TWI424856B - 用於治療神經疾病之新穎劑型 - Google Patents
用於治療神經疾病之新穎劑型 Download PDFInfo
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- TWI424856B TWI424856B TW097106936A TW97106936A TWI424856B TW I424856 B TWI424856 B TW I424856B TW 097106936 A TW097106936 A TW 097106936A TW 97106936 A TW97106936 A TW 97106936A TW I424856 B TWI424856 B TW I424856B
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- dosage form
- tetrahydro
- cyclobutyl
- pyridyl
- pyrrolidone
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Description
本發明係關於新穎的劑型、製備該劑型之方法及該劑型於醫藥之用途。
國際專利申請案公開編號WO2004/056369揭示了包括1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之特定苯并氮呯衍生物。
WO2004/056369教導,苯并氮呯衍生物可使用標準技術來調配。然而並無明確地揭示包含1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之劑型。
在第一方面,本發明係提供一劑型,其包含:a)1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽;b)一安定劑,當與缺乏該安定劑的劑型相比較時,其減低了劑型中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之降解;及c)一醫藥上可接受賦形劑。
此劑型可調適成以任何所欲的給藥路徑來投予病患。例如,劑型包括該等適合(1)口服給藥,如錠劑、膠囊、片
劑、丸劑、口含錠、散劑、糖漿、酏劑、懸浮液、溶液、乳液、小袋劑及囊劑;(2)非經腸給藥,如無菌溶液、懸浮液、植入劑及重建用散劑;(3)經皮給藥,如透皮貼布;(4)直腸及陰道給藥,如栓劑、子宮托及泡沫劑;(5)吸入及鼻內給藥,如乾粉、氣霧、懸浮液及溶液(噴霧及滴劑);(6)局部給藥,如乳霜、軟膏、乳液、溶液、糊劑、滴劑、噴霧、泡沫及凝膠;(7)眼部,如滴劑、軟膏、噴霧、懸浮液及嵌入劑;及(8)頰內及舌下給藥,如口含錠、貼布劑、噴霧劑、滴劑、口嚼膠及錠劑。
在本發明內文中,術語「醫藥上可接受賦形劑」係指存在於劑型中,1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑以外之任何醫藥上可接受物質。適合的醫藥上可接受賦形劑將依所選的特定劑型而不同,且包括稀釋劑、結著劑、崩解劑及超崩解劑、潤滑劑、助滑劑、成粒劑、塗膜劑、濕潤劑、溶劑、共溶劑、懸浮劑、乳化劑、甜味劑、調味劑、風味遮蔽劑、調色劑、抗結劑、保濕劑、螯合劑、增塑劑、增稠劑、速率改良劑、防腐劑、介面活性劑。熟習技術者應了解,特定的醫藥上可接受賦形劑可作為一種以上的功能,且依照存在調配物中之賦形劑的多寡及存在調配物中之其他成份,可作為另外的功用。選擇適合的醫藥上可接受賦形劑之指南可參看雷氏藥學大全(Remington's Pharmaceutical Sciences)(馬克出版公司)。
本發明之劑型可使用熟習本項技術者已知之技術和方
法來製備。一些本項技術中常用的方法係描述於雷氏藥學大全(馬克出版公司)中。
在一實例中,本發明係關於包括1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽、安定劑及稀釋劑之固體口服劑型(例如錠劑或膠囊)。適合的稀釋劑包括糖類(例如乳糖、蔗糖、右旋糖)、糖醇(例如甘露醇、山梨糖醇)、澱粉(例如玉米澱粉、馬鈴薯澱粉及預膠化澱粉)、纖維素及其衍生物(例如微晶纖維素)、硫酸鈣及磷酸氫鈣。劑型可進一步包含其他習用的賦形劑,例如結著劑、崩解劑、潤滑劑及助滑劑。適合的結著劑包括澱粉(例如玉米澱粉、馬鈴薯澱粉及預膠化澱粉)、明膠、阿拉伯膠、海藻酸鈉、海藻酸、角叉菜膠、關華豆膠、聚乙烯吡咯酮及纖維素和其衍生物(例如乙基纖維素、甲基纖維素、羧甲基纖維素、羥丙基纖維素及羥丙基甲基纖維素)。適合的崩解劑包括澱粉、交鏈聚乙烯吡咯酮、葡萄糖酸澱粉鈉、交鏈羧甲基纖維素、海藻酸及羧甲基纖維素鈉。適合的潤滑劑包括硬脂酸、硬脂酸鎂及硬脂酸鈣。適合的助滑劑包括滑石或膠體二氧化矽。口服的固體劑型可進一步包含具有美化或功能特性之外部膜衣。
在一更特別的方面,本發明係提供包含一載體錠劑供口服給藥之劑型,其中該載體錠劑係至少部分覆蓋膜衣,而該膜衣係包含:a)1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽;及
b)一安定劑,當與缺乏該安定劑的劑型相比較時,其減低了劑型中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之降解。
在此申請書之內文中,術語「載體錠劑」係指實質上無1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-yI)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽類之錠劑。雖然於載體錠劑中含有一或多種治療劑之實施例係涵蓋在本發明中,但典型地該錠劑不含任何治療劑。
載體錠劑之組成並不重要,但其限制條件為該組成需為醫藥上可接受的。然而,該載體錠劑必須具適當的大小及形狀以具口服給藥錠劑之功能。任何形式的錠劑皆可使用,例如於雷氏(Remington)之2005年第21版的藥學與配藥(Ed.D.B.Troy)中所描述的。在一實施例中,載體錠劑係以習用壓製技術所形成並包含至高100%重量/重量稀釋劑或稀釋劑之混合物。習用的稀釋劑包括糖類(例如乳糖、蔗糖、右旋糖)、糖醇(例如甘露醇、山梨糖醇)、澱粉(例如玉米澱粉、馬鈴薯澱粉及預膠化澱粉)、纖維素及其衍生物(例如微晶纖維素)、硫酸鈣及磷酸氫鈣。該錠劑可另外包含至高100%重量/重量結著劑,或結著劑之混合物。適合的結著劑包括澱粉(例如玉米澱粉、馬鈴薯澱粉及預膠化澱粉)、明膠、阿拉伯膠、海藻酸鈉、海藻酸、角叉菜膠、關華豆膠、聚乙烯吡咯酮及纖維素和其衍生物(例如乙基纖維素、甲基纖維素、羧甲基纖維素、羥丙基纖維素及羥丙基甲基纖維素)。載體錠劑亦可含有其他習用的賦形劑,例如潤滑
劑(例如硬脂酸、硬脂酸鎂及硬脂酸鈣)及助滑劑(例如滑石或膠體二氧化矽)。在一實施例中,潤滑劑及助滑劑各以至高10%重量/重量,更特而言之至高5%重量/重量之量存在。在另一實施例中,藉由注射成型所形成之物質(例如膜製錠或膠囊鞘)可用作載體錠劑。適合的注射成型之熱塑性物質包括羥丙基纖維素、乙基纖維素、甲基丙烯酸酯及聚乙烯乙酸酯。
在一實施例中,載體錠劑為包含微晶纖維素(例如Avicel PH-102)、預膠化澱粉(例如Starch 1500)及硬脂酸鎂之錠劑。在一更特別的實施例中,該載體錠劑具有下列組成:
在另一實施例中,載體基質可調配成當以口服給藥時能在口中崩解,即所謂的「口腔崩解錠」或「ODT」基質。另外,該載體基質可調配成於水中崩解,即所謂的「速溶錠」或「FDT」基質。
載體錠劑係提供膜衣之基質或撐體。在一實施例中,載體錠劑係羥塗膜以實質上防止1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其
醫藥上可接受鹽被載體錠劑吸收。然而,其中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽經載體錠劑吸收之實施例係涵蓋在本發明中。
適合的載體錠劑之膜衣包括水性膜衣,如市售的Colorcon公司之膜衣,例如Opadry膜衣(「OPADRY WHITE OOFI 8484」或「OPADRY WHITE YS-1-7003」)。其他適合的膜衣包括Surelease(乙基纖維素)。劑型可另外塗覆抗胃酸或腸溶性聚合物質之膜衣。適合的聚合物質包括乙醯鄰苯二甲酸纖維素、乙醯丙酸纖維素、偏苯三酸纖維素及丙烯和甲基丙烯共聚物。亦可添加調色劑。
在一實施例中,載體錠劑係塗覆上2-6%重量增加率之膜衣。
應了解,在實施例中當載體錠劑塗膜以實質上防止1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽被吸收時,該所選擇的膜衣在製造錠劑的過程中,必須不溶於所用的溶劑中。例如,當使用水性溶劑系統時,水性膜衣(如Opadry)將會立即崩解,則適合的為不溶於水之膜衣(例如Surelease或Eudragit)。
在一實施例中,含有1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽之膜衣僅部份塗覆於載體錠劑。在一更特定的實施例中,該等載體錠劑係塑成含有一或多個凹槽或凹處
之形狀。在此等實施例中,含有1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽之膜衣可實質上存在於載體錠劑的凹槽內。
劑型及/或至少部分覆蓋載體錠劑之膜衣包含1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮(「游離鹼」)或其醫藥上可接受鹽。在本發明內文中,所指的游離鹼或醫藥上可接受鹽涵蓋游離鹼或醫藥上可接受鹽之溶劑化物或水合物。
1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮可根據已知製程來製備,例如該等揭示於WO2004/056369中之製程。WO2004/056369之揭示文係以引用的方式併入本文中。
1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之醫藥上可接受酸加成鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、琥珀酸鹽、馬來酸鹽、甲酸鹽、乙酸鹽、丙酸鹽、延胡索酸鹽、檸檬酸鹽、酒石酸鹽、乳酸鹽、苯甲酸鹽、水楊酸鹽、麩胺酸鹽、天門冬胺酸鹽、‘對甲苯磺酸鹽、苯磺酸鹽、甲磺酸鹽、乙磺酸鹽、萘磺酸鹽(例如2-萘磺酸鹽)或己酸鹽。此等鹽類可藉由與適合的酸,視需要於適合的溶劑中(例如有機溶劑)反應來形成,得到的鹽可(例如)藉由結晶及過濾來分離。
劑型及/或膜衣可含有游離鹼、醫藥上可接受鹽(化學計量或非化學計量)或其任何混合物。在一實施例中,該劑型
含有游離鹼。在一實施例中,該膜衣含有游離鹼。
在本發明一實施例中,劑型及/或膜衣當測量所存的鹼之量係含有介於1微克至1毫克1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮(其不包括添加以形成鹽類之任何酸量)。在一更特別的實施例中,劑型及/或膜衣當測量所存的鹼之量係含有介於1微克至200微克,更特而言之含有介於1微克至100微克,又更特而言之介於2微克至100微克的1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮。
劑型及/或膜衣額外含有醫藥上可接受安定劑,當與缺乏該安定劑的劑型相比較時,其在含有安定劑的劑型中減低了1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮(或其醫藥上可接受鹽)之降解。劑型中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮(或其醫藥上可接受鹽)之降解可藉由測量劑型之總不純物/降解產物含量,使用梯度HPLC、使用下述方法來分析。熟習技術之讀者應了解,除了有或無安定劑之外,該等劑型在其他方面應相類似,且應儲存於類似條件下歷經類似的時間。
在一實施例中,由至少3個含安定劑、於40℃及75%相對溼度下儲存1個月之劑型樣本所計算之平均總不純物/降解產物含量,比由至少3個不含該安定劑、儲存於類似條件下之類似劑型樣本所計算之平均總不純物/降解產物
含量,至少低50%。
在另一實施例中,至少3個含安定劑之劑型樣本,於30℃及65%相對溼度下儲存3個月時間其平均總不純物/降解產物含量應不超過10%,更特而言之5%。
在本發明內文中,特定的醫藥上可接受抗氧化劑可作為安定劑。醫藥上可接受抗氧化劑包括描述於2000年第三版醫藥賦形劑手冊(Ed.A.H.Kibbe)之抗氧化劑。在一實施例中,安定劑係由下列組成之群中選出:檸檬酸、蘋果酸、抗壞血酸及其鹽類、碳酸氫鈉、丁基羥基茴香醚(butylated hydroxyanisole)及丁基羥基甲苯(butylated hydroxytoluene)。安定劑之組合物亦可用於本發明。
在一實施例中,該安定劑為檸檬酸及視需要丁基羥基茴香醚。在一實施例中,膜衣含有檸檬酸及視需要丁基羥基茴香醚。
劑型及/或膜衣中之一或多種安定劑必須以有效量存在以減少1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽之降解。在包含檸檬酸之特定實施例中,游離鹼與檸檬酸之莫耳比率係在1.5:1至1:500之範圍內。
膜衣可額外含有造膜劑,例如羥丙基纖維素、羥丙基甲基纖維素、羥乙基纖維素、羧甲基纖維素、聚乙烯醇、聚乙烯吡咯酮、角叉菜膠(kappa(卡鉑)、iota(阿歐塔)或lambda(萊姆達))、明膠、聚乙二醇、聚氧化乙烯、普路蘭(pullulan)、丙烯聚合物(例如EUDRAGIT等級RL、RS、E、
L、S、FS30D)或其任何組合。在一實施例中,該造膜劑為羥丙基纖維素。熟習本項技術者應了解,包含於劑型中之任何造膜劑其在製造期間應可溶於所用的溶劑中。
膜衣可額外含有其他賦形劑。例如,已發現特定的溶劑系統,例如水性系統,需要添加介面活性劑(例如聚山梨醇酯(20、40、80)、Triton 100、月桂基硫酸鈉或泰洛醇(tyloxopol))及/或消泡劑(聚二甲基矽氧烷(polydimethylsiloxane)或矽靈(dimethicone))。因此,在另一實施例中,膜衣額外含有一或多種介面活性劑及/或一或多種消泡劑。
劑型可進一步塗膜。適合的膜衣包括上述所列適合塗覆載體錠劑之膜衣。在一實施例中,該劑型係塗覆至2-6%重量增加率。
劑型可視需要包裝於低氧環境中。其可藉由將脫氧劑包含於劑型的包裝內來達成。適合的脫氧劑包括PharmaKeepKH和KD(Sud Chemie公司之市售商品)及StabilOxTM
專業脫氧劑(Multisorb Technologies公司之市售商品)。另外,劑型可包裝於不透氧的瓶子中。
亦可使用鋁-鋁泡罩將劑型包裝於低氧的環境中。
在另一方面,本發明係提供製備本發明劑型之方法。此方法包括將1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液分散於載體錠劑上。任何的溶劑皆可使用,但其限制條件為存在於膜衣中之安定劑及任何其他
的賦形劑需可溶於此溶劑中。溶劑典型地為揮發性的,且在完成的劑型中出現之(殘餘)量必須為醫藥上可接受的。
適合的溶劑包括水、有機溶劑、推劑進、液化氣體及揮發矽。在一實施例中,1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液係使用有機溶劑(例如甲醇、乙醇、丙酮、乙酸或二氯甲烷)來製備。溶劑之混合物(例如水-乙醇)亦可使用。在一實施例中,該溶劑為甲醇。
在另一方面,本發明係提供1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑溶於溶劑系統之溶液或懸浮液。在一實施例中,該溶液或懸浮液進一步包含一或多種造膜劑及/或介面活性劑及/或消泡劑。在另一實施例中,該溶劑為有機溶劑,例如甲醇、乙醇、丙酮、乙酸或二氯甲烷,更特而言之為甲醇。
在特定的實施例中,其中該安定劑為檸檬酸,其係以介於2-3%重量/體積,特別是3%重量/體積之量存在於溶液或懸浮液中。在特定的實施例中,其中該安定劑為丁基羥基茴香醚,其係以介於0.01-0.1%重量/體積,特別是0.02%重量/體積之量存在於溶液或懸浮液中。
在特定的實施例中,其中該造膜劑為羥丙基纖維素,其係以介於4-6%重量/體積,特別是4%重量/體積之量存在於溶液或懸浮液中。
載體錠劑及分散溶液/懸浮液可經加熱(例如於熱風爐
中)以蒸發過量的液體並使至少部分的載體錠劑表面形成膜衣。該劑型然後可視需要根據本項技術中已知之方法塗覆膜衣。
於製備該劑型之方法中所用的載體錠劑可具有提供在分散後接收1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液蓄存之凹槽或凹處。典型地,係使用在錠劑的二面具有凹槽之雙凹錠劑。此二處凹槽可用來接收1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液。另外,其中一個凹槽可用來接收1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液,剩餘的凹槽可用來接收另一種治療劑之溶液或懸浮液,而產生含二種不同治療劑之劑型。在另一實施例中,不同治療劑之溶液可覆蓋在另一種治療劑之上方。
本發明之劑型可使用WO2005/123569(該公開案全文係併入本文)中所述之裝置來製造。更特而言之,本發明之劑型可藉由將含有預定量之1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液準確地分散於載體錠劑上之滴膠機裝置來製備。該裝置亦可具有容納載體錠劑之組成部件,當滴膠機將溶液/懸浮液分散至各載體錠劑上時,該部件可沿著裝置持續移動。
該裝置亦可具有從沉積在各載體錠劑之溶液/懸浮液中乾燥或蒸發溶劑之乾燥系統。當乾燥系統在乾燥各載體錠劑之劑型時,該組成部件可沿著裝置持續移動。該乾燥系統可藉由使用熱風、紅外線或微波加熱來乾燥劑型。
該裝置亦可具有塗覆膜衣於劑型上之塗膜系統。該塗膜系統可具有將膜衣塗覆於各載體基質之移印元件或噴霧器。當塗膜系統將膜衣塗覆於各載體錠劑時,該組成部件可沿著裝置持續移動。該裝置亦可具有將各載體錠劑上之膜衣乾燥之膜衣乾燥器。
應了解,上列所述之裝置可將載體錠劑再加工無數次,以加入不同治療劑之溶液或懸浮液。另外,該裝置可具有連續額外的分散系統以便將各溶液/懸浮液加到載體錠劑中。
1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮及其醫藥上可接受鹽類為具有有效治療性質之H3拮抗劑。更特而言之,咸信1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮及其醫藥上可接受鹽類具治療下列病症之潛在用途:神經性疾病,包括阿茲海默症、失智症(包括路易體失智症及血管型失智症)、年老記憶障礙、輕微智能缺損、認知障礙、癲癎、偏頭痛、帕金森氏症、多發性硬化症(包括疲勞)、中風、神經源疼痛(包括神經痛、神經炎及背部疼痛)、發炎性疼痛(包括骨關節炎、類風濕性關節炎、急性發炎疼痛及背部疼痛)及睡眠障礙(包括過度嗜睡、日間過度嗜睡、瘁睡
症、與帕金森氏症及疲勞(特別是多發性硬化症)有關的睡眠障礙);精神性病症,包括精神病(例如精神分裂症(特別是精神分裂症之認知障礙)及躁鬱症)、注意力缺乏過動症、憂鬱症(包括重度憂鬱症)、焦慮症及成癮;及其他疾病(包括肥胖症及胃腸病症)。
因此,在另一方面,本發明係提供用於治療之劑型。更特而言之,本發明係提供用於治療或預防上述病症,特別是神經及精神性病症之劑型。
本發明進一步係提供治療或預防哺乳動物(包括人類)上述病症之包含本發明劑型的醫藥組合物。
在另一方面,本發明係提供1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽於製造本發明劑型供用於治療上述病症之用途。
1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽可與其他治療劑組合使用。當1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽係希望用於治療阿茲海默症時,其可與聲明能有效用於阿茲海默症之疾病減輕或癥狀治療的醫藥組合使用。此等其他治療劑之適合的實例可為對症藥劑,例如該等已知用於修飾膽鹼激素傳導之治療劑,如M1蕈毒鹼受體促進劑或變構調節劑、M2蕈毒鹼拮抗劑、乙醯膽酯酶抑制劑(例如四氫胺基吖啶、多奈呱齊鹽酸鹽(donepezil hydrochloride)及利斯
的明(rivastigmine))、菸鹼酸受體促進劑或變構調節劑(例如α7促進劑或變構調節劑或α4β2促進劑或變構調節劑)、PPAR促劑進(例如PPARγ促劑進)、5-HT4
受體部分促進劑、5-HT6
受體拮抗劑或5HT1A受體拮抗劑及NMDA受體拮抗劑或調節劑,或疾病減緩劑(例如β或γ-分泌酶抑制劑)。
當1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽係希望用於治療瘁睡症時,其可與聲明能有效用於治療瘁睡症的醫藥組合使用。此等其他治療劑之適合的實例包括莫達非尼(modafinil)、阿莫達非尼(armodafinil)及單胺吸收阻斷劑。
當1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽係希望用於治療精神分裂症時,其可與聲明能有效治療精神分裂症之醫藥組合使用,其包括:i)抗精神病藥物包括典型的抗精神病藥劑(例如氯丙嗪(chlorpromazine)、硫利噠嗪(thioridazine)、美索達嗪(mesoridazine)、氟奮乃靜(fluphenazine)、奮乃靜(perphenazine)、丙氯拉嗪(prochlorperazine)、三氟拉嗪(trifluoperazine)、硫西鋅(thiothixine)、氟哌丁苯(haloperidol)、嗎茚酮(molindone)及洛沙平(loxapine)),非典型抗精神病藥劑(例如氯氮平(clozapine)、奧氮平(olanzapine)、利培酮(risperidone)、喹硫平(quetiapine)、阿立比唑(aripirazole)、齊拉西酮(ziprasidone)、阿米舒必利(amisulpride)及阿立哌唑
(aripiprazole)),甘胺酸轉運體1抑制劑及代謝型受體配體;ii)椎體外徑副作用之藥物,例如抗膽鹼劑(如苯托品(benztropine)、比哌立登(biperiden)、丙環定(procyclidine)及苯海索(trihexyphenidyl))及多巴胺藥劑(如金剛胺(amantadine));iii)抗憂鬱藥劑包括血清素再吸收抑制劑(例如西酞普蘭(citalopram)、依他普侖(escitalopram)、氟西汀(fluoxetine)、帕羅西汀(paroxetine)、達泊西汀(dapoxetine)及舍曲林(sertraline))、雙重血清素/去甲腎上腺素再吸收抑制劑(如文拉法新(venlafaxine)、度洛西汀(duloxetine)及米那普崙(milnacipran)),去甲腎上腺素再吸收抑制劑(如瑞波西汀(reboxetine))、三環抗憂鬱藥劑(如阿米替林(amitriptyline)、氯米帕明(clomipramine)、丙咪嗪(imipramine)、馬普替林(maprotiline)、去甲替林(nortriptyline)及曲米帕明(trimipramine)),單胺氧化酶抑制劑(如異唑肼(isocarboxazide)、嗎氯貝胺(moclobemide)、苯乙肼(phenelzine)及反苯環丙胺(tranylcypromine))及其他藥劑(如安非他酮(buproprion)、米安色林(mianserin)、米氮平(mirtazepine)、奈法唑酮(nefazodone)及曲唑酮(trazodone));iv)焦慮藥劑包括苯并二氮呯,例如阿普唑嗆(alprazolam)及羅拉氮半(lorazepam);及v)認知增強劑,例如膽鹼酯酶抑制劑(如他可林(tacrine)、多奈呱齊(donepezil)、利斯的明(rivastigmine)及加蘭他敏(galantamine))。
在另一方面,本發明因此係提供包含載體錠劑之劑
型,該載體錠劑係至少部分塗覆包含1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之膜衣,而該劑型進一部係包含一或多種額外的治療劑。
應了解,該額外的治療劑可存在於載體錠劑中。另外,如上列論述,含額外治療劑之膜衣可沉積在載體錠劑上。當載體錠劑具有二個凹槽時,一個凹槽可包括含有1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之膜衣,而第二個凹槽可包括含有額外的一或多種治療劑之膜衣。另外,含1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽和安定劑之膜衣,及額外的治療劑之膜衣可覆蓋在其他治療劑之上方。
當1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽與有效對抗相同疾病症狀之第二治療劑組合使用時,1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮(或其醫藥上可接受鹽)之劑量可與單獨調配1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮(或其醫藥上可接受鹽)時不同。適當的劑量已為熟習本項技術者所了解。
下列實例係說明本發明而非在任何方面限制本發明。
將錠心組份通過30號篩網,然後於適當的攪拌器中攪拌及於旋轉壓錠機上打壓產生直徑9.525毫米及在錠劑二側帶有約0.8毫米深的凹槽之圓形雙凹錠劑。打壓後接著除塵及金屬檢測。將錠劑轉置於塗膜槽中並塗覆至目標4%(重量/重量)重量增加率。
載體錠劑之組份係如下所示:
載體溶液係藉由將4克的羥丙基纖維素(Grade EF;HPC)、2克的檸檬酸酐及0.02克丁基羥基茴香醚(BHA)溶於甲醇中,以10微米過濾器過濾並加入甲醇使最終的體積為100毫升所製備。
將1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮以超音波粉碎儀溶於載體溶液中,直到得到最終濃度5毫克/克(重量/重量)之均勻溶液。
將10毫克劑量溶液分散於一排的載體錠劑之各錠劑上。將錠劑於熱風爐中以約40℃乾燥10-20分鐘。
完成的錠劑之組成係如下:
含0.002毫克、0.01毫克或0.2毫克1-{6-[(3-環丁基
-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之錠劑係如實例1中所述之方法來製備,但是劑量溶液中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之濃度不同。
將錠心組份通過30號篩網,然後於適當的攪拌器中攪拌及於旋轉壓錠機上打壓產生尺寸15.9毫米x 8毫米x 3.4毫米及在二側帶有約0.9毫米深的凹槽之橢圓形雙凹錠劑。打壓後接著除塵及金屬檢測。將錠劑轉置於塗膜槽中並塗覆至目標4%(重量/重量)重量比。
載體錠劑之組成係如下所示:
載體溶液係藉由將4克的羥丙基纖維素(Grade EF;HPC)、2克的檸檬酸酐及0.02克丁基羥基茴香醚(BHA)溶於甲醇中,以10微米過濾器過濾然後加入甲醇使最終的體積為100毫升所製備。
將1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮以超音波粉碎儀溶於載體溶液中,直到得到最終濃度35毫克/克(重量/重量)之均勻溶液。
將28.5毫克劑量溶液分散於一排的載體錠劑之各錠劑上。將錠劑於熱風爐中以約50℃乾燥10-20分鐘。
完成的錠劑組成係如下:
將錠心組份通過30號篩網,然後於適當的攪拌器中攪拌及於旋轉壓錠機上打壓產生直徑7.9毫米及在錠劑二側帶有約0.8毫米深的凹槽之圓形雙凹錠劑。打壓後接著除塵及金屬檢測。將錠劑轉置於塗膜槽中並塗覆至目標4%(重量/重量)重量比。
載體錠劑之組份係如下所示:
載體溶液係藉由將5克的羥丙基纖維素(等級EF;
HPC)、3克的檸檬酸酐溶於甲醇中,以10微米過濾器過濾並加入甲醇使最終的體積為100毫升所製備。
將1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮以超音波粉碎儀(亦可使用磁力攪拌器)溶於載體溶液中,直到得到最終濃度12.5毫克/克(重量/重量)之均勻溶液。
將4毫克載體溶液分散於一排載體錠劑之各錠劑上。將錠劑於熱風爐中以約50℃乾燥10-20分鐘。
完成的錠劑組成係如下:
含0.002毫克、0.005毫克、0.02毫克、0.05毫克或0.1毫克1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之錠劑係如實例6中所述之方法來
製備,但是載體溶液中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之濃度不同。
下列實例(實例12及實例13)為根據本發明所製備之實例錠劑之代表:
a)製備ODT載體基質
將澱乳(StarLac)及紐甜(Neotame)通過20號篩網。將混合物及未過篩的薄荷調味劑轉置於適合的攪拌器中並攪拌約10分鐘。將硬脂酸鎂通過30號篩網,轉置於攪拌器中並將整個混合物攪拌約2分鐘。所用原料的重量係由表A中所示之百分比重量來計算。將混合物於適合的旋轉製錠機中使用適合的錠劑壓印來打壓以符合所需的規格(例如直徑範圍從約8毫米至約9.5毫米之圓形雙凹錠劑)。將錠劑通過除塵機及金屬檢測器。
b)製備藉由移印塗覆於錠劑之乙基纖維素膜衣
攪拌下將乙基纖維素溶於甲醇中,並加入檸檬酸三乙酯。所用原料的重量係由表B所示之百分比重量來計算。加入足夠的甲醇,以達到重量/重量基準目標。將溶液轉置於移印機之色料杯中,該移印機裝有適合的圓形影像(直徑比實際錠劑直徑稍小)之影像電氣版。安裝適合的聚合物槽以配合電氣版影像盤。錠劑係以所定義的排列(配合電氣版)放置在移印機中。移印機可塗覆2-4次至載體錠劑以塗覆膜衣提供保護層,於液體噴散的過程中防止溶劑滲透至未塗膜的載體基質中。
將甘露醇、交鏈聚維酮XL、木糖醇及紐甜通過20號篩網。將混合物及未過篩的薄荷調味劑轉置於適合的攪拌器中並攪拌約10分鐘。將硬脂酸鎂及膠體二氧化矽通過30號
篩網,轉置於攪拌器中並將整個混合物攪拌約2分鐘。所用原料的重量係由表C中所示之百分比重量來計算。將混合物於適合的旋轉製錠機中使用適合的錠劑壓印來打壓以符合所需的規格(例如直徑範圍從約8毫米至約9.5毫米之圓形雙凹錠劑)。將錠劑通過除塵機及金屬檢測器。
可如實例12所述,製備及塗覆乙基纖維素膜衣。
將5顆錠劑溶於稀釋劑中(1:9乙腈:50 mM正磷酸二
氫鉀,以正磷酸調整至pH 3)產生活性藥劑之最終濃度介於1-10微克/毫升並以超音波處理10分鐘。檢查是否完全崩解,若需要再以超音波處理。使其冷卻至周圍溫度,然後以14,000 rpm將一等份的樣本離心。使用安慰劑錠劑製備樣本作為對照樣本。
使用下列儀器條件,以95% A、5% B平衡色層分析系統。記錄樣本及安慰劑製備物之色層圖。
管柱:XBridge C18 3 μM 15公分x4.6毫米內徑管柱溫度:40℃移動相A:10 mM碳酸氫銨,pH 10帶有氨移動相B:乙腈流速:1毫升/分鐘偵測器波長:250 nm注射量:100微升
梯度資料:
依照比較色層圖來辨識不純物/降解產物,對照組及樣本注射物中各不純物/降解產物之百分比含量可藉由將不
純物/降解產物波峰之面積除以1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮及所有不純物/降解產物波峰之面積總合再乘以100來計算。
總不純物/降解產物含量可藉由將所存在的各不純物/降解產物之百分比含量加總來計算。典型地,在計算不純物/降解產物總量中,不純物/降解產物僅以大於或等0.05或0.03%之量存在。
Claims (14)
- 一種固體口服劑型,其包含一載體錠劑,該載體錠劑至少被一膜衣部分覆蓋,而該膜衣係包含:a)1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽;及b)一安定劑,當與缺乏該安定劑的劑型相比較時,其減低了劑型中1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮之降解,其中該安定劑係由下列組成之群中選出:檸檬酸、蘋果酸、抗壞血酸及其鹽類、碳酸氫鈉、丁基羥基茴香醚(butylated hydroxyanisole)及丁基羥基甲苯(butylated hydroxytoluene)。
- 如申請專利範圍第1項之固體口服劑型,當測量所存在的游離鹼之量時,其包含介於1微克至1毫克1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮。
- 如申請專利範圍第1項之固體口服劑型,其係包含1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮作為游離鹼。
- 如申請專利範圍第1項之固體口服劑型,其中該安定劑為檸檬酸且游離鹼與檸檬酸之莫耳比率係介於1.5:1至1:500之間。
- 如申請專利範圍第1項之固體口服劑型,其中該載體錠劑具有至少一個凹槽。
- 如申請專利範圍第5項之固體口服劑型,其中膜衣係存 在於該載體錠劑之凹槽中。
- 如申請專利範圍第1項之固體口服劑型,其中該載體錠劑係經塗膜。
- 如申請專利範圍第7項之固體口服劑型,其中該劑型係進一步塗膜。
- 如申請專利範圍第1項之固體口服劑型,其由下列組成:a)一載體錠劑,其由錠心及膜衣組成,其中該錠心由210mg微晶纖維素、21mg預膠化澱粉及2.3mg硬脂酸鎂組成,而該膜衣由9.3mg Opadry White YS-1-7003組成,及b)剩餘之分散液由0.4mg羥丙基纖維素、0.2mg檸檬酸、0.002mg丁基羥基茴香醚及由0.002mg、0.01mg、0.05mg或0.2mg之1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮組成。
- 如申請專利範圍第1項之固體口服劑型,其由下列組成:a)一載體錠劑,其由錠心及膜衣組成,其中該錠心由286.2mg微晶纖維素、28.6mg預膠化澱粉及3.2mg硬脂酸鎂組成,而該膜衣由12.7mg Opadry White 00F1848組成,及b)剩餘之分散液由1.14mg羥丙基纖維素、0.57mg檸檬酸、0.006mg丁基羥基茴香醚及由1mg之1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮組成。
- 如申請專利範圍第1項之固體口服劑型,其由下列組成: a)一載體錠劑,其由錠心及膜衣組成,其中該錠心由162mg微晶纖維素、16.2mg預膠化澱粉及1.8mg硬脂酸鎂組成,而該膜衣由7.2mg Opadry White YS-1-7003組成,及b)剩餘之分散液由0.25mg羥丙基纖維素、0.15mg檸檬酸、0.002mg丁基羥基茴香醚及由0.002mg、0.005mg、0.01mg、0.02mg、0.05mg或0.1mg之之1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮組成。
- 一種製備如申請專利範圍第1項之劑型之方法,係包括將1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽及安定劑之溶液或懸浮液分散至載體錠劑上,其中該安定劑係由下列組成之群中選出:檸檬酸、蘋果酸、抗壞血酸及其鹽類、碳酸氫鈉、丁基羥基茴香醚及丁基羥基甲苯。
- 一種治療神經性疾病之醫藥組合物,其包括如申請專利範圍第1至11項任一項中之劑型。
- 一種1-{6-[(3-環丁基-2,3,4,5-四氫-1H-3-苯并氮呯-7-基)氧基]-3-吡啶基}-2-吡咯酮或其醫藥上可接受鹽之用途,係用於製造如申請專利範圍第1至11項任一項中之劑型供治療神經性疾病。
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