TWI603730B - 含左旋甲狀腺素之固態醫藥製劑 - Google Patents
含左旋甲狀腺素之固態醫藥製劑 Download PDFInfo
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- TWI603730B TWI603730B TW102129710A TW102129710A TWI603730B TW I603730 B TWI603730 B TW I603730B TW 102129710 A TW102129710 A TW 102129710A TW 102129710 A TW102129710 A TW 102129710A TW I603730 B TWI603730 B TW I603730B
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- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
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Description
本發明係關於一種包含左旋甲狀腺素鈉、明膠、檸檬酸及填充劑之固態醫藥製劑。該固態醫藥製劑具有增進之安定性。
左旋甲狀腺素鈉係用於治療甲狀腺荷爾蒙缺陷症,且間或預防甲狀腺癌的復發。在甲狀腺荷爾蒙缺陷症的治療中,使用25至300μg極低日常劑量的左旋甲狀腺素鈉。由於其高效力,因此避免劑量變化係非常重要,因為此可引起嚴重的甲狀腺機能減退症狀,若左旋甲狀腺素鈉的劑量不足,會引起(例如)嚴重抑鬱症、疲勞、增重、便秘、畏寒、腫脹及注意困難;若左旋甲狀腺素鈉劑量過高,會引起諸如疼痛、心悸或心律失常的甲狀腺機能減退症。因此,包含左旋甲狀腺素鈉之醫藥製劑之儲存安定性係關鍵因素。
DE 195 41 128教示藉由添加硫代硫酸鈉來使甲狀腺素製劑安定。然而,就毒物學角度而言,於醫藥製劑中使用諸如硫代硫酸鈉成分係非所欲。
WO 2004/096177 A1教示藉由對包含左旋甲狀腺素鈉的醫藥製劑添加小於0.4的水活性來使其安定。不利地,該等調配物之水活性隨存放期間的相對濕度的變化而變化,因此必須採取額外措施(例如防潮包裝),此導致額外成本及廢物管理問題。
Patel等人測驗各種pH修飾添加劑對左旋甲狀腺素鈉錠劑之安定性之效應(Patel H.等人:The effect of excipients on stability of
levothyroxine sodium pentahydrate tablets,Int J Pharm 264(2003)35-43)。發現鹼性pH修飾添加劑碳酸鈉、碳酸氫鈉及氧化鎂會導致左旋甲狀腺素鈉錠劑之安定性增進,而酸性pH修飾添加劑酒石酸及檸檬酸會導致安定性減少。
WO 99/59551 A1教示可藉由使用明膠作為黏合劑來增進含左旋甲狀腺素鈉之固態醫藥製劑之儲存安定性。如引言中所述,為符合食品藥物管理局(FDA)於1996年所制定的有關安定性的高要求,已開發該等經安定調配物。根據該等FDA要求,在整個錠劑存放期間,其中的左旋甲狀腺素鈉降解最多為10%。
2007年,FDA已提高有關包含左旋甲狀腺素鈉之產品之安定性之要求以進一步降低由此引起的風險。事實上,錠劑中的左旋甲狀腺素鈉降解的限值已自10%降低至5%(來自2007年10月3日的FDA新聞發佈)。
具有安定性增進之醫藥製劑仍需滿足另一要求。該等醫藥製劑應確保根據該等要求釋放活性化合物,應不包含任何毒物學上不可接受之佐劑且應可以安定方式長期儲存。
令人驚訝地,已發現若除左旋甲狀腺素鈉之外亦包含明膠、檸檬酸及填充劑,則可提供符合此等要求且具有儲存安定性增進之固態醫藥製劑。因此,本發明之一目標係關於包含左旋甲狀腺素鈉、明膠、檸檬酸及填充劑之固態醫藥製劑。
就Patel等人(如上所引用)之先前技術教示而言,添加檸檬酸不僅不會增進錠劑中之左旋甲狀腺素鈉並甚至導致其降解,而固態醫藥製劑之安定性增進尤其令人驚訝。
US 6,649,186 B1揭示藉由熱熔擠壓製得且可包含左旋甲狀腺素鈉的發泡顆粒。該等發泡顆粒包含酸性組分(例如檸檬酸)及鹼性組分(例如碳酸鈉或碳酸氫鈉(其在與水接觸後便反應生成二氧化碳))。本
發明之醫藥製劑較佳不是發泡製劑。因此,本發明之另一目標係關於一種特徵為其不是發泡製劑的固態醫藥製劑。
US 5,753,254 A揭示一種包含甲狀腺荷爾蒙的固態快速分散劑型,其亦可包含檸檬酸以引起形成唾液。固態快速分散劑型係口服劑型,其在口服時與唾液接觸後便在口中於數秒內容易快速崩解。本發明之醫藥製劑較佳不是固體快速分散劑型。因此,本發明之另一目標係關於一種特徵為其不是固體快速分散劑型的固態醫藥製劑。
根據本發明之適當實施例,固態醫藥製劑包含5至400μg(較佳10至300μg,特定言之25至300μg)左旋甲狀腺素鈉。較佳地,該固態醫藥製劑包含25、50、75、88、100、112、125、137、150、175、200或300μg左旋甲狀腺素鈉。
若左旋甲狀腺素鈉係以微細化形式(尤其具有5μm至25μm的粒度)存在,則該固態醫藥製劑之溶解度增進。因此,本發明之一較佳目標係關於一種特徵為其包含具有5μm至25μm粒度的微細化左旋甲狀腺素鈉的固態醫藥製劑。
根據本發明之適當實施例,該固態醫藥製劑中存在0.5至20重量%(較佳1至10重量%,特別佳2至10重量%,最佳約5%)含量的明膠。
根據本發明之另一適當實施例,該固態醫藥製劑中存在0.1至5重量%(較佳0.2至3重量%,特別佳0.4至2重量%)含量的檸檬酸。
根據本發明之一較佳實施例,該醫藥製劑除左旋甲狀腺素鈉以外包含三碘甲狀腺胺酸鈉作為另一活性組分。因此,本發明亦關於一種特徵為其包含三碘甲狀腺胺酸鈉的固態醫藥製劑。
填充劑係一種藉由提供形成醫藥製劑所需的材料數量來增加該醫藥製劑體積的試劑。本發明固態製劑中存在的填充劑較佳係糖醇、糖、澱粉、纖維素或其混合物。
糖醇係指其中反應性羰基已被還原成醇基的單醣,例如己糖醇
或戊糖醇。根據本發明之固態製劑較佳包含己糖醇,如(例如)甘露醇、山梨糖醇、半乳糖醇、木糖醇或核糖醇作為糖醇。以存在甘露醇及/或山梨糖醇特別佳,以甘露醇最佳。
糖係指單醣(如,例如己糖醇或戊糖醇)及由經糖苷鍵結合的兩個單醣組成的二醣。根據本發明之固態製劑較佳包含葡萄糖、果糖或甘露糖作為單醣或乳糖、蔗糖或麥芽糖作為二醣。以乳糖特別佳。
澱粉係指包含螺旋直鏈澱粉及支鏈澱粉的多醣,其係由綠色植物(例如馬鈴薯、小麥、玉米、米及木薯)所製造。根據本發明之固態製劑較佳包含馬鈴薯澱粉、米澱粉、玉米澱粉或預煮澱粉(即預膠化澱粉)。以玉米澱粉及預膠化澱粉特別佳,以玉米澱粉最特別佳。
纖維素係指由具有幾百至超過一萬個β(1→4)連接型D-葡萄糖的直鏈組成的多醣。根據本發明之固態製劑較佳包含纖維素粉或微晶纖維素,以微晶纖維素特別佳。
根據本發明之適當實施例,該固態醫藥製劑之特徵係該填充劑為糖醇,例如山梨糖醇或甘露醇、半乳糖醇、木糖醇或核糖醇,較佳山梨糖醇或甘露醇,特別佳甘露醇;糖,例如葡萄糖、果糖、甘露糖、乳糖、蔗糖或麥芽糖,較佳乳糖、蔗糖或麥芽糖,特別佳乳糖;澱粉,例如馬鈴薯澱粉、米澱粉、玉米澱粉或預膠化澱粉,較佳玉米澱粉或預膠化澱粉,特別佳玉米澱粉;纖維素,例如纖維素粉或微晶纖維素,較佳微晶纖維素;或其混合物。
根據本發明之一特別佳實施例,固態醫藥製劑之特徵係該填充劑為甘露醇及/或玉米澱粉。
根據本發明之一適當實施例,該固態醫藥製劑中存在70至98重量%,較佳80至98重量%,特別佳85至95重量%含量的該填充劑。
若該固態醫藥製劑包含選自由生育酚、抗壞血酸鈉、沒食子酸丙酯、第三丁基氫醌、丁基化羥基茴香醚及丁基化羥基甲苯(BHT)(較
佳丁基化羥基茴香醚或丁基化羥基甲苯,特別佳丁基化羥基甲苯)組成之群之抗氧化劑,則可進一步增進其安定性。因此,本發明之一較佳目標係關於一種固態醫藥製劑,其特徵係其另外包含選自由生育酚、沒食子酸丙酯、第三丁基氫醌、丁基化羥基茴香醚及丁基化羥基甲苯(較佳丁基化羥基茴香醚或丁基化羥基甲苯,特別佳丁基化羥基甲苯)組成之群之抗氧化劑。根據本發明之固態醫藥製劑包含0.01至2重量%,較佳0.05至0.5重量%,特別佳0.08至0.2及最佳0.1%至0.15重量%的抗氧化劑。
該固態醫藥製劑可呈顆粒、丸粒、膠囊或錠劑形式。雖然膠囊及錠劑提供在各情況下欲攝取的活性化合物量作為明確指定的個別劑量,但可藉由丸粒及顆粒以簡單方式調適各情況中所需的活性化合物量。
可藉由製粒來製備顆粒。丸粒係具有極窄粒度範圍的較小固態球形藥物形式(如(例如)顆粒或微錠劑)。顆粒及丸粒表示獨立藥物形式,但亦可用作製造錠劑的中間物。若希望可藉由顆粒或丸粒方式投與預定量的活性化合物,則其等亦提供作為成份顆粒或被引入膠囊中以確保適當劑量的準確性。根據本發明之固態醫藥製劑較佳呈顆粒、丸粒、膠囊或錠劑形式,特別佳呈膠囊或錠劑形式,極特別佳呈錠劑形式。
因此,本發明之另一目標係關於一種固態醫藥製劑,其特徵係呈顆粒、丸粒、膠囊或錠劑形式,特佳呈膠囊或錠劑形式。本發明之一極特佳目標係關於一種特徵為錠劑的固態醫藥製劑。
該固態醫藥製劑可包含崩解劑,以縮短錠劑或顆粒的崩解時間,使活性化合物自其快速釋放。因此,本發明之另一目標係關於一種固態醫藥製劑,其特徵係存在崩解劑。
本發明固態醫藥製劑中之適當崩解劑係澱粉羥乙酸鈉、羧甲基
纖維素鈉、交聯羧甲基纖維素鈉或其混合物。因此,本發明之另一目標係關於一種固態醫藥製劑,其特徵係崩解劑為澱粉羥乙酸鈉或羧甲基纖維素鈉或其混合物。
該固態醫藥製劑之一較佳實施例包含作為崩解劑的羧甲基纖維素鈉,特佳交聯羧甲基纖維素鈉。因此,本發明之一較佳目標係關於一種固態醫藥製劑,其特徵係崩解劑為羧甲基纖維素鈉,特佳交聯羧甲基纖維素鈉。
視該崩解劑的特性而定,其可以0.01至20重量%的重量比例存在於本發明之固態製劑中。本發明之固態製劑較佳包含0.1至10重量%,特佳1至5重量%的崩解劑。
根據本發明之一適當實施例,該固態醫藥製劑包含1至10重量%的明膠、0.1至3重量%的檸檬酸、50至80重量%的甘露醇或乳糖及10至30重量%的玉米澱粉。因此,本發明之另一目標係關於一種固態醫藥製劑,其特徵係其包含1至10重量%的明膠、0.1至3重量%的檸檬酸、50至80重量%的甘露醇或乳糖、10至30重量%的玉米澱粉。
根據本發明之一較佳實施例,該固態醫藥製劑包含0.05至0.5重量%的丁基化羥基甲苯。因此,本發明之另一目標係關於一種特徵為其包含0.05至0.5重量%丁基化羥基甲苯的固態醫藥製劑。較佳地,該固態醫藥製劑中存在0.05至0.5重量%的丁基化羥基甲苯,該固態醫藥製劑的特徵在於其包含1至10重量%的明膠、0.1至3重量%的檸檬酸、50至80重量%的甘露醇或乳糖、10至30重量%的玉米澱粉。
本發明之一特別佳目標係關於一種固態醫藥製劑,其特徵係其包含2至8重量%的明膠、0.5至2重量%的檸檬酸、60至75重量%的甘露醇或乳糖、15至25重量%的玉米澱粉及視需要0.08至0.2重量%的丁基化羥基甲苯。
若本發明之固態醫藥製劑係錠劑,則其亦可包含潤滑劑,以在
製錠操作期間減少錠劑材料與模具中之柱塞的滑動摩擦並防止黏著至該等柱塞。適宜潤滑劑係脂肪酸之鹼土金屬鹽,例如硬脂酸鎂或硬脂酸鈣;脂肪酸,例如硬脂酸;高級脂肪醇,例如十六烷醇或硬脂醇;脂肪,例如二棕櫚油硬脂酸甘油酯、二硬脂酸甘油酯、硬脂酸甘油酯或二山萮酸甘油酯;C16-C18烷基取代型二碳酸之鹼土金屬鹽,例如富馬酸硬脂鈉;水合植物油,例如水合蓖麻油或水合棉籽油或礦物質(例如矽石或滑石)。根據本發明之固態製劑較佳包含作為潤滑劑的硬脂酸鎂、硬脂酸或富馬酸硬脂鈉,特別佳硬脂酸鎂。根據本發明之固態製劑中較佳存在0.1至5重量%,較佳0.25至4重量%,特佳0.5至3重量%,最佳約1重量%的比例的潤滑劑。
可藉由熟習此項技術者已知的方法製備本發明之固態製劑。
顆粒係藉由製粒來產生,其基本上可藉由潮濕或乾燥途徑來進行。在潮濕製粒的情況下,例如將製粒液體(其較佳包含黏合劑)添加至包含該活性化合物及糖醇及任何其他適宜佐劑的粉末混合物中,使該混合物轉化成具有適宜尺寸的聚集體(顆粒)且後續乾燥。亦可藉由使該活性化合物懸浮於製粒液體中而引入該等顆粒中。粉末混合物至具有適宜尺寸的聚集體的轉化可藉由以下方法來進行:(例如)藉由所謂的積聚製粒(例如於塗覆盤中);藉由板製粒或流化床方法(例如藉由格拉特(Glatt)或渥斯特(Wurster)方法)或藉由所謂的還原製粒(其中該粉末混合物首先被潤濕並轉化成可塑性成型體及隨後轉化成具有所需尺寸的聚集體),例如藉由擠壓通過具有適宜尺寸網目的網篩。在乾式製粒的情況下,(例如)藉由兩個反向旋轉壓輥之間的壓實擠壓該粉末混合物,以獲得薄片,隨後將其粉碎以獲得顆粒。
丸粒係可藉由製粒及後續修圓(滾圓)來製造,例如藉由板製粒或者藉由擠壓粉末或顆粒以獲得微錠劑。
呈錠劑形式的根據本發明之製劑係可藉由擠壓粉末混合物(直接
壓縮)或藉由擠壓顆粒來製造。在最簡單的直接壓縮情況下,首先將該活性化合物與賦形劑混合並直接擠壓所得粉末混合物以獲得根據本發明之固態製劑。
根據本發明之一較佳實施例,該固態醫藥製劑係藉由具有以下特徵的方法來製備:(a)將左旋甲狀腺素鈉及視需要之三碘甲狀腺胺酸鈉懸浮於明膠水溶液中,(b)將藉由步驟(a)獲得的懸浮液噴霧至流化床製粒中的填充劑上並乾燥以形成顆粒,(c)收集藉由步驟(b)獲得的顆粒;及視需要地,(d)將崩解劑及視需要之潤滑劑與藉由步驟(c)獲得的顆粒混合,及(e)壓縮藉由步驟(d)獲得的混合物以獲得錠劑。
因此,本發明之一目標係另外關於一種製造固態醫藥製劑之方法,其特徵係:(a)將左旋甲狀腺素鈉及視需要之三碘甲狀腺胺酸鈉懸浮於明膠水溶液中,(b)將藉由步驟(a)獲得的懸浮液噴霧至流化床製粒中的填充劑上並乾燥以形成顆粒,(c)收集藉由步驟(b)獲得的顆粒;及視需要地,(d)將崩解劑及視需要之潤滑劑與藉由步驟(c)獲得的顆粒混合,及(e)壓縮藉由步驟(d)獲得的混合物以獲得錠劑。
進行步驟(a)至(c)所獲得的顆粒可直接用作藥物形式而無需進行可選步驟(d)及(e)。如上所述,若使用該等顆粒,則其等提供作為成份顆粒或引入膠囊中以確保適當劑量正確性。
根據本發明之另一適當實施例,該固態醫藥製劑係藉由以下方法製備,其特徵係將檸檬酸及(若存在)抗氧化劑溶解於步驟(a)中使用
的明膠水溶液中或與步驟(d)中的顆粒混合。因此,本發明之另一目標係關於一種製造固態醫藥製劑的方法,其特徵係將檸檬酸及(若存在)抗氧化劑溶解於步驟(a)中使用的明膠水溶液或與步驟(d)中的顆粒混合。
根據本發明之一個適當實施例,對該等顆粒或錠劑提供包衣。因此,本發明之另一目標係關於一種製造固態醫藥製劑之方法,其特徵係對該等顆粒或錠劑提供包衣。
適宜包衣係薄膜形成聚合物,例如選自纖維素衍生物、糊精、澱粉、天然樹膠(例如***樹膠、黃原膠)、藻酸鹽、聚乙烯醇、聚甲基丙烯酸酯及其衍生物(例如聚丙烯酸樹脂(eudragites))之群者,可藉由各種醫藥習知方法(例如薄膜塗佈)以溶液或懸浮液施加至錠劑。此處,通常使用溶液/懸浮液,其除薄膜形成聚合物以外亦包含其他佐劑,例如親水劑、增塑劑、界面活性劑、染料及白色顏料(例如二氧化鈦)。
該等實例說明本發明而不限於彼等。
實例1
錠劑(批料015093),其包含:0.075mg左旋甲狀腺素鈉;68.525mg甘露醇;20.00mg玉米澱粉;5.00mg澱粉羥乙酸鈉;5.00mg明膠;0.40mg檸檬酸;1.00mg硬脂酸鎂。
將明膠攪拌稀釋於熱水(總水量的約90%,溫度90℃±10℃)中。使用Ultraturrax將左旋甲狀腺素鈉懸浮於冷水(總水量的10%)中。當該
明膠溶液已冷卻至50℃±5℃時,將左旋甲狀腺素鈉懸浮液提供至其中,而該製粒液體之最終溫度係40-45℃。
將包含明膠及活性化合物的製粒液體噴霧至流化床中的甘露醇及玉米澱粉上。該製粒液體的溫度保持在約40℃。一旦出口氣體溫度已上升至40℃,便最終形成顆粒。
將檸檬酸、澱粉羥乙酸鈉及硬脂酸鎂與該等顆粒混合,將所得混合物擠壓以獲得錠劑。就代替與該等顆粒混合而言,亦可於製備包含左旋甲狀腺素鈉之明膠溶液期間藉由溶解的方式添加檸檬酸。
實例2
錠劑(批料015099),其包含:0.30mg左旋甲狀腺素鈉;68.20mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;2.00mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。
實例3
錠劑(批料014916),其包含:0.105mg左旋甲狀腺素鈉;70.295mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.10mg丁基化羥基甲苯;
0.80mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。將丁基化羥基甲苯攪拌稀釋於熱水(總水量的約90%,溫度90℃±10℃)中。然後,將該明膠攪拌提供至此溶液中。使用Ultraturrax將左旋甲狀腺素鈉懸浮於冷水(總水量的10%)中。一旦該BHT-明膠溶液已冷卻至50℃±5℃時,便將左旋甲狀腺素鈉懸浮液提供至其中,而該製粒液體之最終溫度係40-45℃。
實例4
錠劑,其包含:0.300mg左旋甲狀腺素鈉;73.100mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;2.00mg明膠;0.10mg丁基化羥基甲苯;0.80mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例3的方式來製造。
實例5
錠劑,其包含:0.025mg左旋甲狀腺素鈉;65.375mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;10.00mg明膠;
0.10mg丁基化羥基甲苯;0.80mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例3的方式來製造。
實例6
錠劑,其包含:0.105mg左旋甲狀腺素鈉;70.395mg異麥芽酮糖醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.40mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。
實例7
錠劑,其包含:0.105mg左旋甲狀腺素鈉;81.645mg纖維素微晶;3.50mg交聯羧甲基纖維素鈉;4.50mg明膠;1.50mg檸檬酸;0.25mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。
實例8
錠劑,其包含:0.105mg左旋甲狀腺素鈉;
70.295mg山梨糖醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.10mg丁基化羥基甲苯;0.80mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例3的方式來製造。
實例9
錠劑,其包含:0.105mg左旋甲狀腺素鈉;70.295mg蔗糖;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.10mg丁基化羥基甲苯;0.80mg檸檬酸;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例3的方式來製造。
實例10
錠劑,包含:0.105mg左旋甲狀腺素鈉;70.395mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;
2.00mg檸檬酸;0.10mg抗壞血酸鈉;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。
實例11
顆粒,其包含:0.105mg左旋甲狀腺素鈉;70.295mg甘露醇;20.00mg玉米澱粉;5.00mg明膠;0.10mg丁基化羥基甲苯;0.80mg檸檬酸。
將檸檬酸及明膠攪拌稀釋於熱水(總水量的約90%,溫度90℃±10℃)中。使用Ultraturrax將左旋甲狀腺素鈉懸浮於冷水(總水量的10%)中。當具有檸檬酸的明膠溶液已冷卻至50℃±5℃時,將左旋甲狀腺素鈉懸浮液提供至其中,而該製粒液體之最終溫度係40-45℃。
將包含明膠及活性化合物的製粒液體噴霧至流化床中的甘露醇及玉米澱粉上。該製粒液體的溫度保持在約40℃。一旦出口氣體溫度已上升至40℃,便最終形成顆粒。
實例12
包含顆粒的膠囊
將實例11之顆粒填充至膠囊(明膠或HPMC)中。
比較實例1
錠劑(批料127494),其包含:0.105mg左旋甲狀腺素鈉;
65.895mg乳糖;25.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.50mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。
比較實例2
錠劑(批料014698),其包含:0.105mg左旋甲狀腺素鈉;70.395mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.50mg硬脂酸鎂;該等錠劑係以類似於實例1的方式來製造。
比較實例3
錠劑(批料014842),其包含:0.105mg左旋甲狀腺素鈉;70.295mg甘露醇;20.00mg玉米澱粉;3.50mg交聯羧甲基纖維素鈉;5.00mg明膠;0.10mg丁基化羥基甲苯;1.00mg硬脂酸鎂。
該等錠劑係以類似於實例1的方式來製造。如實例3中所述般混合丁基化羥基甲苯。
安定性測試
為評定該等組分(尤其檸檬酸及/或抗氧化劑)對儲存安定性的影響,將實例1至4及比較實例1及2的醫藥製劑轉移至無封蓋的玻璃瓶中並於高溫及濕度(60攝氏度及75%相對濕度(r.h.))下儲存。儲存時間及各情況中測得的活性化合物的含量係顯示於表1中。
表1中的數據說明:檸檬酸的存在會導致安定性的增進,該安定性係進一步藉由抗氧化劑來增進。若存在抗氧化劑而無檸檬酸,則無法獲得增進的安定性,抗氧化劑在組合檸檬酸時令人意外地顯示協同安定效應。
將實例3及4及比較實例之醫藥製劑轉移至HDPE瓶中,密封並於40℃及75%r.h.下儲存。儲存時間及各情況中測得的活性化合物的含量係顯示於表2中。
如表2明顯可知,在不存在檸檬酸的情況下,抗氧化劑的存在不顯示顯著安定效應。另外令人驚訝地,檸檬酸與抗氧化劑之組合會導致使得於高溫及濕度(40℃及75%r.h.)下儲存半年後左旋甲狀腺素鈉於該製劑中的含量僅減少0.1重量%的良好安定效應。
分析測試方法:在製備後及安定性研究期間,藉由高效液相層析或超高效液相層析及UV檢測,使用反相管柱及梯度系統測試包含左旋甲狀腺素鈉的固態醫藥製劑之同一性、純度及分析。所使用的萃取介質及流動相係乙腈、水及磷酸之混合物。
Claims (16)
- 一種固態醫藥製劑,其包含左旋甲狀腺素鈉、明膠、檸檬酸及填充劑。
- 如請求項1之固態醫藥製劑,其中包含三碘甲狀腺胺酸(liothyronine)鈉。
- 如請求項1或2之固態醫藥製劑,其中該填充劑係糖醇、糖、澱粉、纖維素或其混合物。
- 如請求項3之固態醫藥製劑,其中該糖醇係山梨糖醇、甘露醇、半乳糖醇、木糖醇或核糖醇;該糖係葡萄糖、果糖、甘露糖、乳糖、蔗糖或麥芽糖;該澱粉係馬鈴薯澱粉、米澱粉、玉米澱粉或預膠化澱粉;該纖維素係纖維素粉或微晶纖維素。
- 如請求項4之固態醫藥製劑,其中該填充劑係甘露醇及/或玉米澱粉。
- 如請求項1或2之固態醫藥製劑,其另外包含選自由生育酚、沒食子酸丙酯、第三丁基氫醌、丁基化羥基茴香醚及丁基化羥基甲苯(BHT)組成之群之抗氧化劑。
- 如請求項1或2之固態醫藥製劑,其係呈顆粒、丸粒、膠囊或錠劑形式。
- 如請求項7之固態醫藥製劑,其係錠劑。
- 如請求項1或2之固態醫藥製劑,其另外包含至少一種崩解劑。
- 如請求項9之固態醫藥製劑,其中該崩解劑係澱粉羥乙酸鈉或羧甲基纖維素鈉或其混合物。
- 如請求項10之固態醫藥製劑,其中存在之崩解劑係羧甲基纖維素鈉。
- 如請求項4之固態醫藥製劑,其中包含1至10重量%的明膠、0.1 至3重量%的檸檬酸、50至80重量%的甘露醇或乳糖、10至30重量%的玉米澱粉。
- 如請求項12之固態醫藥製劑,其另外包含0.05至0.5重量%的丁基化羥基甲苯。
- 一種製造如請求項8至13中任一項之固態醫藥製劑之方法,其特徵在於:(a)將左旋甲狀腺素鈉及視需要之三碘甲狀腺胺酸鈉懸浮於明膠水溶液中;(b)將步驟(a)獲得的懸浮液噴霧至流化床製粒中的填充劑上並乾燥形成顆粒;(c)收集步驟(b)獲得的顆粒;及視需要,(d)將崩解劑及視需要之潤滑劑與步驟(c)獲得的顆粒混合,及(e)壓縮步驟(d)獲得的混合物以獲得錠劑。
- 如請求項14之製造固態醫藥製劑之方法,其中將檸檬酸及(若存在)抗氧化劑溶解於步驟(a)中使用的明膠水溶液中或與步驟(d)中的顆粒混合。
- 如請求項14或15之製備固態醫藥製劑之方法,其中對該等顆粒或錠劑提供包衣。
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