TWI305778B - Peptides of an expressing unit for igf-i minimal activity and their pharmaceutical use - Google Patents
Peptides of an expressing unit for igf-i minimal activity and their pharmaceutical use Download PDFInfo
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- TWI305778B TWI305778B TW091134925A TW91134925A TWI305778B TW I305778 B TWI305778 B TW I305778B TW 091134925 A TW091134925 A TW 091134925A TW 91134925 A TW91134925 A TW 91134925A TW I305778 B TWI305778 B TW I305778B
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Landscapes
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- Medicinal Preparation (AREA)
Description
1305778 玖、發明說明: (發明說明應敘明:發明所屬之技術領域、先前技術、內容、實施方式及圖式簡單說明) (一) 發明所屬之技術領域 本發明係相關於含有Ser — Ser—Ser—Arg表示的胺基酸 序列之新穎胜肽,含有此胜肽爲有效成分之醫藥組成物,及 以含有Ser— Ser—Ser—Arg表示的胺基酸序列之胜肽和含 有Phe— Gly— Leu — Met — Nfh表示的胺基酸序列之胜肽爲有 效成分之角膜障礙治療劑或皮膚創傷治療促進劑。 (二) 先前技術 角膜係一直徑約1 cm、厚度約1 mra的透明無血管的組織。 角膜的透明性對視機能有重要的影響,角膜中的各種生理生 化學現象之主要目的係爲要維持角膜的透明性。 角膜潰瘍、角膜上皮剝離、角膜炎或乾眼症等各種疾患所 引起的角膜上皮損傷,若無倂發混合感染則會自然修復。惟 ’因某種原因而延緩其修復或不進行修復而延遲上皮損傷後 ’不僅對上皮的正常構築有不良影響,亦會損壞實質和內皮 的結構和機能。從前的治療法之原理係藉著從外界的刺激而 保護角膜表面,希望自然地伸展上皮而覆蓋在損傷部,爲一 被動的原理。近年,隨著細胞生物學的發展,已了解細胞的 分裂、移動、接合、伸展等相關因子,亦有報告指出(臨眼 ,_11,738 - 743 ( 1 992 )、眼科手術,互,7 1 9 - 727 ( 1 992) )’促進角膜上皮伸展之化合物在角膜上皮損傷的修復過程 中扮演重要的角色。 ™ 6 - 1305778 惟,胰島素類成長因子如表皮成長因子、纖維芽細胞成長 因子、血小板成長因子、形質轉換成長因子等般,爲一調節 正常人類細胞的成長之成長因子,可分爲2種亦即胰島素類 成長因子_ I (以下簡稱爲「I GF - I」)和胰島素類成長因 子—II (以下簡稱爲「IGF — II」)。近年曾報告IGF — I 會刺激甲狀腺細胞的增殖(J . Biol. Chera. , 264, 18485-18488 ( 1989)),和IGF — II可調節的血管成長和 分化(Hum. Mol. Genel·,J_,1117-1121 ( 1994))等現象 。在眼科領域中揭示,IGF — I、IGF-II及這些的機能衍生 物可促進網膜神經元的生存(特表平7-500839號公報)、 IGF — I I對角膜移植時的損傷等廣泛範圍的各種傷害之治 療有效(特開昭63-233925號公報)、藉著使用含上述成長 因子的溶液,可使供爲移植用的角膜等眼組織保存在新鮮的 組織狀態(特開平5 - 2 500 1號公報、特開平6 - 4890 1號公報 )等現象。又,揭示通常含成長因子的膠體掺合物對前眼部 等創傷之治療有效(特開平2 - 1 1 2號公報)。 另一方面’ P物質係一種具有血管擴張、平滑肌收縮、促 進唾液腺的分泌、利尿作用等,且由1 1個胺基酸組成之多 胜肽。曾有報告揭示,在眼科領域中P物質可改善眼障害中 結膜杯細胞的異常分泌(國際特許W095 / 1 3087號公開公報 )、及角膜炎等炎症時P物質的動態(曰本眼科學會雜誌,9 1 , 982-987 ( 1987)、日本眼科學會雜誌,ϋ,448 - 452 ( 1 988 ))等,正在進行各種硏究。又,特開平10-17489號公報 中記載,Ρ物質的碳末端的四胜肽Phe— Gly-Leu— Met—NH2 1305778 (以下稱爲「FGLM」)和IGF — I倂用,可促進角膜上皮的 創傷治療,且FGLM係發現此作用P物質的部分胜肽之最小 單位。惟’ IGF— I係70個胺基酸結合之多胜狀,至於其中 的哪一個胺基酸序列部位具有效果,則完全不清楚。 皮膚創傷係指裂傷、擦傷、外科手術、皮膚潰瘍、燒傷等 表面組織的損傷。有關皮膚創傷的治療,在受傷部位進行應 急處理後通常利用身體本身的回復力等待自然治癒,這類的 自然治癒到回復爲止需要長時間且持續疼痛,因此期望在受 傷部位給予創傷治療劑,積極地促進創傷治癒。 創傷的治癒過程中,細胞的移動和增殖而形成新的上皮組 織和結合組織,因此促進或刺激有關創傷治癒的細胞的移動 、分化、增殖之藥劑可作爲創傷治療劑。這類的創傷治療劑 例如氯化溶菌酶、血活素(Sol cose rye 1 )等。 惟’既有的創傷治療劑,其促進創傷治癒的作用不足,在 短時間內無法完全治癒創傷。推測其原因係這類的創傷治療 劑對創傷的治癒過程中重要的要素,例如表皮的再包覆、膠 原蛋白的合成、末梢循環的改善、肉芽形成、血管新生等之 影響小。 無報告記載有關I GF - I的最小活性表現單位,亦無報告 記載有關由Ser— Ser — Ser— Arg表示的胺基酸序列組成之 胜肽。又,亦無報告記載有關倂用含有Ser — Ser — Ser — Arg 表示的胺基酸序列之胜狀和含有Phe — Gly — Leu — Me t — NEh 表示的胺基酸序列之胜肽,對角膜障礙的作用和對皮膚疾病 的作用。 -8 - 1305778 通常,由多數的胺基酸組成的胜肽饋入生物體內後 中的胜肽鍵結容易因代謝而被切斷,又,爲要作爲醫 用而製劑化時容易發生分解等。期望胜肽鏈儘量短, 必須維持藥理活性,因此,發現長鏈胜肽的最小活性 單位即成爲開發醫藥品時重要的課題。IGF- I係由70 基酸組成的長鏈胜肽,在創製更有助益的醫藥品時, I GF - I的最小活性表現單位成爲非常重要的課題。又, 其最小活性表現單位,對具體的藥理作用即對角膜障 用和對皮膚創傷作用的硏究爲非常有趣之課題。 (三)發明內容 本發明者們合成IGF-I的各種部分胜肽,進行倂用 部分胜肽和P物質或FGLM之角膜上皮伸展相關藥理試 發現I GF - I的最小活性表現單位爲 Se r — Se r — S 八^(3£〇10_:1)表示的胺基酸序列(以下表示爲「 」)。又,發現若倂用包含SSSR表示的胺基酸序列之 和P物質或FGLM,可促進角膜的障礙治療及皮膚的創 療。亦即,含有(1)胺基酸序列爲Ser— Ser— Ser—A: 示的胜肽、其類似物或其可使用於醫藥之鹽類和(2 ) 酸序列爲 Phe— Gly-Leu— Met—NH2(SEQ ID NO:9)表 胜肽、其類似物或其可使用於醫藥的鹽類之組成物, 爲由各種因素引起的角膜損傷所導致的角膜潰瘍、角 皮層離、角膜炎或乾眼症等角膜障礙之治療劑,或裂 擦傷、外科手術、皮膚潰瘍、燒傷等皮膚創傷或由這 因引起的壞死等疾病之治療劑。又,本發明的角膜障 ,其 藥使 惟仍 表現 個胺 發現 使用 礙作 這些 驗, e r — SSSR 胜肽 傷治 .g表 胺基 示的 可作 膜上 傷、 些原 礙治 -9- 1305778 療劑及皮膚創傷治療促進劑亦可和公認具有創傷治療效果 之抗壞血酸、抗壞血酸酯、抗壞血酸鹽、泛酸、泛酸鹽等 掺合使用。 IGF-Ι係由A、B、C及D各範圍構成,因A範圍及B範圍 係具有和胰島素、IGF-II類似之結構者,本發明者們著眼 於IGF-Ι的C範圍及D範圍,硏究角膜上皮伸展作用。倂用 組成C範圍的胜肽或組成D範圍的胜肽和P物質,進行角膜 上皮伸展試驗時,組成 C 範圍的胜肽 Gly-Tyr-Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro-Gln-Thr(SEQ ID N0:18)(以下稱爲「GYGSSSRRAPQT」)具有活性。其次 ,因分別去除GYGSSSRRAPQT兩邊末端的2個胺基酸後仍具 有活性’使用丙胺酸掃瞄方法合成依序將 Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro(SEQ IDN0:7)(以下稱 爲「GSSSRRAP」)的胺基酸轉變成丙胺酸者,在p物質或 FGLM的共存下進行角膜上皮伸展試驗時,因發現含有SSSR 表示的胺基酸序列之所有胜肽皆具有活性,因此確定SSSR 係具有角膜上皮伸展作用所需最小的I GF - I之部分胜狀。 本發明者們主要完成下列4個發明。 弟一發明係相關於胺基酸序列爲Ser-Ser-Ser-Arg表示 的新穎胜肽或其衍生物或其可用於醫藥之鹽類。 第一發明的特徵係I GF - I的最小活性表現單位之新穎胜 肽,亦即發現胺基酸序列爲S e r - S e r - S e r - A r g表示的新穎 胜肽。因此,胺基酸序列爲Ser-Ser-Ser-Arg的胜肽或其 衍生物(以下將此胜肽和其衍生物稱爲「SSSR衍生物」) -10- 1305778 ’只要爲含有Ser-Ser-Ser-Arg表示的胺基酸序列之新穎 胜肽即可,無特別的限制。此胜肽的衍生物係指在 Ser-Ser-Ser-Arg表示的胜肽上鍵結1個或多個不影響發 現活性之胺基酸者、N末端被醯基等泛用於胜肽之保護基保 護者、C末端被酯、醯胺等泛用於胜肽之保護基保護者等, 又,亦包括Ser殘基的羥基被泛用的保護基保護者、和Arg 殘基的胺基被泛用的保護基保護者》更具體而言,SSSR衍 生物例如 SSSR、GSSSRRAP、Ser-Ser-Ser-Arg-Arg(SEQ ID N0:2)(以下簡稱爲「SSSRR」)、Gly-Ser-Ser-Ser-Arg(SEQ ID NO: 3)(以下簡稱爲 「 GSSSR」 ) 、
Gly-Ser-Ser-Ser-Arg-Arg(SEQ ID N0:4)(以下簡稱爲「 GSSSRR」)、Ala-Ser-Ser-Ser-Arg-Arg-Ala-Pro(SEQ ID NO: 5) (以 下 稱 爲 「 ASSSRRAP 」 ) 、
Gly-Ser-Ser-Ser-Arg-Ala-Ala-Pro(SEQ ID N0:6)(以下 簡稱爲 「 GSSSRAAP 」 ) 、 G 1 y - Ser - Ser-Ser-Arg-A 1 a - A 1 a - A 1 a-Pro ( SEQ ID N0:8)( 以下簡稱爲「GSSSRAAAP」)等。組成這些胜肽的胺基酸具 有L-型、D-型、D L -型,皆包含於本發明。如在藥理試驗 項中具體的舉例般,發現因倂用胜肽鏈中所有包含SSSR表 示的胺基酸序列之SSSR衍生物和P物質或FGLM,而具有角 膜上皮伸展效果及促進皮膚創傷治癒效果。 可使用胜肽自動合成機,以公認的方法製造本發明的 SSSR衍生物,其詳情如實例中所述。 第二發明係相關於含有胺基酸序列爲s e r - S e r - s e r - A r g -11- 1305778 表示的新穎胜肽、其衍生物或其可用於醫藥的鹽類等爲有效 成分且掺合可使用於醫藥的添加物所組成之醫藥組成物。 第三發明係相關於含有 (1) 胺基酸序列爲Ser-Ser-Ser-Arg表示的胜肽、其類 似物或其可用於醫藥的鹽類,和 (2) 胺基酸序列爲Phe-Gly-Leu-Met-NH2表示的胜肽、 其類似物或其可用於醫藥的鹽類 爲有效成分之角膜障礙治療劑。 第四發明係關於含有上述成份(1)及上述成分(2)爲有效 成份之皮膚創傷治癒促進劑之發明。 第三及第四發明的特徵係因倂用最小活性表現單位爲 Se r - Se r - Se r - Ar g表示的胜肽和最小活性表現單位爲 Phe-Gly-Leu-Met-NIh表示的胜肽,發現具有優異的角膜上 皮伸展效果及促進皮膚創傷治癒效果。 在第三及第四發明中,胺基酸序列爲Ser-Ser-Ser-Arg 的胜肽或其衍生物(以下將此胜肽和其衍生物稱爲「SS SR 衍生物」),只要爲含有Ser-Ser-Ser-Arg表示的胺基酸序 列之胜肽即可,無特別的限制。此胜肽的衍生物係指在 Ser-Ser-Ser-Arg表示的胜肽上鍵結1個或多個不影響發現 活性之胺基酸者、N末端被醯基等泛用於胜肽之保護基保護 者、C末端被酯、醯胺等泛用於胜肽之保護基保護者等,又 ,亦包括Ser殘基的羥基被泛用的保護基保護者、和Arg 殘基的胺基被泛用的保護基保護者。更具體而言,SS SR類 似物除了上述的SSSR衍生物之外,尙有GYGSSSRRAPQT等。 -12- 1305778 構成SSSR類似物的胜肽的胺基酸具有L-型、D-型、D L-型 ,這些皆包含於本發明。較理想的型態爲全部由L-型的胺 基酸組成之胜肽。 又’胺基酸序列爲Phe-Gly-Leu-Met-NHz表示的胜 狀或其類似物(以下此胜肽和其類似物稱爲「FGLM類 似物」)只要爲含有Phe-Gly-Leu-Met-NH2表示的胺 基酸序列之胜肽即可,無特別的限制。此胜肽的類似 物係指在 Phe-Gly-Leu-Met-NH2表示的胜肽上鍵結 ! 個或多個不影響發現活性之胺基酸者、和N末端被醯 基等泛用於胜狀之保護基保護者。更具體而言,FGLM 類似物例如P物質、FGLM、美國特許3862114號中具 體揭示的由 4~12 個胺基酸構成之多胜肽 Tyr-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO:17) ' Prο - G1 η-G1 η-Phe-Phe-G1y-Leu-Met- NH2 (SEQ ID NO : 15) Gln-Gln-Phe-Phe-Gly-Leu-Met -NH2(SEQ IDN0:14) 、 Gln-Phe-Phe-Gly-Leu-Met- NH2(SEQ ID N0:13) 、 Phe-Phe-Gly-Leu-Met- NH“SEQ ID N0:12)、 Tyr - Phe-G1y-Leu - Met- NH2 ( SEQ ID NO : 11) 、
Gly-Phe-Gly-Leu-Met- NH2(SEQ ID N0:10)等。較理想者爲 P物質、FGLM。構成這些的胺基酸亦具有l-型、D-型、DL-型’皆包含於本發明。較理想的型態爲全部由L -型的胺基 酸組成之胜肽。 本發明中可使用於醫藥之鹽類例如鹽酸鹽、硫酸鹽、磷 酸鹽、乳酸鹽、馬來酸鹽、富馬酸鹽、草酸鹽、甲磺酸鹽 -13- 1305778 、對甲苯基磺酸鹽等。 在本發明中發現倂用SSSR類似物和FGLM類似物可促進 角膜上皮的伸展及皮膚的創傷治癒。具有這些作用的SSSR 類似物之種類及FGLM類似物之種類無特別的限制,惟較理 想的進行形態例如倂用IGF- I的最小活性表現單位SSSR和 P物質的最小活性表現單位FGLM。 可採用泛用的技術調製本發明的角膜障礙治療劑及皮膚 創傷治癒促進劑,SSSR類似物或其可用於醫藥的鹽類和 FGLM類似物或其可用於醫藥的鹽類之個別的單獨製劑或掺 合製劑,可由非經口或經口的給藥方式饋入生物體,惟以 非經口給藥方式較理想。角膜障礙治療劑的理想給藥劑型 例如眼藥水、眼軟膏等。可採用泛用的技術調製這些劑型 。例如可使用氯化鈉等的等張劑、磷酸鈉等緩衝劑、氯化 苄烷銨等防腐劑調製眼藥水。其pH需在眼科製劑所需的範 圍內,以pH4 - 8的範圍較理想。 角膜障礙治療劑的給藥量可依症狀、年齡、藥劑型等適 當地選擇,若爲眼藥水,其中SSSR類似物或其可用於醫藥 之鹽類的用量爲0.001~10°/。 (w/v),較理想爲0·01~1% (w/v)之藥劑1日點藥1~數次。又’ FGLM類似物或其可 用於醫藥之鹽類的用量爲〇·〇〇〇1~〇·1% (w/v) ’較理想爲 0.001~0.01% (w/v)之藥劑1日點藥丨~數次。 亦可同時掺合上述的二成分,製成眼藥水等製劑。 又,皮膚創傷治癒促進劑的理想製劑形態例如軟膏劑、 膠狀劑、濕敷劑、黏貼劑、乳液劑、乳霜劑、噴霧劑、氣 -14- 1305778 溶膠劑、硬膏劑、懸浮劑、乳劑等,又,亦可選擇適當的 溶劑調製成液劑。爲要調製皮膚創傷治癒促進劑,可因應 其劑型而添加充塡劑、賦形劑、基劑、增量劑、pH調節劑 、溶液化劑、懸浮劑、緩衝劑、安定劑、保存劑、界面活 性劑、抗氧化劑、分散劑、乳化劑、溶解劑、溶解輔助劑 等。 上述製劑用的載體例如白色凡士林、液態石蠟、膠化烴 、鯨蠟醇、聚乙二醇、明膠、玉米澱粉、褐藻酸鈉、甲基 纖維素、羥乙基纖維素、羧甲基纖維素、塑膠製氟鈣石類 、明膠、糊精、鯨蠟醇、硬脂醇、聚乙二醇、聚乙烯醇' 甲氧乙烯-馬來酸酐共聚物、聚乙烯醚、作爲組成乙烯吡咯 烷酮成分之聚合物·共聚物、硬脂酸鈉、硬脂酸鎂、氯化 苄烷銨、橄欖油、山茶油、大豆油等油脂類、乳糖、水等 〇 可依創傷部位和創傷程度給予各種型態的本發明的皮膚 創傷治癒促進劑。例如以外用劑的型態使用時,在皮膚等 需求部位(患部)直接塗抹、噴霧或黏貼本劑。 本發明的皮膚創傷治癒促進劑的給藥量可依症狀、年齡 、劑型等適當地選擇。SSSR類似物或其可用於醫藥的鹽類 之給藥量’通常每1日約0.〇〇l~l〇〇〇mg,較理想爲 〇.〇1〜500mg’ 1次或分成數次給藥。又,FGLM類似物或其 可用於醫藥的鹽類之給藥量,通常每1日約〇.〇1〜5000rag ’較理想爲0 . 1 ~ lOOOmg,1次或分成數次給藥。 亦可同時掺合上述的二成分,製成軟膏等製劑。 -15- 1305778 以下爲製造例、製劑例及藥理試驗的結果,惟這些例子 係爲要更容易地理解本發明,並不限定本發明的範圍。 【進行發明之最佳型態】 (四)實施方式 (製造例) 本發明中使用的SSSR類似物之代表性製造例如下所示。 1 . SSSR的製造 使用胜肽自動合成機430A (生物系統應用公司製),根 據已設定的軟體’以第三丁基羥基羧基(B0C)法合成保護 胜肽樹脂。使用4-(羥甲基)苯基乙醯胺基甲基[B〇c_Arg (Tos) PAM]樹脂載體(0.5毫莫耳尺度)作爲起始原料。 本合成法中使用30%三氟醋酸(TFA) /二氯甲烷、70% TF A / 一氯甲垸去除Na-胺基酸保護基的Boc基,並使用N -甲 基-2·吡咯烷酮(NMP) /二氯甲烷清洗。相對於胺基,縮合 劑的N,N —二環己基碳化二亞胺(DCC )及1-經基苯并三哩 (HOBt )和N-保護胺基酸的Boc-Ser ( OBzl )衍生物之用 量分別爲4當量,使用二甲亞楓(DMS0 ) — NMP ( 8 : 2 )作 爲反應溶劑。縮合反應結束後,爲要完全地擋住殘存的胺 基,所進行的操作係在醋酸酐/ N,N—二異丙基乙胺(DIEA )中防止缺陷胜肽的生成。重複操作Boc基的去除和 Bo c-Ser( OBzl)的縮合以進行最終保護胜肽的構築。經由 無水氟化氫(HF)的處理(HF:對甲酚=8: 2( v/v),-2~-5 °C,6 0分鐘)可從製得的保護胜肽樹脂切斷胜肽並使全部 的保護基脫離。 -16- 1305778 反應後蒸飽去除HF,在o.i%三氟醋酸水中萃取胜肽, _得粗生成物的凍結乾燥粉末後繼續進行分取精製。使用 島津製作所製的HPLC LC8A (管柱:YMC製ODS 30x24mm ) 進行分取精製’在乙腈/水系(含有〇.1% TFA)中以0.5~2 %的梯度(80分鐘)進行。收集目的物的高純度部分,蒸 館去除乙腈後凍結乾燥,可製得目標化合物TFA鹽70mg ( 回收率32% )。 胺基酸分析(水解條件:6N鹽酸,1 1 0。(:,22小時) Ser(3) 2.74, Arg(l) 1.00 HPLC 分析[管柱:ymc Pak ODS-A ( 4. 6mm I .D. χ 15 0mm),溶 析液:1-60% CH3CN / 5mM CF3CF2COOH ( 25 分鐘),溫度 :25°C,流速:l.〇mi/min,偵測器:220nm] 純度(HPLC) : 98. 5% 質量分析(ESI-MS) MH+ = 436_2(理論値= 436.2,單一同位素) 2. SSSR類似物的製造 進行和SSSR相同的操作,製造GSSSR、SSSRR、GSSSRR 、GSSSRRAP、ASSSRRAP、GSSSRAAP、GSSSRAAAP。代表性的 胜肽之相關物性如下所示。
(1 ) GSSSR 胺基酸分析(水解條件:6N鹽酸,1 1 (TC,22小時) Ser(3) 2.76, Gly(l) 1.00, Arg(l) 1.00 HPLC 分析[管柱:YMCPak ODS-A (4.6mmI.D.xl50mra),溶 析液:1-60% CHsCN / 5mM CF3CF2COOH ( 25 分鐘),溫度 1305778 :25t:,流速:l.Oml/min,偵測器:220nm] 純度(HPLC ) :98.5% 質量分析(ESI-MS) MW= 492 · 3 (理論値=492 · 5 )
(2 ) SSSRR 胺基酸分析(水解條件:6N鹽酸,1 1 0°C,22小時) Ser(3) 2.76, Arg ( 2) 2.00 HPLC 分析[管柱:YMC Pak ODS-A ( 4 . 6mml . D · χ 1 50mm ),溶 析液:1 - 60% CHaCN / 0 . 1% CF3COOH ( 25 分鐘),溫度: 25X:,流速:l.Oml/rain,偵測器:220nm] 純度(HPLC ) : 9 8.5% 質量分析(ESI-MS) MW = 591 . 5 (理論値=591 . 6 )
(3 ) GSSSRR 胺基酸分析(水解條件:6N鹽酸,1 1 0°C , 22小時) Ser(3) 2.73, G 1 y ( 1 ) 0.98, Arg ( 2) 2.00 HPLC 分析[管柱:YMC Pak ODS-A ( 4.6mml .D. xl5 0mra),溶 析液:1 - 60% CHsCN / 0 . 1% CFsCOOH ( 25 分鐘),溫度: 2 5 °C,流速:1 · 0 ra 1 / m i η,偵測器:2 2 0 n m ] 純度(HPLC ) : 9 9.3% 質量分析(ESI-MS) MW= 648 _ 5 (理論値=648 . 7 )
(4 ) GSSSRRAP 胺基酸分析(水解條件:6N鹽酸,1 10°C , 22小時) _ 1 8 _ 1305778 rg ( ,溶 溫度
Ser(3) 2.68, Gly(l) 〇·99, Ala(l) 1.01, A 2 ) 2.00 HPLC 分析[管柱· YMCPakODS-A(4.6mmI.D.x150mm) 析液:1-60% CHsCN / 0.1% CF3COOH(25 分鐘), :2 5 °C,流速:1 . 0 m 1 / m i n,偵測器:2 2 〇 n m ] 純度(HPLC ) :98.6% 質量分析(ESI -MS ) MW = 816.7 (理論値=816.9) (製劑例) 本發明中代表性的製劑例如下所#。 1 .眼藥水 採用泛用的方法調製下列處方的眼藥水。 0 1 mg 之眼 處方例1 1 00m1 中 SSSR 1 rag 氯化鈉 900rag 氫氧化鈉 適量 鹽酸 適量 滅菌精製水 適量 和處方例1相同的操作’可調製100m 1中含有SSSR 0 . 、0.05mg' O.lmg' 〇.5rag' 5rag' lOrag' 50rag' lOOrag 藥水。 處方例2 lOOral 中 1305778 GSSSR 1 rag FGLM 1 OOrag 氯化鈉 9 OOrag 氫氧化鈉 適量 鹽酸 適量 滅菌精製水 適量 和處方例2相同的操作,可調製i〇〇ml中含有fGLM img 、5mg、10mg、50mg、500mg、lOOOmg 之眼藥水。 處方例3 100ml 中 SSSR 1 rag FGLM 1 0 Ora g 氯化鈉 9 0 Ora g 氫氧化鈉 適量 鹽酸 適量 滅菌精製水 適量 和處方例3相同的操作,可調製含有sSSR0.01mg、0.05mg 、O.lmg、0.5rag、l〇mg、50mg、100mg 及含有 FGLMlmg、5mg 、10mg、50mg、500mg、lOOOmg的任意組合方式之眼藥水。 2 .軟膏劑 處方例4 100g 中 SSSR 1〇rag
FGLM 1 OOrag -20- 1305778 液態石蠟 l〇g 白色凡士林 適量 適當地改變SSSR的添加量及FGLM的添加量可調製各種濃 度的軟膏。 處方例5 100g 中 GSSSR lmg P物質 1 0 0 m g 液態石蠟 log 白色凡士林 適量 和處方例5相同的操作,適當地改變GSSSR的添加量及P 物質的添加量,可調製各種濃度的軟膏。 處方例6 100g 中 SSSRR 5rag FGLM 1 OOmg 液態石蠟 1 0g 白色凡士林 適量 適當地改變SSSRR的添加量及FGLM的添加量可調製各種 濃度的軟膏。 處方例7 100g 中 GSSSRR 50mg 1 Orag P物質 _ 2 1 - 1305778 抗壞血酸 3rag 液態石鱲 10g 塑膠製氟鈣石類 適量 適當地改變GSSSRR的添加量及P物質的添加量,可調製 各種濃度的軟膏。 [藥理試驗] (1 )對角膜上皮伸展的作用(試管試驗) 使用雄性日本白色兔子的角膜,以Nishida等的方法( J.Cell Biol·,£1,1653-1657 ( 1983))爲基準,以角膜片 的組織培養系中的角膜上皮伸展長爲指標,探討對角膜上皮 伸展的影響。 (實驗方法) 從兔子角膜片切下的角膜群集(1群6個)置於含有被驗 化合物之培養液(TC-199)中,在37°C · 5%二氧化碳的條 件下培養24小時。培養後將角膜群集固定在乙醇一冰醋酸 (體積比95: 5)的混合液中,使用石蠟包埋並製作成切片 。去除切片中的石蠟後以蘇木精染色,在顯微鏡下測定上皮 細胞層的伸展長。 對照組係在不含被驗化合物的培養液中進行相同的培養。 (被驗化合物) 實驗中使用的胜肽之代表例如表1所示。 (結果) 實驗結果如表1所示。又,表中的伸展率係以對照組的伸 展長爲基準(1 〇 〇 % ),算出各6例的平均値。 -22- 1305778 表1 被驗藥物 伸展率(% ) 對照組 100 SSSR(lnM) 101 GSSSR (InM) 101 SSSRR ( InM) 98 GSSSRR ( InM) 94 GSSSRRAP ( InM) 97 GSSSRAAAP ( InM) 100 GYGSSSRRAPQT ( InM) 104 P 物質(20μΜ) 94 FGLM (20μΜ) 99 SSSR ( InM) + P 物質(20μΜ) 138 GSSSR ( InM) + P 物質(20μΜ) 135 SSSRR(lnM) + P 物質(20μΜ) 136 GSSSRR ( InM) + P 物質(20μΜ) 142 GSSSRRAP (InM) + P 物質(20μΜ) 140 ASSSRRAP(lnM) + P 物質(20μΜ) 134 GSSSRAAP(lnM) + P 物質(20μΜ) 150 GSSSRAAAP (InM) + P 物質(20μΜ) 139 GYGSSSRRAPQT (InM) + P 物質(20μΜ) 134 SSSR (InM) + FGLM (20μΜ) 145 -23- 1305778 如表1所示般SSSR類似物單獨、P物質單獨及FGLM單獨 ,對角膜上皮的伸展無影響,在含有SSSR類似物和P物質 (或FGLM )二種成分之培養液中進行培養後,明顯地促進 角膜上皮的伸展。 (2 )對皮膚創傷治癒的作用 根據下列表示的方法可測試皮膚創傷治癒效果。 使老鼠吸入二乙醚被麻醉後使用理髮剪剃除背部的體毛 ,以去毛用乳液除毛。2 4小時後使用5mm徑的皮膚生檢用 環鑽在背部皮膚以等間隔的方式作出5處表皮•真皮的全 層性創傷,確定止血後將含有SSSR的軟膏、含有FGLM的軟 膏、含有SSSR和FGLM的軟膏分別塗抹在患部1日1次。塗 抹各軟膏前先拍照老鼠的背部創傷並測定其面積。比較塗抹 含有SSSR的軟膏、含有FGLM的軟膏及含有SSSR和FGLM 的軟膏後各創傷的面積,藉此可硏討皮膚創傷治癒效果。 【應用在產業上的可能性】 - 從藥理試驗的結果可知,倂用含有I GF - I的最小活性表現 單位Ser-Ser-Ser-Arg表示的胺基酸序列之SSSR類似物和 含有Phe-Gly-Leu-Met-NH2表示的胺基酸序列之FGLM類似 物,明顯地促進角膜上皮的伸展及皮膚的創傷治癒。因此倂 用SSSR類似物和FGLM類似物可使這些藥劑具有相乘作用, 可發揮針對角膜潰瘍、角膜上皮層離、角膜炎、乾眼症等角 膜障礙的治療劑,和針對裂傷、擦傷、外科手術、皮膚潰瘍 、燒傷等皮膚創傷,和由此引起的壞死等疾病的治療劑之效 果。 (五)圖式簡單說明:無 -24 — 1305778 第91134925號發明專利申請案序列表 <110> 1.西田輝夫 2.參天製藥股份有限公司 <120> IGF-I最小活性表現單位之胜狀及其醫藥用途 <130> <140〉 <141> <150> JP 2001-369103 <151〉2001-12-03 <160> 18 <170> Patentln version 3.3 <210> 1 <211〉 4 <212> PRT <213>人造 <400> 1
Ser Ser Ser Arg <210> 2 <211> 5 <212> PRT <213>人造 <400> 2
Ser Ser Ser Arg Arg 5 <210> 3 <211> 5 <212> PRT <213>人造 <400> 3
Gly Ser Ser Ser Arg 1305778 <210> 4 <211> 6 <212> PRT <213>人造 <400> 4
Gly Ser Ser Ser Arg Arg 5 <210〉 5 <211> 8 <212> PRT <213>人造 <400〉 5
Ala Ser Ser Ser Arg Arg Ala Pro 5 <210> 6 <211> 8 <212> PRT <213>人造 <400> 6
Gly Ser Ser Ser Arg Ala Ala Pro 5 <210〉 7 <211> 8 <212> PRT <213>人造 <400> 7
Gly Ser Ser Ser Arg Arg Ala Pro 5 <210> 8 <211> 9 <212> PRT <213>人造 <400> 8
Gly Ser Ser Ser Arg Ala Ala Ala Pro 5 2 1305778 <210> 9 <211> 4 <212> PRT <213>人造 <400> 9
Phe Gly Leu Met <210> 10 <211> 5 <212> PRT <213>人造 <400> 10
Gly Phe Gly Leu Met 5 <210> 11 <211> 5 <212> PRT <213>人造 <400〉 11
Tyr Phe Gly Leu Met 5 <210> 12 <211> 5 <212> PRT <213>人造 <400> 12
Phe Phe Gly Leu Met 5 <210〉 13 <211> 6 <212〉PRT <213〉人造 <400> 13
Gin Phe Phe Gly Leu Met 5 1305778 <210〉 14 <211> 7 <212〉PRT <213>人造 <400> 14
Gin Gin Phe Phe Gly Leu Met 5 <210〉 15 <211> 8 <212> PRT <213>人造 <400〉 15
Pro Gin Gin Phe Phe Gly Leu Met 5 <210> 16 <211> 11 <212> PRT <213〉人造 <400〉 16
Arg Pro Lys Pro Gin Gin Phe Phe Gly Leu Met 5 10 <210> 17 <211> 12 <212〉PRT <213>人造 <400> 17
Tyr Arg Pro Lys Pro Gin Gin Phe Phe Gly Leu Met 5 10 <210> 18 <211> 12 <212> PRT <213>人造 <400〉 18
Gly Tyr Gly Ser Ser Ser Arg Arg Ala Pro Gin Thr 5 10 4
Claims (1)
- 97 9. -5 1305778 第9 1 1 34925號「IGF-I最小活性表現單位之胜肽及其醫藥 用途」專利案 (2008年9月5日修正) 拾、申請專利範圍 1 . 一種胜肽或其可用於醫藥之鹽類,其特徵在於胜肽係胺 基酸序列爲 Ser-Ser-Ser-Arg(SEQ ID NO:1) 、 Ser- Ser —Ser — Arg — Arg(SEQ I D N0:2)、Gly—Ser — Ser — Ser -A r g ( SEQ ID N0:3)、Gly — Ser — Ser - Ser - Arg — Arg(SEQIDN0:4)、Ala—Ser—Ser—Ser—Arg—Arg — Ala-Pro(SEQ ID N0:5)、Gly—Ser - Ser— Ser— Arg — Ala — Ala — Pro(SEQ ID N0:6)、Gly — Ser—Ser—Ser — Arg—Arg—Ala-Pro(SEQIDN0:7)SGly—Ser-Ser-Ser — Arg — Ala — Ala - Ala — Pro(SEQ ID N0:8)所表不之 胜肽。 2 . —種角膜障礙治療劑或皮膚創傷治療促進劑,其特徵係 含有胺基酸序列爲 Ser-Ser-Ser-Arg(SEQIDNO:l)、Ser —Ser — Ser — Arg — Arg(SEQ ID N0:2)' Gly — Ser — Ser —Ser — Arg(SEQ ID N0:3)、Gly — Ser — Ser — Ser — Arg —A r g ( SEQ ID NO : 4 ) ' Ala — Ser — Ser — Ser — Arg — Arg —Ala — Pro(SEQ ID N0:5) ' Gly — Ser — Ser — Ser — Arg 一 Ala — Ala — Pro(SEQ ID N0:6)、Gly — Ser — Ser — Ser 一 Arg — Arg — Ala — Pro(SEQ ID N0:7)或 Gly — Ser — Ser —Ser — Arg — Ala - Ala — Ala — Pro(SEQ ID N0:8)所表示 之胜肽、或其可用於醫藥的鹽類爲有效成分,並掺合可 1305778 使用於醫藥的添加物。 3.—種角膜障礙治療劑,其特徵係含有下列成分; 1 )胺基酸序列爲 Ser-Ser-Ser-Arg(SEQ ID NO: 1)、Ser 一 Ser— Ser — Arg — Arg(SEQ ID N0:2)、Gly— Ser — Ser — Ser— Arg(SEQ ID N0:3)、Gly — Ser — Ser — Ser —Arg — Arg(SEQ ID N0:4)、Ala — Ser — Ser — Ser — Arg — Arg — Ala — Pro(SEQ ID N0:5)、Gly — Ser — Ser —Ser — Arg — Ala — Ala — Pro(SEQ ID NO :.6)、Gly — Ser — Ser — Ser — Arg — Arg — Ala — Pro(SEQ ID N0:7) 或 Gly — Ser — Ser — Ser — Arg — Ala — Ala — Ala — Pro(SEQ ID NO :8)所表示之胜肽、或其可用於醫藥的 鹽類, 2)胺基酸序列爲 Phe-Gly-Leu-Met-NH2(SEQIDNO:9)、 Gly- Phe- Gly- Leu- Met- NH2(SEQ ID NO:10)' Tyr -Phe — Gly — Leu - Met— NHKSEQ ID NO: 1 1)、Phe -Phe— Gly- Leu- Met— NHKSEQ ID NO:12)、Gin— Phe —Phe — Gly - Leu - Met— NH2(SEQ ID N〇:1 3)、Gin -Gin— Phe— Phe — Gly— Leu— Met— NH2(SEQ ID NO:14) 、Pro — Gin — Gin — Phe — Phe — Gly — Leu — Met — NHa(SEQ ID NO:15)' Arg - Pro - Lys - Pro - Gin - Gin 一 Phe— Phe— Gly- Leu— Met— NH2(SEQ ID NO:16)或 Tyr— Arg— Pro— Lys— Pro— Gin—Gln—Phe—Phe — Gly-Leu—Met—NH2(SEQ ID NO:17)所表示之胜肽 、或其可用於醫藥的鹽類。 -2- 1305778 4 .如申請專利範圍第3項之角膜障礙治療劑,其中角膜障 礙係指角膜潰瘍、角膜上皮層離、角膜炎或乾眼症。 5 .如申請專利範圍第3項之角膜障礙治療劑,其中藥劑型 係眼藥水劑。 6 . —種皮膚創傷治癒促進劑,其特徵係含有下列成分; 1 )胺基酸序列爲 Ser -Se r-Ser-Arg( SEQ ID NO : 1 )、Ser 一 Ser — Ser — Arg—Arg(SEQIDN0:2)、Gly—Ser — Ser - Ser-Arg(SEQ ID NO :3) ' Gly - Ser - Ser - Ser Arg—Arg(SEQ ID N0:4)、Ala — Ser — Ser — Ser — Arg — Arg — Ala — Pro(SEQ ID N0:5) ' Gly — Ser — Ser _ Ser — Arg — .Ala — Ala — Pro(SEQ ID N0:6)、Gly — Ser — Ser — Ser — Arg — Arg — Ala — Pro(SEQ ID N0:7) 或 Gly — Ser — Ser — Ser — Arg — Ala — Ala — Ala — Pro(SEQ ID NO :8)所表示之胜肽、或其可用於醫藥的 鹽類, 2)胺基酸序列爲 Phe-Gly-Leu-Met-NH2(SEQ ID NO:9)、 Gly- Phe— Gly — Leu- Met — NH2(SEQ ID NO:10)、Tyr —Phe — Gly — Leu — Met — NH2(SEQ ID N〇:ll)、Phe — Phe — Gly — Leu - Met - NH2(SEQ ID NO:12)、Gin — Phe —Phe — Gly — Leu — Met — NH2(SEQ ID NO:13)、Gin — Gin — Phe — Phe — Gly — Leu — Met — NH2(SEQ ID NO:14) 、Pro — Gin — Gin — Phe — Phe — Gly — Leu — Met — NHh(SEQ ID NO:15)、Arg— Pro— Lys— Pro— Gin — Gin 一 Phe— Phe- Gly — Leu— Met— NH2(SEQ ID NO:16)或 -3- V 1305778 Tyr— Arg — Pro— Lys— Pro — Gin— Gin— Phe— Phe — Gly_Leu — Met—NH2(SEQ ID NO:17)所表示之胜肽、 或其可用於醫藥的鹽類。 7 .如申請專利範圍第6項之皮膚創傷治癒促進劑,其中皮 膚創傷係指裂傷.、擦傷、外科手術、皮膚潰瘍或燒傷。 8 .如申請專利範圍第6項之皮膚創傷治癒促進劑,其中藥 劑型係軟膏劑或黏貼劑。 -4-
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CN101395179B (zh) * | 2006-03-06 | 2013-01-02 | 凯尔杰有限公司 | 具有胰岛素样生长因子-i活性的肽及其用途 |
WO2008086358A1 (en) | 2007-01-08 | 2008-07-17 | University Of Southern California Usc Stevens | Skin wound healing compositions and methods of use thereof |
IL287292B (en) | 2008-01-31 | 2022-09-01 | Genentech Inc | and fusion antibody-drug-cd79b engineered antibodies cysteine- |
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US8865654B2 (en) | 2009-09-25 | 2014-10-21 | Santen Pharmaceutical Co., Ltd. | Eye drops |
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US10307456B2 (en) * | 2015-02-25 | 2019-06-04 | Mackay Memorial Hospital | Use of short synthetic peptide for the treatment and/or prophylaxis of dry eye disease |
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Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4885163A (en) * | 1987-02-24 | 1989-12-05 | Eli Lilly And Company | Topical use of IGF-II for wound healing |
JPS6417489A (en) * | 1987-07-13 | 1989-01-20 | Hitachi Ltd | Extended substrate |
NZ226171A (en) | 1987-09-18 | 1990-06-26 | Ethicon Inc | Gel formulation containing polypeptide growth factor |
US5652214A (en) | 1989-06-05 | 1997-07-29 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factors and analogs |
US5093317A (en) * | 1989-06-05 | 1992-03-03 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factor |
US5104787A (en) | 1990-03-05 | 1992-04-14 | Lindstrom Richard L | Method for apparatus for a defined serumfree medical solution useful for corneal preservation |
US5616562A (en) * | 1990-04-27 | 1997-04-01 | Murphy; Christopher J. | Methods and compositions using substance P to promote wound healing |
JPH0525001A (ja) | 1991-07-08 | 1993-02-02 | L Lyndstrom Richard | 血清不含有医療用溶液および眼組織の品質を高める方法 |
US6310040B1 (en) * | 1991-11-08 | 2001-10-30 | Cephalon, Inc. | Treating retinal neuronal disorders by the application of insulin-like growth factors and analogs |
WO1993023067A1 (en) * | 1992-05-08 | 1993-11-25 | Thomas Jefferson University | Igf-1 analogs |
US5545617A (en) | 1993-11-12 | 1996-08-13 | The Schepens Eye Research Institute, Inc. | Therapeutic regulation of abnormal conjunctival goblet cell mucous secretion |
JP3191038B2 (ja) | 1996-06-26 | 2001-07-23 | 輝夫 西田 | 眼科用医薬組成物 |
JP4096115B2 (ja) * | 2000-08-10 | 2008-06-04 | 輝夫 西田 | 皮膚創傷治癒促進剤 |
EP1308165B1 (en) * | 2000-08-10 | 2010-06-09 | Santen Pharmaceutical Co., Ltd. | Skin wound healing promoters |
AUPR030900A0 (en) * | 2000-09-22 | 2000-10-12 | Queensland University Of Technology | Growth factor complex |
JP4253743B2 (ja) * | 2001-12-03 | 2009-04-15 | 輝夫 西田 | 新規ペプチドおよびその医薬用途 |
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- 2002-12-03 ES ES02786015T patent/ES2422081T3/es not_active Expired - Lifetime
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- 2002-12-03 CA CA2469134A patent/CA2469134C/en not_active Expired - Fee Related
- 2002-12-03 PT PT2786015T patent/PT1462455E/pt unknown
-
2007
- 2007-03-20 US US11/725,761 patent/US7795222B2/en not_active Expired - Fee Related
-
2008
- 2008-03-17 JP JP2008067259A patent/JP4310588B2/ja not_active Expired - Lifetime
-
2010
- 2010-07-29 US US12/804,773 patent/US8183343B2/en not_active Expired - Fee Related
-
2013
- 2013-07-10 CY CY20131100584T patent/CY1114330T1/el unknown
Also Published As
Publication number | Publication date |
---|---|
KR20100002291A (ko) | 2010-01-06 |
ES2422081T3 (es) | 2013-09-06 |
EP1462455A4 (en) | 2008-12-31 |
AU2002354188A1 (en) | 2003-06-17 |
EP2172474B1 (en) | 2013-04-17 |
US20090005317A1 (en) | 2009-01-01 |
US20050009752A1 (en) | 2005-01-13 |
EP2172474A1 (en) | 2010-04-07 |
US7232881B2 (en) | 2007-06-19 |
KR20050044630A (ko) | 2005-05-12 |
TW200302108A (en) | 2003-08-01 |
JP2008163044A (ja) | 2008-07-17 |
EP1462455A1 (en) | 2004-09-29 |
US7795222B2 (en) | 2010-09-14 |
US8183343B2 (en) | 2012-05-22 |
PT1462455E (pt) | 2013-07-09 |
EP1462455B1 (en) | 2013-04-10 |
CA2469134A1 (en) | 2003-06-12 |
KR100967152B1 (ko) | 2010-07-05 |
CN1599748A (zh) | 2005-03-23 |
CY1114330T1 (el) | 2016-08-31 |
CN1263770C (zh) | 2006-07-12 |
US20110059897A1 (en) | 2011-03-10 |
SI1462455T1 (sl) | 2013-09-30 |
JP4310588B2 (ja) | 2009-08-12 |
KR100993233B1 (ko) | 2010-11-10 |
WO2003048192A1 (fr) | 2003-06-12 |
CA2469134C (en) | 2013-10-29 |
DK1462455T3 (da) | 2013-07-01 |
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