TWI249409B - Sustained release of microcrystalline peptide suspensions - Google Patents
Sustained release of microcrystalline peptide suspensions Download PDFInfo
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Description
1249409 A7 ______ B7 五、發明説明(1 ) 發明背景 (請先閱讀背面之注意事項再填寫本頁) 在調配物中經常須要能持續釋出活性成份以便遞送具 生物活性的肽類給動物及人類。該調配物可以將活性成份 倂入生物可降解的以及生物相容的聚合物,形成微膠囊、 微顆粒或植入型棒狀物提供,或者可使用機械裝置,例如 微泵或非生物可降解的容器。若此肽可高度溶解於水溶 液,則彼可與非降解型聚合物(例如纖維素衍生物)調製成複 合體,或與聚合物溶液混合(其在非經腸注射下形成凝膠), 自其中緩慢地釋出活性的肽。 所有上述的調配物之缺點及限制爲,例如懸浮液體積 大或須要移除非降解型裝置。而形成凝膠之肽類常有生物 效性上的問題,會干擾所要求的活性成份延釋作用。 經濟部智慧財產局員工消費合作社印製 某些問題是起因於肽類的物理化學性質,如參.見R. Deghenghi 丨丨Antarelix’丨 in Treatment with GnRH Analogs: Controversies and PerspectivesM, edited by M. Filicori and C. Flamigni,The Parthenon Publishing Group, New York and London 1996, pages 89-91。其他的問題則參見 J. Rivier "GnRH analogues towards the next millennium丨· in GnRH Analogues, edited by B. Lunenfeld, The Parthenon Publishing Group,New York and London 1999,pages 31-45 以及 M.F. Powell et al.丨,Parenteral Peptide Formulations: Chemical and Physical Properties of NativeLHRHand Hydrophobic Analogues in Aqueous Solution” in Pharmaceutical Research, Vol. 8, 1258-1263 (1991)。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -4 - 1249409 A7 B7 五、發明説明(2) 據此,須要新穎的調配物及投藥方法以避開此類問 題’本發明係著眼於此項需要。 (請先閱讀背面之注意事項再填寫本頁) 本發明槪要 本發明係關於預防厭水性肽類形成凝膠的方法。本方 法有利地包含使厭水性肽與相對離子接觸,其用量及莫耳 比足以使肽形成流體狀之乳濁微晶粒懸浮水溶液,而不形 成凝膠。 本發明亦關於厭水性肽與相對離子在水中形成之流體 狀、乳濁的微晶粒懸浮水溶液,其中肽及相對離子之存在 含量以及莫耳比在攪拌下可充分的形成懸浮液而不形成凝 膠。 由於不致於形成凝膠,因此可調製成注射懸浮液。當 此類懸浮水溶液以非經腸型式(即皮下的或肌肉內的)注射於 哺乳動物(例如人類)時可長期持續地釋出厭水性肽。 經濟部智慧財產局員工消費合作社印製 較佳之相對離子爲強酸(例如三氟乙酸或硫酸)之鹽類。 厭水性肽可爲GnRH類似物,較佳者爲GnRH拮抗劑。更佳 的 GnRH 洁抗劑係選自:Azaline B、Abarelix、Antide、 Ganirelix、Cetrorelix、或 FE200486 之強酸鹽類形式(例如: 三氟基醋酸鹽或硫酸鹽)。
Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH2 三氟基醋酸鹽及 Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-AlaNH2硫酸鹽是最佳的化合物。 厭水性肽鹽,較佳者宜懸浮於濃度等於或高於25毫克/ 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) -5 - 1249409 A7 ___ B7 五、發明説明(3 ) 毫升且酸:肽之莫耳比至少爲1.6 : 1之水溶液。至少有一 部份肽鹽形成針狀形式,其粒度介於約5至1 50微米之 間。 (請先閱讀背面之注意事項再填寫本頁) 視須要,懸浮水溶液中可含有等張劑,例如甘露糖 醇。懸浮水溶液中亦可含有醫藥學上可接受的賦形劑。懸 浮液可乾燥成冷凍乾燥的狀態,其可與水或緩衝液混合而 重組。本發明的具體實施例亦包含此類乾燥懸浮液的冷凍 乾燥組成物及製作乾燥懸浮液之方法。 圖形簡述 圖1說明對老鼠以皮下注射本發明之teverelix®三氟基 醋酸鹽懸浮液後得到的藥物動力學效應(抑制睪酮); 圖2說明對老鼠注射本發明之teverelix®三氟基醋酸鹽 懸浮液後數週持續釋出之肽。 較佳具體實施例的詳細說明 經濟部智慧財產局員工消費合作社印製 我們意外的發現一種分子式爲 Ac-D-Nal-D-pClPhe-D-Pal-Ser-Tyr-DHci-Leu-Lys(iPr)-Pro-D-Ala-NH2(teverelix®,一種GnRH拮抗劑)之肽的三氟基醋 酸鹽(TFA)或硫酸鹽,其高度濃縮之懸浮水溶液(預期爲厭水 性)並不會形成凝膠而是形成微晶粒的乳濁懸浮液,其可易 於對動物或人類進行非經腸注射,在數週內釋放出活性成 份(參閱圖1及2)。其它種鹽類,例如乙酸鹽,並不具有該 作用,而會在活體內形成生物效性不良之凝膠。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -6- 1249409 A7
本發明簡單而明確的解決了如何抑制厭水性肽類凝膠 作用方面的問題,得到使該肽類長期長效傳輸之微晶粒高 度濃縮懸浮液的形式。 (請先閲讀背面之注意事項再填寫本頁) 本發明另一個優點是該懸浮液之體積小,可用細針進 行非經腸注射,並可改進注射材料的局部耐受性。在注射 時’所投用之懸浮液中肽類之用量約〇·!至5毫克/公斤哺 乳動物體重。 相對離子之較佳用量是超過形成鹽類的必須含量。該 含量一般至少在1.6莫耳酸/莫耳肽,較佳者爲2莫耳/莫耳 或更高。此外,應能將注射懸浮液濃縮至其釋放型式最令 人滿意。濃縮意指肽用量應是整體調配物重量的2.5%以 上。 懸浮液可用冷凍乾燥法或噴霧乾燥法乾燥以形成可儲 存之冷凍乾燥組成物,在製備注射調配物時可與水或緩衝 液重組。 實施例 實施例1 經濟部智慧財產局員工消費合作社印製 將200微升之5%甘露糖醇加入大約15毫克之LHRH拮 抗劑teverelix®三氟基醋酸鹽中。使用振盪器攪拌混合物i 分鐘,得到流體狀的乳濁的珍珠狀懸浮液。懸浮液由約1〇 微米長度之微結晶組成。微結晶可聚集而形成類似海膽之 構造。老鼠於皮下注射懸浮液(1毫克)後,可提供持續45 天以上的抑制睪酮藥物動力效應(圖1)。藥物動力學分析顯 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) 1249409 Α7 Β7 五、發明説明(5) 示在數週持續釋出肽(圖2)。 實施例2 將200微升之水加入大約15毫克之LHRH拮抗劑 teverelix®三氟基醋酸鹽中。使用振盪器攪拌混合物一分 鐘,得到流體狀的乳濁珍珠狀懸浮液。 實施例3 將200微升之水加入大約15毫克之LHRH拮抗劑 teverelix®乙酸鹽中。使用振盪器攬拌混合物一分鐘,得到 透明的凝膠。凝膠中加入20微克之TFA(3莫耳/莫耳),結 果形成流體狀的乳濁的珍珠狀懸浮液流體。 實施例4 將200微升之100毫莫耳濃度的TFA加入大約15毫克 之LHRH拮抗劑teverelix®乙酸鹽(2莫耳/莫耳)中,得到流 體狀的乳濁懸浮液。此外,攪拌200微升之75毫莫耳濃度 之TFA與大約15毫克之LHRH拮抗劑teverelix®乙酸鹽(1.5 莫耳/莫耳),結果於攪拌之後得到透明的凝膠。在另一硏究 中,將100微升各種濃度之TFA加入7.5毫克之LHRH拮抗 齊!1 teverelix®乙酸鹽中(TFA/Teverelix之莫耳比介於1至 3)。得到流體狀的乳濁懸浮液(莫耳比1 1·6),而在其它莫耳 比之下得到凝膠。 (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -- I -- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) _ 8 - 、 1249409 經濟部智慧財產局員工消費合作社印製 A 7 _ B7_五、發明説明(6 ) 實施例5 將200微升之150毫莫耳濃度的TFA加入含量介於5 至30毫克(濃度介於25至150毫克/毫升)之LHRH拮抗劑 teverelix®乙酸鹽中。得到濃度多至〗〇〇毫克/毫升的流動乳 濁狀懸浮液。 實施例 6 將200微升之150毫莫耳濃度的TFA加入大約15毫克 之LHRH拮抗劑teverelix®乙酸鹽(3莫耳/莫耳)中,於攪拌 之後得到流體狀的乳濁懸浮液。將懸浮液冷凍乾燥過夜。 在冷凍乾燥物中加入200微升之水或5%甘露糖醇,於攪拌 及重新調製之後得到流體狀的乳濁懸浮液。 實施例7 將1毫升之150毫莫耳濃度的TFA加入大約75毫克之 LHRH拮抗劑teverelix®乙酸鹽(3莫耳/莫耳)中,於攪拌之 後得到流體狀的乳濁懸浮液。將懸浮液冷凍乾燥過夜。在 冷凍乾燥物中加入1毫升水以及0.2莫耳濃度乙酸鹽緩衝溶 液酸鹼度4.0,於攪拌以及重新調製之後得到流體狀的乳濁 懸浮液。此類懸浮液在室溫下至少可穩定3天。 實施例δ 將100微升之250毫莫耳濃度的H2S〇4加入.5毫克之 LHRH拮抗劑 teverelix®乙酸鹽(5莫耳/莫耳)中,於數個小 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) 1249409 A7 B7 五、發明説明(7) 時之後得到流體狀的乳濁懸浮液。懸浮液由約100微米長 度之微結晶組成。微結晶可共同形成類似海膽的構造。將 懸浮液冷凍乾燥過夜。在冷凍乾燥物中加入100微升之水 或5%甘露糖醇,於攪拌以及重新調製之後得到流體狀的乳 濁懸浮液。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210x297公釐) -10 -
Claims (1)
- 六、申請專利範圍 附件2A: 第911 19713號專利申請案 中文申請專利範圍替換本 (請先閱讀背面之注意事項再填寫本頁) 民國94年1〇月17日修正 1. 一種預防teverelix形成凝膠之方法,其包含令 teverelix與源自三氟乙酸或硫酸之相對離子接觸,該 teverelix和相對離子之量及莫耳比係足以使teverelix形成 流動乳濁狀微晶粒懸浮水溶液而不形成凝膠。 2.如申請專利範圍第1項之方法,其中該t e v e r e 1 i X鹽 係懸浮於該水溶性基質中且其濃度等於或高於25毫克/毫 升。 3 ·如申請專利範圍第1或2項之方法,其中該懸浮水 溶液含有等張劑。 4.如申請專利範圍第3項之方法,其中該等張劑爲甘 露糖醇。 5 ·如申請專利範圍第1或2項之方法,其中該懸浮水 溶液含有醫藥上可接受的賦形劑。 經濟部智慧財產局員工消費合作社印製 6. 如申請專利範圍第1或2項之方法,其中自冷凍乾 燥的肽鹽立即配製成該懸浮水溶液。 7. —種teverelix與源自三氟乙酸或硫酸之相對離子在 水中所形成之流動乳濁狀微晶粒懸浮水溶液,其中 teverelix及該相對離子之存在量及莫耳比在攪拌下係足以 形成懸浮液而不形成凝膠。 8. 如申請專利範圍第7項之懸浮液,其中該tevei.elix 鹽係懸浮於該水溶性基質中且其濃度等於或高於25毫克/毫 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ' Α8 Β8 C8 D8 1249409 六、申請專利範圍 升。 (請先聞讀背面之注意事項再填寫本頁) 9 ·如申請專利範圍第7或8項之懸浮液,其中該懸浮 水溶液含有等張劑。 10.如申請專利範圍第9項之懸浮液,其中該等張劑 是甘露糖醇。 1 1 ·如申請專利範圍第7或8項之懸浮液,其進一步 包含醫藥上可接受的賦形劑。 12. 如申請專利範圍第7或8項之懸浮液,其中該微 結晶係呈顆粒大小介於約5至1 50微米間之針狀型式。 13. —種冷凍乾燥組成物,其包含申請專利範圍第7 至1 2項中任一項之乾燥懸浮液。 14· 一種製備teverelix之持續釋出型調製劑之方法, 其包含令teverelix與源自三氟乙酸或硫酸之相對離子接 觸’其中teverelix及該相對離子之存在量及莫耳比在攪拌 下係足以形成懸浮液而不形成凝膠。 經濟部智慧財產局員工消費合作社印製 15.如申請專利範圍第14項之方.法,其中該tevereiix 鹽係懸浮於該水溶性基質中且其濃度等於或高於25毫克/毫 升。 16·如申請專利範圍第14或15項之方法,其中該懸浮 水溶液含有等張劑。 Π·如申請專利範圍第16項之方法,其中該等張劑爲 甘露糖醇。 18·如申請專利範圍第14或15項之方法,其中該懸浮 水溶液含有醫藥上可接受的賦形劑。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公ίίΐ "^ ;-- -2- 1249409 | D8 六、申請專利範圍 19. 如申請專利範圍第14或15項之方法,其中自冷凍 乾燥的肽鹽立即配製成該懸浮水溶液。 20. —種製備申請專利範圍第1 3項之冷凍乾燥組成物 之方法,其包含申請專利範圍第1至6項中任一項之方 法,及隨後藉由冷凍乾燥或噴霧乾燥以得到該組成物。 21. —種製備teverelix之可注射的流動乳濁狀微晶粒懸 浮水溶液之方法,其包含利用水或緩衝溶液重新組合申請 專利範圍第1 3項之冷凍乾燥組成物。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) -3-
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112423776A (zh) * | 2018-07-05 | 2021-02-26 | 安迪威有限公司 | 冻干方法和由该方法获得的替维瑞克-tfa冻干物 |
CN112423776B (zh) * | 2018-07-05 | 2024-05-31 | 安迪威有限公司 | 冻干方法和由该方法获得的替维瑞克-tfa冻干物 |
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