1235669 五、發明説明（/ ) 發明所屬之拮術領域 本發明有關於一種不含有毒賦型劑的改良乳劑，尤其是^ 5 DB67(Silatecan)無水的非水溶性藥品製劑新處方。 先前技術 10 15 20 25 -般在藥物學上所個的具有義學療效社成份約略可 分為水溶性與非水溶性兩種。水溶性藥物其製備方法相對而古 較為簡單；例如止咳藥Dextromethorphen很容易溶解於水中， 因此可以製備成非常多樣化的藥學劑型，如錠劑、溶液劑、糖 漿劑等等，又例如抗癌藥小紅莓（dox〇rubicin)其水溶性相當 好，所以可以很順利的製成水溶液注射針劑。相對而言非水: 性的藥物其製制方法默相當賴難及複雜，例如抗癌藥太 平洋紫杉醇(Paclitaxel)的開發初期一直不順利，克服了藥品來 源問題之後，在進行第-^皆段人體試驗時，又因發現嚴重的過 敏反應而使該藥在臨床試驗第一階段（phase 〇時幾乎終止。 這個過敏反應的症狀包括呼吸困難、低血壓、血管水腫與全身 性蓴麻療，與血管造影則起的反應類似。後來制多種藥物 事先預防，並且修改藥品的注射速度，才降低了這項過敏反應 的發生率。至於過敏原，則為製劑所使用的溶解劑，而非太平 洋紫杉醇本身。 太平洋紫杉醇的斥水性極高，非常難溶於水(小於1〇A g/mL)。所以必須使用特殊的助溶劑才能做成注射劑。這項困 本紙張尺度適用中國國家標準（CNS ) 公釐 1235669 五、發明説明（ 難也是當初開發藥品的阻礙 美國施貴寶公司門料做 所核准的唯一處方是由 5 貝寶q開發的靜脈注射劑⑽灿⑧），而該產品中的 助溶劑為乙醇和CremGphw EL(不含聚氧乙網麻油)以5〇: 卞比例混合。其中的Cremophor EL為—非離子強力界面活性 =，因此本身也為_有毒性物質。注射後會引發嚴重的過敏反 應，已有死亡的報導。 10 15 顯而易見，紫杉醇注射劑劑型的缺點主要來自Cr_ph〇r EL。因此，這種缺點應可藉由更換不同的溶劑來去除 C_Ph〇r EL所引發的副作用。這可使得病患無須做前藥物處 理進而增加了藥品使用的方便性，同時也降低產品的毒性。 改良類似紫杉醇這種水溶性很低的注射劑方法中，最為人所熟 知的為微脂體劑型。但是有報導紫杉醇仍舊在數週的架儲期内 產生沈殿的現象。因此，進一步將微脂體製成柬晶的粉末，以 便儲存。繁雜的微脂體製程再加上耗時、耗資源的冷束乾燥將 使得品成本居高不下，而失去商f化的意義。 當然，簡易的製程及改良方法也有研究人員提出。例如以 某些有機溶媒來替代Cremophor EL，例如二曱基乙醯胺 經濟部中央標準局員工消費合作社印製 20 (dimethylacetamide, DMA)、N-methylpyr〇〇lidinone (NMP)等來 增加紫杉醇的溶解度i，2。雖然擁有簡易的製造優勢，但是，這 些有機溶劑仍舊具有相當的毒性，因此，也未受廣泛的接納。 較為特殊的方法為將紫杉醇與其他無毒的物質製成複合 物。例如NeilDesai等人以人體血漿蛋白來吸附紫杉醇而得一 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X297公釐） 1235669 A7 B7 五、發明説明（3 ) 無毒且溶於水的紫杉醇注射劑3。 像务、杉醇&樣難溶的化合物，在藥劑學上常麵成乳劑來克 5服。因此，有相當多的科學人員著力於此方法。例如恤細〇心 等人R J•等人、ChU，磁㈣等人皆有非常傑出的研究 成果。但疋，乳劑的製作相對於Taxol%液劑較為繁複，成本 $對也就較為高昂。另外，乳繼f含有相#比例的水份，這造成 紫杉醇長期保存的安定性降低，同時也如同微脂體劑型一樣，在架 10儲期内產品有結晶的疑慮。 ’、 DB-67 (Silatecan)經美國匹茲堡大學研究，是一種拓樸酵 素抑制物，可抑制癌細胞的分裂，該大學證實它在動物實驗中可抑 制腦癌細胞的生長。DB-67 (Silatecan)的斥水性極高，非常難溶 於水。所以必須使用特殊的助溶劑才能做成注射劑。 15其化學結構式如下： C03 cm 20 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）1235669 V. Description of the invention (/) Field of invention to which the invention belongs The present invention relates to an improved emulsion that does not contain toxic excipients, especially a new formulation of DB67 (Silatecan) anhydrous water-insoluble pharmaceutical preparation. The prior art 10 15 20 25-The pharmacologically beneficial social ingredients can be roughly divided into water-soluble and water-insoluble. The preparation method of water-soluble drugs is relatively old and simple; for example, the cough medicine Dextromethorphen is easy to dissolve in water, so it can be prepared into a variety of pharmaceutical dosage forms, such as lozenges, solutions, syrups, etc. Cranberry (dox〇rubicin) is quite water soluble, so it can be made into aqueous injections smoothly. Relatively non-aqueous: sex drugs are very difficult and complicated to make. For example, the development of the anticancer drug Paclitaxel has not been successful in the early stage. After overcoming the problem of drug source, the first step is to proceed. In human tests, the drug was found to have stopped in the first phase of the clinical trial (phase 0) due to the discovery of a severe allergic reaction. The symptoms of this allergic reaction include dyspnea, hypotension, angioedema, and systemic ramie therapy, and Angiography has a similar response. Later, many drugs were prepared in advance and the injection speed of the drug was modified to reduce the incidence of this allergic reaction. As for the allergen, it is the dissolving agent used in the preparation instead of paclitaxel. It itself. Paclitaxel has extremely high water repellency and is very difficult to dissolve in water (less than 10A g / mL). Therefore, special co-solvents must be used to make injections. This paper size applies the Chinese National Standard (CNS) 1235669 mm V. Description of the invention (It is also the only place where the development of pharmaceuticals hindered Bristol-Myers Squibb's approval. Is an intravenous injection developed by 5 PayPal Q), and the co-solvent in this product is ethanol and CremGphw EL (without polyoxyethylene reticulum) mixed at a ratio of 50: 。. Among them Cremophor EL is- Nonionic strong interfacial activity =, so it is also a toxic substance. Serious allergic reactions after injection have been reported, and death has been reported. 10 15 It is clear that the disadvantages of the paclitaxel injection dosage form mainly come from Cr_Phor EL. Therefore, this This kind of disadvantages should be able to remove the side effects caused by C_Ph〇r EL by changing different solvents. This can make patients without the need for pre-drug treatment, which increases the convenience of drug use, and also reduces the toxicity of the product. Improved similar to paclitaxel In this injection method with very low water solubility, the most well-known is the liposome formulation. However, it has been reported that paclitaxel still produces Shen Dian during the shelf life of several weeks. Therefore, the liposome is further made into Cambodia Crystal powder for easy storage. The complicated microfabrication process coupled with time-consuming and resource-consuming cold beam drying will make the cost of the product high, and lose the quotient. Significance. Of course, simple processes and improvement methods have also been proposed by researchers. For example, Cremophor EL was replaced with some organic solvents, such as printed by 20 (dimethylacetamide, DMA) N-methylpyrolidolone (NMP), etc. to increase the solubility of paclitaxel i, 2. Although they have simple manufacturing advantages, these organic solvents are still quite toxic, so they have not been widely accepted. More special methods In order to make a compound of paclitaxel and other non-toxic substances. For example, Neil Desai et al. Used human plasma protein to adsorb paclitaxel to obtain a paper with a standard of China National Standard (CNS) A4 (210X297 mm) 1235669 A7 B7 V. Description of the invention (3) Non-toxic and water-soluble paclitaxel injection 3. Insoluble compounds such as wu, paclitaxel & are often emulsified in pharmacology to give 5 grams. As a result, a considerable number of scientists have worked on this method. For example, Rong Xing et al., R.J. et al., ChU, Cili et al., Have outstanding research results. But alas, the production of emulsion is more complicated than Taxol% solution, and the cost is high. In addition, the milky phase contains water in a phase ratio, which causes the stability of paclitaxel to be reduced for a long time. At the same time, like the liposome formulation, the product has doubts about crystallization during the storage period of the shelf. ’, DB-67 (Silatecan) is a topological inhibitor that can inhibit the division of cancer cells after research by the University of Pittsburgh. The university confirmed that it can inhibit the growth of brain cancer cells in animal experiments. DB-67 (Silatecan) is extremely water-repellent and very poorly soluble in water. Therefore, special co-solvents must be used to make injections. 15 Its chemical structural formula is as follows: C03 cm 20 This paper size is applicable to China National Standard (CNS) A4 specifications (210X297 mm)
HsC HsC 33C 7HsC HsC 33C 7
此原料之學名為：7+ butyldimethylsilyl-10-hydroxycamptothecin 此原料代稱為：DB-67 經濟部中央標準局員工消費合作社印製 1235669 A7 五、發明説明（彳） B7 5 10 15 20 綜合以上對於水不溶性藥物的製備方式約略可分為使用有 機/谷媒田♦解劑、使用界面活性劑、使用特殊攜帶性介質（例 如微脂體）等等，但是這些方法多多少少面臨了毒性過高、製 備過程太過德崎娜以控制、賦型則起的雜以及過敏 等等嚴重的臨床問題。參考文獻 1. Andersson, B, Parenteral Paclitaxel in a Stable Non-toxic Formulation，USP5,877,205, March 2, 1999 2. Hausheer，F:H·，Murali，D·，and，Seetharamulu，P·，USP6,040,330 Pharmaceutical Formulations of Taxanes, March 21, 2000 ’ 3· Desai，Ν·〒_，and Soon-Shiong，P·，USP6,096,331 Methods and Compositions Useful for Administration of Chemotherapeutic Agents Aug· 1，2000 ’ 4. Panayiotis, P. et al5 W002/26208 Emulsion Vehicle for Pooly Soluble Drugs，April 4, 2002 經濟部中央標準局員工消費合作社印製 5. Kaufman，J.R·，and Richard，T.J·，USP5,616,330 Stable Oil-In- 25 Water Emulsions Incorporating a Taxine (Taxol) and Method of Making Same, April 1, 1997 30 6. Chu，I.M·，and Wang，T.R·，USP6,348,491 Oil-In-Water Emulsion for Encapsulation Paclitaxel，Feb· 19, 2002發明内容本發明的目的就是創造出一不含有毒賦型劑的改良乳劑，可以廣泛應用於各種非水溶性的具藥理活性的藥品，使之毒性The scientific name of this raw material is: 7+ butyldimethylsilyl-10-hydroxycamptothecin This raw material is called: DB-67 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1235669 A7 5. Invention Description (发明) B7 5 10 15 20 The preparation methods of insoluble drugs can be roughly divided into the use of organic / cereal media, antidote, the use of surfactants, the use of special carrying media (such as microlipids), etc., but these methods are more or less facing high toxicity, The preparation process is too serious for Dezanna to control, shape, and other serious clinical problems such as allergies and allergies. References 1. Andersson, B, Parenteral Paclitaxel in a Stable Non-toxic Formulation, USP 5,877,205, March 2, 1999 2. Hausheer, F: H ·, Murali, D ·, and, Seetharamulu, P ·, USP 6,040,330 Pharmaceutical Formulations of Taxanes, March 21, 2000 '3. Desai, Ν.〒_, and Soon-Shiong, P., USP 6,096,331 Methods and Compositions Useful for Administration of Chemotherapeutic Agents Aug. 1, 2000' 4. Panayiotis, P et al5 W002 / 26208 Emulsion Vehicle for Pooly Soluble Drugs, April 4, 2002 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 5. Kaufman, JR ·, and Richard, TJ ·, USP 5,616,330 Stable Oil-In- 25 Water Emulsions Incorporating a Taxine (Taxol) and Method of Making Same, April 1, 1997 30 6. Chu, IM ·, and Wang, TR ·, USP 6,348,491 Oil-In-Water Emulsion for Encapsulation Paclitaxel, Feb 19, 2002 Invention The purpose of the present invention is to create an improved emulsion that does not contain toxic excipients, which can be widely used in various non-water-soluble pharmacologically active drugs to make them poisonous. Sex
本紙張尺度適用中國國家標準（CNS) A4規格（210x297公釐 1235669This paper size applies to China National Standard (CNS) A4 (210x297 mm 1235669
„乍用大巾田的降低,服用更為方便。更重要的是具有簡易的 製造特點，以增加大規模製造的可行性。如此的發明將可嘉惠 病患，進而提昇醫療的品質。 本發明的產品為_ DB67(silatecan)無水的非水溶性藥品製 綱處方，在服用時先以可注射靜脈液稀釋至使用濃度，本發 明以無水溶液為載體，使該產品將有更為理想的安定性。另 外，在製程上只是單純的將各項溶劑混合，生產的難度也更為 10簡單。 經濟部中央標準局員工消費合作社印製 —利用無毒性的有機溶媒或界面活性劑溶解無水的非水溶性 藥⑽例如·乙醇(Ethanol)、丙二醇(Pr〇pylene glyc〇1)、界面活性 背J (Tween 80)、其他磷脂（ph〇sph〇lipid)類產品（例如： Phospholipoi^OG)等等。這些溶劑的混合製造工程只需一般簡 15易攪拌器與加熱即可，不須應用到任何特殊的設備。由於這無 水濃縮液不含有水份，因此非水溶性類化合物可長期保存其 中。根據本發明中的加速安定性試驗推知，鋪產品在室溫的 儲存環境下，可達兩年以上的架儲期。如果使用方式為將該無 水/辰縮液直接注入可靜脈注射稀釋液中，即可得到一含有非水 20溶性類藥品的注射乳劑。調劑後24小時之内，非水溶性藥品 在這乳劑中十分安定，無任何降解或結晶析出。事實上，非水 溶性類化合物如果為對光敏感物質，乳劑劑型正可提供這類藥 品的阻光效果，以使該產品在使用時更為安定和安全。 25 本紙張尺度適用中國國家標準（CNS ) A4規格(210X297^^] 1235669 |五、發明説明（4) 實施方式 本發明目的是設計出一個DB67(silatecan)無水的非水溶性 5藥品製劑新處方，以使新處方產品能更安全和更方便。 非水溶性藥品為一溶解度極低的化合物品項，例如市售產 口口 Taxol製背]中加入非離子強力界面活性劑crem〇ph〇r el以 增加其溶解度。但是Cremophor EL本身即為一有毒性物質， /主射後會引發尚脂血症及脂蛋白(lip〇pr〇tein)的不正常的電泳模 1〇式、血液黏度改變、呼吸困難、低血壓、血管水腫與全身性蓴 麻疹、甚至無預防性休克症狀，因此並不適合藥劑製劑使用。 在沒有更安全的溶劑可使用之下，將低溶解度的化合物製成乳 劑是常使用的變通方法。 製作一個安定的靜脈注射乳劑製劑並非易事。首先必須考 15里到礼滴顆粒的體積大小，是否能注射入人體内；在架儲期間 顆粒體積是否改變和乳析(creaming)的現象。同時，乳劑的製 作過程繁項費時，在製造成本上也就更為昂貴，是否在藥物經 濟學上有正面的價值等目素，都應仔細考量。 經濟部中央標準局員工消費合作社印製 本發明就是利用濃縮乳化劑溶解及承載非水溶性藥品，使 2〇非水溶性藥品DB67(Silatecan)均勻分佈於水溶液中，並且不易 析出。因此，本發明在量產和商品化上都有相當高的可行性。 實施例二 本實施例為利用本發明處方系統來調製無水非水溶性 本紙張尺度適用中赠7 1235669 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（1 ) DB67(Silatecan)藥品濃縮溶液，該處方明細列於表一。 表一 DB67(Silatecan) 3mg/ml濃縮溶液組点廬古 化合物 劑量„The reduction of large towel fields at the first use makes it easier to take. The more important thing is to have simple manufacturing features to increase the feasibility of large-scale manufacturing. Such an invention will benefit patients and improve the quality of medical treatment. The product of the invention is a formula of DB67 (silatecan) anhydrous water-insoluble drug. When ingested, it is diluted with injectable intravenous liquid to the use concentration. The invention uses an aqueous solution as a carrier, which makes the product more ideal. Stability. In addition, the process is simply a mixture of various solvents, which is more difficult to produce. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-using non-toxic organic solvents or surfactants to dissolve anhydrous Examples of water-insoluble drugs: Ethanol, Propylene Glycol, Tween 80, other phospholipids (eg, Phospholipoi ^ OG), etc. Etc. The mixing manufacturing process of these solvents only requires simple mixers and heating, and does not need to be applied to any special equipment. Because this anhydrous concentrate does not contain water, so The water-soluble compounds can be stored for a long time. According to the accelerated stability test in the present invention, it is inferred that the product can reach a shelf life of more than two years under the storage environment of room temperature. The solution can be directly injected into an injectable diluent to obtain an injectable emulsion containing non-aqueous 20-soluble drugs. Within 24 hours after the adjustment, the non-water-soluble drugs are very stable in the emulsion without any degradation or crystallization. In fact, if the water-insoluble compound is a light-sensitive substance, the emulsion dosage form can provide the light blocking effect of this kind of medicine, so that the product is more stable and safe in use. 25 This paper standard applies Chinese national standards ( CNS) A4 specification (210X297 ^^) 1235669 | V. Description of the invention (4) Implementation The purpose of the present invention is to design a new formulation of DB67 (silatecan) anhydrous water-insoluble 5 pharmaceutical preparations to make the new prescription products safer. And more convenient. A water-insoluble drug is an extremely low-solubility compound item, such as a commercially available product made by Taxol, and a nonionic strong surfactant cr is added. em〇ph〇r el in order to increase its solubility. But Cremophor EL itself is a toxic substance, after the main shot, it will cause dyslipidemia and abnormal electrophoresis mode of lipoprotein (lipoproutine). Formula, changes in blood viscosity, dyspnea, hypotension, angioedema and systemic measles, and even no preventive shock symptoms, it is not suitable for pharmaceutical preparations. Without the use of safer solvents, compounds with low solubility will be used. Making emulsions is a commonly used workaround. It is not easy to make a stable intravenous emulsion preparation. First of all, we must test whether the size of the particles of 15 drops can be injected into the human body; whether the particle volume changes during storage. And creaming. At the same time, the manufacturing process of the emulsion is time-consuming and time-consuming, and it is more expensive in terms of manufacturing costs. Whether it has a positive value in medicinal economics, etc., should be carefully considered. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The present invention uses concentrated emulsifiers to dissolve and carry water-insoluble drugs, so that 20 water-insoluble drugs DB67 (Silatecan) are evenly distributed in the aqueous solution, and it is not easy to precipitate. Therefore, the present invention has considerable feasibility in mass production and commercialization. Embodiment 2 This embodiment uses the prescription system of the present invention to prepare anhydrous and insoluble water. This paper is suitable for use in this paper. 7 1235669 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (1) DB67 (Silatecan) medicine Concentrated solution, the prescription details are listed in Table 1. Table 1 DB67 (Silatecan) 3mg / ml concentrated solution
DB67(Silatecan) 〇.31g Phospholipon 90G 34.9 g Propylene Glycol 52.9 g Ethanol 14.0 mL 5 在製作上可將 DB67(Silatecan)、Phosphdipon 90G ' PropyleneDB67 (Silatecan) 〇.31g Phospholipon 90G 34.9 g Propylene Glycol 52.9 g Ethanol 14.0 mL 5 In production, DB67 (Silatecan), Phosphdipon 90G 'Propylene
Glycol、Ethanol混合置於70°〜80°C水浴中，以磁石攪拌2小時後 可即得DB67無水濃縮溶液3mg/ml。DB67在此濃縮液儲存於 5°C士2。(：、25°C±2°C、30〇C士2°C 及 40°C土2。〇：下，6 個月内皆無明 顯降解的現象(參閱表二）。 10 表二 DB67(Silatecan) 3mg/ml濃縮溶液加速安定性諕赔結果 濃 度_mg/mL 吋间 _ 5°C±2°C 25°C±2°C 30°C±2°C 40°C±2°C 開始 3.04+0.18 3.04+0.18 3.04+0,18 3.04+0*18 第一個月 3·11±0·22 3.12+0.13 3.18+0*21 3.10+0,24 第二個月 2.98+0.11 3.02±0·17 3.05±0.19 3.12+0.19 第三個月 3.12+028 2.90+0*18 3_12±0·22 3.08+0*26 第六個月 2.97+0.15 3.18+0,22 2.95+0*23 3·11±0·15 取得上述已配置的3.5 mL濃縮溶液注入1〇〇 mL的葡萄糖靜脈 注射液（Dextrose 5%)或靜脈注射水，振搖約1分鐘以使產品能 15完全混合。為了研究DB67在此產品中的安定性及結晶速率，利用 -----__ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1235669 五、發明説明（多） 0.45/mi的滤膜過滤該DB67靜脈注射乳液，再_過爐後產品濃 度值來檢測結晶的速率。這試驗證明在補後Μ小咖難結晶 5的發生（參閱表三）’這產品可以触點滴的方式來施打於患者。 表三 DB67(Silatecan) O.lmg/ml乳劑安定性試驗結果 . 濃度 mg/mL* 日夺間 2 : ~ 過濾前 過濾後 開始 ο·ιι±ο·οι 0.10±0·02 4小時 0·13±0·01 0· ll ±0,03 8小時 0. II ±0*02 0.10+0.03 12 小時 0.10±0Ό2 0.12+0Ό1 24小時 0.12+0Ό1 0.13+0,02 :以 HPLC (High Performance Liquid Chromatography)來檢測 ο 1Χ 實施例. 可 本實施例為利用實施例一之發明處方再加入1 % Tweeii^SO， 以降低乳滴大小為實例一的二分之一，並提升無水非水溶性藥口 DB67濃縮溶液濃度至6mg/ml，該處方明細列於表四。 ' 經濟部中央標準局員工消費合作社印製Glycol and Ethanol were mixed and placed in a water bath at 70 ° ~ 80 ° C, and after stirring for 2 hours with a magnet, 3 mg / ml of DB67 anhydrous concentrated solution was obtained. DB67 is stored at 5 ° C ± 2. (:, 25 ° C ± 2 ° C, 30 ° C ± 2 ° C, and 40 ° C soil 2. 〇: No significant degradation within 6 months (see Table 2). 10 Table 2 DB67 (Silatecan ) 3mg / ml concentrated solution accelerates stability. Concentration results _mg / mL inch_ 5 ° C ± 2 ° C 25 ° C ± 2 ° C 30 ° C ± 2 ° C 40 ° C ± 2 ° C Start 3.04 +0.18 3.04 + 0.18 3.04 + 0,18 3.04 + 0 * 18 First month 3.11 ± 0 · 22 3.12 + 0.13 3.18 + 0 * 21 3.10 + 0,24 Second month 2.98 + 0.11 3.02 ± 0 · 17 3.05 ± 0.19 3.12 + 0.19 Third month 3.12 + 028 2.90 + 0 * 18 3_12 ± 0 · 22 3.08 + 0 * 26 Sixth month 2.97 + 0.15 3.18 + 0,22 2.95 + 0 * 23 3 · 11 ± 0 · 15 Obtain the above-mentioned 3.5 mL concentrated solution and inject 100 mL of glucose intravenous solution (Dextrose 5%) or intravenous water, and shake for about 1 minute so that the product can be completely mixed. For research of DB67, here Product stability and crystallization rate, use -----__ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1235669 V. Description of the invention (multiple) 0.45 / mi filter membrane to filter the DB67 Emulsion is injected intravenously, and the concentration of the product after the furnace is used to detect the rate of crystallization This test proves the occurrence of crystallization of M Xiaoca Difficulty 5 after supplementation (see Table 3) 'This product can be applied to patients in the form of contact drops. Table 3 DB67 (Silatecan) O.lmg / ml emulsion stability test Result. Concentration mg / mL * Day 2: ~ Filtered before filtration started ο · ιι ± ο · οι 0.10 ± 0 · 02 4 hours 0 · 13 ± 0 · 01 0 · ll ± 0,03 8 hours 0. II ± 0 * 02 0.10 + 0.03 12 hours 0.10 ± 0Ό2 0.12 + 0Ό1 24 hours 0.12 + 0Ό1 0.13 + 0,02: Detection by HPLC (High Performance Liquid Chromatography) 1 × Example. This example can be used as an example Add 1% Tweeii ^ SO to the prescription of the invention, reduce the droplet size as one half of Example 1, and increase the concentration of the DB67 concentrated solution in anhydrous and water-soluble medicine to 6mg / ml. The prescription details are listed in Table 4. '' Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs
化合物 劑量 DB67 〇.61g Phospholipon 90G 34.5 g Propylene Glycol 52.4 g Tween 80 1.0 ml Ethanol 13.9 mL 一上 一尺 張 【用中國國家標準（CNS ) Α4規格（210X297公釐） 1235669 A7 B7 5 五、發明説明（今 配製方法可將 DB67、Phospholipon 90G、pr0pylene Glyc〇1、Tween 80、Ethanol等混合置於70〜80°C水浴中，以磁石攪拌2小時後可 得DB67無水濃縮溶液。DB67在此濃縮液儲存於5〇c±2〇c、 25〇C±2〇C、30诚及40WC下，6個月内皆無明顯降解的現 象(參閱表五）。 時間 -_jng/mL 表五 DB67 (Silatecan) 6mg/ml濃縮溶液容宏把汾十纟士果 町，日J 5°C±2°C 25°C±2°C 30°C±2°C 40°C±2°C 開始 6.01 土 0_20 6.01±0.20 6·01±0.20 6.01 士 0.20 第一個月 6.04 士 0.23 5·97±0·15 6.15±〇.ll 6·04 土 0·21 第二個月 6.12土 0.18 6.15 土 0.19 5.91±〇.18 6.03 士 0.20 第三個月 5.97 土 0.22 5·96±0·22 6·11 士 0·14 5.91 士 0.11 第六個月 6· 17士 0.23 6.05 士 0.14 5.90 士 0.21 6·01 土 0.14 10 將上述已配置完成取9 mL乳化濃縮溶液注入1〇〇 mL的葡萄 糖靜脈注射液（Dextrose 5%)，振搖約i分鐘以使產品能完全混 合。為研究DB67在此產品中的安定性及結晶速率，利用〇45 的渡膜過_刪7靜躲概液，再侧過義產品濃度值來檢 15測結晶的速率。這試驗證明在調製後24小時内並無結晶的發生 (參閱表六），這產品可糊靜脈闕的方絲施打於患者。 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國CNS)八4規格（no〆297公董^ --- 1235669 A7 B7 五、發明説明（p) 表六 DB67(Silatecan) 0.5mg/ml乳劑安定性試驗結果 時間 _ 濃度 mg/mL* 過濾前 過濾後 開始 0.50±0.03 0.49 土 0.01 4小時 0.49 士 0.02 0.52 士 0.02 8小時 0.55±0.02 0.52±0.03 12小時 0.47 士 0_02 0.49 士 0.04 18小時 NA NA 24小時 0.50 士 0.03 0.52 士 0.02 *以HPLC檢測 本發明之精神與範圍僅受限於下述申請專利範圍，不受限 於上述之特例。 經濟部中央標準局員工消費合作社印製Compound dosage DB67 〇.61g Phospholipon 90G 34.5 g Propylene Glycol 52.4 g Tween 80 1.0 ml Ethanol 13.9 mL one on one foot [using China National Standard (CNS) A4 specification (210X297 mm) 1235669 A7 B7 5 5. Description of the invention ( In this preparation method, DB67, Phospholipon 90G, pr0pylene Glyc01, Tween 80, Ethanol, etc. can be mixed and placed in a water bath at 70 ~ 80 ° C, and after stirring for 2 hours with a magnet, a DB67 anhydrous concentrated solution can be obtained. DB67 is stored in this concentrated solution There was no obvious degradation within 6 months at 50 ° C ± 20 ° C, 25 ° C ± 20 ° C, 30 ° C and 40WC (see Table 5). Time-_jng / mL Table 5 DB67 (Silatecan) 6mg / ml concentrated solution Rong Hong put Fen Shizhang Shiguo, J 5 ° C ± 2 ° C 25 ° C ± 2 ° C 30 ° C ± 2 ° C 40 ° C ± 2 ° C start 6.01 soil 0_20 6.01 ± 0.20 6 · 01 ± 0.20 6.01 person 0.20 first month 6.04 person 0.23 5 · 97 ± 0 · 15 6.15 ± 〇.ll 6 · 04 soil 0 · 21 second month 6.12 soil 0.18 6.15 soil 0.19 5.91 ± 〇.18 6.03 ± 0.20 in the third month 5.97 ± 0.22 5.96 ± 0 · 22 6 · 11 ± 0.14 5.91 ± 0.11 the sixth month 6.17 ± 0.23 6.05 ± 0 .14 5.90 ± 0.21 6 · 01 soil 0.14 10 Put 9 mL of the emulsified concentrated solution into 100 mL of glucose intravenous injection (Dextrose 5%), and shake for about 1 minute to completely mix the product. In order to study the stability and crystallization rate of DB67 in this product, use the 45 ° membrane crossing_deletion 7 static hiding solution, and then check the concentration of the product to detect the crystallization rate of 15. This test proves that after the modulation No crystallization occurred within 24 hours (see Table 6). This product can be applied to patients with venous square wire. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. no 297 public director ^ --- 1235669 A7 B7 V. Description of the invention (p) Table 6 DB67 (Silatecan) 0.5mg / ml emulsion stability test result time _ concentration mg / mL * 0.50 ± 0.03 0.49 after filtration before filtration Soil 0.01 4 hours 0.49 ± 0.02 0.52 ± 0.02 8 hours 0.55 ± 0.02 0.52 ± 0.03 12 hours 0.47 ± 0_02 0.49 ± 0.018 18 hours NA NA 24 hours 0.50 ± 0.03 0.52 ± 0.02 * The spirit and scope of the present invention measured by HPLC are only affected by Limited to Patent application range, the exception is not limited to the above. Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs
本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）This paper size applies to China National Standard (CNS) A4 (210X297 mm)