TWI406861B - 包含阿格列扎(aleglitazar)之醫藥組合物及其製造方法與用途 - Google Patents
包含阿格列扎(aleglitazar)之醫藥組合物及其製造方法與用途 Download PDFInfo
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- TWI406861B TWI406861B TW099101817A TW99101817A TWI406861B TW I406861 B TWI406861 B TW I406861B TW 099101817 A TW099101817 A TW 099101817A TW 99101817 A TW99101817 A TW 99101817A TW I406861 B TWI406861 B TW I406861B
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- Prior art keywords
- pharmaceutical composition
- sodium
- solution
- group
- aglitaza
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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Description
本發明係關於一種醫藥組合物及特定言之係關於一種包含阿格列扎(aleglitazar)或其鹽之醫藥組合物。更特定言之，本發明係關於一種包含0.01mg至0.9mg阿格列扎(aleglitazar)或其鹽之醫藥組合物，其係由以下步驟獲得：
(a)將包含阿格列扎(aleglitazar)或其鹽之溶液噴塗於稀釋劑及崩解劑上；
(b)使步驟(a)中獲得之組合物與潤滑劑混合；及
(c)視需要壓製步驟(b)中獲得之組合物。
本發明亦係關於一種製造醫藥組合物之方法，其包含：
(a)將包含阿格列扎(aleglitazar)或其鹽之溶液噴塗於稀釋劑及崩解劑上；
(b)使步驟(a)中獲得之組合物與潤滑劑混合；及
(c)視需要壓製步驟(b)中獲得之組合物。
阿格列扎為(S)-2-甲氧基-3-{4-[2-(5-甲基-2-苯基-噁唑-4-基)-乙氧基]-苯并[b]噻吩-7-基}-丙酸。其屬於過氧化物酶體增殖物激活受體(PPAR)激動劑類。阿格列扎係描述於WO 02/092084中。阿格列扎之鈉鹽係(S)-2-甲氧基-3-{4-[2-(5-甲基-2-苯基-噁唑-4-基)乙氧基]-苯并[b]噻吩-7-基}丙酸鈉。
過氧化物酶體增殖物激活受體係細胞核激素受體超家族成員，該超家族係經配體活化之調節基因表現的轉錄因子。已識別並選殖出其各種子型。該等包括PPARα、PPARβ(亦稱為PPARδ)及PPARγ。PPARγ至少存在兩種主要的同功異形體。PPARγ1廣泛表現在大多數組織中，而較長的同功異型體PPARγ2幾乎僅出現在脂肪細胞中。反之，PPARα主要表現在肝、腎及心臟中。PPAR調節各種身體反應，包括葡萄糖-及脂類-體內平衡、細胞分化、炎症反應及心血管事件。
研究證實對PPARα與PPARγ之共激動作用使得化合物具有增強的治療潛能，即對葡萄糖-及胰島素濃度之最大程度正常化具有改良的血脂分佈作用(Keller and Wahli: Trends Endocrin. Metab. 1993;4:291-296,Macdonald and Lane: Current Biology，5卷，618-621頁(1995))。
阿格列扎有同時結合並活化PPARα與PPARγ之能力且極其有效。因此，阿格列扎合併了活化PPARγ之抗血糖作用與活化PPARα之抗血脂異常作用。因此，減少血漿葡萄糖及胰島素(=胰島素敏化)，降低甘油三酯及增加HDL膽固醇(=改良的血脂分佈)。另，其減少LDL膽固醇，降低血壓及阻止炎性動脈粥樣硬化。由於II型糖尿病症候群中多個方面係由PPARα及γ共激動劑治療，因此阿格列扎比此項技術中已知的化合物具有增強的治療效果。
令人吃驚地發現，含0.01至0.9mg劑量之阿格列扎的醫藥組合物於治療或預防II型糖尿病特別有效。因特別低的溶解度及高活性，阿格列扎從未成功地包含於適用於商業及工業製程之均質低劑量固體調配物中。
在本說明書中，術語「稀釋劑」指填補錠劑或膠囊之尺寸之賦形劑，使其適用於生產及便於消費者使用。合適的稀釋劑包括如醫藥上可接受的惰性填料，例如，微晶纖維素、乳糖、二鹼價磷酸鈣糖、糖醇、玉蜀黍澱粉、蔗糖、矽酸酐、多醣、N-甲基吡咯啶酮(Pharmasolve(ISP))及其混合物。術語糖及糖醇包含甘露醇、乳糖、果糖、山梨醇、木糖醇、麥芽糖糊精、環糊精類、糊精、乳糖醇及其混合物。
將黏合劑加入錠劑調配物中以增加粉末黏結性進而提供必要結合性，以形成顆粒，壓製該等顆粒形成密實質量的錠劑。黏合劑之合適實例為甲基纖維素、羧甲基纖維素、羥丙基纖維素、羥甲基丙基纖維素、聚乙烯基吡咯啶酮、聚乙烯醇、澱粉及預糊化澱粉。調配物中可使用兩種、三種或更多種黏合劑之混合物。
包含阿格列扎之溶液可係水溶液或有機溶液。較佳的有機溶劑係乙醇。
緩衝溶液係用作保持pH於近似恒定值之方法。緩衝溶液通常係由弱酸及其共軛鹼或弱鹼及其共軛酸之混合物組成之水溶液。其性質為當將少量酸或鹼添加至其中時，該溶液之pH變化很小。緩衝劑之實例係乙酸/乙酸鈉緩衝劑、磷酸二氫鉀或鈉/磷酸氫二鉀或氫二鈉緩衝劑、硼酸/氫氧化鈉緩衝劑、參(參-(羥甲基)-胺基甲烷)緩衝劑、碳酸鹽/碳酸氫鹽及EDTA-緩衝劑。
含阿格列扎之溶液較佳係緩衝水溶液，較佳係使用磷酸鹽緩衝劑緩衝。該磷酸鹽緩衝劑較佳係包含磷酸氫二鈉及磷酸二氫鈉之緩衝劑。
術語「表面活性劑」指降低液體表面張力之賦形劑。表面活性劑之實例包括tween 80、聚氧乙烯-聚氧丙烯共聚物及月桂基硫酸鈉。
術語「崩解劑」指當濕潤時膨脹並溶解之賦形劑，其使錠劑在消化道中分裂開，釋放出用以吸收之活性成份。合適的崩解劑包括例如，輕度交聯的聚乙烯基吡咯啶酮、玉蜀黍澱粉、馬鈴薯澱粉、玉米澱粉、及改質澱粉、交聯羧甲基纖維素鈉、羧甲基纖維素鈣、羧甲基纖維素鈉、交聚維酮(crossprovidone)、澱粉羥基乙酸鈉及其混合物。
包括藉由降低壓製時之顆粒間摩擦及黏合而影響粉末流動性之製劑的合適潤滑劑係膠體二氧化矽，例如，氣溶膠、滑石、硬脂酸、硬脂酸鎂、硬脂酸鈣、甘油山萮酸酯、硬脂基富馬酸鈉及矽膠。
術語「包衣」指施用於錠劑表面及保護錠劑成分免遭空氣濕氣損蝕及使大塊或味道不佳之錠劑更易吞嚥之賦形劑。包衣製劑之實例包括PVA(聚乙烯醇)、HPMC(羥丙基甲基纖維素)及PEG(聚乙二醇)。
術語「阿格列扎或其鹽」指阿格列扎或阿格列扎與鹼之反應產物，其中阿格列扎之羧酸氫原子已被金屬原子取代。阿格列扎鹽較佳係阿格列扎鈉鹽。
除非另外說明，否則所有百分比係以佔組合物總重量之重量百分比表示。
阿格列扎或其鹽之重量範圍指呈游離酸形式之阿格列扎之重量或，若呈鹽型時，指相同莫耳量之呈游離酸形式之阿格列扎之重量。
醫藥組合物或方法中之阿格列扎或其鹽之量較佳係0.01至0.9mg之間，較佳係0.01至0.6mg之間，更佳係0.15至0.6mg之間。阿格列扎之進一步較佳量係0.15或0.3mg。
較佳為醫藥組合物或方法中，步驟(a)中包含阿格列扎或其鹽之溶液係水溶液。
亦較佳為醫藥組合物或方法中，步驟(a)中包含阿格列扎或其鹽之溶液係有機溶液(乙醇溶液較佳)。
較佳為根據本發明醫藥組合物或方法中，步驟(a)之溶液係水溶液，較佳係經磷酸鹽緩衝劑緩衝之水溶液。該緩衝劑較佳係選自上述緩衝劑且更佳係磷酸氫二鈉及磷酸二氫鈉。
當緩衝劑係Na2
HPO4
及NaH2
PO4
時，該緩衝劑系統之莫耳濃度較佳係介於0.05與0.4mM之間，較佳係0.1與0.2mM之間。緩衝溶液之pH較佳係介於6.0與12之間。
亦較佳為根據本發明之醫藥組合物或方法中，稀釋劑係選自糖、微晶纖維素、乳糖、澱粉及其混合物，及較佳係乳糖及微晶纖維素之混合物。
亦較佳為根據本發明之醫藥組合物或方法中，步驟(a)之水溶液包含選自聚維酮(povidone)、HPMC及預糊化澱粉之黏合劑。
黏合劑量較佳佔組合物總重量之1至15%，更佳係2至10%，更佳係4至6%。
該黏合劑係聚維酮較佳。預糊化澱粉亦較佳。
較佳為根據本發明之醫藥組合物或方法中，步驟(a)之溶液包含選自tween 80、聚氧乙烯-聚氧丙烯共聚物及月桂基硫酸鈉之表面活性劑。
表面活性劑量較佳佔組合物總量之0.1至2%，更佳為0.25至1%，更佳為0.4至0.6%。
表面活性劑較佳係月桂基硫酸鈉。
崩解劑較佳係選自交聯聚乙烯吡咯啶酮、澱粉、交聯羧甲基纖維素鈉、羧甲基纖維素鈉及澱粉羥基乙酸鈉。
崩解劑量較佳佔組合物總量之0.5至15%，更佳為1至10%，更佳為2至3%。
崩解劑較佳係交聯羧甲基纖維素鈉。
亦較佳為根據本發明之醫藥組合物或方法中，潤滑劑係選自硬脂酸、硬脂酸鎂、甘油山萮酸酯及硬脂基富馬酸鈉。
潤滑劑量較佳佔組合物總量之0.2至3%，更佳係0.5至1.0%。
潤滑劑較佳係硬脂酸鎂。
組合物較佳包含阿格列扎之鈉鹽。
本發明較佳亦係關於一種醫藥組合物，其包含：
阿格列扎或其鈉鹽 0.01-2%
磷酸氫二鈉 0.5-1.5%
磷酸二氫鈉 0.005-0.25%
月桂基硫酸鈉 0.1-2%
聚維酮或HPMC 1-15%
乳糖 15-85%
微晶纖維素 3-85%
交聯羧甲基纖維素鈉 0.5-15%
硬脂酸鎂 0.2-3%
本發明較佳亦係關於一種醫藥組合物，其包含：
阿格列扎或其鈉鹽 0.01-0.9mg
磷酸氫二鈉 1-1.5mg
磷酸二氫鈉 0.01-0.3mg
月桂基硫酸鈉 0.1-2mg
聚維酮或HPMC 0.1-20mg
乳糖 20-110mg
微晶纖維素 5-100mg
交聯羧甲基纖維素鈉 0.5-20mg
硬脂酸鎂 0.5-3mg
若需要，本發明之醫藥組合物亦可包含一或更多種抗氧化劑，以阻止例如：藥物化合物之任何氧化。本文使用之合適抗氧化劑包括，但不限於，丁基化羥基茴香醚、抗壞血酸鈉、丁基化羥基甲苯、焦亞硫酸鈉、蘋果酸、檸檬酸、抗壞血酸及其混合物。抗氧化劑較佳係以1:1混合之丁基化羥基茴香醚與丁基化羥基甲苯之混合物。
此外，本發明亦係關於一種醫藥組合物，其包含：
阿格列扎 0.01-2%
丁基化羥基茴香醚 0.01-0.5%
丁基化羥基甲苯 0.01-0.5%
月桂基硫酸鈉 0.1-2%
聚維酮 1-15%
乳糖 15-85%
微晶纖維素 3-85%
交聯羧甲基纖維素鈉 0.5-15%
硬脂酸鎂 0.2-3%
本發明亦係關於一種醫藥組合物，其包含：
阿格列扎 0.01-0.9mg
丁基化羥基茴香醚 0.01-0.5mg
丁基化羥基甲苯 0.01-0.5mg
月桂基硫酸鈉 0.1-2mg
聚維酮 0.1-20mg
乳糖 20-110mg
微晶纖維素 5-100mg
交聯羧甲基纖維素鈉 0.5-20mg
硬脂酸鎂 0.5-3mg
當步驟(a)使用乙醇溶液時，以包含抗氧化劑之以上組合物為較佳。
本發明之醫藥組合物可呈錠劑或膠囊形式及較佳係呈錠劑形式。
錠劑之較佳重量係介於50與250mg之間，較佳60與200mg之間，更佳70與150mg之間。最佳重量係130mg。
本發明之醫藥組合物可塗覆有此項技術中已知的任何適宜包衣，較佳為例如白色Opadry II。
本發明亦係關於一種作為藥物之上述醫藥組合物，及較佳作為用於治療或預防II型糖尿病或心血管疾病之藥物。
此外，本發明亦係關於一種以如上述醫藥組合物於治療或預防II型糖尿病或心血管疾病上之用途。
本發明進一步係關於一種治療或預防II型糖尿病或心血管疾病之方法，其包括對有此需求之患者投與如上述之醫藥組合物之步驟。
阿格列扎特別適用於降低尤其具有穩定冠心病症候群及II型糖尿病患者之心血管死亡率、非致命性心肌梗死或中風。
可依照以下步驟製備組合物。
製備一種由水、阿格列扎、緩衝鹽、黏合劑及表面活性劑組成之緩衝溶液。阿格列扎含量較佳係0.2至0.8%(m/v)。活性成份較佳係完全溶於造粒液體中。將稀釋劑及崩解劑添加至流化床造粒機中。將該溶液均勻地噴塗於賦形劑上，使顆粒具有針對低劑量強度及適宜的粒度分佈(d63.2較佳係介於0.15與0.8mm之間(讓63.2%顆粒通過的篩目))之極佳含量均勻度，以避免高度塵粉曝露量並獲得良好的流動性。隨後，較佳於流化床乾燥機中乾燥該粒化物。然後，最佳經由網篩篩分所得的粒子，以獲得流化床粒子(FBG)。經乾燥的粒子較佳與潤滑劑混合，且然後使用習用壓錠裝置壓製成錠劑。本發明之錠劑可呈任何適宜形狀，例如，盤狀、圓形、橢圓形、長方形、圓柱形、三角形、六邊形，等。核中之載藥量係介於0.01與0.3%之間，較佳係0.05與0.15%之間。錠劑硬度較佳係大於60N，以確保良好塗覆性及包裝性。錠劑較佳為橢圓形以易於吞嚥及處理。所有錠劑均崩解迅速(小於300秒，含水介質，標準吊籃法及裝置)。經壓製的錠劑可包覆使重量增加4%的膜衣。
本發明係藉由後文實例說明但並不限制其特徵。
阿格列扎或其鈉鹽 0.3mg
磷酸氫二鈉 1.106mg
磷酸二氫鈉 0.037mg
月桂基硫酸鈉 0.625mg
HPMC 6.25mg
乳糖 100.43mg
微晶纖維素 12.5mg
交聯羧甲基纖維素鈉 2.5mg
硬脂酸鎂 1.25mg
白色Opadry II 5.00mg。
製備一種包含阿格列扎(0.3%(w/v))、磷酸氫二鈉、磷酸二氫鈉、HPMC及月桂基硫酸鈉之緩衝水溶液。使活性成份完全溶於造粒液體中。需進行攪拌以完全溶解。將乳糖、微晶纖維素及交聯羧甲基纖維素鈉添加至流化床造粒機中。將該溶液均勻地噴塗(噴塗率：180-220g/min；進氣溫度：60-80℃，氣壓：2-4巴，產物溫度：22℃-35℃)於固體賦形劑上，以得到粒子。所得粒子具有針對此低劑量強度及適宜粒度分佈(d63.2為250μm)之極佳含量均勻性，由此避免高度粉塵曝露量。此外，該等粒子具有良好流動性。隨後，於流化床乾燥機中乾燥粒化物。接著，經由篩網(2mm篩目，1000rpm轉速)篩分所得的粒子，以獲得流化床粒子(FBG)。將經乾燥的粒子與潤滑劑混合，然後使用習用的壓錠裝置壓製成錠劑。
阿格列扎或其鈉鹽 0.3mg
磷酸氫二鈉 1.106mg
磷酸二氫鈉 0.037mg
月桂基硫酸鈉 0.625mg
聚維酮 6.25mg
乳糖 100.43mg
微晶纖維素 12.5mg
交聯羧甲基纖維素鈉 2.5mg
硬脂酸鎂 1.25mg
白色Opadry II 5.00mg
此處改以聚維酮代替HPMC，重複實例1中所述步驟。該等粒子具有與實例1之粒子類似之含量均勻性、粒度分佈及流動性。將乾燥的粒子與潤滑劑混合，然後使用習用的壓錠裝置壓製成錠劑。
阿格列扎 0.15mg
丁基化羥基茴香醚 0.0125mg
丁基化羥基甲苯 0.0125mg
月桂基硫酸鈉 0.625mg
聚維酮 6.25mg
乳糖 101.7mg
微晶纖維素 12.5mg
交聯羧甲基纖維素鈉 2.5mg
硬脂酸鎂 1.25mg
白色Opadry II 5.00mg。
製備一種包含阿格列扎、丁基化羥基茴香醚、丁基化羥基甲苯、聚維酮及月桂基硫酸鈉之乙醇溶液。使活性成份完全溶於造粒液體中。將乳糖、微晶纖維素及交聯羧甲基纖維素鈉添加至流化床造粒機中。將該溶液均勻噴塗(200至400g/min)於固體賦形劑上，得到粒子。該等粒子具有與實例1及2之彼等粒子相似之含量均勻性、粒度分佈及流動性。將乾燥的粒子與潤滑劑混合，然後使用習用的壓錠裝置壓製成錠劑。
Claims (30)
- 01mg至0.9mg阿格列扎或其鹽之醫藥組合物，其係由以下步驟獲得：(a)將含阿格列扎或其鹽之溶液噴塗於稀釋劑及崩解劑上；(b)使步驟(a)中獲得之組合物與潤滑劑混合；及(c)視需要壓製步驟(b)中獲得之組合物。
- 如請求項1之醫藥組合物，其中步驟(a)之該溶液係水溶液。
- 如請求項1或2之醫藥組合物，其中步驟(a)之該溶液係經磷酸鹽緩衝劑緩衝。
- 如請求項1或2之醫藥組合物，其中該稀釋劑係選自糖、微晶纖維素、乳糖、澱粉及其混合物。
- 如請求項1或2之醫藥組合物，其中步驟(a)之該溶液包含選自聚維酮(povidone)、羥丙基甲基纖維素及預糊化澱粉之黏合劑。
- 如請求項5之醫藥組合物，其中該黏合劑係聚維酮。
- 如請求項1或2之醫藥組合物，其中步驟(a)之該溶液包含選自tween 80、聚氧乙烯-聚氧丙烯共聚物及月桂基硫酸鈉之表面活性劑。
- 如請求項7之醫藥組合物，其中該表面活性劑係月桂基硫酸鈉。
- 如請求項1或2之醫藥組合物，其中該崩解劑係選自交聯聚乙烯基吡咯啶酮、澱粉、交聯羧甲基纖維素鈉、羧甲 基纖維素鈉及澱粉羥基乙酸鈉。
- 如請求項9之醫藥組合物，其中該崩解劑係交聯羧甲基纖維素鈉。
- 如請求項1或2之醫藥組合物，其中該潤滑劑係選自硬脂酸、硬脂酸鎂、甘油山萮酸酯及硬脂基富馬酸鈉。
- 如請求項11之醫藥組合物，其中該潤滑劑係硬脂酸鎂。
- 如請求項1或2之醫藥組合物，其包含阿格列扎之鈉鹽。
- 一種製造阿格列扎或其鹽之醫藥組合物之方法，其包含：(a)將含阿格列扎或其鹽之溶液噴塗於稀釋劑及崩解劑上；(b)使步驟(a)中獲得之組合物與潤滑劑混合；及(c)視需要壓製步驟(b)中獲得之組合物。
- 如請求項14之方法，其中步驟(a)之該溶液係水溶液。
- 如請求項14或15方法，其中步驟(a)之該溶液係經磷酸鹽緩衝劑緩衝。
- 如請求項14或15之方法，其中該稀釋劑係選自糖、微晶纖維素、乳糖、澱粉及其混合物。
- 如請求項14或15之方法，其中步驟(a)之該溶液包含選自聚維酮、羥丙基甲基纖維素及預糊化澱粉之黏合劑。
- 如請求項18之方法，其中該黏合劑係聚維酮。
- 如請求項14或15之方法，其中步驟(a)之該溶液包含選自tween 80、聚氧乙烯-聚氧丙烯共聚物及月桂基硫酸鈉之表面活性劑。
- 如請求項20之方法，其中該表面活性劑係月桂基硫酸鈉。
- 如請求項14或15之方法，其中該崩解劑係選自交聯聚乙烯基吡咯啶酮、澱粉、交聯羧甲基纖維素鈉、羧甲基纖維素鈉及澱粉羥基乙酸鈉。
- 如請求項22之方法，其中該崩解劑係交聯羧甲基纖維素鈉。
- 如請求項14或15之方法，其中該潤滑劑係選自硬脂酸、硬脂酸鎂、甘油山萮酸酯及硬脂基富馬酸鈉。
- 如請求項24之方法，其中該潤滑劑係硬脂酸鎂。
- 如請求項14或15之方法，其包含阿格列扎之鈉鹽。
- 一種醫藥組合物，其包含：阿格列扎或其鈉鹽 0.01-0.9mg磷酸氫二鈉 1-1.5mg磷酸二氫鈉 0.01-0.3mg月桂基硫酸鈉 0.1-2mg聚維酮 0.1-20mg乳糖 20-110mg微晶纖維素 5-100mg交聯羧甲基纖維素鈉 0.5-20mg硬脂酸鎂 0.5-3mg。
- 2或27之醫藥組合物，其係呈錠劑形式。
- 2或27之醫藥組合物，其係用作治療或預防II型糖尿病或心血管疾病之藥物。
- 一種以如請求項1至13及27至29中任一項之醫藥組合物於製造用於治療或預防II型糖尿病或心血管疾病之藥物上之用途。
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