶在包膜製程期間’可 能形成低程度之密封及導致生產力的低落。 因此，根據本發明製備不含甘油成形劑之明膠殼帶的 方法，爲採用一種空氣冷卻法，代替先前水冷卻法’該膠 囊殼帶藉由風扇所供應之氣流，而被冷卻到最適溫度，因 此，能很容易地自冷卻圓筒移除，且更進一步，該膠囊殼 帶被保持在最適溫度大約攝氏2 1度，以增加其在包膜製 程的封裝程度及確保高生產力。 如上所述，該產物藉由使用無甘油明膠膠囊殼，及對 該不含低沸點揮發性溶劑之乙醇的組成物使用空氣冷卻法 而被生產出來，因此，其具有高度儲存穩定度，在一段時 間後，該組成物少有變異且可增加生物可用度。 更精確地說，本發明關於一種環孢菌素製劑，其包括一組 成物，包含 1 )作爲一種活性成份之環孢菌素；. 2 )聚乙二醇或丙烯碳酸酯或其混合物； 3)作爲一種油成份之一種脂肪酸和伯醇的酯化化合物之 混合物，脂肪酸單酸甘油脂，和選擇地一種中等鏈脂肪酸 三甘油脂；及 4 ) 一種具有H L B (親水親油平衡）値8至1 7之表面 7 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 χ 297公爱） (請先閱讀背面之注意事項再填寫本頁) I--------訂---------線」 491712 A7 _____B7_____ 五、發明說明（W ) 活性劑。 例如，在一包含作爲成形劑之聚乙二醇及丙二醇的明 膠殼內，本發明之另一觀點提供一種環孢菌素製劑，其包 括一組成物，包含 1) 作爲一種活性成份之環孢菌素；及 2) 丙烯碳酸酯。 一組成物可選擇地添加任何其他此處所描述之成份， 則該組成物亦爲本發明之組成物，如果需要的話，其份量 可爲此處所描述。 根據本發明之環孢菌素被使用作爲該組成物之藥物活性成 份，如上所述，環孢菌素爲一具備有效免疫抑制活性及抗 炎活性之環肽化合物，雖然環孢菌素A、B、C、D、G 及同類物皆可作爲本發明之環孢菌素成份，既然環孢菌素 A其臨床效果及藥理性質已在此技術中被完整建立，因此 其爲最佳選擇。 根據本發明，作爲組成物之第二成份及共同表面活性 劑的聚乙二醇，其具有高沸點，非揮發性，不會滲透該軟 膠囊之明膠殼之性質，且對環孢菌素具有高溶解度，可使 用作爲親水性物質。根據本發明之組成物，雖然可使用任 何可液化之聚乙二醇，但具有分子量2 0 0至6 0 0之聚 乙二醇（PEG)，特別是PEG 200爲最佳。 兩者擇一地，丙烯碳酸酯（沸點約攝氏2 4 2度）亦可被 作爲非親水性成份。在本發明中，亦可使用上述定義之非 親水性物質及親水性物質之混合物。當本發明使用聚乙二 8 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)I order -l · ---- line 丨 t 491712 A7 _ B7___ V. Description of the invention (,) How to find a cyclosporine preparation suitable for effective oral administration, which can provide a suitable uniform dose and appropriate Bioavailability. In the prior art, cyclosporin preparations lacking water solubility suitable for oral administration have generally been prepared in the form of a first concentrated emulsion. A typical method is to use the composition taught in U.S. Patent No. 4,38,308, issued on June 14, 1983. The patent discloses a cyclosporin liquid formulation using ethanol. According to the method disclosed in the US patent specification, cyclosporin and a carrier composed of ethanol as a common surfactant; olive oil as a vegetable oil; a transesterified product of natural vegetable oil triglyceride; and a Polyolefinic hydrocarbon-based polyols as surfactants are combined to form the liquid formulation. However, when the resulting liquid formulation is administered as an aqueous diluent, it becomes very difficult for the patient to adapt the method of administration and to provide a uniform dose when administered orally. In order to alleviate the inconvenience of diluting the cyclosporin liquid composition in water before oral administration, a liquid composition in the form of a concentrated emulsion has been made into a soft capsule preparation. The soft capsule is currently commercially available Such as San Dei Meng (S andimmune) (registered trademark) obtained. In this case, the cyclosporine soft capsule thus contained ethanol due to the need for cyclosporin solubility. However, since ethanol is volatile even at normal temperature, it can penetrate the gelatin shell of the capsule. To prevent ethanol from volatilizing from the soft capsule preparation during storage and distribution, the soft capsule preparation can be packed in a special packaging material. Inside, for example, an aluminum-aluminum foam packaging. Recently developed a kind of "stability during storage" and further provides the substance 4 paper size applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 g t) (Please read the precautions on the back before filling this page) _ · » * Order --------- Line-491712 A7 _____ Β7 ___ 5. Description of the Invention (々) Land will not change its bioavailability, and the difference in cyclosporin preparations between individual patients has become possible Therefore, the biological effect of the cyclosporin can be uniformly maintained. A formulation developed for this purpose, which is disclosed in Korean Public Patent Publication No. 9 3-113, has been commercialized with the registered trademark of Sandimmun Neoral. However, since the formulation also uses ethanol, there may be some disadvantages in storage stability and changes in the ethanol composition of the previous formulation containing ethanol. From the above, the inventors of the present case have investigated various combinations of different surfactants, oil components, common surfactants, etc., and found a cyclosporin composition that is stable and provides a high degree of bioavailability. From the perspective of pharmacokinetic properties, the cyclosporin composition has lower blood grade differences among individual patients than other previous cyclosporin preparations. Therefore, we have identified a specific cyclosporin composition that includes the components defined below, and that meets the above-mentioned needs and can be accomplished by the present invention. Therefore, an aspect of the present invention is to provide a composition suitable for making a soft capsule formulation, comprising cyclosporin as an active ingredient; a polyethylene glycol with a hydrophilic ingredient or a propylene carbonate with a non-hydrophilic ingredient. Or a mixture thereof, an oil component as defined below; and a surfactant. A still further aspect of the present invention is to provide a soft capsule preparation comprising a cyclosporin composition as an active ingredient; a hydrophilic ingredient polyethylene glycol or a non-hydrophilic ingredient propylene carbonate or a mixture thereof, A mixture of fatty acids and primary alcohol esterified compounds as an oil component, medium chain fatty acid triglycerides (if required) and fats 5 This paper is sized to the Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) · * Order l · ------- line—should 491712 A7 __B7_ V. Description of the invention (4r) Fatty acid monoglyceride; Hydrophilic-lipophilic balance) 8 to 17 surfactants. A still further aspect of the present invention is to provide a method for preparing a soft and soft capsule formulation as defined above. Even with the present invention, what is described herein, especially with regard to soft capsules, it can be understood that the scope of the present invention includes that the composition itself can be used as, for example, a concoction solution, for example, San de Imonio fever ( Sandimmun Neoral), or other uniform dosage forms. In one aspect, the present invention relates to a capsule containing cyclosporin, which has a high storage stability. After a period of time, the composition does not change much, and it can improve bioavailability. A cyclosporin composition as an active ingredient; a polyethylene glycol as a hydrophilic ingredient or a propylene carbonate as a non-hydrophilic ingredient or a mixture thereof as a second ingredient; an oil ingredient as defined below; and a surface Active agent. To make the cyclosporin-containing composition into a soft capsule preparation, a gelatin shell is used. However, when a soft capsule is made of a capsule shell that generally contains glycerin as a shaping agent, the soft capsule preparation has some disadvantages. As the glycerol influent enters the emulsion, the emulsified state of the previously concentrated emulsion is thus possible. The change, therefore, significantly reduces the solubility of the cyclosporin and causes precipitation of the cyclosporin from the emulsion. From the above, a preferred gelatin shell of the present invention is to use a mixture of glycerol and polyethylene glycol as a molding agent for a soft capsule shell, rather than glycerin, which can solve the problem of influx of glycerin. However, according to the present invention, when the capsule containing propylene glycol and polyethylene glycol 6 paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) Order -Bu ------- line "491712 A7 ___B7 _ 5. Description of the invention (<) When the shell belt is prepared by a traditional water cooling method using a cooling cylinder, the capsule shell belt is not easy to remove Remove from the cylinder. The movability of the capsule shell belt removed from the cooling cylinder can be improved by making the cooling cylinder too cold, and a cooling water can be continuously circulated to reduce the temperature of the belt to 17 degrees Celsius. However, the capsule shell tape cooled to a low temperature may form a low degree of sealing during the coating process and cause a decrease in productivity. Therefore, according to the present invention, the method of preparing a gelatin shell tape without glycerin forming agent is to use an air cooling method instead of the previous water cooling method. The capsule shell tape is cooled to an optimal temperature by the air flow supplied by a fan. Therefore, it can be easily removed from the cooling cylinder, and further, the capsule shell strip is maintained at an optimal temperature of about 21 degrees Celsius to increase its degree of packaging in the coating process and ensure high productivity. As described above, the product is produced by using a glycerin-free gelatin capsule shell and using an air-cooling method for a composition containing no low-boiling volatile solvent ethanol, and therefore, it has a high degree of storage stability. After time, the composition has few variations and can increase bioavailability. More precisely, the present invention relates to a cyclosporin preparation comprising a composition comprising 1) cyclosporin as an active ingredient; 2) polyethylene glycol or propylene carbonate or a mixture thereof; 3 ) A mixture of an esterified compound of a fatty acid and a primary alcohol as an oil component, a fatty acid monoglyceride, and optionally a medium-chain fatty acid triglyceride; and 4) an HLB (hydrophilic-lipophilic balance) 値 8 to 1 7 of the surface 7 This paper size applies the Chinese National Standard (CNS) A4 specification (21〇χ 297 public love) (Please read the precautions on the back before filling this page) I -------- Order-- ------- line "491712 A7 _____B7_____ 5. Description of the invention (W) Active agent. For example, in a gelatin shell containing polyethylene glycol and propylene glycol as forming agents, another aspect of the present invention provides a cyclosporin preparation comprising a composition comprising 1) cyclosporin as an active ingredient Bacteriocin; and 2) propylene carbonate. A composition may optionally include any other ingredients described herein, and the composition is also a composition of the present invention, and its portion may be described herein if necessary. The cyclosporin according to the present invention is used as a pharmaceutically active ingredient of the composition. As described above, cyclosporin is a cyclic peptide compound having effective immunosuppressive activity and anti-inflammatory activity. Although cyclosporin A, B, C, D, G and the like can be used as the cyclosporin component of the present invention. Since the clinical effect and pharmacological properties of cyclosporin A have been completely established in this technology, it is the best choice. According to the present invention, polyethylene glycol, which is the second component of the composition and a co-surfactant, has a high boiling point, is non-volatile, does not penetrate the gelatin shell of the soft capsule, and has the property of cyclosporin High solubility, can be used as a hydrophilic substance. According to the composition of the present invention, although any liquefiable polyethylene glycol can be used, polyethylene glycol (PEG) having a molecular weight of 200 to 600, especially PEG 200 is most preferable. Alternatively, propylene carbonate (boiling point is about 242 ° C) can also be used as a non-hydrophilic ingredient. In the present invention, a mixture of a non-hydrophilic substance and a hydrophilic substance as defined above may also be used. When this invention uses polyethylene 8 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)
491712 A7 ___^____ —一 五、發明說明（7 ) 醇及丙烯碳酸酯之混合物作爲組成物時，其重量組成比例 通常爲1 : 0 · 1 — 5，較佳爲1 : 0 · 1 - 3，更佳爲 1 : 0 · 2 - 2。 在本發明中，使用聚乙二醇及丙烯碳酸酯可提供若干 優點，即改善該包含環孢菌素之組成物在儲存期間的穩定 度，且因此該組成物包含之成份的含量，實質上可統一地 保持。此外，使用丙烯碳酸酯可增加活性成份環孢菌素之 溶解度，且抑制水從明膠膠囊殼流入組成物中，因而提供 較穩定之組成物。 在本發明之組成物中，該第二成份較佳是使用以每一 份重量的環孢菌素爲基準之比例爲0 . 1至10，更佳爲 〇.5至8，最佳爲1至5。 根據本發明之第三成份是使用先濃縮之乳劑作爲一種 油成份。可使用脂肪酸和伯醇的酯化化合物之混合物，中 等鏈脂肪酸三甘油脂（當存在時）和脂肪酸單酸甘油脂作 爲本發明之油成份。使用於本發明之脂肪酸和伯醇的酯化 化合物可包括具有8至2 0個碳原子之脂肪酸，及具有2 至3個碳原子之伯醇的一種酯化化合物，例如，肉豆蔻酸 異丙酯、軟脂酸異丙酯、亞油酸乙酯、油酸乙酯等，以亞 油酸及乙醇之酯化化合物特別佳。此外，最佳是使用一種 具有8至10個碳原子飽和脂肪酸的三甘油脂與作爲飽和 脂肪酸之植物油三甘油脂的辛酸/癸酸三甘油脂，作爲中 等鏈脂肪酸三甘油脂（當存在時）。在本發明中使用作爲 油成份之脂肪酸單酸甘油脂，其包括具有1 8至2 0個碳 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) -I-------丨訂--------- 491712 A7 _______B7_ 五、發明說明（2 ) 原子之脂肪酸單酸甘油脂，特別是油酸單酸甘油脂。 根據本發明的先濃縮之微乳劑中，該油成份可使用以 每一份重量的環孢菌素爲基準之比例爲1至1 0，較佳爲 2至6。 較佳地，作爲油成份之脂肪酸單酸甘油脂及脂肪酸酯 類的比例，例如，1 : 1至1 : 2，例如，1 ·· 1至1 : 1 · 2 〇 亦可選擇地使用辛酸/癸酸三甘油脂，例如亞油酸乙 脂之比例從1 : 0 · 1至0 · 2。 根據本發明所使用作爲油成份之油混合物中，該脂肪 酸單酸甘油脂：一脂肪酸及伯醇之酯化化合物：中等鏈脂 肪酸三甘油脂（當存在時）之混合比例以重量爲基準，通 常在1 : 0 . 1 - 5 : 0 · 1 — 10的範圍內，較佳在1 : 〇·1 — 3·〇：〇·1 — 3.0的範圍內。 根據本發明所使用作爲組成物之第四成份爲表面活性 劑。使用於本發明適合之表面活性劑包括任何具有H L Β (親水親油平衡）値8至1 7之藥物可接受表面活性劑， 該表面活性劑可穩定乳化組成物之親油性部份，其包括該 包含環孢菌素之油成份及該親水性部份其包括共同表面活 性劑於水中形成一穩定微乳劑。根據本發明較佳之表面活 性劑範例，包括氫化植物油之聚氧乙烯產物、聚氧乙烯山 梨醇脂肪酸酯及其類似物，例如，Ν I Κ Κ〇L H C〇一 5 0 ^ Ν I Κ Κ 0 L HC〇一40、NIKK〇L H C 〇〜60、聚山梨醇酯二十（TWEEN 20)、聚 10 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)491712 A7 ___ ^ ____ —15. Description of the invention (7) When a mixture of alcohol and propylene carbonate is used as a composition, the weight composition ratio is usually 1: 0 · 1-5 and preferably 1: 0 · 1-3 , More preferably 1: 0 · 2-2. In the present invention, the use of polyethylene glycol and propylene carbonate can provide several advantages, namely, improving the stability of the cyclosporin-containing composition during storage, and therefore the content of the ingredients contained in the composition is substantially Can be maintained uniformly. In addition, the use of propylene carbonate can increase the solubility of the active ingredient cyclosporin and inhibit water from flowing into the composition from the gelatin capsule shell, thereby providing a more stable composition. In the composition of the present invention, the second component preferably uses a ratio of 0.1 to 10, more preferably 0.5 to 8, and most preferably 1 based on the weight of cyclosporin per serving. To 5. The third ingredient according to the present invention is to use a previously concentrated emulsion as an oil ingredient. Mixtures of fatty acid and primary alcohol esterified compounds, medium chain fatty acid triglycerides (when present) and fatty acid monoglycerides can be used as the oil component of the present invention. The esterified compound of a fatty acid and a primary alcohol used in the present invention may include a fatty acid having 8 to 20 carbon atoms, and an esterified compound of a primary alcohol having 2 to 3 carbon atoms, for example, isopropyl myristate Esters, isopropyl palmitate, ethyl linoleate, ethyl oleate, etc., esterified compounds with linoleic acid and ethanol are particularly preferred. In addition, it is best to use a triglyceride having a saturated fatty acid of 8 to 10 carbon atoms and a caprylic / capric triglyceride as a vegetable oil triglyceride as a saturated fatty acid, as a medium chain fatty acid triglyceride (when present) . The fatty acid monoglyceride used as an oil component in the present invention, which includes 18 to 20 carbons 9 The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the back first Please pay attention to this page, please fill in this page) -I ------- 丨 Order --------- 491712 A7 _______B7_ V. Description of the invention (2) Atomic fatty acid monoglycerides, especially oleic acid Monoglycerides. In the pre-concentrated microemulsion according to the present invention, the oil component can be used in a ratio of 1 to 10, preferably 2 to 6, based on the weight of each cyclosporin. Preferably, the ratio of fatty acid monoglyceride and fatty acid ester as the oil component is, for example, 1: 1 to 1: 2, for example, 1 ·· 1 to 1: 1 · 20. Alternatively, caprylic acid / The ratio of triglyceride decanoate, such as ethyl linoleate, is from 1: 0 · 1 to 0 · 2. In the oil mixture used as the oil component according to the present invention, the mixing ratio of the fatty acid monoglyceride: an esterified compound of a fatty acid and a primary alcohol: a medium chain fatty acid triglyceride (when present) is based on weight, and generally It is in the range of 1: 0. 1-5: 0 · 1-10, and preferably in the range of 1: 0 · 1-3 · 0: 0 · 1-3.0. The fourth component used as a composition according to the present invention is a surfactant. Suitable surfactants for use in the present invention include any pharmaceutically acceptable surfactant having HL Β (hydrophilic-lipophilic balance) 値 8 to 17, which can stabilize the lipophilic portion of the emulsified composition, including The cyclosporin-containing oil component and the hydrophilic portion include a common surfactant to form a stable microemulsion in water. Preferred examples of surfactants according to the present invention include polyoxyethylene products of hydrogenated vegetable oils, polyoxyethylene sorbitol fatty acid esters, and the like, for example, N I KK KOLHC 0-5 0 ^ N I KK 0 L HC〇-40, NIKK〇LHC 〇 ~ 60, Polysorbate Twenty (TWEEN 20), Poly 10 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the back first (Notes for filling in this page)
491712 A7 __ B7 _ 五、發明說明（f ) 山梨醇酯廿一（TWEEN 21)、聚山梨醇酯四十（丁 WEEN 40)、聚山梨醇酯六十（TWEEN 60)、 聚山梨醇酯八十（TWEEN 80)、聚山梨醇酯八十 -(TWEEN 8 1 )等，特別地，較佳使用是一種商品 化商標 NIKKOL HCO—50 ( N I K K 0 Chemical Co·，Ltd·)聚氧乙烯（5 0 )氫化蓖麻油及一種 商品化商標T W E E N 20 ( I C I Chemicals )聚氧 乙烯（2 0 )山梨醇單桂酸酯，其具有低於1之酸値，約 4 8至5 6之皂化値，約4 5至5 5羥基値及4 · 5至7 . 〇 的 pH 値（5 %)。 該表面活性劑可包括任何上述之表面活性劑單獨使 用，或較佳地，從上述表面活性劑中選擇兩種或兩種以上 之表面活性劑共同使用。根據本發明之組成物中，該表面 活性劑可使用以每一份重量的環孢菌素爲基準之比例爲1 至10,較佳爲2至8。 此外，當兩種表面活性劑之混合物，即使用於本發明 之組成物中的聚氧乙烯（5 0 )氫化蓖麻油及聚氧乙烯（2 0 )山梨醇單桂酸酯，該聚氧乙烯（5 0 )氫化蓖麻油： 聚氧乙烯（2 0 )山梨醇單桂酸酯之構成比例以重量爲基 準，較佳爲在1 : 0 · 1 — 5的範圍內，更佳爲在1 : 0 · 5 — 4的範圍內。 根據本發明之組成物中的四種成份，環孢菌素：第二 成份：油成份：表面活性劑之較佳存在重量比例爲1 : 〇 · 1 — 10*1 — 1〇-1 一 1〇’且環抱园素·弟—·成份. 11 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之注意事項再填寫本頁) · I ϋ n n n n^eJ· n n n ϋ n an I n n 1 n 491712 A7 ----------B7__ 五、發明說明（、〇) 油成份：表面活性劑之更佳重量比例爲1 : 0 · 5 - 8 : 2 〜6 : 2 - 8。 除了組成物外，根據本發明列舉於下列實施例之組成 物，其可作爲更進一步較佳之組成物。 爲了口服施藥，本發明包含上述成份之組成物可製成 一軟膠囊的形式。既然根據本發明之軟膠囊製劑並不使用 低沸點揮發性溶劑之乙醇，因此其具有藥物穩定性及可樹 立所意欲改良之處，其包括生物可用度之改善。 然而，藉由製備軟膠囊之傳統方法來再生製備傳統軟 膠囊殼是困難的。當該軟膠囊以傳統包含作爲成形劑之甘 油膠囊殼製備時，該製備之軟膠囊可能有一些缺點。由於 甘油流入乳劑，使該先濃縮之乳劑的乳化狀態可能改變， 因而該環孢菌素之溶解度明顯偏低，且可導致環孢菌素從 乳劑中沉澱。 由上所述，本發明之另一觀點爲發現當該軟膠囊殻使 用聚乙二醇及丙二醇之混合物，而非甘油作爲成形劑製備 時，獲得之軟膠囊製劑可以穩定一段時間。雖然任何能液 化之聚乙二醇皆可被使用當作成形劑，但較佳是使用具有 分子量2 0 0至6 0 0之聚乙二醇。 特別地，較佳是使用聚乙二醇2 0 0。根據本發明之 軟膠囊殼內，該聚乙二醇及丙二醇之混合物較佳是使用以 每一份重量的明膠爲基準之比例爲0 · 1至0 · 5，更佳 是使用重量比例爲0 . 1至0 . 4，最佳是使用重量比例 爲0 · 2至0 · 3，以作爲製備膠囊殼。在作爲成形劑之 12 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) · n { m n flu n n 一 —0, I n n n >ϋ n 1 mmn a· 491712 A7 _ B7 _五、發明說明（) 聚乙二醇及丙二醇之混合物中，丙二醇較佳的組合以每一 份重量的聚乙二醇爲基準之比例是1至10，更佳的重量 比例是3至8，最佳的重量比例是3至6。 爲了增加該膠囊殼帶從冷卻圓筒移除的可移動性，該 製備明膠囊殼帶的方法，根據本發明採用空氣冷卻法，取 代水冷卻法。根據該空氣冷卻法，當保持在最適溫度大約 攝氏2 1度時，既然膠囊殼帶並沒有過熱，因而能容易地 自冷卻圓筒移除，使其包膜製程的封裝程度可高至確保高 生產力，因此，該方法能被有效地處理。 在根據本發明之製備軟膠囊中，適合冷卻圓筒冷卻膠 囊殼的空氣體積流量較佳爲5至1 5立方公尺/分鐘，更 佳爲大約1 0立方公尺/分鐘。 在根據本發明之組成物製備成軟膠囊時，如果需要， 該膠囊製劑可以進一步包含傳統使用在軟膠囊製備之藥物 可接受添加物。該添加物包括，例如，卵磷脂、黏性調節 劑、香料（如歐薄荷等）、抗氧化劑（如生育酚，維生素 E等）、防腐劑（如葩熱奔（parabene)等）、著色劑，胺 基酸等。 根據本發明之軟膠囊製劑能藉由將共同表面活性劑、 油成份及表面活性劑統一地混合製備，當在其中溶解的環 孢菌素經由攪拌及逐漸地暖至接近攝氏6 0度，然後製成 結果濃縮物，含有或不含有上述之傳統使用在軟膠囊製備 之藥物可接受添加物，及與具有包含作爲成形劑之聚乙二 醇及丙二醇的明膠殼，於機器內藉由空氣冷卻法製備軟膠 13 (請先閱讀背面之注意事項再填寫本頁) ··491712 A7 __ B7 _ V. Description of the invention (f) Sorbitol Twenty-one (TWEEN 21), polysorbate forty (butyl WEEN 40), polysorbate sixty (TWEEN 60), polysorbate eight Ten (TWEEN 80), polysorbate eighty- (TWEEN 8 1), etc., in particular, the preferred use is a commercialized trademark of NIKKOL HCO-50 (NIKK 0 Chemical Co., Ltd.) polyoxyethylene (5 0) hydrogenated castor oil and a commercialized trademark of TWEEN 20 (ICI Chemicals) polyoxyethylene (20) sorbitol monolaurate, which has an acid hydrazone below 1, and a saponified hydrazone of approximately 48 to 56, approximately 4 5 to 5 5 hydroxyamidine and 4.5 to 7.5 pH ammonium (5%). The surfactant may include any of the above-mentioned surfactants used alone, or preferably, two or more kinds of surfactants selected from the above-mentioned surfactants and used together are used. In the composition according to the present invention, the surfactant can be used in a ratio of 1 to 10, preferably 2 to 8, based on cyclosporin per part by weight. In addition, when a mixture of two surfactants is used, even polyoxyethylene (50) hydrogenated castor oil and polyoxyethylene (20) sorbitol monolaurate used in the composition of the present invention, the polyoxyethylene (5 0) hydrogenated castor oil: The composition ratio of polyoxyethylene (20) sorbitol monolaurate is based on weight, preferably in the range of 1: 0 · 1-5 and more preferably in the range of 1: 0 · 5-4 range. According to the four components in the composition of the present invention, the cyclosporin: the second component: the oil component: the surfactant is preferably present in a weight ratio of 1: 〇 · 1-10 * 1-1〇-1 -1 〇 'and huanyuansu · di— · ingredients. 11 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 public love) (Please read the precautions on the back before filling this page) · I ϋ nnnn ^ eJ · nnn ϋ n an I nn 1 n 491712 A7 ---------- B7__ V. Description of the invention (, 〇) The better weight ratio of oil component: surfactant is 1: 0 · 5- 8: 2 to 6: 2-8. In addition to the composition, the compositions listed in the following examples according to the present invention can be used as further preferable compositions. For oral administration, the composition of the present invention containing the above-mentioned ingredients may be prepared in the form of a soft capsule. Since the soft capsule preparation according to the present invention does not use ethanol with a low-boiling volatile solvent, it has drug stability and can set up desired improvements, including improvements in bioavailability. However, it is difficult to regenerate the conventional soft capsule shell by the conventional method of preparing soft capsules. When the soft capsule is prepared with a conventional glycerin capsule shell containing a forming agent, the prepared soft capsule may have some disadvantages. Since glycerol flows into the emulsion, the emulsification state of the previously concentrated emulsion may change, so the solubility of the cyclosporin is significantly lower, and cyclosporin can be precipitated from the emulsion. From the foregoing, another aspect of the present invention is to find that when the soft capsule shell is prepared by using a mixture of polyethylene glycol and propylene glycol instead of glycerin as a molding agent, the obtained soft capsule preparation can be stabilized for a period of time. Although any liquefiable polyethylene glycol can be used as the molding agent, it is preferable to use a polyethylene glycol having a molecular weight of 200 to 600. In particular, it is preferable to use polyethylene glycol 200. In the soft capsule shell according to the present invention, the mixture of polyethylene glycol and propylene glycol is preferably used in a ratio of 0. 1 to 0. 5 based on each portion of gelatin, and more preferably, a weight ratio of 0 is used. From 1 to 0.4, it is best to use a weight ratio of 0.2 to 0.3 as the preparation of the capsule shell. As a forming agent, the paper size of 12 papers is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) (please read the precautions on the back before filling this page) · n {mn flu nn 1—0, I nnn > ϋ n 1 mmn a · 491712 A7 _ B7 _V. Description of the invention () In the mixture of polyethylene glycol and propylene glycol, the preferred combination of propylene glycol based on each weight of polyethylene glycol is 1 To 10, a better weight ratio is 3 to 8, and an optimal weight ratio is 3 to 6. In order to increase the mobility of the capsule shell strip removal from the cooling cylinder, the method for preparing a capsule shell strip adopts an air cooling method according to the present invention instead of a water cooling method. According to this air cooling method, when the optimal temperature is maintained at about 21 degrees Celsius, since the capsule shell belt is not overheated, it can be easily removed from the cooling cylinder, so that the degree of encapsulation in the coating process can be as high as possible. Productivity, therefore, the method can be effectively processed. In the preparation of the soft capsule according to the present invention, the air volume flow rate suitable for cooling the cylindrical cooling capsule shell is preferably 5 to 15 m3 / min, and more preferably about 10 m3 / min. When the soft capsule is prepared according to the composition of the present invention, the capsule preparation may further include a pharmaceutically acceptable additive conventionally used in soft capsule preparation, if necessary. The additives include, for example, lecithin, viscosity modifiers, flavors (such as peppermint, etc.), antioxidants (such as tocopherol, vitamin E, etc.), preservatives (such as parabene, etc.), colorants , Amino acids and so on. The soft capsule preparation according to the present invention can be prepared by uniformly mixing a common surfactant, an oil component and a surfactant, and when the cyclosporine dissolved therein is gradually stirred and gradually warmed to approximately 60 degrees Celsius, and then prepared The resulting concentrate, with or without the aforementioned pharmaceutically acceptable additives traditionally used in soft capsules, and gelatin shells with polyethylene glycol and propylene glycol as forming agents, are air-cooled in the machine Preparation of soft glue 13 (Please read the precautions on the back before filling this page) ··
I 訂-!--------線· -n I n a— n I n ϋ .1 ϋ ϋ n n n 1 n ϋ ϋ ϋ ϋ n - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 ___B7_ 五、發明說明（丨/) 囊，以成爲所需合適之環孢菌素軟膠囊。 (請先閱讀背面之注意事項再填寫本頁) 本發明的組成物及製劑對相同的適應證有效，且可用 相同的方式及已知環孢菌素組成物劑量範圍施藥於動物， 例如下文所述之狗或人類等之標準生物可用度試驗之基 礎，且如果需要的話，可調整該劑量。 在任何賦形藥或成份之組成物的詳述範圍內，此處並沒有 明確地描述，它們被描述在文獻中，例如，H.P. Fiedler， Lexikon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf,德 國，第四版 1996，Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, 華盛 頓，以及 The Pharmaceutical Society,倫敦，第二版，1 9 9 4，以及於一九九四年九月十一日所申請之韓國專利 申請案號94 — 29208。 本發明將以下列實施例作更明確地舉例說明。然而， 可了解的是本發明並不以任何方式而被限定於這些實施例 中。 14 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 B7 五、發明說明（ 實施例1 : 成份 含量（毫克/膠囊） 環孢菌素 聚乙二醇 2〇〇 丙烯碳酸酯 聚氧乙烯（5 0 )氫化蓖麻油 聚氧乙烯（2 0 )山梨醇單桂酸酯 亞油酸乙酯 辛酸/癸酸三甘油脂 油酸單酸甘油脂 總計 2 5 4 5 2 5 3 5 8 5 4〇 5 3 5 2 9 5毫克 實施例2 : 成份 含量（毫克/膠囊） 環孢菌素 聚乙二醇 2〇〇 聚氧乙烯（5 0 )氫化蓖麻油 聚氧乙烯（2 0 )山梨醇單桂酸酯 亞油酸乙酯 辛酸/癸酸三甘油脂 油酸單酸甘油脂 總計 2 5 7〇 3 5 8 5 4 0 5 3 5 2 9 5毫克 15 (請先閱讀背面之注意事項再填寫本頁)I order-! -------- line · -n I na— n I n ϋ .1 ϋ ϋ nnn 1 n ϋ ϋ ϋ ϋ n-This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 491712 A7 ___B7_ 5. Description of the invention (丨 /) Capsules to become the appropriate cyclosporin soft capsules. (Please read the notes on the back before filling this page) The composition and preparation of the present invention are effective for the same indications, and can be administered to animals in the same manner and known cyclosporin composition dosage range, such as the following The basis of the standard bioavailability test for dogs or humans, etc., and if necessary, the dose can be adjusted. Within the scope of the detailed description of any excipient or ingredient composition, they are not explicitly described here, they are described in the literature, for example, HP Fiedler, Lexikon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf, Germany, fourth Edition 1996, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, and The Pharmaceutical Society, London, Second Edition, 194, and Korean Patent Application Number filed on September 11, 1994 94 — 29208. The invention will be more clearly illustrated by the following examples. However, it is understood that the present invention is not limited to these embodiments in any way. 14 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 491712 A7 B7 V. Description of the invention (Example 1: Ingredient content (mg / capsule) cyclosporin polyethylene glycol 2) 〇 Propylene carbonate polyoxyethylene (50) hydrogenated castor oil polyoxyethylene (20) sorbitol monolaurate ethyl linoleate caprylic / capric triglyceride oleic acid monoglyceride total 2 5 4 5 2 5 3 5 8 5 4 0 5 3 5 2 9 5 mg Example 2: Ingredient content (mg / capsule) cyclosporin polyethylene glycol 200 polyoxyethylene (50) hydrogenated castor oil polyoxyethylene ( 2 0) Sorbitol monolaurate ethyl linoleate caprylic acid / capric triglyceride oleate monoglyceride total 2 5 7〇3 5 8 5 4 0 5 3 5 2 9 5 mg 15 (Please read the back first (Notes for filling in this page)
本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 B7 五、發明說明（（七 實施例3 : 成份_ 含量（毫克/膠囊） 環孢菌素 聚乙二醇 2〇〇 丙烯碳酸酯 聚氧乙烯（5 0 )氫化蓖麻油 聚氧乙烯（2 0 )山梨醇單桂酸酯 亞油酸乙酯 辛酸/癸酸三甘油脂 油酸單酸甘油脂 總計 2 5 1 0〇 5〇 3 5 8 5 4〇 5 3 5 7 5毫克 (請先閱讀背面之注意事項再填寫本頁) 實施例4 : 成份 含量（毫克/膠囊） 環孢菌素 聚乙二醇2〇〇 丙烯碳酸酯 聚氧乙烯（5 0)氫化蓖麻油 聚氧乙烯（2 0)山梨醇單桂酸酯 亞油酸乙酯 辛酸/癸酸三甘油脂 油酸單酸甘油脂 總計 2 5 4 5 2 5 5 0 1〇0 4〇 5 3 5 3 2 5毫克 16 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 B7 五、發明說明（W) 實施例5 : 成份 環孢菌素 聚乙二醇 2〇0 丙烯碳酸酯 聚氧乙烯（5 0 )氫化蓖麻油 聚氧乙烯（2 0)山梨醇單桂酸酯 亞油酸乙酯 辛酸/癸酸三甘油脂 油酸單酸甘油脂 總計 含量（毫克/膠囊） 2 4 8 5 8〇 10 7〇 3 7 5毫克 (請先閱讀背面之注意事項再填寫本頁) 實施例6 : 從實施例1之組成物及使用下列作爲膠囊殼之組成 物，製備軟膠囊製劑，然後由於甘油之流入，可從視覺上 觀察到其改變性質及內容物的狀態。 重量比例 2〇 16 9 6 . 1 (控制組） 成份 明膠 純水 甘油 17 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7B7 五、發明說明（A) 6 . 2 (試驗組） 成份 明膠 純水 丙二醇 聚乙二醇2〇〇 重量比例 2〇 16 4 1 其結果如下列表1所述。 表1:根據該膠囊殼所製備的膠囊製劑之內容物的穩定度 膠囊組成物 在剛製備後 一天後 二天後 五天後 十天後 三十天後 控制組 〇 + + + + + + + + + + 試驗組 〇 〇 〇 〇 〇 〇 〇 + + + + + + 內容物穩定 =少量乳化 :輕度沉澱 :沉澱 n n n n I! n n : ------ n I n n n I i I i i 一°Jf n 1^1 n HI n ϋ ! I (請先閱讀背面之注意事項再填寫本頁) 從表1所描述之結果得知，使用6 . 1控制組包含作爲成 形劑之甘油組成物所製備之膠囊製劑，由於甘油之流入而 導致一些問題，其包括沉澱的形成。而使用6 . 2試驗組 18 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 ______B7 五、發明說明（) 包含作爲成形劑之聚乙二醇及丙二醇組成物所製備之膠囊 製劑，其保持在穩定狀態。 (請先閱讀背面之注意事項再填寫本頁) 實施例7 : 使用在上述實施例6的6 · 2試驗組膠囊殼組成物，所製 備的具有實施例1之組成物的軟膠囊製劑，個別藉由水冷 卻法（水溫大約攝氏1 2度）及空氣冷卻法（空氣體積流 大約1 0公尺立方/分鐘）冷卻。 在每一例子中，觀察及比較自冷卻圓筒中的膠囊殼帶之可 移動性。其結果如下列表2所述。 表2 :依照冷卻法其自冷卻圓筒中的明膠囊殼帶之可移動 性 (單位：角度） 組成物 水冷卻法 空氣冷卻法 實施例6 · 2 >1〇〇度 < 5〇度 (極差可移動性） （良好可移動性） 從表2所描述之結果得知，根據本發明藉由空氣冷卻法所 製備之軟膠囊製劑比由水冷卻法所製備之軟膠囊製劑，顯 示其自冷卻圓筒中具有極爲良好可移動性。精確地說，通 常被認爲如果明膠殼帶自冷卻圓筒中移除之角度大約爲7 〇或更大，則可移動性極差，如果殼帶之移除角度低於7 19 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 __B7 五、發明說明（θ ) 〇，其可移動性良好。即使當製劑在1 Ο 0度或更多角度 移除時，藉由水冷卻法所製備之軟膠囊製劑自冷卻圓筒中 移除並不明顯。 ----------------- (請先閱讀背面之注意事項再填寫本頁) 對比之下，根據本發明藉由空氣冷卻法所製備之軟膠 囊製劑，能很容易地在5 0度及低於5 0度之角度自冷卻 圓筒中移除，因此，能提供良好封裝強度及生產力。 實施例8 : 藉由包膜之實施例1的組成物，及具有實施例2之組 成物的明膠殼所製備之製劑，作爲測試製劑的生物可用 度，與商業產品包含乙醇之散德依蒙（S ANDIMMUM )膠囊 作爲控制組製劑的生物可用度比較，評估根據本發明之環 孢菌素製劑在環孢菌素的生物可用度及在個別患者間之差 異性的影響。 在該實驗中，測試製劑及控制組製劑皆以兔子每公斤 重量施與3 0 0毫克之環孢菌素。 在鐵籠內相同的狀況下，兔子被統一地餵養傳統兔子 固體飼料組成物四天或更多天。當製劑以口服方式施與 時，兔子被限制在鋼籠內斷食四十八小時，在此期間允許 兔子自由地喝水。 具有5公釐直徑之雷文氏管（Levin’s tube )，在該雷 文氏管的表面覆以一層凡士林以降低摩擦後，穿過食道插 入深度達3 0公分。每一試驗組製劑及控制組製劑以5 0 毫升水進行乳化，然後導入一連接雷文氏管之注射器。使 用二甲苯擴張兔耳靜脈，然後在試驗之前，血液藉由肝素 20 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 491712 A7 B7 五、發明說明（tf) 處理之丟棄式注射器於0 . 5、1、1 · 5、2、3、4、 6、1 0及2 4小時後從每隻兔子的耳靜脈取出。所獲得 之1毫升血液加入0 · 5毫升水性飽和氯化鈉溶液及2毫 升乙醚，然後將該混合物振盪5分鐘及在5 0 0 0 rpm下離 心1 0分鐘以分離出上淸液（乙醚層）。收集到之1毫升 上淸液然後在一活性二氧化矽sep-pakR(華特斯（Waters )) 顯層。該顯層sep-pak以5毫升正己烷淸洗及2毫升甲醇洗 出，該洗出物在降壓之氮氣中蒸發乾燥。該殘餘物藉由Η P L C (高性能液相層析法）分析〔Η P L C條件：管柱 // —BondapakRC18 (華特斯（Waters ))，流動相 CH3CN : MeOH : H20 — 5 5 : 1 5 : 3 0，2 1 〇 nm 偵測，流速 1 · 0毫升/分鐘，管柱溫度7 0 °C，靈敏度0 · 0 1 Aufs. 注射體積1 0 0微升〕。 試驗組製劑及控制組製劑所獲得之結果列於表3。 表3 :本發明試驗組製劑及商業化產品散得依蒙 (SANDIMMUNR)之生物可用度 參數 控制組製劑（A) 試驗組製劑（Β) Ρ(Β/Α) Μ土 S.D. (n= 6 ) CV% (S.D./M) Μ土 S.D. C V% (n= 6 ) (S.D./M) AU C 13.5±10.0 74.0% 57·0±17·0 29.8% 4.1 (微克. 小時/毫升） C m a X 0·8±0·3 37.5% 6·0±1.5 25.0% 7.5 (微克. .小時/毫升） 21 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---訂·-------- 491712 A7 _____B7_ 五、發明說明（θ) 符號：A U C =在血液濃度曲線下之面積 Cmax =環孢菌素最大血液濃度 Μ 土 S.D. =平均値土標準偏差 c V =標準偏差對平均値之比値 p ( B / A )=試驗組製劑之平均値對控制組製 劑之平均値的比値 從上表可以得知，該試驗組製劑顯示高於控制組製 劑，可增加A U C及C ma x値個別地大約4倍或更多及大約 7倍或更多。由上所述，與控制組製劑相比，其可被鑑定 爲該試驗組製劑之生物可用度明顯增加。此外，本發明之 試驗組製劑與控制組相比，顯示一種降低個別試驗患者間 之差異性（C V % )的效果，在AUC値大約2倍或更多及 在C m a X値大約1 · 5倍或更多。 由上所述，其可決定當根據本發明之軟膠囊製劑以口服方 式施與時，其顯示增加環孢菌素之生物可用度高於先前包 含乙醇之商業化產品，散德依蒙（sandimmunr )膠囊4 倍，及亦降低環孢菌素在個別患者間之生物可用度的差異 性，且於同一時間，在長期儲存期間保持穩定而沒有任何 變化。因此，其很明顯地顯示根據本發明之軟膠囊製劑， 提供在製備環孢菌素軟膠囊的領域內之明顯改進。 22 本纸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) —r訂·：--------線· 491712 A7 _ B7 五、發明說明（Η ) 實施例9 : 製成之軟乳膠體包含= I Π 環孢菌素A 聚乙二醇2〇〇 丙烯碳酸酯 聚氧乙烯5 0—氫化蓖麻油 聚山梨醇酯2〇 亞油酸乙酯 油酸單酸甘油脂 維生素E 總計 2 5毫克 1〇0毫克 4 5毫克 18〇毫克 2 5毫克 1〇〇毫克 4〇毫克 1 6〇毫克 8 5毫克 3 4〇毫克 4〇毫克 1 6〇毫克 4〇毫克 1 6〇毫克 1毫克 4毫克 〇1毫克 12〇4毫克 (請先閱讀背面之注意事項再填寫本頁) · 訂---------線IAV--- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 491712 A7 B7 V. Description of the invention ((Seventh Example 3: Ingredient _ Content (mg / capsule) Cyclosporin polyethylene glycol 2 〇〇propylene carbonate polyoxyethylene (50) hydrogenated castor oil polyoxyethylene (20) sorbitol monolaurate ethyl linoleate caprylic acid / capric triglyceride oleic acid monoglyceride total 2 5 1 0 〇5〇3 5 8 5 4〇5 3 5 7 5 mg (Please read the precautions on the back before filling out this page) Example 4: Ingredient content (mg / capsule) Cyclosporin polyethylene glycol 2 0 Propylene carbonate polyoxyethylene (50) hydrogenated castor oil polyoxyethylene (20) sorbitol monolaurate ethyl linoleate caprylic / capric triglyceride oleic acid monoglyceride total 2 5 4 5 2 5 5 0 1 0 0 4 0 5 3 5 3 2 5 mg 16 This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 491712 A7 B7 V. Description of the invention (W) Example 5: Composition ring Sporosporin polyethylene glycol 200 propylene carbonate polyoxyethylene (50) hydrogenated castor oil polyoxyethylene (20) sorbitol monolaurin Ethyl linoleate caprylic acid / capric triglyceride oleic acid monoglyceride total content (mg / capsule) 2 4 8 5 8〇10 7〇3 7 5 mg (Please read the precautions on the back before filling in this (Page) Example 6: A soft capsule preparation was prepared from the composition of Example 1 and the following composition used as a capsule shell, and then, due to the inflow of glycerin, its changing properties and the state of the contents can be visually observed. Proportion 2016 9 6. 1 (Control group) Ingredients Gelatin Pure water glycerin 17 The paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 491712 A7B7 V. Description of the invention (A) 6. 2 ( Test group) Ingredients: gelatin, pure water, propylene glycol, polyethylene glycol, 200% by weight, 2016 4 1 The results are shown in Table 1. Table 1: Stability of the contents of the capsule preparation prepared according to the capsule shell. Capsule composition The content was stabilized in the control group 0 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + = Small amount of emulsification: slight precipitation: precipitation nnnn I! nn: ------ n I nnn I i I ii-° Jf n 1 ^ 1 n HI n ϋ! I (Please read the precautions on the back before filling this page) From the description in Table 1 As a result, it was learned that the capsule formulation prepared using the 6.1 control group containing the glycerin composition as a forming agent caused some problems due to the inflow of glycerin, including the formation of a precipitate. And use 6.2 test group 18 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 491712 A7 ______B7 V. Description of the invention () Contains polyethylene glycol and propylene glycol composition as forming agent The prepared capsule preparation is kept in a stable state. (Please read the precautions on the back before filling this page) Example 7: Use the capsule shell composition of the 6.2 test group of Example 6 above, the soft capsule preparations with the composition of Example 1 prepared, individually It is cooled by water cooling method (water temperature is about 12 degrees Celsius) and air cooling method (air volume flow is about 10 m3 / min). In each example, the mobility of the capsule shells in the self-cooling cylinder was observed and compared. The results are described in Table 2 below. Table 2: Mobility (unit: angle) of the gelatin capsule shell in the self-cooling cylinder according to the cooling method Composition 6 Water cooling method Air cooling method Example 6 2 > 100 degrees < 50 degrees ( Very poor mobility) (Good mobility) It is known from the results described in Table 2 that the soft capsule preparation prepared by the air cooling method according to the present invention is more flexible than the soft capsule preparation prepared by the water cooling method. Very good mobility in self-cooling cylinders. To be precise, it is generally considered that if the gelatin shell strip is removed from the cooling cylinder at an angle of about 70 or more, the mobility is extremely poor, and if the shell strip is removed at an angle below 7 19 this paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 491712 A7 __B7 V. Description of the invention (θ) 〇 It has good mobility. Even when the formulation is removed at 100 degrees or more, it is not obvious that the soft capsule formulation prepared by the water cooling method is removed from the cooling cylinder. ----------------- (Please read the notes on the back before filling this page) In contrast, the soft capsule preparation prepared by the air cooling method according to the present invention can It is easily removed from the cooling cylinder at an angle of 50 degrees and below 50 degrees, so it can provide good package strength and productivity. Example 8: A preparation prepared by coating the composition of Example 1 and a gelatin shell having the composition of Example 2 was used as a test preparation for bioavailability, and the commercial product contained ethanol based on Sandemon. The bioavailability comparison of (S ANDIMMUM) capsules as a control group formulation evaluates the impact of the cyclosporin bioavailability according to the present invention on the cyclosporin biodiversity and the differences between individual patients. In this experiment, 300 mg of cyclosporin was administered to the test preparation and the control group preparation per kg of rabbit weight. Under the same conditions in the iron cage, the rabbits were fed the traditional rabbit solid feed composition uniformly for four or more days. When the preparation was administered orally, the rabbits were restricted from fasting in a steel cage for forty-eight hours, during which the rabbits were allowed to drink freely. A Levin's tube having a diameter of 5 mm was coated with petroleum jelly on the surface of the Levin's tube to reduce friction, and was inserted through the esophagus to a depth of 30 cm. Each test group preparation and control group preparation were emulsified with 50 ml of water, and then introduced into a syringe connected to a Raven's tube. Use xylene to dilate the rabbit ear vein, and then before the test, the blood was passed Heparin 20 paper size applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 491712 A7 B7 V. Disposal of Disposal (tf) Disposal The syringe was removed from the ear vein of each rabbit at 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours later. The obtained 1 ml of blood was added with 0.5 ml of an aqueous saturated sodium chloride solution and 2 ml of ether, and then the mixture was shaken for 5 minutes and centrifuged at 5000 rpm for 10 minutes to separate the supernatant liquid (ether layer ). One milliliter of the supernatant was collected and then the layer was visualized in an active silica sep-pakR (Waters). The apparent layer sep-pak was washed with 5 ml of n-hexane and 2 ml of methanol, and the eluate was evaporated to dryness under reduced pressure nitrogen. The residue was analyzed by Η PLC (High Performance Liquid Chromatography) [Η PLC conditions: column // —BondapakRC18 (Waters)), mobile phase CH3CN: MeOH: H20 — 5 5: 1 5 : 30, 2 10 nm detection, flow rate 1.0 ml / min, column temperature 70 ° C, sensitivity 0 · 0 1 Aufs. Injection volume 100 microliters]. The results obtained in the test group preparation and the control group preparation are shown in Table 3. Table 3: The bioavailability parameters of the test group formulations and commercial products of the present invention, which were obtained from SANDIMMUNR, were controlled by the control group formulations (A), and the test group formulations (B), PB (B / A), and M SD (n = 6). CV% (SD / M) μ SD SD CV% (n = 6) (SD / M) AU C 13.5 ± 10.0 74.0% 57 · 0 ± 17 · 0 29.8% 4.1 (μg. Hour / ml) C ma X 0 · 8 ± 0 · 3 37.5% 6 · 0 ± 1.5 25.0% 7.5 (μg. .H / ml) 21 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the Please fill in this page again for the matters needing attention) ---- 1 --- Order · -------- 491712 A7 _____B7_ V. Description of the invention (θ) Symbol: AUC = area under the blood concentration curve Cmax = cyclosporon Maximum blood concentration of bacteriocin SD = mean standard deviation of mean soil c V = ratio of standard deviation to mean 値 p (B / A) = average of test group preparations 値 control group preparation average 値 ratio from above As can be seen from the table, the formulation of the test group showed an increase in AUC and C ma x 値 by about 4 times or more and about 7 times or more individually than the control group preparation. From the above, it can be identified that the bioavailability of the preparation of the test group is significantly increased compared with the preparation of the control group. In addition, the preparation of the test group of the present invention showed an effect of reducing the variability (CV%) between individual test patients compared with the control group, which was about 2 times or more at AUC 及 and about 1 · 5 at C ma X 値. Times or more. From the above, it can be determined that when the soft capsule preparation according to the present invention is administered orally, it shows that the bioavailability of increasing cyclosporine is higher than that of a commercial product previously containing ethanol, sandimmunr ) Capsules 4 times, and also reduces the bioavailability of cyclosporin between individual patients, and at the same time, remains stable without any change during long-term storage. Therefore, it is clear that the soft capsule preparation according to the present invention provides a significant improvement in the field of preparing cyclosporin soft capsules. 22 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) —r Order · ： -------- Line · 491712 A7 _ B7 V. Description of the invention (ii) Example 9: The prepared soft latex contains = I Π cyclosporin A polyethylene glycol 2000 propylene carbonate polyoxyethylene 50 0-hydrogenated castor oil polysorbate Ester 20 Ethyl linoleate Ethyl oleate monoglyceride Vitamin E Total 25 mg 100 mg 45 mg 180 mg 25 mg 100 mg 40 mg 160 mg 8 5 mg 3 4 Mg 40 mg 160 mg 40 mg 160 mg 1 mg 4 mg 01 mg 120 mg (Please read the precautions on the back before filling this page) · Order --------- Line IAV --- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)