200425912 A7 B7 五、發明説明（j ) if·. * 5 發'明所屬之技術領域 ‘· •，本發明有關於一種注射製劑之製備法 OmcitabmeHCl微細化之注射製劑製備法。 尤其是指將 10 15 20 經濟部中央標準局員工消費合作社印製 25 先前技| 健擇（Genzar®)康晶粉末靜脈注射製劑，所含主成份為 GemCltabineHC1 ’在臨床上可治療非小細胞之肺癌、肤臟癌。 、非小細胞肺癌-Gemcitabine Ηα併用氣氨銘(cispiaim)是 治縣法手術、局部晚期（第❿期或第脳期）或有轉移 (第IV期）之非小細胞肺癌之第—線治療用藥。胰臟癌一 &咖-Ηα是治療局部惡化性（無法手術治療之第請 Mill期；或有轉移⑷V期）之胰臟腺癌之第—線治療用 樂，亦可祕曾接受過5—Fl^療之病患。 在溶解度方面，Gemcitabme Ηα於水中溶解度可以達到 mg/ml。但疋溶解速率卻是相當的緩慢。 =建修随，康晶粉末靜脈注射製劑，因為使用 八B曰乾H因此成本相當昂貴，而且其溶解速率也並非十 ：也使藥品的製備、給藥、安定性與相容性等問題成 ^«二與^巾的挑戰。例如，為了達到完全溶解的狀 二二事人貝必須於麵彳錢力振搖此項產品，並且必須小心 主思藥品是否已經達到完全溶解狀態。 、 在安定性方面，Ge—eHa水溶液置於相對高於室 μ氏張尺度賴巾1。X 29^y 200425912 五、發明説明（2 ) — —- 溫的環境下並不安定。' . 而為了解決注射用乾粉溶解速度過慢的問題，使用微細化 3的注射用乾粉將可輕易達到這項要求。 因而以注射用微細化乾粉直接充填於小瓶中將可解決 GemdtabmeHCl溶液於儲存時的安定性問題。 1〇 本發明的目的就是創造出一微細化的改良Gemcitabine HC1乾粉注射劑，使之調配難度大幅的降低、溶解速率更快， 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 杈製造的可行性。如此的發明將可嘉惠病患，進而提昇醫療的 品質。 、 15 本發明是針對健擇（G⑶以产）凍晶粉末靜脈注射製劑加 以改良，成為溶解速率好且使用更方便的產品。 經濟部中央標準局員工消費合作社印製 由於健擇（Genza产）凍晶粉末靜脈注射製劑中含有甘露 醇（bulk agent )、醋酸納（酸驗值調整劑），而甘露醇、醋 酸鈉為凍晶乾燥製程中所必須加入的賦型劑，使該產品是否完 20 全溶解難以由醫療人員正確判定。 而本發明即是設計一個無甘露醇、醋酸鈉並且將 GemcitabineHCl乾粉微細化的注射製劑新處方。 實施方式 25 本發明目的是設計出一個無甘露醇、醋酸鈉並且將 313 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0 X 297公釐） 200425912 A7 •、發明説明（3 ) Gemdtabine HC1乾粉微細化的注射製劑新處方，以使新處方 產品能更安全和更方便。 5 將Gemcitabine HC1乾粉以微細化裝置研磨至一定範圍之 微細顆粒，再將此微細化的乾粉充填至注射用已滅菌之玻璃小 瓶中即可。因此，本發明在量產和商品化上都有相當高的可行 性0 10 15 經濟部中央榡準局員工消費合作衽印製 實施例一 本實施例為利用本發明處方系統來製備，該處方明細列於 表一。 表一 Gemdtabine HC1微細化處方 化合物 劑量 *Gemcitabinc HC1 0*2 g * : Micronized particle 之範圍為 10 // m〜40 /z m 在製作上可將Gemdtabine HC1以球磨機（RETSCH Centrifugal Ball Mill S 100)將粉末微細化。Gemdtabine HC1 微細 化粉末儲存於25°C±2°C及40°C±2°C下，6個月内皆無明顯降解的 現象(參閱表二）。 I ^ n I n 訂 I 線 (請先閲讀背面之注意事項炎.馬本頁) 20 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 200425912 A7 B7 五、發明説明（4 ) 時間 Assay Percentage 25°C±2°C 40°C±TC__ 開始 100.5%±0·32% 1003%±〇*44% 第一個月 100·1%±0·42% 100.4%±〇*57% 第二個月 99,8%±0,27% 99J%±〇.61% 第三個月 1 ⑻·2%±0·26% 99.8%±〇屬％ 遵六個月 99·7%±0·33% 100,2%±〇*53% 5 10 (請先閱讀背面之注意事項寫本頁) 經濟部中央標準局員工消費合作社印製 彳： 將上述已微細化之GemcitabineHCl粉末加入定量的注射用 水，振搖約30秒鐘以使產品能完全溶解，使成濃度約40mg/ml之 水溶液。這產品可以靜脈點滴的方式來施打於患者。 表三 Gemcitabine HC1微細化處方 化合物 劑量 *Gemcitabine HC1 1 ♦〇 g * ·· Micronized particle 之範圍為 30 以 m〜1〇〇 " m 在製作上可將GematabineHCUx瑪竭研蛛 dtahine ΗΓΊ 卜私士妙七从、 ---- 1 攻、、、田化。 15 Gemcitabine HC1微細化粉末儲存於25〇c 個月内皆無明顯降解的現象(參閱表四） 下，6 •裝--- 線 本纸張尺度適用中國國家標準（CNS ) A4規格（210X 297公着 200425912 A7 B7 五、發明說明（s ) 参四 Gemcitabine HC1(表三)安定性試驗結果 時間 Assay Percentage 25°C±2°C 40°C±2°C 開始 100·2%±038% 1013%±0*72% 第一個月 100·8%±0·11% 1〇〇·6% 土 0·21% 第二個月 1003%±0,37% 99.9%±036% 第三個月 100·1%±0·47% 100·5% 土 〇·48% 第六個月 99,9%±0·21% 100·7%±0·59% 經濟部智慧財產局員工消費合作社印製 5 將上述已微細化之Gemcitabine HC1粉末加入定量的注射用 水，振搖約30秒鐘以使產品能完全溶解，使成濃度約40mg/ml之 水溶液。這產品可以靜脈點滴的方式來施打於患者。 實施例三 10 表五 Gemcitabine HC1微細化處方 4匕合"物 _ 劑景*Gcmcitabinc HC1 0.2 g * : Micronized particle 之範圍為 〇· i " m〜2〇 〆 m 在製作上可將Gemcitabine HC1以氣磨機（Jetpharma，MC 15 50)將粉末微細化。HC1微細化粉末儲存於25°C±2°C及40°C±2°CT，6個月内皆無明顯降解的現象(參閱表 六）〇 {請先閱讀背面之注意事項再填寫本頁} ' · · team n el n i Is amMm 訂--------- 本紙張尺度適用中國國家標準（CNS)A4規格（21() χ 297公复） 200425912 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（G ) ， 表六 Gemcitabine HC1(表五)安定性試驗結果 時間 Assay Percentage 25°C±2°C 40°C±2°C 開始 99J%±0.62% 100*2%±037% 第一個月 100.2%±0.34% 1 ⑻,6740,46% 第二個月 1 ⑻+3%±0·37% 99J%±0.53% 第三個月 100.1%±033% 99,9%±0.48% 第六個月^ %100.4%±0.42% 99,5%±0.51% 5 將上述已微細化之Gemcitabine HC1粉末加入定量的注射用 水，振搖約30秒鐘以使產品能完全溶解，使成濃度約40mg/ml之 水溶液。這產品可以靜脈點滴的方式來施打於患者。 本發明之精神與範圍僅受限於下述申請專利範圍，不受限 10 於上述之特例。 15 20 本纸張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） (請先閱讀背而之注意事項，\寫本頁)200425912 A7 B7 V. Description of the invention (j) if ·. * 5 The technical field to which the invention belongs ‘· •, the present invention relates to a method for preparing an injection preparation. In particular, it refers to the printing of 10 15 20 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 25 Foreword | Genzar® Kangjing powder intravenous injection preparation, which contains GemCltabine HC1 as the main ingredient in clinical treatment of non-small cells Lung cancer, skin cancer. Non-small cell lung cancer-Gemcitabine Ηα combined with cispiaim is the first-line treatment for non-small cell lung cancer treated with county surgery, locally advanced (stage 或 or 脳) or metastatic (stage IV) Medication. Pancreatic cancer I & ca-Ηα is the first-line treatment of pancreatic adenocarcinoma for the treatment of locally deteriorating (Mill stage that cannot be surgically treated; or metastasis stage V stage). —Fl ^ treated patients. In terms of solubility, Gemcitabme Ηα can reach mg / ml in water. However, the dissolution rate of plutonium is quite slow. = Jianxiu Sui, Kangjing powder intravenous injection preparation, because the use of eight B, dry H, so the cost is quite expensive, and its dissolution rate is not ten: it also makes the drug preparation, drug delivery, stability and compatibility issues ^ «Two with ^ towel challenge. For example, in order to achieve complete dissolution, Er Er Ren Bei must shake the product in the face of money, and must be careful whether the drug has reached a completely dissolved state. In terms of stability, the Ge-eHa aqueous solution was placed relatively higher than the chamber μ's scale Lai towel 1. X 29 ^ y 200425912 V. Description of the invention (2) ----- It is not stable under warm environment. In order to solve the problem that the dry powder for injection dissolves too slowly, the use of micronized 3 dry powder for injection can easily meet this requirement. Therefore, directly filling the vial with the miniaturized dry powder for injection will solve the stability problem of Gemdtabme HCl solution during storage. 10. The purpose of the present invention is to create a micronized and improved Gemcitabine HC1 dry powder injection, which greatly reduces the difficulty of formulating, has a faster dissolution rate, and is more convenient to take. More importantly, it has simple manufacturing features to increase the feasibility of large-scale manufacturing. Such inventions will benefit patients and improve the quality of medical care. The invention aims at improving Jianzhe (produced by GCD) frozen crystal powder intravenous injection preparation, and it becomes a product with good dissolution rate and more convenient use. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Because Jianze (Genza) frozen crystal powder intravenous preparation contains mannitol (bulk agent) and sodium acetate (acid value adjustment agent), while mannitol and sodium acetate are frozen. The excipients that must be added in the crystal drying process make it difficult for medical personnel to determine whether the product is completely dissolved. The present invention is to design a new formulation of an injection preparation without mannitol, sodium acetate and miniaturizing the dry powder of GemcitabineHCl. Embodiment 25 The purpose of the present invention is to design a mannitol-free, sodium acetate and apply 313 paper sizes to the Chinese National Standard (CNS) A4 specification (2 丨 0 X 297 mm) 200425912 A7 • Description of the invention (3) Gemdtabine New formulation of HC1 dry powder miniaturized injection preparation to make new prescription products safer and more convenient. 5 Grind the dry powder of Gemcitabine HC1 to a certain range of fine particles with a miniaturization device, and then fill this fine dry powder into a sterilized glass vial for injection. Therefore, the present invention has a very high feasibility in mass production and commercialization. 0 10 15 The consumption cooperation of employees of the Central and Standard Bureau of the Ministry of Economic Affairs is printed. Example 1 This example is prepared by using the prescription system of the present invention. The details are listed in Table 1. Table 1: Gemdtabine HC1 miniaturized prescription compound dosage * Gemcitabinc HC1 0 * 2 g *: Micronized particle range is 10 // m ~ 40 / zm In production, Gemdtabine HC1 can be powdered with a ball mill (RETSCH Centrifugal Ball Mill S 100) Miniaturization. Gemdtabine HC1 fine powder was stored at 25 ° C ± 2 ° C and 40 ° C ± 2 ° C, and there was no obvious degradation within 6 months (see Table 2). I ^ n I n Order the I line (please read the precautions on the back of the page first. The page on this page) 20 This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 200425912 A7 B7 V. Description of the invention (4 ) Time Assay Percentage 25 ° C ± 2 ° C 40 ° C ± TC__ Start 100.5% ± 0 · 32% 1003% ± 〇 * 44% First month 100 · 1% ± 0 · 42% 100.4% ± 〇 * 57 % 99,8% ± 0,27% in the second month 99J% ± 0.61% in the third month 1 ⑻ · 2% ± 0.26% 99.8% ± 〇% 0 · 33% 100,2% ± 〇 * 53% 5 10 (Please read the notes on the back to write this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 彳: Add the above-mentioned finely divided GemcitabineHCl powder to the quantitative For water for injection, shake for about 30 seconds to completely dissolve the product and make it into an aqueous solution with a concentration of about 40 mg / ml. This product can be administered to a patient by intravenous drip. Table 3. Gemcitabine HC1 miniaturized prescription compound dosage * Gemcitabine HC1 1 ♦ 〇g * ·· Micronized particle range is 30 to m ~ 1〇 " m In the production, GematabineHCUx can be exhausted and researched dtahine ΗΓΊ Qi Cong, ---- 1 attack ,,, Tianhua. 15 Gemcitabine HC1 micronized powder has no obvious degradation during storage within 25 ° C (see Table 4), 6 • Packing --- The size of the paper is in line with Chinese National Standard (CNS) A4 (210X 297mm) Author 200425912 A7 B7 V. Description of the invention (s) Reference 4 Gemcitabine HC1 (Table 3) Stability test result time Assay Percentage 25 ° C ± 2 ° C 40 ° C ± 2 ° C Start 100 · 2% ± 038% 1013% ± 0 * 72% in the first month 100 · 8% ± 0 · 11% 1〇〇 · 6% soil 0.21% in the second month 1003% ± 0,37% 99.9% ± 036% in the third month 100 · 1% ± 0.47% 100 · 5% Soil 〇48% Sixth month 99,9% ± 0 · 21% 100 · 7% ± 0 · 59% Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 Add the above-mentioned micronized Gemcitabine HC1 powder to a volume of water for injection and shake for about 30 seconds to completely dissolve the product into an aqueous solution with a concentration of about 40 mg / ml. This product can be administered to patients by intravenous drip. Example 3 10 Table 5 Gemcitabine HC1 Refinement Formula 4 " 物 _ 剂 景 * Gcmcitabinc HC1 0.2 g *: Micronized particle range is 0 · i " m ~ 2〇 〆m In the production, Gemcitabine HC1 can be refined with an air mill (Jetpharma, MC 15 50). HC1 refined powder is stored at 25 ° C ± 2 ° C and 40 ° C ± 2 ° CT for 6 months There is no obvious degradation in the inside (see Table 6). {Please read the precautions on the back before filling out this page} '' · · team n el ni Is amMm Order --------- This paper size applies to China Standard (CNS) A4 Specification (21 () χ 297 public reply) 200425912 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (G), Table 6 Gemcitabine HC1 (Table 5) Stability Test Results Time Assay Percentage 25 ° C ± 2 ° C 40 ° C ± 2 ° C Start 99J% ± 0.62% 100 * 2% ± 037% First month 100.2% ± 0.34% 1 ⑻, 6740,46% Second month 1 ⑻ + 3% ± 0.37% 99J% ± 0.53% Third month 100.1% ± 033% 99,9% ± 0.48% Sixth month ^% 100.4% ± 0.42% 99,5% ± 0.51% 5 Add the above The micronized Gemcitabine HC1 powder is added to a certain amount of water for injection, and shaken for about 30 seconds to completely dissolve the product, so as to form an aqueous solution with a concentration of about 40 mg / ml. This product can be administered to a patient by intravenous drip. The spirit and scope of the present invention are limited only by the scope of patent application described below, and are not limited by the above-mentioned special cases. 15 20 This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) (Please read the precautions in the back first, write this page)