TWI301761B - Zinc-free and low-zinc insulin preparations having improved stability - Google Patents
Zinc-free and low-zinc insulin preparations having improved stability Download PDFInfo
- Publication number
- TWI301761B TWI301761B TW091105385A TW91105385A TWI301761B TW I301761 B TWI301761 B TW I301761B TW 091105385 A TW091105385 A TW 091105385A TW 91105385 A TW91105385 A TW 91105385A TW I301761 B TWI301761 B TW I301761B
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- Prior art keywords
- insulin
- zinc
- pharmaceutical composition
- concentration
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims description 161
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Description
1301761
、發明說明（！） 發明之概球 本發明為有關於一種增進穩定性之醫藥衾 成物，其包括選自下列之多肽：胰島素(例如: 類騰島素、牛胰島素或豬胰島素）、騰島素㈣ ，、騰島素衍生物、活性胰島素代謝物或其4 組合；一種界面活性劑或許多界面活性劑之金 ，，和選擇性添加一種防腐劑或許多防腐劑3 砠合’以及選擇性添加一種等壓劑、緩衝劑a 賦形劑或其之組合，此醫藥組成物為低鋅或; 鋅。此配方可應用於糖尿病之治療，以及特另 適用於胰島素泵、冑、注射器、吸入器或需名 增加物理穩定性之製劑。本發明同樣為有關友 -種非經口製劑’其含上述可使用於糖尿病戈 配方，以及製備該製劑和增進糖尿病製劑之浪 定性的方法。 經濟部智慧財產局員工消费合作社印製 ^全球約有一億二千萬的人口罹患糖尿病。 這些患者中約一千二百萬的人屬於第一型糖肩 病，其目前唯一治療方法祗有補充内分泌胰磨 素分泌的缺乏。患者終身仰賴每天數次的胰磨 素/射和第一型糖尿病比較，第二型糖尿病 基本上並非胰島素的缺乏，大部分以胰島素％ 療的病例配合口服抗糖尿劑即可得到良好治療 -3- 1301761 五 發明說明（2) A7 B7 效果，特別是在疾病的惡化期。 健康人之胰臟所分泌之胰島素和血糖濃度 有、绝胃的關係。例如在用餐後血糖濃度昇高 時’騰島素之分泌有迅速增加之代償作用。在 禁食期間，細胞質胰島素降至基礎值而可持續 供應葡萄糖至胰島素-敏感之器官和組織，並且 可降低晚間肝糖之產量。大部分從皮下投與以 取代内源性胰島素分泌之外源性胰島素並無法 達到上述血糖之生理調節上的品質Q其通常會 造成血糖上下起伏之波動，其嚴重時有導致死 亡的危險。此外，無初症狀之經年性血糖濃度 過兩仍被視為健康上的一種威脅。在美國大規 模的DCCT研究[糖尿病之控制和併發症試驗研 究小組（1993)·心g/. «/, MeA329,977〜986]清楚說 經濟部智慧財產局員工消費合作杜印裝 月陵性血糖濃度幵咼為造成糖尿病末期損傷的 主要原因。糖尿病未期的損傷主要為微血管和 大血管的病變，在某些特定情況下會呈現視網 膜病、腎病或神經變性病而導致失明，腎衰竭 和四肢病變，以及伴隨心臟血管疾病危險指數 的增加。溽於此，故糖尿病改善療法之主要目 標為使弟血糠儘量保持接近其生理範圍。根據 此胰島素治療觀念的強化，故每天必需持續注 簡4- A7 B7 1301761 ^__-_ 五、發明說明（3) 射速效和緩效騰島素製劑。為了避免餐後血糖 的增加，速效之糖尿病製劑必需於用餐時服 用。缓'效之胰島素製劑主要目的為確保基本胰 島素之供應’特別是避免晚上的低叙糖症。 胰島素為具有51個胺基酸的多肽，其分成 兩種胺基酸鏈：具有21個胺基酸之A鏈和具有 30個胺基酸之B鏈。其藉由兩個二硫化物橋相 互連接。胰島素用於糖尿病之洽療已行之务 年&此處不僅使用天然之膜島素，最近使亦用 胰島素之衍生物和其類似物。 胰島素類似物為天然之胰島素，亦即為人 類胰島素或動物胰島素，其不同在於至少一天 然胺基酸殘基被其它之按基酸殘基所取代，和/ 或從對應或相同之天然胰島素添加/移除至少一 胺基酸殘基。非天然之胺基酸殘基亦可被添加 和/或取代。 經濟部智慧財威扃員工消貲合作社印载 胰島素衍生物為天然胰島素或胰島素類似 物之衍生物，其經過化學修飾而得。此化學修 飾包括，例如，一個或以上的胺基酸添加一個 或以上的特殊化學基。 通常，騰島素衍生物和胰島素類似物和人 類胰島素比較或多或少都經過修飾。 -5- 1301761 A7 ___B7 五、發明說明（4) EP 0 214 826、EP 0 375 437 和 EP 0 678 522描述胰島素具有加速作用的效果。EP 0 124 826為特別有關B27和B28之取代物。EP 0 678 522說明具有各種胺基酸於B29位置之胰島素類 似物，其以脯胺酸（proline)較佳，但非麩胺酸 (glutamic acid)。EP 〇 375 437 述及包括具有離 胺酸（lysine)或精胺酸（arginine)於B28位置之胰 島素類似物，其可選擇另外於B3和/或A21位 置進行修飾。 EP 0 419 504中揭示具有對抗化學修飾之保 護的胰島素類似物，其B3位置之精胺酸以及位 於A5、A15、A18或A21位置至少有一個或更 多的胺基酸被修飾。 經濟部智慧財產局員工消费合作社印製. WO 92/00321中說明B1〜B6位置至少有一 個胺基酸被離胺酸或精胺酸所取代。根據W0 92/00321所述，此類之胰島素具有延長效果的 作用。 市售之天然胰島素製劑有不同於原始胰島 素（例如牛、豬、人類勝島素）之胰島素取代物和 組成，同時亦影響其效果（產生作用和作用時 間）。組合各種不同胰島素製劑’可建立近似生 理狀態的不同作用模式和血糖值。有時，除了 -6- 1301761 Α7 Β7 五、發明說明（5) 上述天然胰島素之外，已上市之胰島素街生物 製劑或胰島素類似物在動力學上亦經過改良。 今曰之DNA重組技術，對製備此類改良姨島素 而言已漸趨成熟。其包括”單體胰島素類似 物’’，例如具有速效之胰島素Lispro、騰島素 Aspart和HMR 1964[人類胰島素離胺酸（B3)，麵 胺酸（B29)〗，以及具有長效之胰島素Giargin。 或 用 均 泵 學 除了作用時間之外，製劑之穩定性對病人 而言亦非常重要。增進胰島素配方之穩定性， 對露暴於特殊機械緊迫或高溫下之製劑而言有 助於增加其長期之物理穩定性。這些情形 括’例如’筆形、吸入系統、無針注射系統 胰島素泵之騰島素投藥系％。胰島素泵可利 穿戴或植入病人體内之方式。上述兩種方式 使製劑必需在承受體溫和振動之下而不影響 浦之輸送動作，因於i v泰a l & 經濟部智慧財產局員工消费合作社印製 ^ 岛此其必需有非常高的熱化， 抗力。由於胰島辛签〆 系幸（了樾棄式和可回收式筆）同 樣必需穿戴在身上，丛女 A _ 故亦必需有相同之抗力 定 兀^之製劑在上述情 I It况下均不具有足夠之穩 性 胰島素以穩定 > 人^ v, . ^ 鋅六聚物（hexamers)的形 式存在於藥用潘疮μα 度的中性溶液中，其由3個相 -7· A7 B7 1301761 五、發明說明（6 ) 同之二聚物（dimmer)單位所組成[Brange等人， 糖尿病之看護，13 : 923〜954 (1990)]。藉胺基 酸順序之修飾，可減少胰島素之結合。因此， 主要以单體形式存在之騰島素類似物，例如 Lispro，可更迅速地被吸收而呈現較短的作用時 經濟部智慧財產局員工消费合作社印製 間（HPT Ammon和C· Werning;抗糖尿病；第2 版；Wiss· Verl.-Ges· Stuttgart，2000 ,第 94.f 頁）。然而，以單體或雙體形式存在之速效胰島 素類似物的穩定性較低並且在熱和機械緊迫下 較易聚集。此可由其混濁狀和出現不可溶解之 沉殿物而得知（Bakaysa等人，美國專利號瑪 547497 8)。這些較高分子量之變形產物（雙體、 三體、多體）和聚積物不僅會降低胰島素之投藥 劑量，亦會導致病人之刺激或免疫反應。該不 可溶解之聚積物甚至會影響以及導致泵浦插管 和導管之阻塞。由於鋅可增加胰島素之穩定 性，而無鋅或低鋅胰島素製劑以及胰島素類似 物則對穩定性特別敏感。速效之單體胰島素類 似物由於其單體胰島素易形成不溶性之聚積 物，因此不具物理上的穩定性。為了維持騰島 素製劑之品質，故必需避免其形成聚積物。 有許多方法可增進胰島素之穩定性。國際 -8- A7 B7 1301761 五、發明說明（Ο 專利申請案WO98/56406中述及以TRIS或精胺 酸緩衝液增加騰島素之穩定性。美國專利 5866538述及一種含甘油和5〜100mM(毫莫耳濃 度）之胰島素製劑，其具有增進穩定性之效果。 美國專利5948751述及一種增加物理穩定性之 胰島素製劑，其添加了甘露糖醇或其它類似之 糖類。含辞之胰島素溶液添加過量之鋅時同樣 可增加其穩定性（J· Brange等人，糖尿病醫學， 3 : 532〜5 36，1986)。酸驗度和各種賦形劑對騰 島素製劑之穩定性的影響亦已被廣為討論（j.
Brange 和 L. Langkjaer，Acta Pharm. Nordica 4 : 149〜158) 〇 經濟部智慧財產局貝工消费合作社印製 這些增加穩定性的方法通常無法跟隨日漸 增加之需求的腳步（增進其於室内或體溫以及在 機械緊迫下之穩定性），對物理緊迫特別敏感之，， 單體”胰島素或速效胰島素而言亦是如此。此 外’所有市售含鋅之胰島素製劑，其添加之鋅 全為穩定製劑之用途。因此，Bakaysa等人於美 國專利5474978中述及增進穩定性之胰島素複 合物，其含6個胰島素類似物單體、2個鋅原子 和至少3個苯酚防腐劑分子。這些配方可另外 添加生理學上可接受之缓衝劑和防腐劑。然 -9- 1301761 五、發明說明（s) 經濟部智慧財產局員工消費合作社印製 而’如果在不添加鋅的情 無法達到可上市之要=:，上述之製劑均 在無辞的情況下會喪失其/姨島素Lispr。 rR . 畏失其物理上的穩定性 心等人，蛋白質科學（1996)，S : =21〜2531卜先前之技術中並未提及具有適當穩 疋性’特別是物理穩 咏* i 穩疋性，之有關低鋅或無鋅 胰島素配方。 因此本發明為根據此目標而發現一種無 辞胰島素製劑及其衍生物和類似物，並且其 具有極高之穩定性。 我們目前很驚訝地發現，添加例如 poloxamers 或聚山梨酸酯（p〇iys〇rbate)(TweenTM) 可戲劇化地增進胰島素製劑之穩定性，並且即 使無鋅之製劑亦具有極佳的穩定性，故其可被 用於注入泵或其它投藥系統中。這些製劑特別 是在緊迫之狀況下仍具有極高的穩定性。此原 理可應用於騰島素、胰島素類似物、胰島素衍 生物或其之混合物。 在中性溶液中，胰島素和鋅離子形成複 物。此時’在適當之鋅濃度下，6個胰島素分 和2個鋅離子可形成穩定之六聚物。形成此構 造時’鋅相對胰島素的濃度必需至少 裝 訂
4•I 合子 在 -10· A7 B7 1301761 i、發明說明（9) 0.4%(w/w)以上。此相當於製備100 IU/ml(國際 單位/毫升）之胰島素時，鋅之濃度必需約為 13pg/ml(微克/毫升）。過量之鋅（例如每一個六聚 物供應4個鋅離子）可更明顯增加其對物理緊迫 之穩定性[J· Brange等人，藉添加辞離子增進中 性胰島素之物理穩定性 ，Diabetic Md.3,532〜536(1986)〗。相較於低辞濃度之胰島 素（以重量計其<0·4%之胰島素），則產生較少之 六聚物。因此，會戲劇性地減低胰島素之穩定 性[J· Brange 和 L· Langkjaer ; 經濟部智慧財產局員工消費合作社印製 ，4 : 149〜15 8 (1992)]。此處，”無鋅，，或，，低 辞之含意為其相對騰島素之含量低於以重量計 0 4% ’其相對胰島素以重量計以低於0.2%較 佳°以胰島素製劑之慣例其每毫升含丨〇〇單位 (〇·6μιηο1/ηι1)，亦即，例如，相對1〇〇單位/ml /辰度之騰島素其鋅離子含量低於13pg/ml(〇 2 μπιοΐ/ηιΐ) ’其鋅離子以低於j 較佳0可加 入例如擰檬酸鹽（(：以“約或EDTA之含鋅複合物 以除去鋅離子，而使其無足夠之鋅離子形成胰 島素/鋅之六聚體複合物。 藥用製劑中含6〇〜6,000 nm〇l/ml(納莫耳/毫 升）之胰島素、胰島素代謝物、胰島素類似物或 -11 -
經濟部智慧財產局員工消费合作社印製 1301761 一胰島素衍生物，其以含24〇〜3 ,〇〇〇 nm〇l/ml較 佳。 可使用之界面活性劑特別指非離子或離子 (陰離子、陽離子或兩性離子）之界面活性劑而 言。特別以慣用之藥用界面活性劑較佳，舉例 而言，例如·· 驗金屬肥皂、胺肥息和驗土金屬肥阜I硬脂 酸酯、棕櫚酸酯、油酸酯、蓖麻酸酯 (ncinoleates)]、烷基硫酸酯和烷基亞磺酸酯 (alkylsulfonates)[月桂基硫酸鈉（sodium laurylsulfate)、硫酸鯨蠟鈉（s〇dium cetylsulfate)、硬脂硫酸鈉]、天然界面活性劑·[膽 汁酸鹽、皂苷、阿拉伯膠（gum arabic)]、陽離子 界面活性劑I烧基漠化物（alkonium bromides)、 錄蠛基ϋ比咬氣化物（cetylpyridinium chloride)、苯 扎溴銨（cetrimide)]、脂肪醇[鯨蠟醇（cetyl alcohol)、十八烧醇（stearyl alcohol)、膽固醇】、 多元醇之部分和脂肪酸酯，例如甘油、山梨糠 醇（sorbilol)和其類似物（Span®、Tween⑧、 Myrj^、Brij⑧）、Cremophor^i poloxamers。此藥 用組合中之界面活性劑的濃度為 〇.lpg/ml〜10,000gg/m卜以 lpg/mi〜U〇〇〇pg/ml 較
•12- A7 B7 1301761 五、發明說明（11) 佳。 此製劑中可添加防腐劑[例如苯鹼、甲苯 酚、對羥苯甲酸酯（parabens)】、等壓劑[例如甘 露糖醇、山梨糖醇、乳糖、葡萄糖、海藻糖 (trehalose)、氣化鈉、甘油]緩衝物質、鹽、酸和 鹼、和其它之賦形劑。這些物質在個別之製劑 中可單獨存在或任選之混合物。 甘油、葡萄糖、乳糖、山梨糖醇和甘露糖 醇慣常以100〜250mM(毫莫耳濃度）出現於藥用 製劑中，氣化鈉的濃度則可至150mM 〇例如磷 酸鹽、醋酸鹽、檸檬酸鹽、精胺酸、甘胺醯基 甘胺酸（glycylglycine)或TRIS(即2-胺-2-羥曱基-1,3-丙二醇）之緩衝劑和其相關鹽類之濃度為 5〜250mM，以10〜100mM較佳。 其它之賦形劑特別指鹽、離胺酸、魚精蛋 白（protamine)或 Surfer^。 經濟部智慧財產局員工消費合作社印製 因此本發明為有關一種醫藥組成物，其包 括選自含胰島素、胰島素類似物、胰島素衍生 物、活性胰島素代謝物或其組合之族群的多 肽；一種界面活性劑或許多界面活性劑之組 合；選擇性地添加防腐劑或許多防腐劑之組 合；以及選擇性地添加一種等壓劑、緩衝物質 -13- A7 B7 1301761 五、發明說明（12) 經濟部智慧財產局員工消费合作社印製 和/或其它之賦形劑或其之組合，此醫藥組成物 為無鋅或低鋅；此類藥用製劑之界面活性劑以 選自含鹼金屬肥皂、胺肥皂、鹼土金屬肥皂、 燒基硫酸酯、燒基亞續酸酯、天然界面活性 劑、陽離子界面活性劑、脂肪醇、例如甘油和 山梨糖醇之多元醇的部分和脂肪酸酯、多元醇 等之族群較佳；上述之肥息為選自含硬脂酸 酯、棕櫚酸酯、油酸酯、蓖麻酸酯之族群；該 烧基硫酸酯為選自含月桂基硫酸鈉、硫酸鯨蠛 納、硬脂硫酸鈉之族群；該天然界面活性劑為 選自含膽汁酸鹽、皂苷、阿拉伯膠、卵磷酯之 族群；該陽離子界面活性劑為選自含烷基溴化 物、録躐基吼啶氣化物、苯扎溴錄（Cetrimide<gi) 之族群；該脂肪醇為選自含鯨蠟醇、十八烷 醇、膽固醇之族群；該多元醇、甘油、山梨糖 醇之脂肪酸醋及醚類為選自含Span®、Tween⑥、 以㈣⑧、Brij⑧、cremophor⑧之族群；該多元醇為 選自含聚丙烯乙二醇（p〇lypr〇pylene glyc〇ls)、聚 乙稀乙一醇、pl〇iXamers 、 Pluronics 、 Teuomcs(特窻）之族群；該防腐劑為選自含苯 紛、甲苯齡、對羥苯曱酸酯之族群；該等壓劑 為選自含甘露糖醇、山梨糖醇、氣化鈉、甘油 -14- 301761 A7 B7 五 '發明說明（13) 經濟部智慧財產局員工消费合作社印製 之族群；該賦形劑為選自含緩衝物質、酸、鹼 之族群；該膜島素為天然之騰島素，例如人 類、牛或豬之臟島素；該胰島素類似物為選自 含甘胺酸（A21)、精胺酸（B31)、精胺酸（B32)、 人類胰島素、離胺酸（B3)、麩胺酸（B29)、人類 胰島素、離胺酸B28脯胺酸B29人類胰島素、B28 天門冬胺酸人類胰島素、人類胰島素，B28位置 之脯胺酸被天門冬胺酸、離胺酸、亮胺酸、纈 胺酸或丙胺酸所取代，以及在B29位置之離胺 酸被脯胺酸所取代、丙胺酸B26人類胰島素、 des(B28〜B3 0)人類胰島素、des(B27)人類胰島素 或des(B30)人類胰島素之族群；該胰島素衍生 物為選自含 B29-N·肉豆蔻醯基（myristoyl)-des(B30)人類胰島素、B29-N-軟脂醯基 (palmitoyl卜des(B30)人類胰島素、B29-N_肉豆蔻 醯基人類胰島素、B29-N·軟脂醯基人類胰島 素、B28-N-肉豆蔻醯基-離胺酸B28脯胺酸B29人 類胰島素、B28-N-軟脂醯基-離胺酸 B28 脯胺酸 B29 B29人類胰島素、B30-N-肉豆蔻醯基-蘇胺酸 離胺酸B3G人類胰島素、B30-N-軟脂醯基-蘇胺 酸B29離胺酸B30人類胰島素、B29-N-(N-軟脂醯 基_Υ·麩胺醯基）-des(B39)人類胰島素、B29-N· 裝 訂 -15· 經濟部智慧財產局員工消費合作社印製 1301761 Α7 ___ Β7 五、發明說明（14) (N-石膽酸醯基_γ_麩胺醯基）_des(B30)人類胰島 素、Β29-Ν-(ω-羧十七醯基）-des(B30)人類胰島素 和Β29-Ν-(ω-羧十七醯基）人類胰島素等之族 群。 本發明進一步為有關於上述之醫藥組成 物，其胰島素、騰島素類似物、活性胰島素代 謝物和/或胰島素衍生物之濃度為240〜3,000 nmol/ml(此相當於濃度1.4〜35 mg/ml或40〜500 單位/ml);其界面活性劑之濃度為〇丨〜]^ ^⑽ pg/ml，其濃度以1〜1，000 gg/ml較佳。 本發明進一步為有關於上述之醫藥組成 物，其甘油和/或甘露糖醇之濃度為1〇〇〜25〇 mM，和/或氣化物的濃度以150 mM較佳。 本發明進一步為有關於上述之醫藥组成 物’其緩衝物質的濃度為5〜250 mM。 本發明進一步為有關於一種藥用胰島素配 方，其進一步含例如鹽、魚精蛋白或Surfe^可 延遲胰島素釋放之添加物。上述延遲釋 双騰島 素配方之混合物亦包含於其中。 本發明進一步為有關於一種製備該醫藥組 成物的方法。本發明進一步同樣為有關於該配 方之投藥以治療糖尿病〇 Λ
-16- A7 B7 1301761 五、發明說明（15) 本發明進一步為有關於製備胰島素、胰島 素類似物、胰島素衍生物或其製劑的過程中使 用或添加界面活性劑做為其穩定劑。 所述之醫藥組成物中包括一種多肽，其選 自含膝島素、胰島素類似物、胰島素衍生物、 活性胰島素代謝物或其組合之族群，其pH介於 2和12之間，以介於6和8 · 5之間較佳，以介 於7和7.8之間最佳。 此專利申請案配合一些實施例之助說明如 下，其必需根據所述之方法操作。 實施例 經濟部智慧財產局員工消費合作社印製 比較研究：製備含HMR1964胰島素類似物 [離胺酸（B3)、麩胺酸（B29)、人類胰島素】之各 種無鋅製劑。製備完成後，將無辞HMR1964和 其它組成分溶於一份供注射用之水溶液中，以 及用鹽酸/氫氧化鈉將pH調整至7·3± 0.2，並製 成最終体積。下述各實驗中之HMR1964的濃度 為3.5 mg/ml(相當於1〇〇單位/mi)。以相同方法 製備第二製劑，但添加特殊量之界面活性劑。 將溶液分配於5 ml或1〇 ml玻璃容器（玻璃瓶） 中，並蓋上皇冠蓋。然後將這些玻璃瓶置於下 述之緊迫環境中： •17- 1301761
旋轉實驗：此旋轉實驗分成試驗組和對照 組，其各含5支玻璃瓶。將玻璃瓶置於離心器 内，並於37t：60rPm之下旋轉36〇。。在一定時 間之後，以標準濁度比較玻璃瓶内製劑之濁度 或利用實驗濁度光度計（濁度計）測定其 formazine濁度單位（FNU)。此實驗進行至全部 玻璃瓶達18 FNU濁度值為止 振盪實驗：將玻璃瓶置於保溫箱内之振盪 器上’並於30eC下以100次擺動/分鐘進行振 盪。在一定時間之後，利用實驗濁度光度計（濁 度計）測定測定樣本之formazine濁度單位 (FNU) 〇 實例1·旋轉實驗中添加鋅之jjMRI964的穩定 性 經 部 智 慧 財 產 局 員 工 消 费 合 作 社 印 (a)將無鋅HMR1964(最終配方之濃度為 3·5 mg/ml)溶於水溶液中，其最終濃度為27 mg/ml之m-甲苯酚、20 mg/ml之甘油和6 mg/ml 之Trometamoi(三羥甲基胺基甲烷/TRIS)，以及 利用1N(當量）鹽酸/in氫氧化鈉將pH調整至 7.2〜7,4(於室溫下）。以水將溶液配成最終体積， 並通過0·2 μπι之濾過器進行無菌過濾c然後將 其注入5 ml之注射瓶内，並以皇冠蓋加封。 -18- 經濟部智慧財產局員工消費合作社印製 1301761 a7 B7 五、發明說明（I7) (b)以相同方法製備對照溶液，但以水配製 之前加入相當於0.1 %強度之鋅氣化物儲備液， 而使最終配方之鋅含量為15 pg/ml。 各組以5件樣本進行旋轉實驗，然後在各 種不同時間測定其濁度。其結果列於下表： 說 明 濁度 >18 FNU之樣本數 胸碕 躱/J铸 第16,㈣ 餅'㈣ 第和摘 簌6狀 無添加物之 HMR1964 0 5 - - • - HMR1964+15pg/ml 辞 0 0 0 0 4 5 添加辞隨著時間增加可明顯延緩溶液濁度 之發生，因此可穩定HMR1964製劑。無添加辞 之製劑，甚至在第8小時之後即有明顯之混濁 發生。 實例2:旋轉實驗中添加聚山梨酸酯20(Τινββηφ) 之HMR1964的穩定性 (a)將無鋅HMR1964(最終配方之濃度為 3.5 mg/ml)溶於水溶液中，其最終濃度為3,15 mg/ml之 m_甲苯紛、5 mg/ml之氯化納和 6 mg/ml之Trometamol，以及利用 1N之鹽酸/1N 氫氧化鈉將pH調整至7.2〜7·4(於室溫下以水 將溶液配成最終体積，並通過0.2 μιη之濾過器 進行無菌過濾。然後將其注入5 ml之注射瓶 -19-
A7 B7 1301761 五、發明說明（1〇 内，並以皇冠蓋加封。 (b)以相同方法製備對照溶液，但以水配製 之前加入相當於 0.1%強度之聚山梨酸酯 20(Tweer^20)儲備液，而使最終配方之濃度為 1 0 pg/ml 〇 各組以5件樣本進行旋轉實驗，然後在各 種不同時間測定其濁度。其結果列於下表： 說 明 濁度>18 FNU之樣本數 第Μ碕 鄴4铸 第16⑽ 韌0批 無添加物之 HMR1964 0 5 - 虐 - - HMR1964+l(^g/ml 之 Tweenho 0 0 0 0 5 • 添加聚山梨酸酯20可明顯延緩溶液濁度之 發生。 實例 3: 旋轉實驗中添加 poloxamer 之 HMR1964的穩定性 (a) 將無鋅 HMR1964(最終配方之濃度為 經濟部智慧財產局員工消费合作社印製 3.5 mg/ml)溶於水溶液中，其最終濃度為 4.5 mg/ml之笨紛、5 mg/ml之氣化納和6 mg/ml之
Trometamol，以及利用1N之鹽酸/1N氫氧化納 將pH調整至7.2〜7.4(於室溫下）。以水將溶液配 成最終体積，並通過0.2 μιη之濾過器進行無菌 過濾。然後將其注入5 ml之注射瓶内，並以皇 -20- A7 B7 1301761 五、發明說明（19 ) 冠蓋加封。 (b)以相同方法製備對照溶液，但以水配製 之前加入相當於0.1%強度之poloxamer 171(例 如Genapol,儲備液，而使最終配方之鋅含量為 10 pg/m卜 各組以5件樣本進行旋轉實驗，然後在各 種不同時間測定其濁度。其結果列於下表： 說 明 濁度 >18 FNU之樣本數 躱摘 第16梢 粒Μ碣 ^40^ 無添加物之HMR1964 0 5 - - - - HMR1964+0,01mg/ml 之 poloxamer 171 0 0 0 2 5 _ 添加poloxamer 171亦可明顯延緩溶液濁度 之發生，並且可穩定製劑。 實例4:振盪實驗中添加聚山梨酸酯20或聚山 梨酸酯80之HMR1964的穩定性 經濟部智慧財產局員工消费合作社印製 (a) 將無鋅HMR1964(最終配方之濃度為 3,5 mg/ml)溶於水溶液中，其最終濃度為 3.15 mg/ml之 m-甲苯驗、5 mg/ml之氯化鈉和 6 mg/ml之Trometamol，以及利用 1N之鹽酸/1N 氫氧化鈉將pH調整至7.2〜7·4(於室溫下以水 將溶液配成最終体積，並通過0.2 μιη之濾過器 進行無菌過濾。然後將其注入5 ml之注射瓶 -21- A7 B7 1301761 五、發明說明（2〇) 内，並以皇冠蓋加封。 0>)以相同方法製備對照溶液，但以水配製 之前加入相當於 0.1%強度之聚山梨酸酯 20(Tween@20)儲備液，而使最終配方之濃度為 10 pg/ml 〇 (c)以（b)之相同方法製備另一對照溶液， 但以聚山梨酸酯 80(Τ\νββη®80)取代聚山梨酸酯 20 - 樣本於37乞之下置於振盪器（60rpm)上進行 振盪，然後在各種不同時間測定其濁度。其結 果列於下表： 添加物 振盪實驗後之濁（FNU) 開始 第1週 第2週 第3週 第4週 i添加 0.55 2.04 4,86 6.12 10.51 (K01mg/ml 之 Tween 20 1.75 2.60 2.44 2.44 3.80 0*01mg/ml 之 Tween 80 2.38 2.98 2.86 3.01 4.14 經濟部智慧財產局員工消费合作社印製 在振盪實驗中添加聚山梨酸酯20和聚山梨 酸酯80對HMR1 964均具有穩定效果。 實例 5:振盡實驗中添加鋅或 poloxamer (Genapol,之 HMR1964 的穩定性 (a) 將無鋅HMR1964(最终配方之濃度為 •22· 1301761 at ______B7_ 五、發明說明（21) 3.5 mg/ml)溶於水溶液中，其最終濃度為3.3 mg/ml之苯齡、5 mg/ml之氣化納和6 mg/ml之 Trometamol，以及利用1N之鹽酸/in氫氧化鈉 將pH調整至7.2〜7·4(於室溫下）。以水將溶液配 成最終体積，並通過0.2 μιη之濾過器進行無菌 過滤。然後將其注入5 ml之注射瓶内，並以皇 冠蓋加封。 (b) 以相同方法製備對照溶液，但以水配製 之前加入相當於 0,1%強度之 poloxamer PUGenapol®)儲備液，而使最終配方之濃度為 10 pg/ml〇 (c) 如（a)所述之方法製備另一對照溶液， 但以水配製之前溶液中加入相當於0.1%強度之 鋅氣化物以取代poloxamer，而使最終配方含15 gg/ml濃度之辞。 添加物 振盪實驗後之濁（FNU) 開始 第1週 第2週 第3週 第4週 無添加 0.39 0.70 4.46 8.74 14.11 (K01mg/ml 之 poloxamer 0.36 0.57 0.52 1.59 ~~一峰 0.89 0.015mg/ml 之鋅 1.02 0.68 0.70 0.56 0.86 經濟部智慧財產局員工消费合作社印製 在振盪實驗中添加辞和添加poloxamer均可 避免濁度之發生。 -23· A7 B7 1301761 五、發明說明（22) 實例 6: 旋轉實驗中添加 po丨oxamer 之 HMR1964的穩定性 (a) 將無鋅HMR1964(最終配方之濃度為 3,5 mg/ml)溶於水溶液中，其最終濃度為3.3 mg/ml之苯齡、5 mg/ml之氣化納和6 mg/ml之 Trometamol，以及利用1N之鹽酸/1N氫氧化鈉 將pH調整至7.2〜7.4(於室溫下以水將溶液配 成最終体積，並通過0·2 μπι之濾過器進行無菌 過濾。然後將其注入5 ml之注射瓶内，並以皇 冠蓋加封。 (b) 以相同方法製備對照溶液，但以水配製 之洳加入相當於 0.1%強度之 p〇l〇xarller l7l(Genapol,儲備液，而使最終配方之濃度為 100 pg/ml。 經濟部智慧財產局員工消费合作社印製 (c) 如（a)所述之方法製備另一對照溶液， 但以水配製之前溶液中加入相當於〇 i %強度之 鋅亂化物以取代poloxamer，而使最終配方含15 kg/ml濃度之鋅。 各組以5件樣本進行旋轉實驗，然後在各 種不同時間測定其濁度。其結果列於下表： -24- A7 B7 1301761 五、發明說明（23) 說 明 濁度 >18 FNU之樣本數 胸畴 勒树 第 16 笨24,㈣ 料 斜(H硪 無添加物之HMR1964 0 5 雜 - - - HMR1964+0.10mg/ml 之 poloxamer 171 0 0 0 0 1 5 添加100 pg/ml之poloxamer同樣明顯可穩 定HMR1964製劑。 經濟部智慧財產局員工消費合作社印製 -25-
Claims (1)
- 971301761 A8 B8 C8 D8 六、申請專利範圍 專利申請案第91105385號 ROC Patent Appln. No. 91105385 修正之申請專利範圍中文十替換頁-附件（二 Amended Claims in Chinese - Encl.HI) (民國97年3月7曰送呈） (Submitted on March 7, 2008) 經濟部智慧財產局員工消費合作社印製 • 一種具有增進穩定性之醫藥組成物，其包括胰島素類似 物Lys(B3)、Gln(B29)人類胰島素； 界面活性劑聚山梨酸酯； 其中此醫藥組成物為無鋅或含低於〇,4%重量比 之鋅，以組成物之胰島素含量為基準。2.如申請專利範圍第1項之醫藥組成物，其中胰島素類 似物之濃度為60〜6,000 nmol/ml。 3·如申請專利範圍第2項之醫藥組成物，其中胰島素類 似物之濃度為240〜3,000 nmol/ml。 4·如申請專利範圍第1項之醫藥組成物，其中界面活性 劑的濃度為0.1〜l，〇〇(^g/ml。 5· 如申請專利範圍第4項之醫藥組成物，其中界面活性 劑的濃度為1〜l，〇0(^g/m卜 6· 一種製造如申請專利範圍第1項之醫藥組成物的方 法，其中組成分係以水溶液形式混合一起，然後調 整所需之pH值’並以水將該混合物製成最終體積。 7·如申請專利範圍第6項之製造醫藥組成物的方法，其 最終濃度為3.15 mg/ml之甲苯酚、3.5 mg/ml之HMR 1964、6.0 mg/ml 之 Trometamo卜 5.0 mg/ml 之氣化鈉 和 〇·1 mg/ml 之 Tween⑧ 20 〇 -26 - 本紙張尺度翻+關家鮮(CNS)A4 規格（210x297公釐） 91067範圍-接3
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2002
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2004
- 2004-06-19 HK HK04104454A patent/HK1061521A1/xx not_active IP Right Cessation
- 2004-12-09 US US11/007,154 patent/US7205276B2/en not_active Expired - Lifetime
- 2004-12-09 US US11/007,155 patent/US7205277B2/en not_active Expired - Lifetime
-
2007
- 2007-03-08 US US11/683,747 patent/US7452860B2/en not_active Expired - Lifetime
-
2008
- 2008-10-06 US US12/285,464 patent/US7696162B2/en not_active Expired - Lifetime
-
2011
- 2011-03-03 CY CY20111100253T patent/CY1111413T1/el unknown
-
2012
- 2012-11-08 CY CY20121101060T patent/CY1113318T1/el unknown
-
2014
- 2014-05-21 AR ARP140102020A patent/AR096376A2/es not_active Application Discontinuation
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