TW202412747A - 經塗覆的腸溶軟膠囊 - Google Patents
經塗覆的腸溶軟膠囊 Download PDFInfo
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- TW202412747A TW202412747A TW112130295A TW112130295A TW202412747A TW 202412747 A TW202412747 A TW 202412747A TW 112130295 A TW112130295 A TW 112130295A TW 112130295 A TW112130295 A TW 112130295A TW 202412747 A TW202412747 A TW 202412747A
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- delayed
- soft capsule
- minutes
- release soft
- shell composition
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Abstract
本文揭示一種軟膠囊,其包含一填充材料、殼組合物及具有一腸溶性聚合物之一塗層,其中該塗層提供該膠囊之約1%至約10%之增重。該塗層改良腸溶性質之穩健性且最小化該軟膠囊之溶解期間之吸濕性。
Description
本發明係關於包含一填充組合物及一殼組合物之軟膠囊,其中該殼組合物包含果膠。本發明之軟膠囊進一步包含具有一腸溶性聚合物之一塗層。
軟膠囊,特定言之軟明膠膠囊(或軟膠囊),提供一種更容易由患者接受之劑型,因為膠囊易於吞嚥且不需要調味以掩蓋活性劑之任何令人不快之味道。藥物之軟膠囊囊封進一步提供提高藥劑之生物有效性之潛力。例如,一旦明膠外殼破裂,活性成分即可以液體形式迅立即釋放放。
已作出努力創造腸溶劑型。腸溶劑型經設計以保護劑型之內容物不受胃部狀況影響。例如,已開發其中在膠囊殼中添加習知腸溶性聚合物(即,酸不溶聚合物)之腸溶劑型。然而,習知腸溶性聚合物之添加可導致膠囊歸因於不充分密封而易於洩漏。此外,已發現在膠囊殼中添加腸溶性聚合物可引起殼吸收大量水,其削弱機械強度且可潛在地影響原料藥之化學穩定性。
因此,目前需要一種能夠最大化水分吸收且保持機械強度之軟膠囊。
本發明係針對包含一輕量腸溶性聚合物塗層之軟膠囊。本發明之軟膠囊包含一填充組合物及一殼組合物,其中該殼組合物包含果膠。軟膠囊進一步具有包含一腸溶性聚合物之一塗層。已發現在軟膠囊中包含一輕量塗層可改良腸溶性質之穩健性。亦發現使用一輕量塗層可在軟膠囊上實現一更均勻塗層以導致劑型之更一致效能。此外,塗層亦增加膠囊之pH臨限值,使得其可在消化系統中進一步輸送,諸如結腸輸送。
本發明亦針對一種製造腸溶軟膠囊之程序。
相關申請案之交叉参考
本申請案主張2022年8月12日申請之美國臨時專利申請案第63/397,558號之優先權,該案之全部內容以引用的方式併入本文中。
本發明藉由開發改良一軟膠囊之腸溶性質之腸溶口服劑型、特定言之腸溶軟膠囊來推進習知技術。本發明之腸溶軟膠囊不溶解於胃之一胃部環境中,而進一步溶解於消化系統中(例如,溶解於腸或結腸中)。此機制有益於輸送可引起胃刺激或對胃之酸性環境敏感之活性成分。
如本文所使用,術語「腸溶」用於係指一物質之抗溶解或抗解體性質使得在一胃部環境中不發生溶解或解體。例如,本文所描述之實施例包含溶解於生物、人工或仿真腸液中而非溶解於生物、人工或仿真胃液中之一腸溶殼組合物。本文所描述之實施例亦包含具有一腸溶性聚合物之一塗層。
如本文所使用,「藥物活性成分」係指可用於診斷、治癒、減輕、治療或預防一症狀之一藥物或化合物。術語「症狀」係指可藉由給藥於一有效量之一活性劑之一受試者而治療或預防之該等醫療症狀。可受益於腸溶軟膠囊之例示性非限制性症狀可包含(但不限於)含有乳酸菌、魚油膠囊、質子泵抑制劑、阿司匹林及類似產品之膠囊。
如本文所使用,術語「活性成分」係指意欲產生一治療、預防或其他預期效應之任何材料,無論是否為該目的獲得一政府機構之批准。相對於一特定藥劑之此術語包含藥物活性劑,及其所有藥學可接受鹽、溶劑化物及其結晶形式,其中鹽、溶劑化物及結晶形式具有藥物活性。
任何藥物活性成分均可用於本發明之目的,包含水溶性成分及難溶於水中之成分兩者。適合藥物活性成分包含(但不限於):鎮痛劑及抗炎劑、抗酸劑、驅蟲劑、抗心律失常劑、抗菌劑、抗凝血劑、抗抑鬱劑、抗糖尿病劑、抗腹瀉劑、抗癲癇劑、抗真菌劑、抗痛風劑、抗高血壓劑、抗瘧疾劑、抗偏頭痛劑、抗蕈毒鹼劑、抗腫瘤藥及免疫抑制劑、抗原生動物劑、抗風濕劑、抗甲狀腺劑、抗病毒劑、抗焦慮劑、鎮靜劑、催眠藥及精神抑制劑、β-阻斷劑、心臟強心劑、皮質類固醇、咳嗽抑制劑、細胞毒素、去充血劑、利尿劑、酶、抗帕金森劑、胃腸道劑、組織胺接受體拮抗劑、脂質調節劑、局部麻醉劑、神經肌肉劑、硝酸鹽及抗心絞痛劑、營養劑、阿片類鎮痛劑、口服疫苗、蛋白質、多肽及重組藥物、性激素及避孕藥、殺精劑、興奮劑及其等之組合。在某些實施例中,本發明亦針對利用本文所揭示之活性成分之任何者來治療可由該活性成分治療之一疾病或症狀之治療方法。
在一些實施例中,活性藥物成分可無限制地自由達比加群、屈奈達龍、替格瑞洛、依呱立酮、伊伐克弗特、米多斯托林、阿西馬多林、倍氯米松、阿普雷米司特、薩帕他濱、利西替尼、阿比特龍、維生素D類似物(例如鈣化二醇、骨化三醇、帕利西醇、多鐵鈣化醇)、COX-2抑制劑(例如塞來昔布、伐地昔布、羅非昔布)、他克莫司、睾固酮、魯比前列酮、藥學可接受之其鹽類及其等之組合組成之群組中選擇。
在一些實施例中,劑型中之脂質可無限制地選自由以下組成之群組:杏仁油、摩洛哥堅果油、鰐梨油、琉璃苣種子油、芥花油、腰果油、蓖麻油、氫化蓖麻油、可可脂、椰子油、菜籽油、玉米油、棉籽油、葡萄籽油、榛子油、大麻油、羥基化卵磷脂、卵磷脂、亞麻籽油、夏威夷果油、芒果油、馬尼拉油、蒙古堅果油、橄欖油、棕櫚仁油、棕櫚油、花生油、山核桃油、紫蘇油、松子油、開心果油、罌粟子油、南瓜籽油、米糠油、紅花子油、芝麻油、乳木果油、大豆油、葵花籽油、氫化植物油、核桃油、西瓜籽油。其他油及脂肪可包含(但不限於)魚油(omega-3)、磷蝦油、動物或植物脂肪,例如以其氫化形式之遊離脂肪酸及具有C8-、C10-、C12-、C14-、C16-、C18-、C20-及C22-脂肪酸之單、二、三甘油酯及其等之組合。
根據某些實施例,活性劑可包含降脂劑,包含(但不限於)斯他汀(例如洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、瑞舒伐他汀及匹伐他汀)、貝特類藥物(例如氯貝特、環丙貝特、貝紮貝特、非諾貝特及吉非纖維唑)、菸鹼酸、膽汁酸螯合劑、依折替米貝、洛米他特、植物甾醇及藥學上可接受之鹽、水合物、溶劑化物及其等之前體藥物、前述之任何者之混合物及其類似者。
適合類藥劑營養品活性劑可包含(但不限於):5-羥色氨酸、乙醯左旋肉鹼、α硫辛酸、α-酮戊二酸、蜂產品、鹽酸甜菜鹼、牛軟骨、咖啡因、鯨脂酸酯、木炭、殼聚糖、膽鹼、硫酸軟骨素、輔酶Q10、膠原蛋白、初乳、肌酸、氰鈷胺素(維生素812)、二甲氨基乙醇、胡馬酸、氧化鍺、腺產物、氨基葡萄糖HCI、硫酸氨基葡萄糖、羥丁酸甲酯、免疫球蛋白、乳酸、左旋肉鹼、肝臟產品、蘋果酸、無水麥芽糖、甘露糖(d-甘露糖)、甲基磺醯基甲烷、植物甾醇、吡啶酸、丙酮酸、紅麴提取物、S-腺苷蛋氨酸、酵母硒、鯊魚軟骨、可可鹼、硫酸氧釩及酵母。
適合營養補充活性劑可包含維生素、礦物質、纖維、脂肪酸、氨基酸、草藥補充劑或其等之一組合。
適合維生素活性劑可包含(但不限於)以下:抗壞血酸(維生素C)、B族維生素、生物素、脂溶性維生素、葉酸、羥檸檬酸、肌醇、礦物抗壞血酸、混合生育酚、菸鹼酸(維生素B3)、山梨酸、對氨基苯甲酸、泛酸鹽、泛酸酸(維生素B5)、鹽酸吡哆醇(維生素B6)、核黃素(維生素B2)、合成維生素、硫胺素(維生素B1)、生育三烯醇、維生素A、維生素D、維生素E、維生素F、維生素K、維生素油及油溶性維生素。
適合草藥補充活性劑可包含(但不限於)以下物質:山金車、越桔、黑升麻、貓爪、洋甘菊、紫錐菊、月見草油、胡蘆巴、亞麻籽、小白菊、大蒜、薑根、銀杏葉、人參、黃花、山楂、卡瓦卡瓦、甘草、乳薊、車前草、山楂、番瀉草、大豆、聖若望草、鋸棕櫚、薑黃、纈草。
礦物活性劑可包含(但不限於)以下:硼、鈣、螯合礦物、氯化物、鉻、包膜礦物、鈷、銅、白雲石、碘、鐵、鎂、錳、礦物預混料、礦產品、鉬、磷、鉀、硒、鈉、釩、蘋果酸、丙酮酸、鋅及其他礦物。
其他可能活性劑之實例包含(但不限於)抗組織胺(例如雷尼替丁、氯茶鹼二苯安明、苯海拉明、氯菲安明及順丁烯二酸右撲爾敏)、非類固醇型消炎劑(例如阿司匹林、塞來昔布、Cox-2抑制劑、雙氯芬酸,苯惡洛芬、氟白普洛芬、非諾洛芬、氟布芬、吲哚洛芬、吡洛芬、卡洛芬、奧沙普秦、普拉洛芬、咪洛芬、三氧洛芬、舒洛芬、氨布洛芬、氟洛芬、布氯酸、吲哚美辛、舒林酸、佐美匹拉克、硫平酸、齊多美辛、阿西美辛、芬紮克、环氯茚酸、奧昔平酸、美氯芬酸、氟芬尼酸、尼氟酸、托芬那酸、二氟利沙、氟苯沙酸、吡羅西康、蘇多西康、異西康、醋氯芬酸、阿洛普令、阿唑丙酮、苯丙酸、溴芬酸、卡洛芬、水楊酸膽鹼鎂、二氟尼松、依託度酸、依託昔布、法斯拉胺、芬布芬、非諾洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮洛酸、洛索洛芬、美洛昔康、甲芬那酸、安乃近、水楊酸甲酯、水楊酸鎂、那布美酮、萘普生、尼美舒利、羟基保泰松、帕瑞昔布、丁二苯吡唑二酮、水楊酸鹽、舒林酸、苯磺唑酮、替诺昔康、噻洛芬酸、妥美丁,其藥學上可接受之鹽及其等之混合物)及乙醯胺酚、止吐藥(例如甲氧氯普胺、溴化甲基納曲酮)、抗癲癇藥(例如苯醚、甲丙酸酯及硝西泮)、血管擴張劑(例如硝苯地平、罌粟鹼、地爾硫卓及尼卡地平)、止咳藥及祛痰藥(例如磷酸可待因)、抗酸藥、抗痙攣藥(例如阿托品、東莨菪鹼)、抗糖尿病藥(例如胰島素)、利尿劑(例如乙丙酸)、苯且氟噻嗪)、抗低血壓藥(例如普萘洛爾、可樂定)、抗高血壓藥(例如可樂定、甲基多巴)、支氣管擴張劑(例如沙丁胺醇)、類固醇(例如氫化可體松、曲安奈德、強體松)、抗生素(例如,四環素)、抗痔瘡藥、催眠藥、精神藥物、止瀉藥、黏液解藥、鎮靜劑、減充血藥(例如假麻黃鹼)、瀉藥、維生素、興奮劑(包含食欲抑制劑,諸如苯丙醇胺)及大麻素;以及藥學上可接受之鹽、水合物、溶劑化物及其前體藥物。
活性劑亦可為苯二氮平類藥物、巴比妥酸鹽、興奮劑或其等之混合物。術語「苯二氮平類藥物」係指苯二氮平類藥物及能夠抑制中樞神經系統之苯二氮平類藥物之衍生物。苯二氮平類藥物包含(但不限於)阿普唑侖、溴西泮、氯二氮環氧化物、氯拉西泮、地西泮、艾司唑侖、氟西泮、哈拉西泮、酮唑侖、蘿拉西泮、硝西泮、惡西泮、普拉西泮、喹西泮、替馬西泮、三唑侖、派醋甲酯及藥學上可接受之鹽、水合物、溶劑化物、前體藥物及其等之混合物。可用作為活性劑之苯二氮平類藥物拮抗劑包含(但不限於)福瑪珍及藥學上可接受之鹽、水合物、溶劑化物及其等之混合物。
術語「巴比妥酸鹽」係指自巴比妥酸(2, 4, 6,-三氧雜六氫化嘧啶)衍生之鎮靜催眠藥物。巴比妥酸鹽包含(但不限於)阿莫巴比妥、阿巴比妥、仲丁比妥、丁巴比妥、甲氧己酮、甲氧巴比妥、戊巴比妥、苯巴比妥、西巴比妥及藥學上可接受之鹽、水合物、溶劑化物、前體藥物及其等之混合物。可用作為活性劑之巴比妥酸鹽拮抗劑包含(但不限於)安非他明及藥學上可接受之鹽、水合物、溶劑化物及其混合物。
術語「興奮劑」包含(但不限於)安非他命,諸如右旋苯丙胺樹脂複合物、右旋苯丙胺、甲基苯丙胺、派醋甲酯以及藥學上可接受之鹽、水合物、溶劑化物及其等之混合物。可用作為活性劑之興奮劑拮抗劑包含(但不限於)苯二氮平類藥物,及藥學上可接受之鹽、水合物、溶劑化物及其等之混合物。
根據本發明之劑型包含各種活性劑及其藥學上可接受之鹽。藥學上可接受之鹽包含(但不限於)無機酸鹽,諸如鹽酸、氫溴化物、硫酸鹽、磷酸鹽等;有機酸鹽,諸如甲酸鹽、乙酸鹽、三氟乙酸鹽、馬來酸鹽、酒石酸鹽等;磺酸鹽,如甲磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽等;氨基酸鹽如精氨酸鹽、天冬氨酸鹽、谷氨酸鹽及其類似者,及金屬鹽如鈉鹽、鉀鹽、銫鹽等;鹼土金屬如鈣鹽、鎂鹽等;有機胺鹽如三乙胺鹽、吡啶鹽、甲吡啶鹽、乙醇胺鹽、三乙醇胺鹽、雙環己胺鹽、N,N′-二苄基乙二胺及其類似者。
如本文所使用,術語「治療有效」及一「有效量」係指產生一所要治療結果所需之活性劑之量或其施用之速率。
如本文所使用,「殼」或「殼組合物」係指囊封一填充材料之一軟膠囊之殼。
如本文所使用,「習知腸溶性聚合物」係指(但不限於)丙烯酸及甲基丙烯酸聚合物,其可在商品名EUDRAGIT®及其他習知酸不溶性聚合物下獲得,例如丙烯酸甲酯-甲基丙烯酸共聚物。其他習知酸不溶性聚合物包含(但不限於)丙烯酸聚合物、甲基丙烯酸聚合物、醋酸琥珀酸纖維素、鄰苯二甲酸乙酸纖維素、醋酸丁酸纖維素、羥丙基甲基纖維素鄰苯二甲酸酯、羥丙基甲基纖維素乙酸琥珀酸酯(醋酸琥珀酸超甲纖維素)、聚乙酸乙烯酯鄰苯二甲酸酯(PVAP)、藻膠酸鹽(諸如海藻酸鈉及褐藻酸鉀)、硬脂酸及蟲膠。在一些實施例中,本發明之腸溶殼組合物不包含一酸不溶性聚合物。換言之,腸溶殼組合物及腸溶軟膠囊「不含或實質上不含習知腸溶性聚合物」。
如本文所使用,「游離或實質上游離」係指包括該組分之小於約1重量%、小於約0.5重量%、小於約0.25重量%、小於約0.1重量%、小於約0.05%重量%、小於約0.01%重量%或0重量%之一組合物。
在整個說明書及請求項中,所有參考重量%均係指相對於整個組合物之重量之組分之重量且亦可指定為w/w。
如本文所使用,「填充材料」或「填充」係指由腸溶膠囊殼囊封且含有至少一種藥物活性成分之組合物。
如本文所使用,「延遲釋放」係指在通過胃之後釋放活性劑。
如本文所使用,「約」係指在±10%之一變動內之任何值,使得「約10」將包含自9至11。如本文所使用,除非另有指定,否則「一」或「該」係指一或多個。因此,例如,參考「一種賦形劑」包含一單一賦形劑以及兩種或更多種不同賦形劑之一混合物及其類似者。
除非本文另有指示,否則本文中之值之範圍之敘述僅意欲充當個別參考落在該範圍內之各單獨值之一簡略方法,且各單獨值宛如其在本文中個別敘述般併入說明書中。除非本文另有指示或與上下文明顯相矛盾,否則本文所描述之所有方法可以任何適合順序執行。
使用本文所提供之任何及所有實例,或例示性語言(例如,「諸如」)僅意欲說明某些材料及方法且不對範疇施加限制。說明書中之任何語言均不應被解釋為指示任何非主張元件對於所揭示之材料及方法之實踐必不可少。
根據一個實施例,一延遲釋放軟膠囊包含具有一活性劑之填充材料、包含果膠之一殼組合物及包含一腸溶性聚合物之一塗層。
在膠囊之一些實施例中,軟膠囊之塗層可提供膠囊之約0.1%至約10%、約0.5%至約5%、約1%至約10%、約1%至約5%、約1%至約3%或約2%至約5%之一增重。
適合填充材料包括至少一種藥物活性成分且可根據已知方法製備。除至少一種藥學活性成分之外,適合填充材料可包括額外填充組分,諸如調味劑、甜味劑、著色劑及填料或其他藥學上可接受之賦形劑或添加劑,諸如合成染料及礦物氧化物。適合量之藥物活性成分及藥學上可接受之賦形劑可由一般技術者容易地判定。
在一些實施方案中,殼組合物中之果膠可為一低甲氧基果膠。在一實施例中,低甲氧基果膠可為LM果膠(P-25)、LM果膠(445C)、LM果膠(100C)或其等之一組合。在另一實施例中,果膠可為醯胺化果膠或非醯胺化果膠。果膠之添加促成劑型之腸溶本質。然而,劑型中之過多果膠可降低軟膠囊之凝膠強度,其可繼而對軟膠囊之密封性產生不利影響。因此,可將果膠以足夠高之一濃度添加至劑型中以形成一腸溶劑型同時足夠低以減輕凝膠強度之降低。在一實施例中,基於殼組合物之總重量,腸溶殼組合物中之果膠之量係約2重量%至約30重量%,約2重量%至約25重量%,約2重量%至約20重量%,自約3重量%至約15重量%,自約3重量%至約5.5重量%、自約5重量%至約10重量%、約2.5重量%至約20重量%、約5重量%至約18重量%、7.5重量%至約15重量%或約10重量%至約12重量%。併入殼組合物中之果膠之酯化程度可低於約50%或可在自約10%至約50%、自約20%至約40%或自約25%至約35%之範圍內。
在膠囊之一些實施例中,殼組合物可進一步包含一增塑劑。增塑劑包括丙三醇、甘油、山梨醇、山梨醇山梨糖醇溶液、甘油三乙酸酯、聚山梨醇酯或其等之組合。在一個實施例中,增塑劑可包含甘油及山梨醇山梨糖醇溶液。在一些實施例中,聚山梨醇酯可包含聚山梨醇酯20 (亦稱為Tween 20)、聚山梨酯80(亦稱為Tween 80)或其等之組合。其他適合增塑劑可包含(但不限於)糖醇增塑劑,諸如異麥芽糖醇、麥芽糖醇、木糖醇、赤藻糖醇、甘露糖醇、甘露糖醇、季戊四糖醇或甘露糖醇;或多元醇增塑劑,如二甘油、乙二醇、二甘醇、三甘醇、四甘醇、二丙二醇、高達10,000 MW之聚乙二醇、新戊二醇、丙二醇、1,3-丙二醇、2-甲基-1,3-丙二醇、三甲基丙烷、聚醚多元醇、乙醇胺;及其等之混合物。其他例示性增塑劑亦可包含(但不限於)低分子量聚合物、低聚物、共聚物、油、小有機分子、具有脂肪羥基之低分子量多元醇、酯型增塑劑、乙二醇醚、聚(丙二醇)、多嵌段聚合物、單嵌段聚合物、檸檬酸酯型增塑劑及三乙酸素。此類增塑劑可包括1,2-丁二醇、2,3-丁二醇、苯乙烯乙二醇、單丙二醇單異丙醚、丙二醇單乙醚、乙二醇單乙醚、二乙二醇單乙醚、乳酸山梨醇酯、乳酸乙酯、乳酸丁酯、乙醇酸乙酯、癸二酸二丁酯、乙醯三乙酸檸檬酸酯、檸檬酸三乙酯、單硬脂酸甘油、乙醯三乙基檸檬酸酯、乙醯檸檬酸三丁酯及乙醇酸烯丙酯及其等之混合物。
在一些實施例中,基於殼組合物之總重量,增塑劑之量可以約5重量%至約75重量%、約2重量%至約40重量%、約2重量%至約15重量%、約4重量%至約12重量%、約5重量%至約60重量%、約10重量%至約55重量%、約15重量%至約50重量%、約20重量%至約45重量%或約25重量%至約35重量%之量。
在一些實施例中,增塑劑可為甘油。基於殼組合物之總重量,甘油可以約5重量%至約30重量%、約8重量%至約26重量%、約12重量%至約22重量%或約15重量%至約22重量%之量包含。
在一些實施例中,增塑劑可為山梨醇山梨糖醇溶液。基於殼組合物之總重量,山梨醇山梨糖醇溶液可以約2重量%至約40重量%、約5重量%至約36重量%、約8重量%至約30重量%、約10重量%至約27重量%或約15重量%至約22重量%之量包含。
在軟膠囊之一些實施例中,殼組合物可進一步包含明膠。明膠可包含單獨或組合使用之A型明膠、B型明膠、一阿膠及/或一骨膠。在一個實施例中,明膠係一250華明膠。在另一實施例中,僅存在一種明膠。在另一實施例中,明膠係至少兩種類型之明膠之一組合。在一實施例中,基於殼組合物之總重量,腸溶殼組合物中之明膠之量係約10重量%至約80重量%、約15重量%至約60重量%、約20重量%至約55重量%、約25重量%至約50重量%、約30重量%至約45重量%或約35重量%至約40重量%。
在一些實施例中,軟膠囊之殼組合物可包含一纖維素衍生物,諸如羥丙基甲基纖維素(HPMC)。在一實施例中,殼組合物中之纖維素衍生物(例如,HPMC)之量係約0.15重量%至約4.0%重量%,更佳地係約0.20重量%至約2.0重量%,且最佳地係約0.25重量%至約1.4重量%。在一些實施例中,腸膠囊殼組合物可包括HPMC、甲基纖維素(MC)、羥丙基纖維素(HPC)或其等之組合。可將纖維素衍生物添加至殼組合物中以減輕凝膠強度之潛在降低。腸溶殼組合物中之纖維素衍生物之濃度可以有效量以改良凝膠強度但不高至干擾密封之程度。
在一些實施例中,軟膠囊之殼組合物亦可包含結蘭膠、葡萄糖、水或其等之一組合。在一些實施例中,基於殼組合物之總重量,葡萄糖之量可為約0.001重量%至約10重量%、約0.001重量%至約5重量%、約0.01重量%至約4.5重量%、約0.01重量%至約4重量%、約0.1重量%至約3重量%或約1重量%至約2.5重量%。
在一實施例中,軟膠囊之殼組合物可視情況包括額外劑,諸如著色劑、調味劑、甜味劑、填料、抗氧化劑、稀釋劑、pH改質劑或其他藥學上可接受之賦形劑或添加劑(諸如合成染料及礦物氧化物)。
例示性適合著色劑可包含(但不限於)諸如(例如)白色、黑色、黃色、藍色、綠色、粉色、紅色、橙色、紫色、靛藍及棕色之顏色。在特定實施例中,劑型之顏色可指示含於其中之內容物(例如,一或多種活性成分)。
例示性適合調味劑可包含(但不限於)藉由通常使用諸如乙醇或水之一溶劑提取一原料(例如動物或植物材料)之一部分而獲得之「風味提取物」;藉由自花、果、根等或自整個植物提取精油而獲得之天然香精。
可在劑型中之其他例示性調味劑可包含(但不限於)口氣清新化合物,諸如薄荷醇、綠薄荷及肉桂、咖啡豆、其他風味或香水,諸如水果風味(例如櫻桃、橘子、葡萄等),尤其係用於口腔衛生之風味或香水,以及用於牙齒及口腔清潔之活性物質,諸如季銨鹼。可使用諸如酒石酸、檸檬酸、香蘭素之風味增強劑來增強風味之效應。
例示性甜味劑可包含(但不限於)一或多種人工甜味劑、一或多種天然甜味劑或其等之一組合。人工甜味劑包含(例如)安賽蜜及其各種鹽,諸如鉀鹽(如Sunett®)、阿利甜、阿斯巴甜(如NutraSweet®及Equal®)、阿斯巴甜-安賽蜜鹽(如Twinsweet®)、新橘皮苷二氫查酮、柚苷二氫查酮、二氫查耳酮化合物、紐甜、環己基氨基磺酸鈉、糖精及其各種鹽,如鈉鹽(可作為Sweet'N Low®)、甜葉菊、氯代蔗糖衍生物,如三氯蔗糖(可作為Kaltame®及Splenda®使用)及甜菊苷。天然甜味劑包含(例如)葡萄糖、葡萄糖、轉化糖、果糖、蔗糖、甘草酸;甘草酸一銨(商品名MagnaSweet®);甜菊(甜菊苷)、天然強化甜味劑,諸如羅漢果、多元醇,諸如山梨醇、甘露醇、木糖醇、赤藻糖醇及其類似者。
在一些實施例中,塗層之腸溶性聚合物可為該腸溶性聚合物係丙烯酸聚合物、甲基丙烯酸聚合物、醋酸琥珀酸纖維素、鄰苯二甲酸乙酸纖維素、醋酸丁酸纖維素、羥丙基甲基纖維素鄰苯二甲酸酯、羥丙基甲基纖維素乙酸琥珀酸酯(醋酸琥珀酸超甲纖維素)、聚乙酸乙烯酯鄰苯二甲酸酯(PVAP)、藻膠酸鹽(諸如海藻酸鈉、褐藻酸鉀)、硬脂酸、蟲膠或其等之一組合。在一些實施例中,腸溶性聚合物可為丙烯酸聚合物、甲基丙烯酸聚合物或其等之一組合。在一些實施例中,腸溶性聚合物可為基於丙烯酸甲酯、甲基丙烯酸甲酯及甲基丙烯酸之一陰離子共聚物之一水性分散液。
在延遲釋放軟膠囊之一些實施例中,塗層可進一步包含一增塑劑。增塑劑可為甘油酯、檸檬酸三乙酯或其等之一組合。
在一些實施例中,基於塗層之總重量,塗層中之腸溶性聚合物以約10重量%至約60重量%、約15重量%至約50重量%、約20重量%至約40重量%、約25重量%至約35重量%或約30重量%之量。在一些實施例中,基於塗層之總重量,塗層中之增塑劑之量可以約2重量%至約10重量%、約3重量%至約9重量%、約4重量%至約8重量%或約5重量%之量。
在一些實施例中,軟膠囊可具有每劑量約100 mg至約1000 mg、約150 mg至約900 mg、約200 mg至約800 mg、約300 mg至約700 mg、約350 mg至約600 mg或約400 mg至約500 mg之omega-3之一劑量。
在一些實施例中,可在約37°C±2°C之一1000 mL燒杯中在一籃架總成NT-40H模型設備中執行一崩解試驗中測試延遲釋放軟膠囊(下文更詳細描述)。腸溶軟膠囊根據此實施例可在酸性介質中保持完整約一個小時、約兩個小時,約三個小時、約四個小時、約五個小時或至少1小時、至少約2小時、至少約3小時、至少約4小時、至少約5小時或至少約6小時或約1小時至約6小時、約1小時至約4小時或約1小時至約2小時。在一些實施例中,軟膠囊在腸液中可在約30分鐘或更短、在約20分鐘或更短、在約10分鐘或更短、在約5分鐘或更短時間內崩解。在某些實施例中,對於一軟膠囊,在1個月、3個月、6個月、12個月、18個月、22個月或24個月內,在25°C/60% RH、30°C/65% RH或40°C/75% RH之加速穩定性條件下,亦可實現上述結果。
本文中所執行之崩解測試與歐洲藥典及美國藥典之腸溶塗覆製劑相一致。用於崩解測試之設備係NT-40H型(由Toyama Sangyo Co. Ltd.製造)。設備係一籃架總成,一1000 mL低形燒杯,高度為138 mm至160 mm且具有97 mm至115 mm之一內徑,用於浸泡流體,用於在35°C與39°C之間加熱流體之一恒溫配置,及用於在不小於53 mm且不大於57 mm之一距離內以29至32週期每分鐘之一恒定頻率提高及降低浸泡流體中之籃之裝置。容器中之流體之體積使得在向上行程之最高點,金屬絲網保持在流體表面以下至少15 mm,且在向下行程時自容器底部下降至不小於25 mm。在任何時候,籃架組件之頂部均不應被淹沒。向上行程所需之時間與向下行程所需之時間相等,且行程方向中之變化係一平滑過渡,而非一突然運動逆轉。籃架總成沿其軸線垂直移動。不存在明顯水平運動或軸線自垂直之移動。
本文所揭示之崩解測試在約37°C±2°C下以1000 mL之一流體體積執行。崩解測試流體1 (本文亦指稱「人工胃液」)係具有1.2之一pH之2 g/L氯化鈉-鹽酸溶液。崩解測試流體2 (本文亦指稱「人工腸液」)係具有6.8之一pH之0.2 mol/L磷酸二氫鉀-0.2 mol/L氫氧化鈉溶液。
使用第一流體執行行崩解測試約120分鐘,藉由在籃子之六個管之各者中放置一個單元、將籃子(及因此單元)浸入第一測試流體中且將籃子自流體抬起以觀察單元是否崩解。崩解界定為單元破裂或腸溶殼組合物裂斷或破裂之狀態。若6個單元均未崩解,則滿足該測試。在選定持續時間內,使用第二崩解測試流體執行一類似測試。
在一些實施例中,崩解測試可執行約150分鐘、約120分鐘、約105分鐘、約90分鐘、約75分鐘、約60分鐘、約45分鐘、約30分鐘、約15分鐘、約10分鐘或約5分鐘。
在某些實施例中,可對本發明之軟膠囊執行一兩階段崩解測試。在兩階段崩解測試下,軟膠囊經受一酸性介質(pH = 1.2)中其後接著一緩衝介質(pH = 6.8)。當曝露於酸性及緩衝介質兩者時,軟膠囊可保持完整至少1小時、至少約2小時、至少約3小時、至少約4小時、至少約5小時、至少約6小時或約1小時至約6小時、約1小時至約5小時、約1小時至約4小時、約1小時至約3小時或約1小時至約2小時。在某些實施例中,對於一軟膠囊,在1個月、3個月、6個月、12個月、18個月、22個月或24個月內,在25°C/60% RH、30°C/65% RH或40°C/75% RH之加速儲存條件下,亦可實現上述結果。在某些實施例中,在本文所揭示之加速儲存條件之任何者之後,在1小時、4小時或8小時內,完整時間自時間0改變不超過20%、不超過10%或不超過5%。
在某些實施例中,可對本發明之軟膠囊執行一兩階段崩解測試。在兩階段崩解測試下,軟膠囊經受一酸性介質(pH = 1.2)其後接著一緩衝介質(pH = 7.5)中。當曝露於酸性及緩衝介質兩者時,軟膠囊可保持完整至少1小時、至少約2小時、至少約3小時、至少約4小時、至少約5小時、至少約6小時或約1小時至約6小時、約1小時至約5小時、約1小時至約4小時、約1小時至約3小時或約1小時至約2小時。在某些實施例中,對於一軟膠囊,在1個月、3個月、6個月、12個月、18個月、22個月或24個月內,在25°C/60% RH、30°C/65% RH或40°C/75% RH之加速儲存條件下,亦可實現上述結果。在某些實施例中,在本文所揭示之加速儲存條件之任何者之後,在1小時、4小時或8小時內,完整時間自時間0改變不超過20%、不超過10%或不超過5%。
在一些實施例中,崩解測試可使用具有7.5之一pH之一緩衝液執行。在此等條件下,軟膠囊可在約30分鐘或更短、約25分鐘或更短、約20分鐘或更短、約15分鐘、約10分鐘或更短或約5分鐘或更短時間內崩解。在一些實施例中,可使用具有7.5之一pH之一緩衝液且在5°C/60% RH、30°C/65% RH或40°C/75% RH之加速儲存條件下在1個月、3個月、6個月、12個月、18個月、22個月或24個月內執行崩解。在此等條件下,軟膠囊可在約45分鐘或更短、約40分鐘或更短、約35分鐘或更短、約30分鐘或更短、約25分鐘或更短、約20分鐘或更短、約15分鐘或更短、約10分鐘或更短或約5分鐘或更短時間內崩解。
在一些實施例中,藉由將軟膠囊曝露於一含水介質,可在一吸濕測試下對軟膠囊執行測試。在軟膠囊曝露5分鐘、10分鐘、15分鐘、30分鐘、45分鐘、60分鐘、120分鐘之後,軟膠囊可具有小於2%、小於1.5%、小於1%、小於0.8%、小於0.6%、小於0.5%、小於0.4%、小於0.3%、小於0.2%、小於0.1%或小於0.05%之一吸濕率。在某些實施例中,對於一軟膠囊,在1個月、3個月、6個月、12個月、18個月、22個月或24個月內,在25°C/60% RH、30°C/65% RH或40°C/75% RH之加速儲存條件下,亦可實現上述結果。
填充材料之囊封可以任何習知方式完成。作為一實例,可使用一轉動螺模囊封。
根據一實施例,一腸溶軟膠囊由包括以下步驟之程序製備:製備填充材料,該填充材料包含一活性劑;將該填充材料囊封於殼組合物中,其中該殼組合物包含果膠,且因此形成一軟膠囊。接著,將該膠囊塗覆包括一腸溶性聚合物之一塗層組合物,使得該膠囊具有約1%至約10%之增重。
製備軟膠囊之方法包含製備殼組合物,其中殼組合物可包含果膠、增塑劑、明膠、結蘭膠、葡萄糖、水或其等之一組合,如本文所描述。
接著,藉由製備包含一腸溶性聚合物、一增塑劑、水或其等之一組合之一塗層懸浮液來製備塗層組合物。在某些實施例中,腸溶性聚合物可包含基於丙烯酸甲酯之一陰離子共聚物。
在某些實施例中,本發明係針對下列條目列表之一或多者:
1.一種延遲釋放軟膠囊,其可包含:一填充材料,其中該填充材料包括一活性劑;一殼組合物,其中該殼組合物包括果膠;及一塗層,其包括一腸溶性聚合物。
2.如條目1之延遲釋放軟膠囊,其中該塗層提供該膠囊之約1%至約10重量%,或約2%至約5%之一增重。
3.如條目1或2之延遲釋放軟膠囊,其中該殼組合物進一步包括一增塑劑。
4.如條目3之延遲釋放軟膠囊,其中該增塑劑包括丙三醇、甘油、山梨醇、山梨醇山梨糖醇溶液、甘油三乙酸酯、聚山梨醇酯或其等之組合。
5.如條目3至4中任一項之延遲釋放軟膠囊,其中該增塑劑包括甘油及山梨醇山梨糖醇溶液。
6.如條目4之延遲釋放軟膠囊,其中該聚山梨醇酯包括Tween 20、Tween 80或其等之組合。
7.如前述條目中任一項之延遲釋放軟膠囊,其中該殼組合物進一步包括明膠。
8.如條目7之延遲釋放軟膠囊,其中該明膠選自由A型明膠、B型明膠及其等之混合物組成之群組。
9.如條目7之延遲釋放軟膠囊,其中該明膠選自由魚膠、阿膠、骨膠及其等之混合物組成之群組。
10.如前述條目中任一項之延遲釋放軟膠囊,其中該殼組合物進一步包括結蘭膠。
11.如前述條目中任一項之延遲釋放軟膠囊,其中該殼組合物進一步包括葡萄糖。
12.如前述條目中任一項之延遲釋放軟膠囊,其中該殼組合物進一步包括水。
13.如前述條目中任一項之延遲釋放軟膠囊,其中該果膠係一低甲氧基果膠。
14.如前述條目中任一項之延遲釋放軟膠囊,其中該腸溶性聚合物係丙烯酸聚合物、甲基丙烯酸聚合物、醋酸琥珀酸纖維素、鄰苯二甲酸乙酸纖維素、醋酸丁酸纖維素、羥丙基甲基纖維素鄰苯二甲酸酯、羥丙基甲基纖維素乙酸琥珀酸酯(醋酸琥珀酸超甲纖維素)、聚乙酸乙烯酯鄰苯二甲酸酯(PVAP)、藻膠酸鹽、硬脂酸、蟲膠或其等之一組合。
15.如條目14之延遲釋放軟膠囊,其中該藻膠酸鹽係海藻酸鈉、褐藻酸鉀或其等之一組合。
16.如條目14之延遲釋放軟膠囊,其中該腸溶性聚合物係丙烯酸聚合物、甲基丙烯酸聚合物或其等之一組合。
17.如前述條目中任一項之延遲釋放軟膠囊,其中該塗層進一步包括一增塑劑。
18.如條目17項之延遲釋放軟膠囊,其中該增塑劑包括甘油酯、檸檬酸三乙酯或其等之一組合。
19.如前述條目中任一項之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該果膠以約2.5重量%至約20重量%、5重量%至約18重量%、7.5重量%至約15重量%或約10重量%至約12重量%之量。
20.如條目7至9中任一項之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該明膠以約15重量%至約60重量%、約20重量%至約55重量%、約25重量%至約50重量%、約30重量%至約45重量%或約35重量%至約40重量%之量。
21.如條目11之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該葡萄糖以約0.001重量%至約5重量%、約0.01重量%至約4.5重量%、約0.01重量%至約4重量%、約0.1重量%至約3重量%或約1重量%至約2.5重量%之量。
22.如條目4至6中任一項之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該增塑劑以約5重量%至約60重量%、約10重量%至約55重量%、約15重量%至約50重量%、約20重量%至約45重量%或約25重量%至約35重量%之量。
23.如前述條目中任一項之延遲釋放軟膠囊,其中基於該塗層之總重量,該腸溶性聚合物以約20重量%至約40重量%、約25重量%至約35重量%或約30重量%之量。
24.如條目17之延遲釋放軟膠囊,其中基於該塗層之總重量,該增塑劑以約2重量%至約10重量%、約3重量%至約9重量%、約4重量%至約8重量%或約5重量%之量。
25.如前述條目中任一項之延遲釋放軟膠囊,其中當使用一USP設備II量測時,該殼組合物在15分鐘、30分鐘、45分鐘或60分鐘時在1.2之一pH值下不破裂,其中攪拌槳在50 RPM下,750 ml 0.1N HCL酸性介質使用磷酸鹽緩衝劑調整至pH。
26.如前述條目中任一項之延遲釋放軟膠囊,其中當使用一USP設備II量測時,該殼組合物在15分鐘、30分鐘、45分鐘或60分鐘時在6與7之間的一pH下不破裂,其中攪拌槳在50 RPM下,750 ml 0.1N HCL酸性介質使用磷酸鹽緩衝劑調整至pH。
27.一種製備如前述條目中任一項之延遲釋放軟膠囊之程序,其包含:
製備包括一活性劑之一填充材料;
使用包括果膠之一殼組合物囊封該填充材料以形成一膠囊;及
使用包括一腸溶性聚合物之一塗層組合物塗覆該膠囊。
實例
現將藉由參考以下實例來展現本發明之具體實施例。應理解,此等實例僅以繪示本發明之方式而揭示且不應以任何方式來限制本發明之範疇。
一延遲釋放軟膠囊之塗層
根據本發明製造一批經塗覆的延遲釋放軟膠囊。一批1000 mg之延遲釋放軟膠囊用於塗覆實驗。填充材料為含有300 mg Omega-3之魚油精製。延遲釋放軟膠囊之殼組合物如表1概述。
表1. 軟殼組合物
條目描述 | % ( 重量 %) |
果膠 | 5.0 – 18.0 |
明膠 | 25.0 – 48.0 |
葡萄糖 | 0.01 – 2.20 |
甘油 | 8.0 – 22.0 |
山梨醇山梨糖醇溶液 | 4.0 – 36.0 |
純淨水 | 5.0 – 18.0 |
總計 | 100.00 |
製備一種包含EUDRAGIT ® FS30D之塗層組合物,一種基於丙烯酸甲酯、甲基丙烯酸甲酯及甲基丙烯酸之一陰離子共聚物之一水性懸浮液,用於塗層聚合物。塗層組合物亦包含作為一增塑劑之PlasACRYL® T20,其中PlasACRYL ® T20被理解為包含具有一抗黏著劑、一增塑劑及一穩定劑之一20%含水懸浮液。塗層組合物製備為一塗層懸浮液,其概述於表2中。
表2. 塗層懸浮液組合物
條目描述 | 塗層懸浮液 ( 重量 %) |
EUDRAGIT ® FS30D | 30.305 |
PlasACRYL® T20 | 4.545 |
純淨水, USP, EP | 65.000 |
總計 | 100.00 |
塗覆延遲釋放之魚油軟膠囊1000 mg以實現2%之增重。經塗覆的軟膠囊經受各種測試以評估其腸溶性質之穩健性。經塗覆的膠囊亦封裝為感應密封HDPE瓶中且根據穩定性協定ISS-21-047在加速條件下放置於發展穩定性上。
比較經塗覆的立即釋放軟膠囊
製造一批經塗覆的魚油軟膠囊進行比較。一批立即釋放之魚油軟膠囊1000 mg用於塗覆試驗。填充材料係含有300mg Omega-3之魚油。立即釋放之軟膠囊之殼配方概述於表3中。
表3. 軟凝膠殼配方
條目描述 | % ( 重量 %) |
明膠 | 28.0 – 56.0 |
甘油 | 12.0 – 35.0 |
純淨水 | 5.0 – 18.0 |
總計 | 100.00 |
將立即釋放之魚油軟膠囊1000 mg使用表2中所描述之相同經塗覆的懸浮液塗覆以分別實現2% (子批21SC-12A)及3.6% (子批21SC-12B)之增重效應。經塗覆的膠囊經受各種測試以評估其腸溶性之穩健性。經塗覆的立即釋放膠囊亦封裝至感應密封HDPE瓶中且根據穩定性協定ISS-22-027及ISS-22-028在加速條件下放置於發展穩定性上。
崩解及破裂測試
經塗覆的魚油延遲釋放軟膠囊1000 mg及經塗覆的魚油立即釋放軟膠囊1000 mg經受兩階段崩解測試及兩階段破裂測試。
崩解測試使用一崩解設備B, ERWEKA, Model: ZT 224執行。在酸性階段中,使用0.1N HCl;在緩衝階段中,分別使用pH 6.8及pH 7.5磷酸鹽緩衝溶液。
兩階段破裂測試使用一溶解設備II, Distek, Model: 2500執行。在酸性階段中,使用具有酶(胃蛋白酶) pH 1.6之生物相關介質FaSSGF;在緩衝階段中,使用酶(胰酶) pH 7.5之磷酸鹽緩衝溶液。
經塗覆的延遲釋放魚油軟膠囊1000 mg、經塗覆的立即釋放魚油軟膠囊1000 mg及未經塗覆的延遲釋放魚油軟膠囊1000 mg亦經受吸濕測試,其中比較各種時間曝露之後的膠囊增重。本研究中利用之浸漬介質係用於崩解測試中之相同酸性介質0.1N HCl。
膠囊崩解測試結果
表4概述未經塗覆及增重2%經塗覆的延遲釋放魚油軟膠囊之爆裂強度資料。在塗覆步驟之前及之後的爆裂強度資料相似。因此,塗層似乎不影響延遲釋放軟膠囊之物理穩健性。
表4. 經塗覆的延遲釋放魚油軟膠囊1000 mg之爆裂強度
樣本 | 爆裂強度 (kg) | 行進距離 (mm) |
批4701394 (未塗覆) | 99.4 | 4.91 |
21SC-09 A (增重2%) | 110.7 | 4.74 |
表5概述時間0處(即,在塗覆軟膠囊之後)之兩階段崩解之測試結果。
表5. 經塗覆的延遲釋放軟膠囊1000 mg在T0處之崩解結果
樣本 | 崩解時間 | 結果 | ||||||
21SC-09A | 容器 | 1 | 2 | 3 | A | B | C | ( 分鐘 ) |
酸 (pH 1.2) 2 小時 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | |
緩衝液(pH 6.8) 1 小時 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | |
緩衝液(pH 7.5) | 24分鐘 | 24分鐘 | 22分鐘 | 26分鐘 | 27分鐘 | 23分鐘 | 24分鐘 |
上述結果展示增重2%導致具有穩健腸溶性質之軟膠囊。應注意經塗覆的軟膠囊導致pH 1.2 HCl酸性介質及pH 6.8磷酸鹽緩衝液兩者中之完整軟膠囊。然而,增重2%之經塗覆的軟膠囊在pH 7.5緩衝液中平均24分鐘內仍破裂。經塗覆的軟膠囊之增加臨限pH允許一劑型之結腸輸送。
表6概述在加速穩定條件下(40°C/75% RH)分別在1個月及3個月時之兩階段崩解之結果。
表6. 經塗覆的延遲釋放軟膠囊1000 mg在T1及T3處之崩解結果
樣本 | 崩解時間( 分鐘) | 結果 | ||||||
21SC-09A ( 增重2%) | 容器 | 1 | 2 | 3 | A | B | C | (分鐘) |
T=lM 穩定性( 40°C/75%RH) | 酸(1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液(6.8) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | |
緩衝液(7.5) | 35 | 31 | 34 | 36 | 36 | 31 | 34 分鐘 | |
T=3M 穩定性 (40°C/75%RH) | 酸(1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液(7.5) | 42 | 41 | 43 | 43 | 44 | 44 | 43 分鐘 |
對於T = 1個月處之具有增重2%之經塗覆的延遲釋放軟膠囊(21SC-09A),軟膠囊在pH 1.2及pH 6.8介質中保持完整且在pH 7.5緩衝液中之34分鐘處破裂。在T = 3個月時,經塗覆的延遲釋放軟膠囊在pH 1.2 HCl介質中保持完整且在pH 7.5磷酸鹽緩衝液中之43分鐘處破裂。
表7概述長期穩定條件(25°C/60% RH)、18個月中間穩定條件(30°C/65% RH)、6個月加速穩定條件(40°C/75% RH)及22個月室溫保持條件下6個月及12個月之兩階段崩解之測試結果。
表7. 經塗覆的延遲釋放軟膠囊1000 mg在T6、T12、T18、T22處之崩解結果(其中圓盤處於緩衝階段)
樣本 | 崩解時間 ( 分鐘 ) | 結果 | ||||||
21SC- 09A ( 增重 2%) | 容器 | 1 | 2 | 3 | A | B | C | (分鐘) |
T=6M 穩定性 (25°C/60%RH) | 酸 (1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液 (7.5) | 9 | 10 | 13 | 10 | 12 | 13 | 11 分鐘 | |
T=6M 穩定性( 40°C/75%RH) | 酸 (1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液 (7.5) | 16 | 17 | 19 | 16 | 17 | 18 | 17 分鐘 | |
T=12M 穩定性 (25°C/60%RH) | 酸 (1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液 (7.5) | 12 | 15 | 15 | 14 | 17 | 17 | 15 分鐘 | |
T=18M 穩定性 (30°C/65%RH) | 酸 (1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液 (7.5) | 14 | 15 | 15 | 15 | 16 | 17 | 15 分鐘 | |
T=22M 穩定性 (RT 保持 ) | 酸 (1.2) | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 | 完整 |
緩衝液 (7.5) | 10 | 11 | 12 | 10 | 10 | 12 | 11 分鐘 |
對於增重2%之經塗覆的延遲釋放軟膠囊(21SC-09A),在T = 6個月(25°C/60% RH)時,軟膠囊在pH 1.2中保持完整且在pH 7.5磷酸鹽緩衝液中之11分鐘處破裂;在T = 12個月(25°C/60% RH)時,軟膠囊在pH 1.2中保持完整且在pH 7.5磷酸鹽緩衝液中之15分鐘處破裂。對於T = 6個月(40°C/75% RH),延遲釋放軟膠囊在pH 1.2 HCl介質中保持完整且在pH 7.5磷酸鹽緩衝液中之17分鐘處破裂。對於T = 18個月(30°C/65% RH),延遲釋放軟膠囊在pH 1.2 HCl介質中保持完整且在pH 7.5磷酸鹽緩衝液中之15分鐘處破裂。對於T = 22個月(RT保持),延遲釋放軟膠囊在pH 1.2 HCl介質中保持完整且在pH 7.5磷酸鹽緩衝液中之11分鐘處破裂。
本文亦呈現經塗覆的立即釋放魚油軟膠囊之結果。表8概述具有增重2%及增重3.6%之經塗覆的立即釋軟膠囊之兩階段崩解資料。
具有增重2%之經塗覆的立即釋軟膠囊(21SC-12A)在pH 1.2 HCl介質中破裂且不滿足腸溶劑型之要求。增重3.6%之經塗覆的立即釋軟膠囊(21SC-12B)在pH 1.2酸性介質中未完全破裂。然而,所有軟膠囊釋放少量填充材料以指示不充分腸溶性質。
表8. 具有增重2%及3.6%之經塗覆的立即釋放軟膠囊1000 mg之崩解結果
兩階段破裂測試
樣本 | 崩解容器 | 結果 | ||||||
21SC- 12 A (2% 塗層 ) | 1 | 2 | 3 | A | B | C | 平均(分鐘) | |
酸 (pH 1.2) 2 小時 | 完整 | 完整 | 破裂 | 完整 | 破裂 | 完整 | 破裂 | |
緩衝液 (pH = 7.5 ) | 由於膠囊在酸性階段破裂,因此未執行 | |||||||
21SC- 12B ( 3.6 % 塗層 ) | 1 | 2 | 3 | A | B | C | 平均(分鐘) | |
酸 (pH 1.2) 2 小時 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | |
緩衝液 (pH = 7.5 ) | 22分鐘 | 22分鐘 | 22分鐘 | 22分鐘 | 22分鐘 | 22分鐘 | 22分鐘 | |
表9總結具有增重2%之經塗覆的延遲釋放軟膠囊(21SC-09A)及具有增重2% (21SC-12A)及增重3.6% (21SC-12B)之兩個階段破裂資料。
對於具有增重2%之經塗覆的延遲釋放軟膠囊(21SC-09A),膠囊使用酶之FaSSGF中保持完整且在pH 7.5之含酶磷酸鹽緩衝液中平均15分鐘破裂。在第一酸化階段中,觀察到6個血管中的4個血管中出現微小油滴,但膠囊保持完整,且未觀察到進一步釋放。
具有增重2% (21SC-12A)及增重3.6% (21SC-12B)之經塗覆的立即釋放軟膠囊在pH FaSSGF介質中釋放少量填充材料(超過10%),其中酶指示不充分腸溶性質。
表9. 具有增重2%之經塗覆的延遲釋放軟膠囊及具有2%及增重3.6%之經塗覆的立即釋放軟膠囊之兩個階段破裂測試結果
*觀察到小液滴。
吸濕測試
樣本 | 階段 | 崩解容器 | 結果 | |||||
21SC- 09A ( 具有 2% 塗層之 OptiGel® DR ) | 1 | 2 | 3 | 4 | 5 | 6 | 平均 ( 分鐘 ) | |
FaSSGF (pH = 1.6) 2 小時 | 完整 * | 完整 * | 完整 * | 完整 * | 完整 * | 完整 * | 完整 * | |
緩衝液 (pH = 7.5 ) | 15分鐘 | 14分鐘 | 16分鐘 | 17分鐘 | 16分鐘 | 16分鐘 | 15 分鐘 | |
21SC- 12 A ( 具有 2% 塗層之立即釋放 ) | 1 | 2 | 3 | 4 | 5 | 6 | 平均 ( 分鐘 ) | |
FaSSGF (pH = 1.6) 2 小時 | 洩漏 | 洩漏 | 完整 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | |
緩衝液 (7.5) | 6分鐘 | 6分鐘 | 6分鐘 | 4分鐘 | 4分鐘 | 5分鐘 | 5 分鐘 | |
21SC- 12B ( 具有 3.6 % 塗層之立即釋放 ) | 1 | 2 | 3 | 4 | 5 | 6 | 平均 ( 分鐘 ) | |
FaSSGF (pH = 1.6) 2 小時 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | 洩漏 | 完整 | 洩漏 | |
緩衝液 (7.5) | 5分鐘 | 4分鐘 | 5分鐘 | 5分鐘 | 4分鐘 | 5分鐘 | 5 分鐘 |
表10分別總結增重2%之經塗覆的延遲釋放膠囊、具有增重2%及增重3.6%之經塗覆的立即釋放軟膠囊及未經塗覆的延遲釋放軟膠囊之吸濕資料。圖1繪示經塗覆的膠囊之膠囊吸濕率。將軟膠囊置於一含水介質中進行吸濕測試。
表10. 選定軟膠囊之膠囊吸濕結果(每膠囊)
曝光時間 ( 分鐘 ) | 經塗覆的果膠膠囊 | 經塗覆的非果膠膠囊 | 未經塗覆的果膠膠囊 | |
批 21SC- 09A | 批 21SC- 12 A | 批 21SC- 12B | 批 4701394 | |
0 | 0.00% | 0.00% | 0.00% | 0.00% |
5 | 0.12% | 0.10% | 0.00% | 14.5% |
10 | 0.12% | 0.17% | 0.07% | 21.3% |
15 | 0.47% | 0.10% | 0.03% | 31.4% |
30 | 0.65% | 0.23% | 0.43% | 46.3% |
45 | 0.97% | -0.97% | 0.56% | 54.6% |
60 | 1.08% | -0.33% | 0.56% | 73.7% |
120 | 2.00% | -4.08% | -2.97% | 92.1% |
經塗覆的延遲釋放軟膠囊在120分鐘之浸泡期間具有有限增重,其突出指示增重2%塗層及果膠殼組合物提供強大防濕屏障。同時,具有2%及3.6%增重之經塗覆的立即釋放軟膠囊在浸泡60分鐘之後重量開始下降,其指示水介質透過經塗覆的層及溶解非果膠殼滲透。未經塗覆的延遲釋放軟膠囊在120分鐘之後增重92%以上,其指示強吸濕性。
因此,資料展示塗覆具有相對較低增重(2%)之延遲釋放軟膠囊顯著改良腸溶性質之穩健性且最小化溶解期間之吸濕性。另外,低增重塗層可實現更一致塗覆均勻性以導致劑型之更高組成效能。另外,使用適當腸溶性聚合物系統塗覆延遲釋放軟膠囊可由於pH臨限值之增加而拓寬應用以將劑型更深入地輸送至消化系統中,諸如結腸輸送。
先前描述闡述許多具體細節,諸如特定系統、組件、方法等之實例以提供本發明之若干實施例之一良好理解。然而,熟習技術者應明白本發明之至少一些實施例可在無需此等具體細節之情況下實施。在其他例項中,未詳細描述熟知組件或方法以避免不必要地致使本發明不清楚。因此,所闡述之具體細節係例示性。特定實施例可字此等例示性細節變動且仍經考慮在本發明之範疇內。
儘管本文以一特定順序描述方法之操作,但可更改各方法之操作之順序使得可以一相反順序執行某些操作或使得可至少部分地與其他操作同時執行某些操作。在另一實施例中,不同操作之指令或子操作可以一間歇及/或交替方式進行。
應理解,以上描述意欲繪示性而非限制性。熟習技術者將在閱讀及理解以上描述之後明白許多其他實施例。因此,本發明之範疇應參考隨附申請專利範圍連同此申請專利範圍所授權之等效物之全部範疇來判定。
本發明以實例之方式而非以限制之方式在附圖之圖中繪示,其中類似參考指示類似元件。應注意,本發明中參考「一」或「一個」實施例不一定是參考相同實施例,且此等參考意謂至少一個。
圖1繪示根據本發明之一實施例之經塗覆的軟膠囊之膠囊吸濕結果。
Claims (27)
- 一種延遲釋放軟膠囊,其包括: 一填充材料,其中該填充材料包括一活性劑; 一殼組合物,其中該殼組合物包括果膠;及 一塗層,其包括一腸溶性聚合物。
- 如請求項1之延遲釋放軟膠囊,其中該塗層提供該膠囊之約1%至約10重量%,或約2%至約5%之一增重。
- 如請求項1之延遲釋放軟膠囊,其中該殼組合物進一步包括一增塑劑。
- 如請求項3之延遲釋放軟膠囊,其中該增塑劑包括丙三醇、甘油、山梨醇、山梨醇山梨糖醇溶液、甘油三乙酸酯、聚山梨醇酯或其等之組合。
- 如請求項4之延遲釋放軟膠囊,其中該增塑劑包括甘油及山梨醇山梨糖醇溶液。
- 如請求項4之延遲釋放軟膠囊,其中該聚山梨醇酯包括Tween 20、Tween 80或其等之組合。
- 如請求項1之延遲釋放軟膠囊,其中該殼組合物進一步包括明膠。
- 如請求項7之延遲釋放軟膠囊,其中該明膠選自由A型明膠、B型明膠及其等之混合物組成之群組。
- 如請求項7之延遲釋放軟膠囊,其中該明膠選自由魚膠、阿膠、骨膠及其等之混合物組成之群組。
- 如請求項1之延遲釋放軟膠囊,其中該殼組合物進一步包括結蘭膠。
- 如請求項1之延遲釋放軟膠囊,其中該殼組合物進一步包括葡萄糖。
- 如請求項1之延遲釋放軟膠囊,其中該殼組合物進一步包括水。
- 如請求項1之延遲釋放軟膠囊,其中該果膠係一低甲氧基果膠。
- 如請求項1之延遲釋放軟膠囊,其中該腸溶性聚合物係丙烯酸聚合物、甲基丙烯酸聚合物、醋酸琥珀酸纖維素、鄰苯二甲酸乙酸纖維素、醋酸丁酸纖維素、羥丙基甲基纖維素鄰苯二甲酸酯、羥丙基甲基纖維素乙酸琥珀酸酯(醋酸琥珀酸超甲纖維素)、聚乙酸乙烯酯鄰苯二甲酸酯(PVAP)、藻膠酸鹽、硬脂酸、蟲膠或其等之一組合。
- 如請求項14之延遲釋放軟膠囊,其中該藻膠酸鹽係海藻酸鈉、褐藻酸鉀或其等之一組合。
- 如請求項14之延遲釋放軟膠囊,其中該腸溶性聚合物係丙烯酸聚合物、甲基丙烯酸聚合物或其等之一組合。
- 如請求項1之延遲釋放軟膠囊,其中該塗層進一步包括一增塑劑。
- 如請求項17之延遲釋放軟膠囊,其中該增塑劑包括甘油酯、檸檬酸三乙酯或其等之一組合。
- 如請求項1之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該果膠以約2.5重量%至約20重量%、5重量%至約18重量%、7.5重量%至約15重量%或約10重量%至約12重量%之量。
- 如請求項7之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該明膠以約15重量%至約60重量%、約20重量%至約55重量%、約25重量%至約50重量%、約30重量%至約45重量%或約35重量%至約40重量%之量。
- 如請求項11之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該葡萄糖以約0.001重量%至約5重量%、約0.01重量%至約4.5重量%、約0.01重量%至約4重量%、約0.1重量%至約3重量%或約1重量%至約2.5重量%之量。
- 如請求項4之延遲釋放軟膠囊,其中基於該殼組合物之總重量,該增塑劑以約5重量%至約60重量%、約10重量%至約55重量%、約15重量%至約50重量%、約20重量%至約45重量%或約25重量%至約35重量%之量。
- 如請求項1之延遲釋放軟膠囊,其中基於該塗層之總重量,該腸溶性聚合物以約20重量%至約40重量%、約25重量%至約35重量%或約30重量%之量。
- 如請求項17之延遲釋放軟膠囊,其中基於該塗層之總重量,該增塑劑以約2重量%至約10重量%、約3重量%至約9重量%、約4重量%至約8重量%或約5重量%之量。
- 如請求項1之延遲釋放軟膠囊,其中當使用一USP設備II量測時,該殼組合物在15分鐘、30分鐘、45分鐘或60分鐘時在1.2之一pH值下不破裂,其中攪拌槳在50 RPM下,750 ml 0.1N HCL酸性介質使用磷酸鹽緩衝劑調整至pH。
- 如請求項1之延遲釋放軟膠囊,其中當使用一USP設備II量測時,該殼組合物在15分鐘、30分鐘、45分鐘或60分鐘時在6與7之間的一pH下不破裂,其中攪拌槳在50 RPM下,750 ml 0.1N HCL酸性介質使用磷酸鹽緩衝劑調整至pH。
- 一種製備如請求項1之延遲釋放軟膠囊之程序,其包括: 製備包括一活性劑之一填充材料; 使用包括果膠之一殼組合物囊封該填充材料以形成一膠囊;及 使用包括一腸溶性聚合物之一塗層組合物塗覆該膠囊。
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