TW202304501A - Glp-1組成物及其用途 - Google Patents
Glp-1組成物及其用途 Download PDFInfo
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- TW202304501A TW202304501A TW111139129A TW111139129A TW202304501A TW 202304501 A TW202304501 A TW 202304501A TW 111139129 A TW111139129 A TW 111139129A TW 111139129 A TW111139129 A TW 111139129A TW 202304501 A TW202304501 A TW 202304501A
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- semaglutide
- phenol
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- phosphate
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Classifications
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Abstract
本發明係關於包含不超過0.01% (w/w)苯酚之GLP-1肽索馬魯肽的醫藥組成物、其製備物、包含此類組成物之套組、以及其用途。
Description
本發明係關於包含GLP-1肽索馬魯肽(semaglutide)之醫藥組成物的領域。
已知GLP-1肽在液體溶液中易於出現穩定性缺乏，例如物理穩定性缺乏。因此，需要穩定性甚至更佳的包含GLP-1肽之液體醫藥組成物。此類改進之穩定性可為物理穩定性及/或化學穩定性。
在一些具體實例中，本發明係關於包含索馬魯肽及不超過0.01% (w/w)苯酚之液體醫藥組成物。在一些具體實例中，本發明係關於包含如本文中所定義之醫藥組成物的套組。在一些具體實例中，本發明係關於如本文中所定義之用於醫藥的醫藥組成物。
在一些具體實例中，本發明係關於包含GLP-1肽索馬魯肽及不超過0.01% (w/w)苯酚之液體醫藥組成物。意外地，本發明者發現此類組成物具有改進之化學及/或物理穩定性。在一些具體實例中，組成物不包含苯酚。在一些具體實例中，組成物包含0.01至10 mg/ml索馬魯肽。在一些具體實例中，組成物之pH值介於6.0至10.0範圍內，例如pH 7.0至7.8。
在一些具體實例中，本發明之組成物為包含索馬魯肽及不超過0.01% (w/w)苯酚之液體醫藥組成物，其中該組成物
a.用於非經腸投予；
b.為包含至少60% w/w水之水溶液；或
c.進一步包含選自由緩衝劑或等張劑組成之群的一或多種醫藥學上可接受之賦形劑。
在一些具體實例中，本發明之組成物為液體醫藥組成物，其包含索馬魯肽、不超過0.01% (w/w)苯酚及視情況之一或多種醫藥學上可接受之賦形劑，其中調配物用於非經腸投予，例如皮下投予。
在一些具體實例中，本發明之組成物為液體醫藥組成物，其包含索馬魯肽、不超過0.01% (w/w)苯酚、至少60% w/w水以及視情況之一或多種醫藥學上可接受之賦形劑。
在一些具體實例中，如本文中所使用之術語「
穩定性」係指索馬魯肽在液體醫藥組成物中之穩定性。在一些具體實例中，穩定性為GLP-1肽之化學穩定性(例如，藉由HPLC所確定，例如本文中之分析(I))，及視情況之GLP-1肽之物理穩定性(例如，藉由硫代黃素T (Thioflavine T)分析所確定，例如本文中之分析(II))。
在一些具體實例中，如本文中所使用之與索馬魯肽有關的術語「
化學穩定性」係指索馬魯肽化合物之共價鍵實質上完整。在一些具體實例中，GLP-1肽之化學穩定性藉由HPLC確定，例如本文中之分析(I)。在一些具體實例中，若在在25℃下儲存3個月後，在至少80% (w/v)之該GLP-1肽中其共價鍵為完整的，則組成物具有化學穩定性。在一些具體實例中，索馬魯肽之化學穩定性藉由本文中之分析(IV)確定。
在一些具體實例中，如本文中所使用之與索馬魯肽有關的術語「
物理穩定性」係指實質上不形成聚集體之索馬魯肽，例如呈原纖維形式。在一些具體實例中，物理穩定性藉由硫代黃素T分析確定，例如本文中之分析(II)。
在一些具體實例中，本發明之組成物為穩定醫藥組成物。當在本文中使用時，術語「穩定醫藥組成物」係指包含GLP-1肽之醫藥組成物，例如溶液或懸浮液，且其組成物在儲存後包含至少80% (w/v)之該GLP-1肽(例如，在25℃下靜態儲存3個月後)。穩定性測試之儲存條件可為2至8℃，例如5℃，或至少在5℃下2.5年。或者，穩定性測試之儲存條件可為至少4週，例如6週或3個月，視情況在30℃下。此穩定醫藥組成物之儲存條件可為在5℃下1或2年。此穩定醫藥組成物之儲存條件可為在5℃下3年。或者，此儲存之條件可為在25℃下24小時或1週。在又一替代例中，此儲存之條件可為室溫下兩個月，例如多達兩個月。
在一些具體實例中，GLP-1肽之化學穩定性需要至少80% (w/v) (例如至少90% (w/v)或至少95% (w/v))之該GLP-1肽在儲存時段結束時保持其共價鍵完整。在一些具體實例中，GLP-1肽之化學穩定性需要至少95% (w/v) (例如至少97% (w/v)或至少99% (w/v))之該GLP-1肽在儲存時段結束時保持其共價鍵完整。
本發明之組成物包含不超過0.01% (w/w)苯酚。在一些具體實例中，組成物實質上不包含苯酚。
醫藥組成物
術語「醫藥組成物」及「組成物」在本文中可互換使用，且係指適用於向有需要之個體投予的醫藥組成物。
在一些具體實例中，組成物包含0.01至100 mg/ml索馬魯肽。在一些具體實例中，組成物包含0.1至50 mg/ml索馬魯肽，例如0.5至25 mg/ml或1至15 mg/ml。在一些具體實例中，組成物包含0.1至10 mg/ml索馬魯肽，例如0.5至5 mg/ml或1至2 mg/ml。在一些具體實例中，組成物包含0.01至10 mg/ml索馬魯肽，例如0.01至5 mg/ml。在一些具體實例中，組成物包含不超過9 mg/ml索馬魯肽，例如不超過8 mg/ml或不超過7 mg/ml。在一些具體實例中，組成物包含不超過6 mg/ml索馬魯肽，例如不超過5 mg/ml或不超過4 mg/ml。在一些具體實例中，組成物包含不超過3 mg/ml索馬魯肽，例如不超過2 mg/ml或不超過1 mg/ml。在一些具體實例中，組成物包含至少0.01 mg/ml索馬魯肽，例如至少0.02 mg/ml或至少0.05 mg/ml。在一些具體實例中，組成物包含1.34 mg/ml索馬魯肽。
在一些具體實例中，本發明之組成物之pH值介於3至10範圍內，例如pH 6至10或6至9。在一些具體實例中，本發明之組成物之pH值介於pH 6.5至8.5範圍內，例如pH 7.0至7.8。
在一些具體實例中，本發明之組成物包含一或多種醫藥學上可接受之賦形劑。
在一些具體實例中，本發明之組成物包含等張劑，例如丙二醇。在一些具體實例中，等張劑為丙二醇或氯化鈉。
在一些具體實例中，本發明之組成物包含緩衝劑，例如磷酸鹽緩衝劑、TRIS、檸檬酸鹽或緩衝劑緩衝劑。在一些具體實例中，磷酸鹽緩衝劑為磷酸鈉緩衝劑，例如磷酸氫二鈉。
在一些具體實例中，本發明之組成物不包含防腐劑。
本發明之組成物呈液體醫藥組成物形式。在一些具體實例中，液體醫藥組成物為溶液或懸浮液。在一些具體實例中，本發明之組成物呈溶液形式，例如水溶液。在一些具體實例中，如本文中所使用之術語「水溶液」係指包含至少60% w/w水的溶液。在一些具體實例中，水溶液包含60-99% w/w水。在一些具體實例中，水溶液包含至少75% w/w水，例如至少80% w/w水或至少85% w/w水。在一些具體實例中，水溶液包含至少90% w/w水，例如至少92% w/w水或至少94% w/w水。
索馬魯肽
GLP-1肽索馬魯肽可如WO2006/097537，實施例4中所描述來製備。索馬魯肽亦稱為N
6.26-{18-[N-(17-羧基十七醯基)-L-γ-麩胺醯基]-10-側氧基-3,6,12,15-四氧雜-9,18-二氮雜十八醯基}-[8-(2-胺基-2-丙酸),34-L-精胺酸]人類升糖素類肽1(7-37)，見WHO藥物信息第24卷第1,2010期。在一些具體實例中，索馬魯肽可以其完全或部分電離化形式存在於組成物中；例如一或多種羧酸基(-COOH)可去質子化為羧酸酯基團(-COO-)，及/或一或多種胺基(-NH
2)可質子化為-NH
3+基團。在一些具體實例中，將索馬魯肽添加至呈鹽形式之組成物。
投予及套組
本發明之組成物用於非經腸投予。在一些具體實例中，組成物用於皮下投予。
在一些具體實例中，本發明之組成物每週投予一次。在一些具體實例中，本發明之組成物每日投予一次、每兩天投予一次或每三天投予一次。
在一些具體實例中，本發明係關於一種包含如本文中所定義之醫藥組成物及使用說明書的套組。在一些具體實例中，使用說明書包含藥物包裝插頁。
在一些具體實例中，本發明係關於一種包含如本文中所定義之醫藥組成物及注射裝置的套組。在一些具體實例中，注射裝置選自由耐用筆及預填充筆組成之群。耐用筆之實例為NovoPen® 4或NovoPen® 5 (兩者均來自丹麥的諾佛．儂迪克股份有限公司)。預填充筆之實例為FlexPen® (諾佛．儂迪克股份有限公司，丹麥)。
適應症
在一些具體實例中，本發明之組成物用於醫藥。在一些具體實例中，本發明之組成物可用於以下醫藥治療：
(i)預防及/或治療所有形式之糖尿病，諸如高血糖症、2型糖尿病、葡萄糖耐受性異常、1型糖尿病、非胰島素依賴性糖尿病、年輕起病成人型糖尿病(maturity onset diabetes of the young；MODY)、妊娠期糖尿病及/或HbA1C減少；
(ii)延緩或預防糖尿病進程，例如2型糖尿病之進程，延緩葡萄糖耐受性異常(impaired glucose tolerance；IGT)發展至需要胰島素之2型糖尿病，及/或延緩非胰島素需要2型糖尿病發展至需要胰島素之2型糖尿病；
(iii)例如藉由減少食物攝入、減輕體重、抑制食慾、誘發飽腹感來預防及/或治療飲食障礙，例如肥胖症；治療或預防暴食症、神經性貪食症及/或由投予抗精神病藥或類固醇引發之肥胖症；減少胃運動；及/或延緩胃排空。
在一些具體實例中，適應症為(i)。在一些具體實例中，適應症為(ii)。在又一特定態樣中，適應症為(iii)。在一些具體實例中，適應症為2型糖尿病及/或肥胖症。
在一些具體實例中，方法或用途包含預防、治療、減輕及/或誘發本文中所定義之一或多種疾病或病況。在一些具體實例中，適應症為(i)及(iii)。在一些具體實例中，適應症為(ii)及(iii)。在一些具體實例中，本發明包含投予有效量之GLP-1肽。在一些具體實例中，本發明係關於投予有效量之GLP-1肽。
一般而言，患有肥胖症之所有個體亦視為患有超重。在一些具體實例中，本發明係關於一種治療或預防肥胖症之方法。在一些具體實例中，本發明係關於一種用於治療或預防肥胖症之組成物的用途。在一些具體實例中，患有肥胖症之個體為人類，諸如成人或孩童(包括嬰兒、兒童及青少年)。身體質量指數(Body mass index；BMI)為基於高度及體重之體脂肪之量度。計算式為BMI = 以公斤為單位之重量/以米為單位之高度
2。患有肥胖症之人類個體之BMI可為＞30；此個體亦可稱為肥胖性的。在一些具體實例中，患有肥胖症之人類個體之BMI可為＞35或介於＞30至＜40範圍內。在一些具體實例中，肥胖症為重度肥胖症或病態肥胖症，其中人類個體之BMI可為＞40。
在一些具體實例中，本發明係關於一種（視情況在至少一種重量相關之共生病症存在下）治療或預防超重之方法。在一些具體實例中，本發明係關於一種用於（視情況在至少一種重量相關之共生病症存在下）治療或預防超重之組成物的用途。在一些具體實例中，患有超重之個體為人類，諸如成人或孩童(包括嬰兒、兒童及青少年)。在一些具體實例中，患有超重之人類個體之BMI可為＞25，例如＞27。在一些具體實例中，患有超重之人類個體之BMI介於25至＜30範圍內或介於27至＜30範圍內。在一些具體實例中，重量相關之共生病症選自由以下組成之群：高血壓、糖尿病(諸如2型糖尿病)、血脂異常、高膽固醇及阻塞性睡眠呼吸暫停。
在一些具體實例中，本發明係關於一種減輕體重之方法。在一些具體實例中，本發明係關於一種用於減少體重之組成物的用途。根據本發明之經受體重減少之人類的BMI可為＞25，例如＞27或＞30。在一些具體實例中，根據本發明之經受體重減少之人類的BMI可為＞35或＞40。術語「體重減少」可包括治療或預防肥胖症及/或超重。
在一些具體實例中，如本文中所使用，相對於數目或時間間隔給定之具體值可理解為具體值或理解為約具體值(例如，加或減具體值之百分之10)。
本發明之具體實例
以下為本發明之非限制性具體實例：
1.一種包含索馬魯肽及不超過0.01% (w/w)苯酚之液體醫藥組成物。
2.一種包含索馬魯肽及實質上無苯酚之液體醫藥組成物。
3.如技術方案1或2之組成物，其中該組成物不包含苯酚。
4.如前述技術方案中任一項之組成物，其中該組成物為包含至少60% w/w水之水溶液，例如至少70% w/w水或至少80% w/w水。
5.如前述技術方案中任一項之組成物，其中索馬魯肽之濃度為0.5至10 mg/ml之該組成物。
6.如前述技術方案中任一項之組成物，其中該索馬魯肽呈醫藥學上可接受之鹽的形式。
7.如前述技術方案中任一項之組成物，其中該組成物包含一或多種醫藥學上可接受之賦形劑。
8.如前述技術方案中任一項之組成物，其中該組成物包含用於調整pH值的一或多種試劑，例如HCl、NaOH或乙酸。
9.如前述技術方案中任一項之組成物，其中該組成物包含緩衝劑及/或等張劑。
10.如前述技術方案中任一項之組成物，其中該緩衝劑存在於濃度為0.01至50 mM之該組成物中。
11.如前述技術方案中任一項之組成物，其中該緩衝劑為磷酸鹽緩衝劑。
12.如前述技術方案中任一項之組成物，其中該磷酸鹽緩衝劑選自由以下組成之群：磷酸二氫鈉、磷酸氫二鈉及磷酸鈉。
13.如前述技術方案中任一項之組成物，其中該等張劑以8 mg/ml至50 mg/ml (例如14 mg/ml至30 mg/ml)之該組成物的濃度存在。
14.如前述技術方案中任一項之組成物，其中該等張劑為丙二醇。
15.如前述技術方案中任一項之組成物，其中該組成物不包含防腐劑。
16.如前述技術方案中任一項之組成物，其中該組成物之pH值介於6.0至10.0範圍內。
17.如前述技術方案中任一項之組成物，其中該組成物用於非經腸投予。
18.如前述技術方案中任一項之組成物，其中該組成物用於皮下投予。
19.一種套組，其包含如前述技術方案中任一項之醫藥組成物及使用說明書。
20.一種包含如前述技術方案中任一項之醫藥組成物及注射裝置之套組，該注射裝置用於向個體投予該組成物，其中該注射裝置選自由耐用筆及預填充筆組成之群。
21.如前述技術方案中任一項之醫藥組成物，其用於醫藥。
22.如前述技術方案中任一項之醫藥組成物，其用於治療糖尿病或肥胖症。
23.一種用於預防或治療糖尿病或肥胖症的方法，其中向有需要之個體投予如前述技術方案中任一項之醫藥組成物。
實施例一般方法及特徵界定
製備索馬魯肽組成物：
除非另外指出，否則索馬魯肽組成物藉由將緩衝劑(例如，磷酸氫二鈉二水合物)、等張劑(例如，丙二醇)及視情況之防腐劑(苯酚)溶解於水中來製備。將索馬魯肽溶解於其中，使用氫氧化鈉及/或鹽酸將pH值調整至7.4，且最後藉由由0.22 μm無菌過濾器過濾對組成物進行滅菌。
製備利拉魯肽 ( liraglutide ) 組成物：
除非另外指出，否則利拉魯肽組成物由溶液1及溶液2製備：溶液1藉由將緩衝劑(磷酸氫二鈉二水合物)、等張劑(甘露醇)及視情況之防腐劑(苯酚)溶解於水中來製備。溶液2藉由在緩慢攪拌時溶解利拉魯肽來製備。將溶液1及溶液2混合，使用氫氧化鈉及/或鹽酸將pH值調整至8.15，且最後藉由由0.22 μm無菌過濾器過濾來對組成物進行滅菌。
分析 (I) ： 確定索馬魯肽組成物之高分子量蛋白質 (High Molecular Weight Proteins ； HMWP) 含量
使用尺寸排外層析法(size exclusion chromatography；SE-HPLC)來進行對HMWP含量之確定，該尺寸排外層析法使用沃特斯(Waters)胰島素HMWP柱，利用移動相之氯化鈉、磷酸鈉、磷酸及異丙醇等度溶離，且在280 nm下檢測。HMWP之含量以%形式給出為相對於HMWP及索馬魯肽單體峰之總面積的早於索馬魯肽單體峰溶離之層析峰(亦即HMWP峰)的組合面積。
分析 (II) ：經由 ThT 評估索馬魯肽組成物之物理穩定性
此分析之目的為評估GLP-1肽在水溶液中之物理穩定性。
肽或蛋白質之低物理穩定性可引起澱粉狀蛋白原纖維形式。原纖維為藉由可溶性蛋白質之聚集形成且由β片層結構主導之結構上非常有序的絲狀巨分子結構。成熟原纖維為不溶性且抗降解。出於藥品質量及患者安全起見，期望最小化及控制在治療性肽及蛋白質之醫藥組成物中的原纖維化事件。可藉由目視檢查樣本來評估蛋白質聚集，包括原纖維化。可藉由使用硫代黃素T (ThT) (對原纖維具有高特異性之小分子指示劑探針)來評估纖維化。當與原纖維結合時，相比於呈溶液狀態之ThT，ThT具有不同螢光標記[Naiki等人(1989) Anal. Biochem. 177, 244-249；LeVine (1999) Methods. Enzymol. 309, 274-284]。
提出部分摺疊之肽中間物之形成作為原纖維化之一般引發機制。少量此等中間物成核以形成其上可組合有其他中間物且進行原纖維化之模板。滯後時間對應於時間間隔，其中產生細胞核之臨界量且表觀速率常數(apparent rate constant)為形成原纖維自身之速率。因此，描述於盤讀取器上進行之ThT分析中的滯後時間視為呈溶液狀態之肽組成物之原纖維化傾向之指示。
在進行分析前，將ThT添加至來自H
2O中之儲備溶液之樣本直至樣本呈20 μM之最終濃度。將包含GLP-1肽之組成物的200 μl等分樣本放入各孔中放入有玻璃細珠(2.8至3.2 mm，Whitehouse Scientific)之96孔微量滴定盤(光學0.4 mL黑色Thermo Scientific Nunc)中。通常，將各樣本之八個複本放在該盤上。該盤用密封帶(Thermo Scientific Nunc)密封。
對ThT螢光發光之在給定溫度下之培養、震盪及量測在BMG FLUOStar Omega或BMG FLUOStar Optima中進行。在40℃下利用2 mm振幅以300 rpm之的雙軌道搖動來培養該盤。使用穿過450 nm濾光器之激發及穿過480 nm濾光器之發射量測來進行螢光量測。每20分鐘對盤進行量測，持續所需時間段。各量測之間，如所描述震盪且加熱該盤。
確定臨限值為在1 h 13 min時間加100 RFU下於該盤上量測之最高ThT螢光(在相對螢光單元(relative fluorescence units；RFU)中)。臨限值隨後用於使用BMG FLUOstar軟體中之「臨限時間(time to threshold)」方法來計算滯後時間。
分析 (III) ：確定利拉魯肽純度
使用高效液相層析法(high performance liquid chromatography；HPLC)來進行純度確定，該高效液相層析法使用沃特斯XTerra™ MS C18柱，利用兩個移動相之梯度溶離，其中一個移動相為水性磷酸銨緩衝劑(pH 8)/乙腈混合物且另一移動相為乙腈/水。檢測在215 nm下進行。
分析 (IV) ：確定索馬魯肽中之雜質總和
使用反相高效液相層析法(reversed phase high performance liquid chromatography；RP-HPLC)來進行索馬魯肽純度之確定，該反相高效液相層析法使用Kinetex C18柱，利用後接兩個移動相之梯度溶離之等度溶離，其中一個移動相為水性磷酸鹽緩衝劑/乙腈混合物且另一移動相為水性乙腈/異丙醇混合物。檢測在210 nm下進行。索馬魯肽之純度作為雜質總和以%形式給出為相對於索馬魯肽單體峰之所有層析峰之組合面積。
實施例 1 ：索馬魯肽
在此實驗中測試包含索馬魯肽之組成物。所測試組成物在pH 7.4下於水溶液中含有索馬魯肽(如表1中所說明)、丙二醇(14 mg/ml)、磷酸氫二鈉二水合物(1.42 mg/ml)及視情況之苯酚(5.5 mg/ml) (如表1中所說明)。如本文中在製備之一般方法部分中所描述來製備此等組成物。藉由本文中在實驗開始時所描述之分析(I)且在25℃、30℃或37℃下儲存後來確定由HMWP表示之化學穩定性。藉由本文中所描述之分析(II)來確定由硫代黃素T (ThT)分析表示之物理穩定性。
結果給出於表2及3中。意外地，此等結果顯示相對於含有苯酚之組成物，在不含苯酚之組成物中，索馬魯肽之物理及化學穩定性得到改進。表3中顯示之結果為8個測試樣本之平均值。
表 1 .實施例1中測試之組成物
表 2.在不同溫度下儲存後，索馬魯肽組成物之化學穩定性，由高分子量蛋白質(HMWP)之含量表示。較低HMWP濃度對應於較佳化學穩定性。
表 3.索馬魯肽組成物之物理穩定性，由硫代黃素T (ThT)分析表示。較長滯後時間對應於較佳物理穩定性。
實施例2 (參考)：利拉魯肽
| 組成物編號 | 描述 |
| 1 | 索馬魯肽1 mg/ml，含有苯酚 |
| 2 | 索馬魯肽1 mg/ml，不含苯酚 |
| 3 | 索馬魯肽1.34 mg/ml，含有苯酚 |
| 4 | 索馬魯肽1.34 mg/ml，不含苯酚 |
| 5 | 索馬魯肽0.5 mg/ml，不含苯酚 |
| 6 | 索馬魯肽0.5 mg/ml，含有苯酚 |
| 7 | 索馬魯肽1.0 mg/ml，不含苯酚 |
| 8 | 索馬魯肽1.0 mg/ml，含有苯酚 |
| 9 | 索馬魯肽2.0 mg/ml，不含苯酚 |
| 10 | 索馬魯肽2.0 mg/ml，含有苯酚 |
| 組成物編號 | HMWP (%) | |||
| 0個月 | 25 ℃6個月 | 30 ℃3個月 | 37 ℃3個月 | |
| 1 | 0.1 | 2.0 | 1.9 | 4.1 |
| 2 (無苯酚) | 0.1 | 0.3 | 0.3 | 0.5 |
| 3 | 0.1 | 1.9 | 1.8 | 3.9 |
| 4 (無苯酚) | 0.1 | 0.3 | 0.4 | 0.6 |
| 組成物 編號 | 滯後時間(小時) | |
| 5 (無苯酚) | ＞ 117 | |
| 6 | 19 | |
| 7 (無苯酚) | ＞ 117 | |
| 8 | 35 | |
| 9 (無苯酚) | ＞ 117 | |
| 10 | 35 |
鑒於GLP-1化合物利拉魯肽(與索馬魯肽相反)在不含苯酚之組成物中較不化學穩定，實例1之結果亦出人意料。此等結果顯示於表5中。
如下獲得表5中之結果：測試包含利拉魯肽之組成物。所測試組成物在pH 7.4下於水溶液中含有利拉魯肽(如表4中所說明)、甘露醇(36.9 mg/ml)、磷酸氫二鈉(1.42 mg/ml)及視情況之苯酚(如表4中所說明)。如本文中在製備之一般方法部分中所描述來製備此等組成物。藉由本文中在實驗開始時所描述之分析(III)且在25℃下或在37℃下儲存後來確定由純度表示之化學穩定性。
表 4 .實施例中2測試之組成物
表 5 .在不同溫度下儲存後，包含利拉魯肽之組成物之化學穩定性，由純度表示。較高純度對應於較佳化學穩定性。
實施例3：索馬魯肽-額外實驗
| 組成物編號 | 描述 |
| 11 | 利拉魯肽(3 mg/ml)，不含苯酚(pH 7.4) |
| 12 | 利拉魯肽(3 mg/ml)，苯酚(0.04 mg/ml) (pH 7.4) |
| 13 | 利拉魯肽(3 mg/ml)，苯酚(0.16 mg/ml) (pH 7.4) |
| 14 | 利拉魯肽(3 mg/ml)，苯酚(0.8 mg/ml) (pH 7.4) |
| 15 | 利拉魯肽(3 mg/ml)，苯酚(2.5 mg/ml) (pH 7.4) |
| 組成物編號 | 純度(%) | ||||||
| 0個月 | 25 ℃下3個月 | 37 ℃ 下3個月 | |||||
| 11 (無苯酚) | 98 | 88 | 72 | ||||
| 12 | 98 | 93 | 80 | ||||
| 13 | 98 | 94 | 81 | ||||
| 14 | 97 | 95 | 83 | ||||
| 15 | 98 | 95 | 84 | ||||
在此實驗中測試包含索馬魯肽之組成物。所測試組成物在pH 7.0、7.4或7.8下於水溶液中含有索馬魯肽、等張劑(丙二醇(14 mg/ml)或氯化鈉(6.3 mg/ml))、視情況之緩衝劑(磷酸氫二鈉二水合物(1.42 mg/ml)或檸檬酸三鈉二水合物(2.35 mg/ml))及視情況之苯酚(5.5 mg/ml或0.1 mg/ml)；所測試各組成物之細節顯示於表6中。如本文中在製備之一般方法部分中所描述來製備該等組成物。由HMWP表示之化學穩定性藉由分析(I)確定，且由雜質總和表示之化學穩定性藉由本文中在實驗開始時所描述之分析(IV)且在30℃下儲存後來確定。由硫代黃素T (ThT)分析表示之物理穩定性藉由本文中所描述之分析(II)確定。
結果給出於表7及8中。與實例1之結果一致，此等結果顯示相對於含有5.5 mg/ml下之苯酚的組成物，在不具有或具有低苯酚濃度之組成物中，索馬魯肽之物理穩定性及化學穩定性得到改進。結果顯示相對於含有苯酚之組成物，在不含苯酚之包含緩衝劑檸檬酸三鈉二水合物或無緩衝劑或等張劑氯化鈉之組成物中，索馬魯肽之物理穩定性及化學穩定性亦得到改進。相對於含有5.5 mg/ml苯酚之組成物，對於類似於不含苯酚之組成物的含有0.1 mg/ml苯酚之組成物，化學及物理穩定性得到改進。此針對pH 7.0至7.8且索馬魯肽濃度0.110 mg/ml之組成物而展示。
表 6.實施例中3測試之組成物
*)磷酸鹽：磷酸氫二鈉二水合物，1.42 mg/ml。**) PG：丙二醇，14 mg/ml。***)檸檬酸鹽：檸檬酸三鈉二水合物，2.35 mg/ml。
#)無：未添加呈緩衝劑形式之醫藥學上之賦形劑
##) NaCl：氯化鈉，6.3 mg/ml。
表 7 .在30℃溫度下儲存後，索馬魯肽組成物之化學穩定性，由高分子量蛋白質(HMWP)之含量及雜質之總和表示。較低HMWP濃度及雜質總和濃度對應於較佳化學穩定性。
DS：索馬魯肽。
1物理上不穩定＞ 30℃下1個月。
表 8.索馬魯肽組成物之物理穩定性，由硫代黃素T (ThT)分析表示。較長滯後時間對應於較佳物理穩定性。
結果為8個測試樣本之平均值。DS：索馬魯肽。
| 組成物編號 | 組成物成分 | ||||||
| 索馬魯肽 (mg/ml) | 苯酚 (mg/ml) | 緩衝劑 | 等張劑 | pH | |||
| 1 | 0.5 | 0 | 磷酸鹽* | PG** | 7.0 | ||
| 2 | 0.5 | 0.1 | 磷酸鹽 | PG | 7.0 | ||
| 3 | 0.5 | 5.5 | 磷酸鹽 | PG | 7.0 | ||
| 4 | 0.5 | 0 | 磷酸鹽 | PG | 7.4 | ||
| 5 | 0.5 | 0.1 | 磷酸鹽 | PG | 7.4 | ||
| 6 | 0.5 | 5.5 | 磷酸鹽 | PG | 7.4 | ||
| 7 | 0.5 | 0 | 磷酸鹽 | PG | 7.8 | ||
| 8 | 0.5 | 0.1 | 磷酸鹽 | PG | 7.8 | ||
| 9 | 0.5 | 5.5 | 磷酸鹽 | PG | 7.8 | ||
| 10 | 10 | 0 | 磷酸鹽 | PG | 7.0 | ||
| 11 | 10 | 0.1 | 磷酸鹽 | PG | 7.0 | ||
| 12 | 10 | 5.5 | 磷酸鹽 | PG | 7.0 | ||
| 13 | 10 | 0 | 磷酸鹽 | PG | 7.4 | ||
| 14 | 10 | 0.1 | 磷酸鹽 | PG | 7.4 | ||
| 15 | 10 | 5.5 | 磷酸鹽 | PG | 7.4 | ||
| 16 | 10 | 0 | 磷酸鹽 | PG | 7.8 | ||
| 17 | 10 | 0.1 | 磷酸鹽 | PG | 7.8 | ||
| 18 | 10 | 5.5 | 磷酸鹽 | PG | 7.8 | ||
| 19 | 0.1 | 0 | 磷酸鹽 | PG | 7.4 | ||
| 20 | 0.1 | 5.5 | 磷酸鹽 | PG | 7.4 | ||
| 21 | 0.5 | 0 | 磷酸鹽 | 檸檬酸鹽*** | 7.4 | ||
| 22 | 0.5 | 5.5 | 磷酸鹽 | 檸檬酸鹽 | 7.4 | ||
| 23 | 0.5 | 0 | 磷酸鹽 | 無# | 7.4 | ||
| 24 | 0.5 | 5.5 | 磷酸鹽 | 無 | 7.4 | ||
| 25 | 0.5 | 0 | NaCl## | PG | 7.4 | ||
| 26 | 0.5 | 5.5 | NaCl | PG | 7.4 | ||
| 組成物 編號 | DS (mg/ml) | 苯酚 (mg/ml) | 化學穩定性 | ||||
| HMWP (%) | 雜誌總和(%) | ||||||
| 0個月 | 30 ℃ | 0個月 | 30 ℃ | ||||
| 3個月 | 3個月 | ||||||
| 1 (pH 7.0) | 0.5 | 0 | 0.1 | 0.3 | 3.1 | 7.0 | |
| 2 (pH 7.0) | 0.5 | 0.1 | 0.1 | 0.3 | 3.2 | 7.2 | |
| 3 (pH 7.0) | 0.5 | 5.5 | 0.1 | 1.4 | 3.2 | 7.8 | |
| 4 (pH 7.4) | 0.5 | 0 | 0.1 | 0.3 | 3.1 | 6.7 | |
| 5 (pH 7.4) | 0.5 | 0.1 | 0.1 | 0.3 | 3.2 | 6.6 | |
| 6 (pH 7.4) | 0.5 | 5.5 | 0.1 | 2.4 | 3.2 | 8.4 | |
| 7 (pH 7.8) | 0.5 | 0 | 0.1 | 0.2 | 3.1 | 6.5 | |
| 8 (pH 7.8) | 0.5 | 0.1 | 0.1 | 0.3 | 3.2 | 6.6 | |
| 9 (pH 7.8) | 0.5 | 5.5 | 0.1 | 4.8 | 3.1 | 10.6 | |
| 10 (pH 7.0) | 10 | 0 | 0.1 | 1.4 | 3.1 | 8.4 | |
| 11 (pH 7.0) | 10 | 0.1 | 0.1 | 0.7 | 3.1 | 7.7 | |
| 12 (pH 7.0) | 10 | 5.5 | 0.1 | N/A 1 | 3.0 | N/A 1 | |
| 13 (pH 7.4) | 10 | 0 | 0.1 | 0.9 | 3.1 | 7.8 | |
| 14 (pH 7.4) | 10 | 0.1 | 0.1 | 0.7 | 3.1 | 6.9 | |
| 15 (pH 7.4) | 10 | 5.5 | 0.1 | 0.8 | 3.0 | 6.9 | |
| 16 (pH 7.8) | 10 | 0 | 0.1 | 0.9 | 3.0 | 6.6 | |
| 17 (pH 7.8) | 10 | 0.1 | 0.1 | 0.6 | 3.1 | 6.8 | |
| 18 (pH 7.8) | 10 | 5.5 | 0.1 | 1.0 | 3.1 | 6.9 | |
| 19 (低DS) | 0.1 | 0 | 0.1 | 0.2 | 3.5 | 7.7 | |
| 20 (低DS) | 0.1 | 5.5 | 0.1 | 4.7 | 3.7 | 11.4 | |
| 21 (檸檬酸鹽) | 0.5 | 0 | 0.1 | 0.2 | 3.1 | 6.2 | |
| 22 (檸檬酸鹽) | 0.5 | 5.5 | 0.1 | 2.2 | 3.2 | 7.7 | |
| 23 (無緩衝劑) | 0.5 | 0 | 0.1 | 0.2 | 3.2 | 6.9 | |
| 24 (無緩衝劑) | 0.5 | 5.5 | 0.1 | 2.3 | 3.2 | 9.3 | |
| 25 (NaCl) | 0.5 | 0 | 0.1 | 0.3 | 3.1 | 6.4 | |
| 26 (NaCl) | 0.5 | 5.5 | 0.1 | 3.4 | 3.2 | 8.9 | |
| 組成物編號 | 索馬魯肽(mg/ml) | 苯酚(mg/ml) | 滯後時間(小時) | |
| 1 (pH 7.0) | 0.5 | 0 | 42 | |
| 2 (pH 7.0) | 0.5 | 0.1 | 63 | |
| 3 (pH 7.0) | 0.5 | 5.5 | 5 | |
| 4 (pH 7.4) | 0.5 | 0 | ＞117 | |
| 5 (pH 7.4) | 0.5 | 0.1 | ＞117 | |
| 6 (pH 7.4) | 0.5 | 5.5 | 87 | |
| 7 (pH 7.8) | 0.5 | 0 | ＞117 | |
| 8 (pH 7.8) | 0.5 | 0.1 | ＞117 | |
| 9 (pH 7.8) | 0.5 | 5.5 | ＞117 | |
| 10 (pH 7.0) | 10 | 0 | 117 | |
| 11 (pH 7.0) | 10 | 0.1 | ＞117 | |
| 12 (pH 7.0) | 10 | 5.5 | 25 | |
| 13 (pH 7.4) | 10 | 0 | ＞117 | |
| 14 (pH 7.4) | 10 | 0.1 | ＞117 | |
| 15 (pH 7.4) | 10 | 5.5 | ＞117 | |
| 16 (pH 7.8) | 10 | 0 | ＞117 | |
| 17 (pH 7.8) | 10 | 0.1 | ＞117 | |
| 18 (pH 7.8) | 10 | 5.5 | ＞117 | |
| 19 (低DS) | 0.1 | 0 | ＞117 | |
| 20 (低DS) | 0.1 | 5.5 | ＞117 | |
| 21 (檸檬酸鹽) | 0.5 | 0 | ＞117 | |
| 22 (檸檬酸鹽) | 0.5 | 5.5 | ＞117 | |
| 23 (無緩衝劑) | 0.5 | 0 | ＞117 | |
| 24 (無緩衝劑) | 0.5 | 5.5 | 4 | |
| 25 (NaCl) | 0.5 | 0 | ＞117 | |
| 26 (NaCl) | 0.5 | 5.5 | 8 | |
儘管已在本文中說明及描述本發明之某些特徵，但一般熟習此項技術者現將想到多種修改、替代、變化及等效物。因此，應瞭解，所附申請專利範圍意欲涵蓋如屬於本發明之真實精神內的所有此類修改及變化。
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Claims (15)
- 一種液體醫藥組成物，其包含索馬魯肽(semaglutide)及不超過0.01% (w/w)苯酚，其中該組成物 a.用於非經腸投予； b.為包含至少60% w/w水之水溶液；或 c.進一步包含選自由緩衝劑或等張劑組成之群的一或多種醫藥學上可接受之賦形劑。
- 如請求項1所述之組成物，其中該組成物不包含苯酚。
- 如前述請求項中任一項所述之組成物，其中該組成物為包含至少60% w/w水之水溶液。
- 如前述請求項中任一項所述之組成物，其中索馬魯肽之濃度為0.5至10 mg/ml或0.01至5 mg/ml之該組成物。
- 如前述請求項中任一項所述之組成物，其中該組成物包含一或多種醫藥學上可接受之賦形劑。
- 如請求項5所述之組成物，其中該一或多種醫藥學上可接受之賦形劑選自由緩衝劑或等張劑組成之群。
- 如前述請求項中任一項所述之組成物，其中該組成物不包含防腐劑。
- 如前述請求項中任一項所述之組成物，其中該組成物之pH值介於6.0至10.0範圍內，例如pH 7.0至7.8。
- 如前述請求項中任一項所述之組成物，其中該組成物用於非經腸投予。
- 如請求項9所述之組成物，其中該非經腸投予為皮下投予。
- 一種套組，其包含液體醫藥組成物及使用說明書，該液體醫藥組成物包含索馬魯肽及不超過0.01% (w/w)。
- 一種套組，其包含液體醫藥組成物及注射裝置，該液體醫藥組成物包含索馬魯肽及不超過0.01% (w/w)苯酚，該注射裝置用於向個體投予該組成物，其中該注射裝置選自由耐用筆及預填充筆組成之群。
- 如請求項11或12所述之套組，其中該醫藥組成物如請求項1至10中任一項所定義。
- 如前述請求項中任一項所定義之醫藥組成物，其用於醫藥。
- 如前述請求項中任一項所定義之醫藥組成物，其用於治療糖尿病或肥胖症。
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