CN116528694A - 延迟释放软凝胶胶囊 - Google Patents
延迟释放软凝胶胶囊 Download PDFInfo
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- CN116528694A CN116528694A CN202180058038.2A CN202180058038A CN116528694A CN 116528694 A CN116528694 A CN 116528694A CN 202180058038 A CN202180058038 A CN 202180058038A CN 116528694 A CN116528694 A CN 116528694A
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Abstract
延迟释放软凝胶胶囊包含填充材料和pH依赖性壳组合物,其特征在于无需pH依赖性包衣或添加常规的pH依赖性聚合物即可实现所述胶囊的延迟释放特性。本文所述的延迟释放软凝胶胶囊特别适用于在结肠环境中的靶点位置启动活性剂的释放。
Description
技术领域
本发明涉及延迟释放软凝胶胶囊(softgel capsule),其中明胶基的壳组合物具有延迟释放特性而无需pH依赖性包衣或添加常规的pH依赖性的合成聚合物。本文所述的延迟释放软凝胶胶囊特别适用于结肠递送。
背景技术
软胶囊(soft capsule),特别是软明胶胶囊(或软凝胶胶囊),提供了更容易被患者接受的剂型,因为胶囊易于吞咽并且不需要调味以掩盖活性剂的任何令人不快的味道。药物的软凝胶胶囊包封进一步提供了提高药剂生物利用度的潜力。例如,一旦明胶壳破裂,活性成分可以以液体形式迅速释放。
人们已经努力创造延迟释放剂型。设计延迟释放剂型以保护剂型的内容物免受胃部条件的影响。例如,延迟释放剂型可以通过将pH依赖性包衣添加到制备的剂型(诸如片剂或胶囊)的表面来制备。这种包衣可以通过对剂型喷雾,然后将剂型干燥(通常在升高的温度)来施加。这种用pH依赖性包衣包被胶囊的方法可能造成性能和外观方面的缺点。例如,胶囊可能看起来粗糙,包衣可能施加不均匀,和/或包衣可能易于从剂型上开裂或剥落。此外,施加pH依赖性包衣的过程非常低效。
已经开发了其它延迟释放剂型,其中将常规pH依赖性聚合物(即,酸不溶性聚合物)添加到胶囊壳中。然而,添加常规pH依赖性聚合物会导致胶囊由于密封不足而易于渗漏。
因此,目前需要一种延迟释放软凝胶胶囊,其不需要在壳中施加pH依赖性包衣或添加常规pH依赖性聚合物。
发明内容
本发明涉及延迟释放软凝胶胶囊。该延迟释放软凝胶胶囊包含(a)填充材料和(2)pH依赖性壳组合物。根据本发明的延迟释放软凝胶胶囊不需要pH依赖性包衣或添加常规pH依赖性聚合物。因此,所述pH依赖性壳组合物消除了添加pH依赖性包衣的需要,这也使包衣过程中损坏胶囊的风险最小化。本文所述的延迟释放软凝胶胶囊特别适用于结肠递送。
在一个实施方案中,pH依赖性壳组合物包含:(a)明胶,(b)右旋糖,(c)果胶(诸如低甲氧基果胶)和任选地(d)增塑剂。可调节/调整/修改pH依赖性壳组合物(例如,果胶的量、右旋糖的量、明胶与果胶的比例)及其制备方法(例如,固化持续时间、带(ribbon)厚度)以获得壳组合物在各种pH环境下的目标pH溶出曲线(例如,在酸性介质和缓冲介质中的破裂/溶出/崩解时间)。本发明还涉及一种制备延迟释放软凝胶胶囊的方法。特别地,可调节本文所述的pH依赖性壳组合物中右旋糖的量以延迟活性剂的释放直至其到达人受试者的结肠环境。
本发明还涉及通过向受试者施用本文所述的任何延迟释放软凝胶组合物来治疗病症(例如,结肠疾病或可通过向结肠靶向施用活性剂来治疗的其他病症)的方法。递送可以用于治疗结肠疾病或病症,也可以用于用适合在结肠中吸收的药物治疗全身病症。
本发明还涉及通过口服施用本文所述的任何延迟释放软凝胶胶囊将活性剂递送至患者的结肠的方法。在某些实施方案中,至少80%、至少85%、至少90%、至少95%或至少99%的活性剂被递送至患者的结肠。
附图说明
结合附图考虑以下详细描述,本公开的上述和其他特征、其性质和各种优点将变得更加明显,其中:
图1说明了具有酰胺化果胶和不具有酰胺化果胶的壳组合物的粘度与老化时间的关系。
具体实施方式
本发明通过开发延迟释放口服剂型(特别是延迟释放软凝胶胶囊)来改进现有技术,该延迟释放口服剂型实现与常规延迟释放剂型相关的优点,而不需要施加pH依赖性包衣或在胶囊壳中添加常规pH依赖性合成聚合物。本发明的延迟释放软凝胶胶囊在胃的胃部环境中不溶出,而是在肠,特别是在人受试者的结肠中溶出。本文所述的延迟释放软凝胶胶囊的溶出曲线可通过改***凝胶胶囊的壳组成来调节。
这种机制有利于递送可引起胃刺激或对胃的酸性环境敏感的活性成分。这种机制还有利于在服用包封了容易导致打嗝的填充材料的胶囊之后减少打嗝。例如,打嗝通常发生在服用维生素、矿物质、补充剂和/或药物产品后,这些产品配制为在到达肠道之前在胃中表现出一些渗漏(即使是非常少量)的剂型。当打嗝与通常以软凝胶递送的具有令人讨厌的感觉的物质(诸如鱼油和大蒜)相关时,这种渗漏可能特别成问题。本文所述的延迟释放软凝胶胶囊可以最小化和/或消除胃的胃部环境中和结肠前胃肠道的任何其他区域中的过早渗漏(以及因此胶囊填充材料的过早释放)的方式配制。
如本文所用,术语“pH依赖性”用于指物质的抗溶出或崩解特性,使得溶出或崩解在胃的胃部环境中和结肠前胃肠道的任何其他区域中不发生或基本上不发生,例如持续至少约15分钟,至少约30分钟,至少约1小时,至少约2小时,至少约3小时,至少约4小时或至少约5小时的时间段。在某些实施方案中,此处可以用0.1N HCl和任选地添加胃蛋白酶来模拟胃的胃部环境。应当注意,药典方法不包括胃蛋白酶,然而,在本文所述的某些溶出/崩解试验中添加胃蛋白酶以更好地模拟/模仿体内条件。因此,不被解释为限制,在某些实施方案中,本文所述的组合物即使在包含胃蛋白酶(一种酶)的0.1N HCl环境(其被认为是比不含胃蛋白酶的0.1N HCl更具侵蚀性的环境)下也能抵抗上述持续时间的溶出/崩解。
例如,本文所述的实施方案包括与生物、人工或模拟胃液相比优先在约3.5或更高的pH(例如,在生物、人工或模拟结肠环境和/或肠液中)溶出的pH依赖性壳组合物。例如,本文所述的pH依赖性壳组合物在约3.5或更高的pH(例如,在生物、人工或模拟结肠环境和/或肠液中)在至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后,或从约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任一值至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟,或大约90分钟中的任一值,或其中的任何单个值或子范围溶出。在某些实施方案中,在本文中结肠或肠道环境可以用pH为6.8的磷酸盐缓冲液和任选地加入胰酶来模拟。应当注意,药典方法不包括胰酶,然而,在本文所述的某些溶出/崩解试验中添加胰酶以更好地模拟/模仿体内条件。因此,不被解释为限制,在某些实施方案中,本文所述的组合物在包括胰酶的pH 6.8缓冲环境下表现出类似的溶出/崩解曲线(其被认为是比没有胰酶的pH6.8缓冲环境更具侵蚀性的环境)。
如本文所用,“药学活性成分”、“活性剂”是指可用于病症的诊断、治愈、缓解、治疗或预防的药物或化合物。在某些实施方案中,合适的“活性剂”包括保健营养品,诸如维生素、矿物质和补充剂(VMS)。示例性的延迟释放软凝胶胶囊可以包括,但不限于,含有乳酸菌、益生菌、鱼油胶囊、丙戊酸、大蒜、薄荷油、聚乙二醇、布洛芬溶液或悬浮液、质子泵抑制剂、阿司匹林和类似产品的胶囊。
术语“病症(condition)”或“病症(conditions)”是指可以通过向受试者施用有效量的活性剂来治疗或预防的那些医学病症。
如本文所用,术语“活性成分”是指旨在产生治疗、预防或其它预期效果的任何物质,无论是否经政府机构批准用于该目的。关于具体药剂的该术语包括药物活性剂及其所有药学上可接受的盐、溶剂化物和晶型,其中该盐、溶剂化物和晶型具有药物活性。
任何药学活性成分可用于本发明的目的,包括水溶性的和难溶于水的那些。合适的药学活性成分包括,但不限于,镇痛剂和抗炎剂(例如,布洛芬、萘普生钠、阿司匹林)、抗酸药、驱虫药、抗心律失常药、抗细菌剂、抗凝血药、抗抑郁药、抗糖尿病药、止泻药、抗癫痫药、抗真菌剂、抗痛风药、抗高血压药、抗疟疾药、抗偏头痛药、抗毒蕈碱剂、抗肿瘤剂和免疫抑制剂、抗原生动物剂、抗风湿药、抗甲状腺剂、抗病毒剂、抗焦虑药、镇静剂、***和精神安定剂、β-受体阻滞剂、心肌收缩剂、皮质类固醇、止咳药、细胞毒素、减充血剂(decongestant)、利尿剂、酶、抗帕金森病药、胃肠药、组胺受体拮抗剂、脂质调节剂、局部麻醉剂、神经肌肉剂、硝酸盐和抗心绞痛剂、营养剂、阿片类镇痛药、抗惊厥药(例如,丙戊酸)、口服疫苗、蛋白质、肽和重组药物、性激素和避孕药、杀精剂、***及其组合。
在某些实施方案中,包含在胶囊中的活性剂可以是希望递送至小肠的任何药学上的活性剂或治疗性活性剂,例如胰酶和其他蛋白水解酶、双氯芬酸、萘普生、阿司匹林、吲哚美辛、奥美拉唑、强心甙、钠盐、钾盐和镁盐的电解质制剂以及钙和铁制剂、比沙可啶制剂和丙戊酸。
在某些实施方案中,活性剂可以是希望递送至结肠的药物,包括用于治疗结肠疾病的药物,例如5-ASA;类固醇,如氢化可的松、布***;泻药;奥曲肽;西沙必利;抗胆碱能类药物;钙通道阻滞剂、5HT3拮抗剂(诸如昂丹司琼)和多肽(诸如胰岛素)。
在某些实施方案中,适用于结肠递送的活性剂是,但不限于,一种或多种抗感染剂,例如抗生素和抗病毒剂;镇痛药和镇痛药组合;减食欲药物;驱虫剂;抗关节炎药;抗哮喘药;抗惊厥药;抗抑郁药;抗糖尿病药;止泻药;抗组胺药;抗炎药;抗偏头痛制剂;抗恶心药;抗肿瘤药;抗帕金森病药物;止痒药;抗精神病药;退烧药;解痉药;抗胆碱药;拟交感神经药;黄嘌呤衍生物;心血管制剂,包括钾和钙通道阻滞剂、β-受体阻滞剂、α-受体阻滞剂和抗心律失常药;抗高血压药;利尿剂和抗利尿剂;血管扩张剂;包括一般冠状动脉、外周和脑;中枢神经******;血管收缩剂;咳嗽和感冒制剂,包括减充血剂;激素如***和其他类固醇,包括皮质类固醇;催眠药;免疫抑制剂;肌肉松弛剂;副交感神经阻滞剂;精神振奋药物;镇静剂;和镇定剂;益生菌;抗癌剂(例如,结肠癌特异性抗癌剂或可以用适合在结肠中吸收的抗癌剂进行全身治疗的癌症类型的抗癌剂)。
结肠癌抗癌剂的实例包括,但不限于,阿瓦斯汀(贝伐珠单抗)、贝伐珠单抗、Camptosar(盐酸伊立替康)、卡培他滨、西妥昔单抗、Cyramza(雷莫芦单抗)、乐沙定(奥沙利铂)、爱必妥(西妥昔单抗)、5-FU(氟尿嘧啶注射液)、氟尿嘧啶注射液、易普利姆玛、盐酸伊立替康、健痊得(派姆单抗)、亚叶酸钙、Lonsurf(曲氟尿苷和地匹福林盐酸盐)、Mvasi(贝伐珠单抗)、纳武单抗、欧狄沃(纳武单抗)、奥沙利铂、帕尼单抗、派姆单抗、雷莫芦单抗、瑞戈非尼、Stivarga(瑞戈非尼)、曲氟尿苷和地匹福林盐酸盐、维克替比(帕尼单抗)、希罗达(卡培他滨)、Yervoy(易普利姆玛)、Zaltrap(阿柏西普)、阿柏西普,及其任何组合。
在一些实施方案中,活性药物成分可以选自,但不限于,由以下组成的组:达比加群酯、决奈达隆、替格瑞洛、伊潘立酮、依伐卡托(ivacaftor)、米哚妥林(midostaurine)、阿西马多林(asimadoline)、倍氯米松、阿普斯特(apremilast)、沙帕他滨(sapacitabine)、林西替尼(linsitinib)、阿比特龙、维生素D类似物(例如,骨化二醇、骨化三醇、帕立骨化醇、度骨化醇(doxercalciferol))、COX-2抑制剂(例如,塞来昔布、伐地昔布、罗非昔布)、他克莫司、睾酮、鲁比前列酮(lubiprostone)、其药学上可接受的盐及其组合。
在一些实施方案中,剂型中的脂质可以选自,但不限于,由以下组成的组:杏仁油、摩洛哥坚果油、鳄梨油、琉璃苣籽油、芥花油、腰果油、蓖麻油、氢化蓖麻油、可可脂、椰子油、菜籽油、玉米油、棉籽油、葡萄籽油、榛子油、羟化卵磷脂、卵磷脂、亚麻籽油、澳洲坚果油、芒果油、马尼拉油、蒙古坚果油、橄榄油、棕榈仁油、棕榈油、花生油、山核桃油、紫苏油、松子油、开心果油、南瓜籽油、薄荷油、米糠油、红花油、芝麻油、乳木果油、大豆油、葵花籽油、氢化植物油、核桃油和西瓜籽油。其它油和脂肪可包括,但不限于,鱼油(ω-3)、磷虾油、动物或植物脂肪,例如以其氢化形式、游离脂肪酸以及与C8-、C10-、C12-、C14-、C16-、C18-、C20-和C22-脂肪酸的甘油单酯、甘油二酯和甘油三酯、脂肪酸酯如EPA和DHA 3及其组合。
根据某些实施方案,活性剂可包括降脂剂,包括但不限于他汀类(例如,洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗素伐他汀和匹伐他汀)、贝特类(例如,氯贝特、环丙贝特、苯扎贝特、非诺贝特和吉非贝齐)、烟酸、胆汁酸螯合剂、依泽替米贝、洛美他派(lomitapide)、植物甾醇及其药学上可接受的盐、水合物、溶剂化物和前药、任意前述物质的混合物等。
合适的营养活性剂可包括,但不限于,5-羟色氨酸、乙酰基L-肉碱、α硫辛酸、α-酮戊二酸、蜂产品、盐酸甜菜碱、牛软骨、咖啡因、鲸蜡醇肉豆蔻脑酸脂(cetylmyristoleate)、木炭、壳聚糖、胆碱、硫酸软骨素、辅酶Q10、胶原蛋白、初乳、肌酸、氰钴胺素(维生素812)、二甲氨基乙醇、富马酸、锗倍半氧化物(germanium sequioxide)、腺产品、氨基葡萄糖盐酸盐、氨基葡萄糖硫酸盐、羟甲基丁酸盐(hydroxyl methyl butyrate)、免疫球蛋白、乳酸、L-肉碱、肝产品、苹果酸、无水麦芽糖、甘露糖(d-甘露糖)、甲基磺酰基甲烷、植物甾醇、吡啶甲酸、丙酮酸盐(pyruvate)、红酵母提取物、S-腺苷甲硫氨酸、硒酵母、鲨鱼软骨、可可碱、硫酸氧钒和酵母。
合适的营养补充活性剂可包括维生素、矿物质、纤维、脂肪酸、氨基酸、草药补充剂或其组合。
合适的维生素活性剂可包括,但不限于以下:抗坏血酸(维生素C)、维生素B、生物素、脂溶性维生素、叶酸、羟基柠檬酸、肌醇、矿物抗坏血酸盐、混合生育酚、烟酸(维生素B3)、乳清酸、对氨基苯甲酸、泛酸盐(panthothenate)、泛酸(维生素B5)、盐酸吡哆醇(维生素B6)、核黄素(维生素B2)、合成维生素、硫胺素(维生素B1)、生育三烯酚、维生素A、维生素D、维生素E、维生素F、维生素K、维生素油和油溶性维生素。
合适的草药补充剂活性剂可包括,但不限于,以下:山金车、越橘、黑升麻、猫爪草(cat's claw)、洋甘菊、紫锥菊、月见草油、胡芦巴、亚麻籽、野甘菊、大蒜油、姜根、银杏、人参、秋麒麟(goldenrod)、山楂、卡瓦-卡瓦(kava-kava)、甘草、水飞蓟、车前草、rauowolfia、番泻叶、大豆、圣约翰草(St.John's wort)、锯棕榈、姜黄、缬草。
矿物质活性剂可以包括,但不限于,以下:硼、钙、螯合矿物质、氯化物、铬、包覆的矿物(coated minerals)、钴、铜、白云石、碘、铁、镁、锰、矿物预混料、矿物产品、钼、磷、钾、硒、钠、钒、苹果酸、丙酮酸盐、锌等矿物质。
其它可能的活性剂的实例包括,但不限于,抗组胺剂(例如,雷尼替丁、茶苯海明、苯海拉明、氯苯那敏和马来酸右氯苯那敏)、非甾体抗炎剂(例如,阿司匹林、塞来昔布、Cox-2抑制剂、双氯芬酸、苯恶洛芬(benoxaprofen)、氟比洛芬、非诺洛芬、氟布芬(flubufen)、吲哚洛芬、吡洛芬(piroprofen)、卡洛芬、奥沙普秦、普拉洛芬(pramoprofen)、莫拉洛芬(muroprofen)、三恶洛芬(trioxaprofen)、舒洛芬、氨布洛芬(aminoprofen)、氟洛芬、布氯酸、吲哚美辛、舒林酸、佐美酸、硫平酸、齐多美辛、阿西美辛、芬替酸(fentiazac)、环氯茚酸、oxpinac、甲氯灭酸、氟芬那酸、尼氟灭酸、托灭酸、diflurisal、氟苯柳、吡罗昔康、舒多昔康、伊索昔康、醋氯芬酸、阿洛普林、阿扎丙宗、贝诺酯、溴芬酸、卡洛芬、胆碱水杨酸镁、二氟尼柳、依托度酸、依托考昔、faislamine、芬布芬(fenbufen)、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、氯诺昔康、氯索洛芬、美洛昔康、甲芬那酸、安乃近、水杨酸甲酯、水杨酸镁、纳布美通、萘普生、尼美舒利、羟布宗、帕瑞考昔、保泰松、水杨酸水杨酯、舒林酸、磺吡酮、替诺昔康、噻洛芬酸、托美丁、其药学上可接受的盐及其混合物)和对乙酰氨基酚、止吐药(例如,甲氧氯普胺、甲基纳曲酮)、抗癫痫药(例如,苯妥英、甲丙胺脂和硝西泮)、血管扩张剂(例如,硝苯地平、罂粟碱、地尔硫卓和尼卡地平)、止咳剂和祛痰剂(例如,磷酸可待因)、抗哮喘药(例如,茶碱)、抗酸药、抗痉挛药(例如,阿托品、东莨菪碱)、抗糖尿病药(例如,胰岛素)、利尿剂(例如,依他尼酸、苄氟噻嗪)、抗低血压药(例如,***、氯压定)、抗高血压药(例如,氯压定、甲基多巴)、支气管扩张剂(例如,沙丁胺醇)、类固醇(例如,氢化可的松、曲安西龙、***)、抗生素(例如,四环素)、抗痔疮药、***、精神药物、止泻药、黏液溶解药、镇静剂、减充血剂(例如,伪麻黄碱)、泻药、维生素、***(包括食欲抑制剂,诸如苯丙醇胺)和***素,以及其药学上可接受的盐、水合物、溶剂化物和前药。
活性剂也可以是苯二氮平类药物(benzodiazepine)、巴比妥类药物(barbiturate)、***或其混合物。术语“苯二氮平类药物”是指苯二氮平类药物和苯二氮平类药物的衍生物,其能够抑制中枢神经***。苯二氮平类药物包括,但不限于,阿普***、溴西泮、利眠宁、氯氮卓(clorazepate)、***、艾司***、氟胺安定、哈拉西泮、凯他***(ketazolam)、劳拉西泮、硝西泮、奥沙西泮、普拉西泮、夸西泮、替马西泮、***仑及其药学上可接受的盐、水合物、溶剂化物、前药和混合物。可用作活性剂的苯二氮平类拮抗剂包括,但不限于,氟马西尼及其药学上可接受的盐、水合物、溶剂化物和混合物。
术语“巴比妥类药物”是指衍生自巴比妥酸(2,4,6,-三氧代六氢嘧啶)的镇静-催眠药物。巴比妥类药物包括,但不限于,异戊巴比妥、阿普比妥(aprobarbotal)、仲丁巴比妥、布他比妥、美索比妥、甲基***、美沙比妥、戊巴比妥、***、司可巴比妥及其药学上可接受的盐、水合物、溶剂合物、前药和混合物。可用作活性剂的巴比妥类拮抗剂包括,但不限于,***类及其药学上可接受的盐、水合物、溶剂化物和混合物。
术语“***”包括,但不限于,***类诸如右旋***树脂复合物、右旋***、甲基***、哌甲酯及其药学上可接受的盐、水合物和溶剂化物和混合物。可用作活性剂的***拮抗剂包括,但不限于,苯二氮平类及其药学上可接受的盐、水合物、溶剂化物和混合物。
根据本公开的剂型包括各种活性剂及其药学上可接受的盐。药学上可接受的盐包括,但不限于,无机酸盐,诸如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等;有机酸盐,诸如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐等;磺酸盐,诸如甲磺酸盐、苯磺酸盐、对甲苯磺酸盐等;氨基酸盐,诸如精氨酸盐、天冬氨酸盐、谷氨酸盐等,以及金属盐,诸如钠盐、钾盐、铯盐等;碱土金属,诸如钙盐、镁盐等;有机胺盐,诸如三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己基胺盐、N,N′-二苄基乙二胺盐等。
如本文所用,术语“治疗有效”和“有效量”是指产生所需治疗结果所需的活性剂的量或其施用速率。
如本文所用,“壳”或“壳组合物”或“pH依赖性壳组合物”是指包封填充材料的软凝胶胶囊的壳。
如本文所用,“常规pH依赖性聚合物”是指(但不限于)丙烯酸和甲基丙烯酸聚合物,其可以商品名和其它常规酸不溶性聚合物(例如丙烯酸甲酯-甲基丙烯酸共聚物)获得。其他常规的酸不溶性聚合物包括,但不限于,醋酸琥珀酸纤维素、邻苯二甲酸醋酸纤维素、乙酸丁酸纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素(醋酸琥珀酸羟丙基甲基纤维素)、聚醋酸乙烯邻苯二甲酸酯(PVAP)、藻酸盐诸如藻酸钠和藻酸钾、硬脂酸和虫胶。果胶和果胶衍生物不被认为是常规的pH依赖性聚合物。在一些实施方案中,本发明的pH依赖性壳组合物不包含酸不溶性聚合物。换言之,在某些实施方案中,pH依赖性壳组合物和pH依赖性软凝胶胶囊“不含或基本上不含常规pH依赖性聚合物”。
如本文所用,“不含或基本上不含”是指组合物包含小于约1wt%,小于约0.5wt%,小于约0.25wt%,小于约0.1wt%,小于约0.05wt%,小于约0.01wt%或0wt%的所述组分。
在整个说明书和权利要求书中,所有提及的wt%是指相对于整个主题组合物的重量的组分的重量,并且也可以指定为w/w。
如本文所用,“填充材料(fill material)”或“填充物(fill)”是指由pH依赖性壳组合物包封并含有至少一种药学活性成分的组合物。
如本文所用,“延迟释放胶囊”或“延迟释放软凝胶胶囊”或“pH依赖性胶囊”或“pH依赖性软凝胶胶囊”是指一旦填充材料被包封在壳中并且胶囊被干燥后就具有延迟或pH依赖性特性的胶囊。在某些实施方案中,这些术语可以指在干燥后也已经固化的胶囊。在某些实施方案中,干燥后不需要进一步的加工步骤。在某些实施方案中,固化后不需要进一步的加工步骤。
如本文所用,“约”是指在±10%变化内的任何值,使得“约10”将包括9至11。如本文所用,除非另有说明,否则“一(a)”、“一(an)”或“所述(the)”是指一个或多个。因此,例如,提及“赋形剂”包括单一赋形剂以及两种或更多种不同赋形剂的混合物等。
除非本文另有说明,否则本文中对值范围的列举仅旨在用作单独提及落入该范围内的每个单独值的速记方法,并且将每个单独值并入说明书中,就好像在本文被单独列举一样。本文所述的所有方法可以任何合适的顺序进行,除非本文另有说明或与上下文明显矛盾。
本文提供的任何和所有实例或示例性语言(例如,“诸如”)的使用仅旨在说明某些材料和方法,而不对范围造成限制。说明书中的语言不应被解释为指示任何未要求保护的元素是实践所公开的材料和方法所必需的。
根据第一实施方案,pH依赖性软凝胶胶囊包含(a)填充材料和(b)pH依赖性壳组合物,其中填充材料包含至少一种药学活性成分,其中pH依赖性壳组合物包含明胶、右旋糖、pH依赖性材料(例如,低甲氧基果胶)和任选地增塑剂。优选地,pH依赖性壳组合物不含另外的pH依赖性聚合物。在某些实施方案中,pH依赖性软凝胶胶囊或pH依赖性壳组合物被配置成在酸性介质,如胃部环境或模拟胃液环境中保持完整(例如,至少约5小时、至少约4小时、至少约3小时、至少约2小时、至少约1小时等的持续时间),并在目标持续时间(例如,至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后,或从超过0分钟、约5分钟、约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任一个至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟,或约90分钟中的任一个,或其中的任何单个值或子范围)在结肠(或模拟肠液环境)中溶出/崩解。
合适的填充材料包含至少一种药学活性成分并且可以根据已知方法制备。除了至少一种药学活性成分之外,合适的填充材料可以包含另外的填充组分,诸如调味剂、甜味剂、着色剂和填充剂或其它药学上可接受的赋形剂或添加剂,诸如合成染料和无机氧化物。药学活性成分和药学上可接受的赋形剂的合适量可由本领域普通技术人员容易地确定。
在一个实施方案中,pH依赖性壳组合物中的明胶可包括单独或组合使用的A型明胶、B型明胶、皮(hide)或皮(skin)明胶(例如,小牛皮、猪皮)和/或骨明胶(例如,小牛骨、猪骨)。在一个实施方案中,明胶为250Bloom明胶。在另一个实施方案中,只有一种类型的明胶。在另一个实施方案中,该明胶为至少两种明胶的组合。在一个实施方案中,基于干胶囊壳组合物的总重量,pH依赖性壳组合物中明胶的量为约30wt%至约85wt%,约30wt%至约75wt%,约30wt%至约65wt%,约30wt%至约55wt%,约30wt%至约40wt%,约40wt%至约80wt%,约45wt%至约65wt%,约45wt%至约75wt%,或约50wt%至约70wt%,或其中的任何单个值或子范围。
在一个实施方案中,pH依赖性胶囊壳组合物包含右旋糖。在一个实施方案中,基于干胶囊壳组合物的总重量,pH依赖性胶囊壳组合物中右旋糖的量为约0.001wt%至约1.0wt%,约0.002wt%至约0.008wt%,约0.005wt%或约0.01wt%至约4wt%,约0.1wt%或约0.15wt%至约3wt%,约0.1wt%至约1wt%,约0.1或约0.15wt%或约0.2wt%或约0.25wt%至约2wt%,约0.1wt%至约0.2wt%,约0.05wt%或约0.1wt%至约0.4wt%或约0.5wt%,或其中的任何单个值或子范围。
可以将右旋糖添加到延迟释放胶囊壳中以减轻凝胶强度的潜在降低。还可以调整pH依赖性壳组合物中右旋糖的量以获得延迟释放软凝胶胶囊的目标溶出曲线,例如,使延迟释放软凝胶胶囊在胃肠道的特定位置(例如,在结肠中)溶出/崩解。在一个实施方案中,调整pH依赖性壳组合物中右旋糖的量以迟延延迟释放软凝胶胶囊的溶出直到它到达结肠并在结肠中获得目标溶出曲线。例如,可以调整pH依赖性壳组合物中右旋糖的量以防止在酸性介质(例如,0.1N HCl,任选地含有胃蛋白酶)中过早渗漏/破裂,同时控制在缓冲介质(例如,pH 6.8磷酸盐缓冲液,任选地含有胰酶以模拟人受试者的结肠环境)中溶出/崩解/破裂的时间。缓冲阶段中溶出/崩解/破裂的时间可控制在至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后,或从约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任何一个至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟或约90分钟中的任何一个,或其中的任何单个值或子范围。可以控制在酸性介质中的溶出/崩解/破裂时间以保持完整的延迟释放软凝胶胶囊至少约15分钟、至少约30分钟、至少约45分钟、至少约60分钟、至少约90分钟、至少约120分钟,或至少约150分钟。
不被理解为限制,认为右旋糖与壳组合物中的明胶相互作用并引起明胶交联。右旋糖的量对壳组合物的溶出特性的影响在实施例中进一步说明。右旋糖在pH依赖性壳组合物中的浓度可以是改善凝胶强度的有效量,但不会高到会干扰胶囊的密封或产品性能的可生产性。
在一些实施方案中,pH依赖性壳组合物可包含果胶,例如,低甲氧基果胶。在一个实施方案中,果胶是酯化度(Degree of Esterification)低于50的低甲酯(LM)果胶。在一些实施方案中,果胶为酰胺化果胶。在其它实施方案中,低甲氧基(LM)果胶为非酰胺化果胶。在某些实施方案中,果胶为酰胺化果胶和非酰胺化果胶的组合。果胶的添加有助于剂型的pH依赖性。
剂型中过多的果胶可能会降低软凝胶胶囊的凝胶强度,这又可能对软凝胶胶囊的密封性产生不利的影响。pH依赖性壳组合物中过多的果胶也可能会增加壳组合物的粘度,使得从制造的角度来看加工具有挑战性或不可能。
因此,果胶可以足够高以形成延迟释放剂型,同时足够低以减轻凝胶强度的降低和减轻粘度增加的浓度添加到剂型中。
在一个实施方案中,基于干胶囊壳组合物的总重量,pH依赖性壳组合物中果胶的量为约2wt%至约20wt%,约3wt%至约15wt%,约3wt%至约5.5wt%,约4wt%至约11wt%,约7wt%至约12wt%,约8wt%至约13wt%,或约5wt%至约10wt%,或其中的任何单个值或子范围。
掺入pH依赖性壳组合物中的果胶的酯化度可低于约50%,或可在约10%至约50%,约20%至约40%,或约25%至约35%的范围内。另外,果胶可以为酰胺化的或非酰胺化的。
在某些实施方案中,pH依赖性壳组合物包含稳定剂和/或粘合剂,其包含结冷胶。在某些实施方案中,果胶与稳定剂和/或粘合剂(例如,结冷胶)的比例为约1:10至约50:1;约1:5至约40:1;约1:1至约25:1或约10:1至约24:1。
在某些实施方案中,基于干胶囊壳组合物的总重量,pH依赖性壳组合物中稳定剂和/或粘合剂(例如,结冷胶)的量为约0.05wt%至约5wt%,约0.1wt%至约3wt%,或约0.2wt%至约2wt%的稳定剂和/或粘合剂(例如,结冷胶),或其中的任何单个值或子范围。
在某些实施方案中,pH依赖性壳组合物的粘度可以为约20000cPs,约30000cPs,约40000cPs,约50000cPs,约60000cPs或约70000cPs中的任一个至约80000cPs,约90000cPs,约100000cPs,约110000cPs,约120000cPs,约130000cPs,约140000cPs或约150000cPs中的任一个,或其中的任何子范围或单个值。在一个实施方案中,pH依赖性壳组合物的粘度为约100000cPs至约130000cPs,或约110000cPs至约125000cPs,或约115000cPs,或约120000cPs。粘度使用流变仪在60℃测量,如与图1相关的实施例中进一步详细描述的。将凝胶团(gel mass)样品(例如,本文所述的任何pH依赖性壳组合物的凝胶团样品)负载到流变仪的平台上,保持在60℃。圆盘以一定速度旋转以提供固定的剪切速率。通过测量剪切应力和剪切速率获得粘度。
在某些实施方案中,即使在加热老化长达约24小时,长达约48小时,长达约72小时,长达约96小时或长达约1周后,pH依赖性壳组合物仍可保持适于可生产性的粘度。在某些实施方案中,在加热老化后(长达约24小时,长达约48小时,长达约72小时,长达约96小时或长达约1周),pH依赖性壳组合物的粘度可降低(从老化前组合物的粘度值)至多约80%,至多约70%,至多约60%,至多约50%,至多约40%,至多约35%,或至多约30%。
在一个实施方案中,pH依赖性壳组合物中的增塑剂可包括丙三醇(glycerol)、甘油(glycerin)、山梨糖醇及其组合。其他合适的增塑剂可以包括,但不限于,糖醇增塑剂,诸如异麦芽酮糖醇、麦芽糖醇、木糖醇、赤藓糖醇、阿东糖醇、半乳糖醇、季戊四醇或甘露糖醇;或多元醇增塑剂,诸如二甘油、二丙二醇、至多10000MW的聚乙二醇、新戊二醇、丙二醇、1,3-丙二醇、2-甲基-1,3-丙二醇、三羟甲基丙烷、聚醚多元醇、乙醇胺;及其混合物。其它示例性增塑剂还可包括,但不限于,低分子量聚合物、低聚物、共聚物、油、有机小分子、具有脂族羟基的低分子量多元醇、酯型增塑剂、乙二醇醚、聚(丙二醇)、多嵌段聚合物、单嵌段聚合物、柠檬酸酯型增塑剂和甘油三乙酸酯。此类增塑剂可以包括1,2-丁二醇、2,3-丁二醇、苯乙二醇、单丙二醇单异丙醚、丙二醇单***、乙二醇单***、二甘醇单***、山梨糖醇乳酸酯、乳酸乙酯、乳酸丁酯、乙醇酸乙酯、癸二酸二丁酯、柠檬酸乙酰基三丁酯、柠檬酸三乙酯、单硬脂酸甘油酯、聚山梨醇酯80、柠檬酸乙酰基三乙酯、柠檬酸三丁酯和乙醇酸烯丙酯,及其混合物。
在一个实施方案中,基于干胶囊壳组合物的总重量,pH依赖性壳组合物中增塑剂的量为约15wt%至约45wt%,约15wt%至约40wt%,约18wt%至约45wt%,约18wt%至约42wt%,约20wt%至约35wt%,约25wt%至约30wt%,或其中的任何单个值或子范围。
在某些实施方案中,调节各种组分(例如,果胶、右旋糖、明胶、增塑剂)的量和各种组分的比例以控制软凝胶胶囊在各种pH范围内的溶出和/或崩解特性。
例如,pH依赖性壳组合物中明胶与果胶的w:w比可以为约2:1,约3:1,约4:1,约5:1,约6:1,约7:1,约8:1或约9:1中的任一个至约10:1,约11:1,约12:1,约13:1,约14:1,约15:1,约16:1,约17:1,约18:1,约19:1或约20:1中的任一个,或其中的任何子范围或单个值。在某些实施方案中,较低的明胶与果胶的w:w比提供在酸性介质(例如,0.1N HCl,任选地具有胃蛋白酶)中更稳定(如果有的话溶出更慢)的pH依赖性壳组合物,而较高的明胶与果胶的w:w比提供在酸性介质(例如,0.1N HCl,任选地具有胃蛋白酶)中较不稳定(溶出较快)的pH依赖性壳组合物。可以调节明胶与果胶的w:w比以获得软凝胶胶囊在酸性介质中的特定溶出时间(例如,约10分钟,约15分钟,约30分钟,约45分钟,约60分钟,约90分钟,或这些持续时间内的任何子范围,等)。
还可以调节pH依赖性壳组合物中明胶与增塑剂的w:w比以获得特定的胶囊硬度水平,并且其范围可以为约5:1至约1:5,约4:1至约1:4,约3:1至约1:3,约2:1至约1:2,约1:1,或其中的任何单个比例值或子范围。
在某些实施方案中,本文所述的pH依赖性壳组合物的硬度可以为约5N,约6N,约7N,约8N,约9N或约10N中的任一个至约11N,约12N,约13N,约14N或约15N中的任一个。胶囊硬度使用硬度测定仪测定。使胶囊变形2.0mm所需的力(以牛顿为单位)被定义为胶囊硬度。
在某些实施方案中,本文所述的pH依赖性壳组合物的壳水分可以为约5%,约6%,约7%,约8%,约9%或约10%中的任一个至约11%,约12%,约13%,约14%或约15%中的任一个。壳水分通过干燥失重法测定。将1至2克的pH依赖性胶囊壳组合物样品置于105℃烘箱中17小时。记录样品的初始重量。在烘箱中在105℃干燥样品17小时之后,记录样品的最终重量。根据以下等式计算的重量损失百分比定义为壳水分:
在某些实施方案中,本文所述的pH依赖性壳组合物的平衡相对湿度可以为约25%,约28%,约30%,约32%,约34%或约35%中的任一个至约38%,约40%,约42%,约45%或约50%中的任一个。平衡相对湿度(%)定义为胶囊保持恒定总重量的湿度条件。其通过使用饱和盐溶液保持在恒定湿度的环境室来测定。
在某些实施方案中,本文所述的pH依赖性壳组合物的爆裂强度可以为约50kg,约60kg,约70kg,约80kg或约90kg中的任一个至约100kg,约110kg,约120kg,约130kg,约140kg或约150kg中的任一个。爆裂强度使用质地分析仪测定。质地分析仪压缩胶囊直至胶囊爆裂。使胶囊爆裂所需的力(以千克为单位)被定义为爆裂强度。
在一个实施方案中,pH依赖性壳组合物和pH依赖性软凝胶胶囊可以不含或基本上不含常规pH依赖性聚合物和/或在软凝胶胶囊壳上不含pH依赖性外包衣。
在一个实施方案中,pH依赖性壳组合物和pH依赖性软凝胶胶囊可包括二价阳离子盐,诸如Ca++(例如,CaCl2)或Mg++(例如,MgCl2)。在另一个实施方案中,pH依赖性壳组合物和pH依赖性软凝胶胶囊可以不含或基本上不含二价阳离子盐,诸如Ca++(例如,CaCl2)或Mg++(例如,MgCl2)。在另一个实施方案中,除了可能存在于其他组分中的一定量的二价阳离子盐之外,pH依赖性壳组合物可以不包括加入二价阳离子盐(诸如Ca++(例如,CaCl2)或Mg++(例如,MgCl2))的步骤。
在一个实施方案中,pH依赖性壳组合物可任选地包含另外的试剂,诸如稳定剂或粘合剂(例如,结冷胶)、着色剂、调味剂、甜味剂、填充剂、抗氧化剂、稀释剂、pH调节剂或其它药学上可接受的赋形剂或添加剂,诸如合成染料和无机氧化物(mineral oxides)。
示例性的合适的着色剂可包括,但不限于,诸如以下的颜色:白色、黑色、黄色、蓝色、绿色、粉红色、红色、橙色、紫色、靛蓝色和棕色。在具体实施方案中,剂型的颜色可指示其中所含的内容物(例如,一种或多种活性成分)。
示例性的合适的调味剂可以包括,但不限于,通过通常使用溶剂(诸如乙醇或水)提取原料(例如,动物或植物材料)的一部分获得的“香料提取物”;通过从花、果实、根等或从整株植物中提取精油而获得的天然香精。
可以在所述剂型中的另外的示例性调味剂可以包括,但不限于,口气清新化合物如薄荷醇、留兰香和肉桂、咖啡豆、其它调味剂或香料如水果调味剂(例如,樱桃、橙子、葡萄等),特别是用于口腔卫生的那些,以及用于牙齿和口腔清洁的活性物质,诸如季铵碱。可以使用风味增强剂如酒石酸、柠檬酸、香草醛等增强风味的效果。
示例性甜味剂可包括,但不限于,一种或多种人工甜味剂、一种或多种天然甜味剂或其组合。人工甜味剂包括,例如,安赛蜜及其各种盐,诸如钾盐(可作为获得)、阿力甜、阿斯巴甜(可作为/>和/>获得)、阿斯巴甜-安赛蜜的盐(可作为获得)、新橙皮苷二氢查耳酮、柚苷二氢查耳酮、二氢查耳酮化合物、纽甜、甜蜜素、糖精及其各种盐,诸如钠盐(可作为Sweet'N/>获得)、甜菊糖(stevia)、蔗糖的氯衍生物诸如三氯蔗糖(可作为/>和/>获得)和罗汉果苷(mogroside)。天然甜味剂包括,例如,葡萄糖、右旋糖、转化糖、果糖、蔗糖、甘草甜素;甘草酸单铵(以商品名出售);甜叶菊(Stevioside)、天然强化甜味剂诸如罗汉果(Lo Han Kuo)、多元醇诸如山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇等。
在一些实施方案中,pH依赖性壳组合物和/或pH依赖性软凝胶胶囊可以在USPApparatus II中用桨以50rpm的速度在酸性介质(例如,pH 1.2(0.1N HCl),任选地具有胃蛋白酶)中,然后在用于模拟结肠环境和/或肠液的缓冲介质(例如,pH 6.8磷酸盐缓冲液,任选地具有胰酶,诸如约1%胰酶)中进行崩解/溶出试验来测试。根据该实施方案的pH依赖性软凝胶胶囊可以在酸性介质中保持完整至少约10分钟,至少约15分钟,至少约30分钟,至少约1小时,至少约2小时,至少约3小时,至少约4小时或至少约5小时,并且可以在肠液和/或结肠环境和/或模拟肠液(例如,缓冲介质)中在至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后,或从约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任一个至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟或约90分钟中的任一个,或其中的任何单个值或子范围崩解。
虽然两相溶出/崩解试验的缓冲介质的pH为6.8,但应当注意,在pH为约3.5或更高的缓冲介质(任选地具有胰酶)中可获得类似的溶出/崩解曲线。还应当注意的是,胃蛋白酶(在酸性介质中)和胰酶(在缓冲介质中)的存在或不是药典方法所必需的,但在某些情况下在本文中用于模拟更好地模仿体内条件的更具侵蚀性的环境。
在一些实施方案中,两相崩解/溶出试验可以进行总共(包括酸性介质和缓冲介质两者)约420分钟,约360分钟,约300分钟,约240分钟,约210分钟,约180分钟,约150分钟,约120分钟,约105分钟,约90分钟,约75分钟,约60分钟,约45分钟,约30分钟,约15分钟,约10分钟或约5分钟。
填充材料的包封可以以任何常规方式完成。例如,可以使用转模包封(rotary dieencapsulation)。
根据一个实施方案,pH依赖性软凝胶胶囊通过包括以下步骤的方法制备:(a)制备填充材料,所述填充材料包含至少一种药学活性成分;以及(b)将步骤(a)的填充材料包封在pH依赖性壳组合物中。根据步骤(b)的包封方法还可以包括制备pH依赖性壳组合物的子步骤,例如通过混合明胶、右旋糖、果胶和任选地增塑剂。优选地,其中pH依赖性壳组合物不含另外的pH依赖性聚合物(诸如常规pH依赖性合成聚合物)。
还可以调节pH依赖性壳组合物的带厚度(例如在转模包封过程中使用的)以控制最终pH依赖性软凝胶胶囊的pH依赖性溶出曲线。pH依赖性壳组合物的带厚度可以为,但不限于,约0.02英寸、约0.022英寸、约0.024英寸、约0.026英寸、约0.028英寸,或约0.030英寸中的任一个至约0.032英寸、约0.034英寸、约0.036英寸、约0.038英寸、约0.04英寸、约0.042英寸、约0.044英寸或约0.050英寸中的任一个,或其中的任何子范围或单个值。
在某些实施方案中,pH依赖性软凝胶胶囊(例如,在包封后)可以被干燥和任选地固化。固化软凝胶胶囊可在约25℃至约75℃,约25℃至约70℃,约30℃至约60℃或约35℃至50℃的温度进行。固化温度应当足够高以增强软凝胶胶囊的延迟释放特性,但不应高到使软凝胶胶囊熔化。
固化的持续时间可以为约12小时至约168小时,约18小时至约120小时,约24小时至约72小时,约24小时,约48小时,约72小时,或其中的任何子范围或单个值。在一个实施方案中,软凝胶胶囊的固化可以在约40℃的温度进行约24小时。在一个实施方案中,软凝胶胶囊的固化可以在约40℃的温度进行约48小时。在一个实施方案中,软凝胶胶囊的固化可以在约40℃的温度进行约72小时。在某些实施方案中,固化可以在空气中发生(对氮或氧的含量或湿度没有任何特定控制)。在某些实施方案中,固化可以在惰性条件下(例如,在氮气中)发生。
在一个实施方案中,制备pH依赖性软凝胶胶囊的方法包括以下步骤,基本上由以下步骤组成或由以下步骤组成:a)制备本文所述的任何填充材料;b)将步骤a)的填充材料包封在本文所述的任何pH依赖性壳组合物中(例如,经由转模包封);c)将包封的pH依赖性软凝胶胶囊干燥(例如,通过滚筒干燥或在篮子中定期干燥而不翻转);以及任选地d)根据本文所述的任何固化条件固化pH依赖性软凝胶胶囊。
在某些实施方案中,干燥在约10℃至约50℃,约15℃至约40℃,或约20℃至约35℃,在约5%至约40%,约10%至约30%,或约15%至约25%的相对湿度进行。
在某些实施方案中,此处应区分提及的干燥和固化。干燥本文所述的延迟释放软凝胶胶囊的目的是在包封后立即从延迟释放软凝胶胶囊中除去过量的水。因此,胶囊将是物理稳定的。固化本文所述的延迟释放软凝胶胶囊的目的是提高延迟释放软凝胶胶囊的延迟释放特性。因此,干燥步骤的存在与固化步骤不同,并且类似地,固化步骤的存在与干燥步骤不同。
在某些实施方案中,具有本文所述的pH依赖性壳组合物的延迟释放软凝胶胶囊是化学和物理稳定的。
例如,其化学稳定性可以通过填充材料中活性剂的含量来证明(例如,当填充材料包括鱼油时,鱼油成分的含量)。在某些实施方案中,与储存前的原材料相比,在储存长达12个月,长达6个月,长达3个月或长达1个月(在环境条件下或在40℃和75%相对湿度的压力条件下,这些持续时间中的任一者)后,填充材料成分的含量基本相似(或在规格范围内)。
在某些实施方案中,延迟释放软凝胶胶囊的物理稳定性可以通过胶囊在酸性介质和缓冲介质中的溶出曲线来证明。例如,与储存前胶囊的溶出曲线相比,在储存长达12个月,长达6个月,长达3个月或长达1个月(在环境条件或在40℃和75%相对湿度的压力条件下,这些持续时间中的任一者)后,胶囊在酸性介质和缓冲介质中的溶出曲线基本相似(或在规格范围内)。
术语“基本相似”可以指特定值在相应比较值的约30%,约25%,约20%,约15%,约10%,约5%或约1%内。百分比是基于比较值的面值计算的。例如,27分钟至33分钟的溶出时间范围可以被视为在30分钟的比较溶出时间的10%内。
在某些实施方案中,本公开还可涉及一种稳定本文所述的任何延迟释放软凝胶胶囊的方法。该方法可以包括通过将本文所述的任何填充材料(包括至少一种活性剂)包封在任何pH依赖性壳组合物中来保护(例如,免受氧化或化学降解的另一潜在来源)本文所述的任何填充材料。
在某些实施方案中,本文所述的pH依赖性壳组合物产生坚固的(robust)延迟释放软凝胶胶囊,其在酸性环境(例如,胃部环境或模拟胃部环境,诸如模拟胃液,0.1N HCl,任选地具有胃蛋白酶)中几乎没有或没有填充材料的过早释放,持续至少约10分钟、至少约15分钟、至少约30分钟、至少约一小时、至少约两小时、至少约三小时、至少约四小时或至少约五小时。例如,在暴露于酸性环境长达约150分钟,长达约120分钟,长达约105分钟,长达约90分钟,长达约75分钟,长达约60分钟,长达约45分钟,长达约30分钟,长达约15分钟,长达约10分钟,或长达约5分钟后,在酸性环境中本文所述的延迟释放软凝胶胶囊可释放至多约10wt%,至多约9wt%,至多约8wt%,至多约7wt%,至多约6wt%,至多约5wt%,至多约4wt%,至多约3wt%,至多约1wt%,或0wt%的填充材料,基于填充材料的总重量,。
在某些实施方案中,固化本文所述的延迟释放软凝胶胶囊(即,用pH依赖性壳组合物包封的那些)可减少或消除在约10分钟、约15分钟、约30分钟、约1小时、约2小时、约3小时、约4小时或约5小时,或这些持续时间内的任何子范围后在酸性环境中表现出任何量的过早释放的胶囊的数量。例如,在酸性环境中(在暴露于酸性环境长达约5小时,长达约4小时,长达约3小时,长达约150分钟,长达约120分钟,长达约105分钟,长达约90分钟,长达约75分钟,长达约60分钟,长达约45分钟,长达约30分钟,长达约15分钟,长达约10分钟或长达约5分钟之后)表现出过早释放的固化胶囊的数目可以为批次中胶囊总数的至多约30%,至多约25%,至多约20%,至多约15%,至多约10%,至多约5%,至多约3%,至多约2%,至多约1%或0%。
相比之下,在未经固化的情况下,在酸性环境中(例如,在暴露于酸性环境长达约5小时,长达约4小时,长达约3小时,长达约150分钟,长达约120分钟,长达约105分钟,长达约90分钟,长达约75分钟,长达约60分钟,长达约45分钟,长达约30分钟,长达约15分钟,长达约10分钟或长达约5分钟之后)表现出过早释放的胶囊(具有相同组成)的数量可大于批次中胶囊总数的约2%,大于约5%,大于约10%,大于约15%,大于约20%,大于约30%,大于约40%,大于约50%,大于约60%,大于约70%,大于约80%或大于约90%。
在某些实施方案中,固化本文所述的延迟释放软凝胶胶囊(即,用pH依赖性壳组合物包封的那些)可减少或消除在酸性环境中(例如,在暴露于酸性环境长达约5小时,长达约4小时,长达约3小时,长达约150分钟,长达约120分钟,长达约105分钟,长达约90分钟,长达约75分钟,长达约60分钟,长达约45分钟,长达约30分钟,长达约15分钟,长达约10分钟或长达约5分钟之后)从表现出一些过早释放的胶囊中释放的填充材料的量。
例如,在酸性环境中(例如,在暴露于酸性环境长达约5小时,长达约4小时,长达约3小时,长达约150分钟,长达约120分钟,长达约105分钟,长达约90分钟,长达约75分钟,长达约60分钟,长达约45分钟,长达约30分钟,长达约15分钟,长达约10分钟或长达约5分钟之后)从表现出一些过早释放的固化胶囊释放的填充材料的量可以为胶囊中填充材料的总重量的至多约5wt%,至多约4wt%,至多约3wt%,至多约2wt%,至多约1wt%或0%。
相比之下,在未经固化的情况下,在酸性环境中(例如,在暴露于酸性环境长达约5小时,长达约4小时,长达约3小时,长达约150分钟,长达约120分钟,长达约105分钟,长达约90分钟,长达约75分钟,长达约60分钟,长达约45分钟,长达约30分钟,长达约15分钟,长达约10分钟或长达约5分钟之后)从表现出过早释放的胶囊(具有相同的组成)释放的填充材料的量可以大于胶囊中填充材料的总重量的约1wt%、大于约2wt%,大于约3wt%,大于约4wt%,大于约5wt%,大于约6wt%,大于约7wt%,大于约8wt%,大于约9wt%,大于约10wt%,大于约15wt%,或大于约20wt%。
在某些实施方案中,本文所述的pH依赖性壳组合物产生坚固的延迟释放软凝胶胶囊,其在酸性环境中(例如,胃部环境或模拟胃部环境,诸如模拟胃液,0.1N HCl,任选地具有胃蛋白酶)保持完整至少约10分钟,至少约15分钟,至少约30分钟,至少约1小时,至少约2小时,至少约3小时,至少约4小时,或至少约5小时,但在结肠环境(或其模拟环境,诸如pH6.8的缓冲介质,任选地具有胰酶),在至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后,或从约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任一个至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟,或约90分钟中的任一个,或其中的任何单个值或子范围,在这样的结肠或模拟结肠环境中,基于填充材料的总重量,释放至少约50wt%,至少约60wt%,至少约70wt%,至少约80wt%,至少约90wt%,至少约95wt%,至少约96wt%,至少约97wt%,至少约98wt%,或至少约98wt%的填充材料。
在一个实施方案中,pH依赖性壳组合物包含:(a)明胶,(b)右旋糖,(c)pH依赖性聚合物(例如,果胶,诸如低甲氧基果胶),(d)增塑剂(例如,甘油、山梨糖醇及其组合)以及任选地(e)稳定剂和/或粘合剂(例如,结冷胶)。这些组分的量和wt:wt比可以符合上文所述的任何值或范围。
在一个实施方案中,pH依赖性壳组合物基本上由以下组成:(a)明胶,(b)右旋糖,(c)pH依赖性聚合物(例如,果胶,诸如低甲氧基果胶),(d)增塑剂(例如,甘油、山梨糖醇、结冷胶及其组合),以及任选地(e)稳定剂和/或粘合剂(例如,结冷胶)。这些组分的量和wt:wt比可以符合上文所述的任何值或范围。
在一个实施方案中,pH依赖性壳组合物由以下组成:(a)明胶,(b)右旋糖,(c)pH依赖性聚合物(例如,果胶,诸如低甲氧基果胶),(d)增塑剂(例如,甘油、山梨糖醇、结冷胶及其组合),以及任选地(e)稳定剂和/或粘合剂(例如,结冷胶)。这些组分的量和wt:wt比可以符合上文所述的任何值或范围。
在一个实施方案中,pH依赖性壳组合物包含:(a)约30wt%至约85wt%,约30wt%至约75wt%,约30wt%至约65wt%,约30wt%至约55wt%,约30wt%至约40wt%,约40wt%至约80wt%,约45wt%至约65wt%,约45wt%至约75wt%,或约50wt%至约70wt%的明胶,(b)约0.01wt%至约4wt%,或约0.1wt%至约3wt%,或约0.2wt%至约2wt%,或约0.01wt%至约0.1wt%,或约0.05wt%至约0.5wt%,或约0.1wt%至约0.2wt%,或约0.15wt%至约0.25wt%,或约0.2wt%至约0.4wt%的右旋糖,(c)约2wt%至约20wt%,约3wt%至约15wt%,约7wt%至约15wt%,约3wt%至约5.5wt%,或约7wt%至约12wt%的pH依赖性聚合物(例如,果胶,诸如低甲氧基果胶),(d)约15wt%至约45wt%,约15wt%至约40wt%,约20wt%至约35wt%,或约25wt%至约30wt%的增塑剂,以及任选地(e)约0.05wt%至约5wt%,约0.1wt%至约3wt%,或约0.2wt%至约2wt%的稳定剂和/或粘合剂(例如,结冷胶)。所有wt%均基于干pH依赖性壳组合物的总重量。
在一个实施方案中,pH依赖性壳组合物基本上由以下组成:(a)约30wt%至约85wt%,约30wt%至约75wt%,约30wt%至约65wt%,约30wt%至约55wt%,约30wt%至约40wt%,约40wt%至约80wt%,约45wt%至约65wt%,约45wt%至约75wt%,或约50wt%至约70wt%的明胶,(b)约0.01wt%至约4wt%,或约0.1wt%至约3wt%,或约0.2wt%至约2wt%,或约0.01wt%至约0.1wt%,或约0.05wt%至约0.5wt%,或约0.1wt%至约0.2wt%,或约0.15wt%至约0.25wt%,或约0.2wt%至约0.4wt%的右旋糖,(c)约2wt%至约20wt%,约3wt%至约15wt%,约7wt%至约15wt%,或约3wt%至约5.5wt%,或约7wt%至约12wt%的pH依赖性聚合物(例如,果胶,诸如低甲氧基果胶),(d)约15wt%至约45wt%,约15wt%至约40wt%,约20wt%至约35wt%,或约25wt%至约30wt%的增塑剂,以及任选地(e)约0.05wt%至约5wt%,约0.1wt%至约3wt%,或约0.2wt%至约2wt%的稳定剂和/或粘合剂(例如,结冷胶)。所有wt%均基于干pH依赖性壳组合物的总重量。
在一个实施方案中,pH依赖性壳组合物由以下组成:(a)约30wt%至约85wt%,约30wt%至约75wt%,约30wt%至约65wt%,约30wt%至约55wt%,约30wt%至约40wt%,约40wt%至约80wt%,约45wt%至约65wt%,约45wt%至约75wt%,或约50wt%至约70wt%的明胶,(b)约0.01wt%至约4wt%,或约0.1wt%至约3wt%,或约0.2wt%至约2wt%,或约0.01wt%至约0.1wt%,或约0.05wt%至约0.5wt%,或约0.1wt%至约0.2wt%的,或约0.15wt%至约0.25wt%,或约0.2wt%至约0.4wt%右旋糖,(c)约2wt%至约20wt%,约3wt%至约15wt%,约7wt%至约15wt%,或约3wt%至约5.5wt%,或约7wt%至约12wt%的pH依赖性聚合物(例如,果胶,诸如低甲氧基果胶),(d)约15wt%至约45wt%,约15wt%至约40wt%,约20wt%至约35wt%,或约25wt%至约30wt%的增塑剂,以及任选地(e)约0.05wt%至约5wt%,约0.1wt%至约3wt%,或约0.2wt%至约2wt%的稳定剂和/或粘合剂(例如,结冷胶)。所有wt%均基于干pH依赖性壳组合物的总重量。
实施例
现在将参考以下实施例说明本发明的具体实施方案。应当理解,这些实施例仅通过说明本发明的方式公开,而不应当以任何方式限制本发明的范围。
实施例1-右旋糖浓度对组合物制备的影响
制备具有不同右旋糖浓度的pH依赖性壳组合物以研究右旋糖浓度对组合物的可生产性的影响。pH依赖性壳组合物列于表1中。
表1-干壳组合物
在pH 6.8,pH依赖性壳组合物中不同量的右旋糖对破裂时间的影响见表2。
表2
右旋糖是还原糖并且被认为通过使明胶交联而与明胶相互作用。当明胶交联时,其溶解度会降低。显示右旋糖使酸性介质中的果胶软凝胶胶囊稳定(即减少渗漏)。右旋糖还可以影响在缓冲介质中释放的活性剂(维生素、矿物质、补充剂或药物成分)的量以及活性剂在缓冲介质中的溶出时间。这在下面的实施例7中针对来自表2的样品3和4进行说明。
尽管表2显示一些胶囊(例如第2、3和4组)在pH 6.8磷酸盐缓冲液中持续60分钟没有破裂,但在向缓冲介质中添加胰酶后(据信这可以更好地模拟体内条件),如以下实施例7所示,壳组合物在少于45分钟内溶解。
实施例2-固化对胶囊释放性能的影响
制备pH依赖性壳组合物以研究固化对胶囊的释放性能的影响。pH依赖性壳组合物列于表3中。
表3-在干胶囊壳中以wt%计的凝胶团制剂
现有商业产品在大量胶囊中表现出过早释放,过早释放的填充材料的量增加,并且在一些情况下,几乎100wt%的填充材料在酸性介质中在10分钟内释放。
考虑了包衣的软凝胶胶囊,但它们在缓冲介质中长时间(长于约60分钟,在一些情况下长达120分钟)不溶解。在缓冲介质中的长时间溶出被认为表明包衣的软凝胶胶囊不能被生物利用。这与两步制备方法的挑战一起促进了对pH依赖性壳组合物的探索,以形成没有单独包衣的延迟释放软凝胶胶囊。
表3中列出的pH依赖性壳组合物用于形成果胶软胶囊(softgel),其在一定程度上减少了过早释放的发生和过早释放的填充材料的量(与现有商业产品相比)。
然而,在固化之前,每批中的大部分软胶囊在酸性环境(例如,0.1N HCl)中仍继续表现出填充材料的一些过早释放,如表3中的“固化前过早释放的胶囊百分比”所总结的。从每个批次中测试约60至约72个胶囊,以评估固化前过早释放的胶囊百分比。
在某些实施方案中,在固化之前,约10wt%的填充材料从具有过早释放的胶囊中释放。在某些实施方案中,在固化之前,超过10wt%的填充材料或小于10wt%的填充材料从具有过早释放的胶囊中释放。
如将在随后的实施例所示的,固化减少了过早释放的发生、在过早释放发生时所释放的填充材料的量,并且在一些情况下完全消除了过早释放。
将果胶软凝胶胶囊固化以增强其在酸性环境(例如,0.1N HCl)中的稳定性。将果胶软胶囊包装在纸盒(用于散装)或高密度聚乙烯(HDPE)瓶中,并置于加热至40℃的烘箱中。未使用湿度控制。样品之间的唯一变量是固化时间。批次1、2和3的固化研究结果总结于下表4中。
表4-固化研究结果
固化后的溶出根据适用于未包衣的肠溶软胶囊的两阶段肠溶溶出试验的USP肠溶试验方法进行评估。除非另有说明,否则本说明书中所有溶出试验的酸性介质、缓冲介质、装置和溶出试验条件均根据该两阶段肠溶溶出试验进行。
使用带有桨的USP Apparatus II,在37℃桨速度为50rpm。酸性阶段介质为0.1NHCl。缓冲阶段介质为pH 6.8的磷酸盐缓冲液。对于维生素矿物质补充剂和/或营养剂产品,肠溶胶囊应在酸性介质中保持完整至少60分钟以通过第一阶段,并在缓冲阶段介质中在45分钟内破裂以通过第二阶段。对于药物产品,肠溶胶囊应在酸性介质中保持完整至少120分钟以通过第一阶段,并在缓冲阶段介质中在45分钟内破裂以通过第二阶段。
在24小时、48小时、72小时、120小时、168小时和288小时评估软凝胶胶囊的固化。尽管本文仅提供长达72小时的数据。
表5描述了在固化前和固化后,在酸性介质中按照USP肠溶试验标准在2小时结束时填充材料从批次3的果胶软凝胶胶囊中过早释放的量。释放的填充材料的最大量为5%。批次3的果胶软凝胶胶囊在填充材料中包含鱼油(其包括二十二碳六烯酸(DHA)和二十碳五烯酸(EPA))。
表5-批次3-按照USP肠溶试验标准在酸性介质(0.1N HCl)中过早释放的填充材料的量
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固化数据表明,固化显著减少或消除了在酸性介质中填充材料从果胶胶囊中的过早释放,导致胶囊具有强大的肠溶特性和高质量的肠溶产品。
注意表5中测试的所有果胶软凝胶胶囊在15分钟内溶解于pH 6.8的缓冲液中。
实施例3-在含有胃蛋白酶的模拟胃液(SGF)中的肠溶溶出数据
对固化果胶胶囊(具有表6A中概括的凝胶团制剂)进行肠溶破裂试验,使用SGF(0.1N HCl)和胃蛋白酶(以模拟人体内条件)进行两阶段肠溶溶出研究。
表6A-干胶囊壳中以wt%计的凝胶团制剂
成分 | 批次4 | 批次5 |
非酰胺化果胶 | 7.0-11.0 | 8.0-13.0 |
右旋糖 | 0.02-0.08 | 0.02-0.08 |
甘油 | 18-42 | 18-42 |
明胶 | 45-65 | 45-65 |
水 | 8-15 | 8-15 |
总计 | 100 | 100 |
表6B-表6A的果胶软凝胶胶囊在含和不含胃蛋白酶的酸性介质中的溶出
批次号 | 0.1N HCl | 含胃蛋白酶的0.1N HCl |
批次4 | 完整120分钟 | 完整120分钟 |
批次5 | 完整120分钟 | 完整120分钟 |
当使用合适的壳组合物,例如明胶与果胶的比例时,胃蛋白酶不会影响果胶壳在0.1N HCl介质中的溶出。在批次4和5中,如表6A和6B所示,明胶比果胶w:w比为7:1。不被解释为限制性的,据信果胶软胶囊是坚固的,并且如通过果胶软凝胶胶囊在0.1N HCl中保持完整120分钟所证明的,即使在胃蛋白酶(其代表与不包括酶的药典方法不同的生物相关介质)的存在下明胶-果胶网络的强度足以耐受胃蛋白酶的作用。因此,认为果胶软凝胶胶囊在体内也足够坚固。
实施例4-通过改变明胶与果胶的比例来调节肠溶介质中的果胶胶囊破裂时间
用不同的明胶与果胶比例制备果胶软凝胶胶囊。不同批次的组成总结于下表7B中。果胶胶囊在含有胃蛋白酶的SGF(0.1N HCl)中的破裂时间随明胶与果胶比例的不同而变化,如下表7A中所总结的。
表7A
表7B-用于明胶-果胶比研究的基于干壳组合物的凝胶团制剂(wt%)
表7A的所有果胶软凝胶胶囊在pH 6.8缓冲液中在45分钟内破裂。表7A说明果胶软凝胶胶囊在酸性介质中的破裂时间可以通过改变明胶与果胶的比例来调节。
实施例5-软胶囊带厚度对果胶软凝胶胶囊肠溶性能的影响
制备具有不同带厚度的果胶软凝胶胶囊。以不同带厚度制备的批次的干pH依赖性壳组合物的组成总结于下表8A中。在固化约72至96小时后,评估了不同带厚度的果胶胶囊在SGF(0.1N HCl)和pH 6.8缓冲液中的溶出。结果总结于下表8B中。
表8A-用于带厚度研究的基于干壳组合物的凝胶团配方(wt%)
表8B-具有不同带厚度的固化的软凝胶果胶胶囊的溶出
表8B中描述的溶出结果说明,具有0.028英寸至0.038英寸的带厚度的果胶软凝胶胶囊在固化后显示是坚固的,并且表现出满足药物产品和VMS(维生素、矿物质、补充剂)产品的肠溶标准。该厚度范围不应理解为限制性的。在某些实施方案中,也可以使用更厚的带或更薄的带。
实施例6-老化时pH依赖性壳组合物粘度
果胶和明胶彼此相互作用形成网络,这有助于凝胶团粘度的显著增加,如图1所示。果胶和明胶之间的相互作用被认为有助于胶囊壳组合物的延迟释放特性。然而,如图1所示,pH依赖性壳组合物的凝胶团粘度随时间降低。粘度和减少百分比总结于下表9中。
在本实施例和整个说明书中的粘度使用流变仪(HAAKE Rheostress6000,ThermoFisher)在60℃测量。测试在环境条件下进行。将凝胶团样品负载到流变仪的平台上,该平台保持在60℃。40mm圆盘以0.1Hz的频率振荡以提供固定的剪切速率。通过测量剪切应力和剪切速率获得粘度。
表9-老化的pH依赖性壳组合物的粘度
从表9可以看出,在60℃老化48小时、在60℃老化72小时和在60℃老化96小时后,与酰胺化果胶的粘度相比,非酰胺化果胶的粘度降低较小的百分比。
据信粘度的降低是由果胶和明胶的分子链长度的热降解引起的。尽管粘度降低,pH依赖性壳组合物的凝胶团仍保持适合于可生产性和可加工性的粘度,即使在将组合物在60℃保持加热4天之后。此外,用老化凝胶制备的软凝胶胶囊仍具有令人满意的pH依赖性延迟释放特性。
实施例7-在胰酶存在的情况下添加右旋糖对缓冲介质中溶出时间的影响
在酸性介质(0.1N HCl,pH=1.2)和缓冲介质(含1%胰酶的pH 6.8磷酸盐缓冲液)中评估在pH依赖性壳组合物中具有不同右旋糖量的果胶软凝胶胶囊的溶出。这些果胶软凝胶胶囊的溶出度根据以上实施例2中描述的两步肠溶溶出试验进行评价。结果总结于下表10中。
表10-添加右旋糖对缓冲介质中溶出时间的影响
对来自上表1和表2(实施例1)的第3组和第4组中的每组的三个样品进行评估并总结平均值。如表10所示,来自第3组的样品(pH依赖性壳组合物中0.1wt%右旋糖)在酸性介质(0.1N HCl,pH 1.2)中保持完整120分钟,并在缓冲介质(含1%胰酶的pH 6.8磷酸盐缓冲液)中在约25.7分钟(平均)破裂。来自第4组的样品(pH依赖性壳组合物中的0.15wt%右旋糖)在酸性介质(0.1N HCl,pH 1.2)中保持完整120分钟,并在缓冲介质(含1%胰酶的pH6.8磷酸盐缓冲液)中在约39.0分钟(平均)破裂。
因此,如表10所示,可以调节pH依赖性壳组合物中右旋糖的量以获得在具有胰酶的缓冲介质中的目标溶出/崩解/破裂时间。这可用于活性剂,诸如维生素、矿物质、补充剂或药物成分的靶向结肠递送。
实施例8–果胶软凝胶胶囊的化学稳定性
下表11描述了包封在果胶pH依赖性壳组合物(根据本文所述的实施方案)中的鱼油在环境条件下和在40℃和75%相对湿度(RH)储存6个月后的化学稳定性。可接受的胶囊应具有EPA TG≥160mg/g,DHA TG≥100mg/g,过氧化物≤5meq O2/kg,对茴香胺≤20,在0.1N HCl(pH1.2)中的溶出时间超过120分钟,并且在缓冲介质(pH 6.8磷酸盐缓冲液)中的溶出时间至多为45分钟。对于对照(鱼油原料)、在环境条件下储存6个月的延迟释放软凝胶果胶胶囊和在40℃和75%RH储存6个月的延迟释放果胶软凝胶胶囊,这些参数的值总结于表11中。
表11-延迟释放软凝胶胶囊的化学稳定性
加速稳定性数据(总结于表11中)表明,pH抗性果胶壳组合物(根据实施方案)保护填充材料(例如,鱼油成分)免于氧化,如与原料相比,根据6个月后(在环境条件下以及在40℃和75%RH的压力条件下)过氧化物和对茴香胺值以及EPA和DHA测定的不显著/实质相似性所证实的。
实施例9-丙戊酸果胶软凝胶胶囊
下表12A描述了在T=0时、在40℃和75%相对湿度(RH)储存3个月(T=3个月)后,以及在40℃和75%RH储存6个月(T=6个月)后,包封在根据本文所述的实施方案的果胶pH依赖性壳组合物(干壳组合物的凝胶配方总结于表12B中)中的丙戊酸的溶出曲线的稳定性。如表11A中所证明,pH依赖性壳组合物在40℃和75%RH储存3个月后和在40℃和75%RH储存6个月后的溶出曲线与T=0时的溶解曲线保持基本相似。
表12A-包封在果胶pH依赖性壳组合物中的丙戊酸的溶出
表12B-干胶囊壳中以wt%计的凝胶团制剂
成分 | 批次15 |
酰胺化果胶 | 6.5-8.0 |
右旋糖 | 无 |
甘油 | 20-45 |
明胶 | 42-56 |
水 | 8-15 |
总计 | 100 |
实施例10-果胶软凝胶胶囊的物理属性
具有本文所述的pH依赖性壳组合物的延迟释放软凝胶胶囊是坚固的,如基于下表13中总结的物理属性所证明的。
表13-延迟释放软凝胶胶囊的物理属性
参数 | 典型规格 |
壳水分(%) | 6-15 |
硬度(牛顿) | 7-14 |
平衡相对湿度(%) | 30-45 |
爆裂强度(kg) | 60-120 |
壳水分通过干燥失重法测定。将1至2克的pH依赖性胶囊壳组合物样品放入105℃烘箱中17小时。记录样品的初始重量。在烘箱中在105℃干燥样品17小时之后,记录样品的最终重量。根据以下等式计算的重量损失百分比定义为壳水分:
胶囊硬度使用硬度测定仪测定。使胶囊变形2.0mm所需的力(以牛顿为单位)被定义为胶囊硬度。
平衡相对湿度(%)定义为胶囊保持恒定总重量的湿度条件。其通过使用饱和盐溶液保持在恒定湿度的环境室来测定。
爆裂强度使用质地分析仪测定。质地分析仪压缩胶囊直至胶囊爆裂。使胶囊爆裂所需的力(以千克为单位)被定义为爆裂强度。
实施例11-果胶和结冷胶延迟释放软凝胶胶囊的示例性组成
制备包含果胶和结冷胶的组合的延迟释放软凝胶胶囊。基于干壳组合物的制剂总结于下表14中。
表14-在干胶囊壳中以wt%计的凝胶团制剂
成分 | 批次15 |
果胶 | 7.0-10.5 |
右旋糖 | 0.02-0.5 |
甘油 | 15-25 |
明胶 | 35-50 |
山梨糖醇溶液 | 25-32 |
结冷胶 | 0.1-2.0 |
水 | 6-15 |
总计 | 100 |
实施例12-根据本文所述的实施方案的凝胶团组合物的稳定性研究
评估了根据本文所述的实施方案的凝胶团组合物的稳定性。制备了三种含有不同水平右旋糖的凝胶团。从凝胶团中制备含有1000mg的鱼油的软凝胶胶囊。将软凝胶胶囊干燥并包装到HDPE瓶中,然后通过感应密封。表15中列出了每种凝胶团(基于干壳质量)的配方。如表15所示,基础凝胶配方相同,右旋糖的量变为0.05wt%、0.10wt%和0.15wt%。
表15-评估稳定性的凝胶团组合物
将所有三批包装在HDPE瓶中的软凝胶胶囊放入40℃/75%相对湿度稳定室中。在第3个月和第6个月的时间点取出样品并进行测试。在稳定性试验期间,在缓冲阶段开始之前添加酶。稳定性和试验结果总结在表16A-16D中。结果表明,含有约0.05wt%至约0.10wt%右旋糖的制剂在加速条件下在约6个月保持稳定性。当包含胰酶时,包含0.15wt%的制剂在加速条件在6个月时表现出良好的稳定性。
表16A-表15中描述的软凝胶胶囊制剂在0个月和1个月时的稳定性
表16B-表15中描述的软凝胶胶囊制剂在0个月和3个月时的稳定性
表16C-表15中描述的软凝胶胶囊制剂在0个月和6个月时的稳定性
表16D-表15中描述的软凝胶胶囊制剂在0个月和6个月时在含有胰酶中的稳定性
表17总结了软凝胶胶囊在环境条件储存两年的稳定性结果。
表17-软凝胶胶囊在环境条件的稳定性结果
如表17所示,含有约0.05wt%至约0.1wt%的制剂在室温条件具有持续两年的良好稳定性。总之,添加不同量的右旋糖改善了果胶软凝胶胶囊的肠溶性能的稳健性(robustness),这为实现某些药物分子的结肠递送提供了可能性。
为了简化说明,将本公开的方法的实施方案描绘和描述为一系列动作。然而,根据本公开的动作可以以各种顺序和/或同时发生,并且与本文未呈现和描述的其它动作一起发生。此外,并非需要所有示出的动作来实现根据所公开的主题的方法。此外,本领域的技术人员将理解并认识到,这些方法可以替代地经由状态图或事件表示为一系列相互关联的状态。
在前面的描述中,阐述了许多具体细节,诸如具体材料、尺寸、工艺参数等,以提供对本发明的透彻理解。特定特征、结构、材料或特性可以以任何合适的方式组合在一个或多个实施方案中。词语“实例”或“示例性”在本文中用于表示用作示例、实例或说明。本文中描述为“实例”或“示范性”的任何方面或设计未必应解释为比其它方面或设计优选或有利。相反,使用“实例”或“示例性”等词旨在以具体方式呈现概念。如在本申请中所使用的,术语“或”旨在表示包括性的“或”而不是排他性的“或”。也就是说,除非另有说明,或从上下文清楚地看出,“X包括A或B”旨在表示任何自然的包含性置换。即,如果X包括A;X包括B;或X包括A和B两者,则“X包括A或B”在任何前述情况下满足。在整个说明书中对“实施方案”、“某些实施方案”或“一个实施方案”的引用意味着结合该实施方案描述的特定特征、结构或特性被包括在至少一个实施方案中。因此,短语“实施方案”、“某些实施方案”或“一个实施方案”在本说明书各处的出现不一定都指相同的实施方案。
已经参考本发明的特定示例性实施方案描述了本发明。因此,说明书和附图被认为是说明性的而不是限制性的。除了在此示出和描述的那些之外,本发明的各种修改对于本领域技术人员将变得显而易见,并且旨在落入所附权利要求的范围内。
Claims (54)
1.延迟释放软凝胶胶囊,其包含:
(a)填充材料;以及
(b)pH依赖性壳组合物,
其中所述填充材料包含至少一种药学活性成分,
其中所述pH依赖性壳组合物包含明胶、果胶和右旋糖,并且
其中所述pH依赖性壳组合物在结肠环境中溶出/崩解/破裂。
2.根据权利要求1所述的延迟释放软凝胶胶囊,其中所述pH依赖性壳组合物还包含增塑剂。
3.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述果胶为低甲氧基果胶。
4.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述果胶选自酰胺化果胶、非酰胺化果胶及其组合。
5.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物重量,所述pH依赖性壳组合物包含约40wt%至约80wt%的明胶。
6.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物重量,所述pH依赖性壳组合物包含约2wt%至约20wt%的果胶。
7.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物重量,所述pH依赖性壳组合物包含约0.01wt%至约4wt%的右旋糖。
8.根据权利要求2-7中任一项所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物重量,所述pH依赖性壳组合物包含约15wt%至约40wt%的增塑剂。
9.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述明胶选自A型明胶、B型明胶及其混合物。
10.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述明胶选自鱼明胶、皮明胶、骨明胶及其混合物。
11.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述果胶为非酰胺化果胶。
12.根据权利要求2-11中任一项所述的延迟释放软凝胶胶囊,其中所述增塑剂选自甘油、山梨醇及其组合。
13.根据权利要求12所述的延迟释放软凝胶胶囊,其中所述增塑剂为甘油。
14.根据权利要求5所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物总重量,所述pH依赖性壳组合物包含约45wt%至约75wt%的明胶。
15.根据权利要求14所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH依赖性壳组合物包含约45wt%至约65wt%的明胶。
16.根据权利要求6所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH依赖性壳组合物包含约3wt%至约15wt%的果胶。
17.根据权利要求16所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH壳组合物包含约7wt%至约15wt%的果胶。
18.根据权利要求2-17中任一项所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH依赖性壳组合物包含约20wt%至约35wt%的增塑剂。
19.根据权利要求18所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH依赖性壳组合物包含约25wt%至约30wt%的增塑剂。
20.根据权利要求1-19中任一项所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH依赖性壳组合物包含约0.05wt%至约0.3wt%的右旋糖。
21.根据权利要求20所述的延迟释放软凝胶胶囊,其中基于所述干pH依赖性壳组合物的总重量,所述pH依赖性壳组合物包含约0.1wt%至约2wt%的右旋糖。
22.根据权利要求1-21中任一项所述的延迟释放软凝胶胶囊,其中基于在USPApparatus II中用桨以50rpm的速度在任选地含有胰酶的pH 6.8磷酸盐缓冲液中进行的溶出/崩解试验,所述胶囊在肠道环境中在至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后、或从约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任一个至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟或约90分钟中的任一个溶出/崩解。
23.根据权利要求1-22中任一项所述的延迟释放软凝胶胶囊,其中基于在USPApparatus II中用桨以50rpm的速度在任选地含有胃蛋白酶的0.1NHCl中进行的溶出/崩解试验,所述胶囊在酸性介质中在至少约15分钟,至少约30分钟,至少约1小时,至少约2小时,至少约3小时,至少约4小时,或至少约5小时内溶出/崩解。
24.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其不含另外的pH依赖性聚合物。
25.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述pH依赖性壳组合物的粘度为约110000cPs至约125000cPs。
26.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述pH依赖性壳组合物的明胶与果胶的w:w比为约2:1至约20:1或约6:1至约18:1。
27.根据前述权利要求中任一项所述的延迟释放软凝胶胶囊,其中所述pH依赖性壳组合物的增塑剂与明胶的w:w比为约5:1至约1:5。
28.制备根据权利要求1-27中任一项所述的延迟释放软凝胶胶囊的方法,其包括以下步骤:
(a)制备包含活性剂的填充材料;以及
(b)用pH依赖性壳组合物包封所述填充材料。
29.根据权利要求28所述的方法,其还包括将所述包封的延迟释放软凝胶胶囊干燥。
30.根据权利要求28-29中任一项所述的方法,其还包括将所述延迟释放软凝胶胶囊固化。
31.根据权利要求30所述的方法,其中固化在约25℃至约75℃,约30℃至约60℃或约35℃至约60℃范围内的温度发生。
32.根据权利要求30-31中任一项所述的方法,其中所述固化的持续时间为约12小时至约168小时,约18小时至约120小时,约24小时至约72小时,约24小时,约48小时或约72小时。
33.根据权利要求28-32中任一项所述的方法,其还包含制备所述pH依赖性壳组合物。
34.根据权利要求33所述的方法,其中制备包含将明胶、右旋糖、果胶和任选地增塑剂混合以形成pH依赖性壳组合物带。
35.根据权利要求34所述的方法,其中所述pH依赖性壳组合物带的厚度为约0.020英寸至约0.050英寸。
36.调节由包封在pH依赖性壳组合物中的填充材料构成的延迟释放软凝胶胶囊的pH依赖性溶出曲线的方法,所述方法包括调整所述pH依赖性壳组合物中果胶和右旋糖的量以在酸性介质和/或缓冲介质中获得目标pH依赖性溶出曲线。
37.根据权利要求36所述的方法,其还包括调整所述延迟释放软凝胶胶囊的固化持续时间。
38.根据权利要求36-37中任一项所述的方法,其还包括调整所述pH依赖性壳组合物中明胶与果胶的wt:wt比。
39.根据权利要求36-38中任一项所述的方法,其还包括调整所述pH依赖性壳组合物中右旋糖的量。
40.根据权利要求36-39中任一项所述的方法,其还包括调整所述pH依赖性壳组合物的带厚度。
41.治疗病症的方法,其包括向有此需要的受试者施用根据权利要求1至27中任一项所述的延迟释放软凝胶胶囊。
42.降低打嗝发生率的方法,其包括向有此需要的受试者施用延迟释放软凝胶胶囊,所述延迟释放软凝胶胶囊包含:
(a)填充材料;以及
(b)pH依赖性壳组合物,
其中所述填充材料包含至少一种药学活性成分,
其中所述pH依赖性壳组合物包含明胶、果胶和右旋糖,并且
其中所述pH依赖性壳组合物在结肠环境中溶出/崩解/破裂。
43.根据权利要求42所述的方法,其中所述填充材料包含鱼油、磷虾油、大蒜油或其组合。
44.根据权利要求42-43中任一项所述的方法,其中基于在USP Apparatus II中用桨以50rpm的速度在任选地含有胃蛋白酶的0.1N HCl中进行的溶出/崩解试验,所述延迟释放软凝胶胶囊在酸性介质中在至少约15分钟,至少约30分钟,至少约1小时,至少约2小时,至少约3小时,至少约4小时,或至少约5小时内溶出/崩解。
45.根据权利要求42-44中任一项所述的方法,其中基于在USP Apparatus II中用桨以50rpm的速度在任选地含有胰酶的pH 6.8磷酸盐缓冲液中进行的溶出/崩解试验,所述延迟释放软凝胶胶囊在肠道环境中在至少约10分钟后、至少约15分钟后、至少约20分钟后、至少约25分钟后、至少约25分钟后、至少约30分钟后、至少约35分钟后、至少约40分钟后、或从约10分钟、约15分钟、约20分钟、约25分钟或约30分钟中的任一个至约35分钟、约40分钟、约45分钟、约50分钟、约55分钟、约60分钟、约75分钟或约90分钟中的任一个溶出/崩解。
46.根据权利要求1-27中任一项所述的延迟释放软凝胶胶囊,其还包含常规pH依赖性聚合物。
47.根据权利要求1-27中任一项所述的延迟释放软凝胶胶囊,其中所述延迟释放软凝胶胶囊基本上不含或不含常规pH依赖性聚合物。
48.延迟释放软凝胶胶囊,其包含:
(a)填充材料;以及
(b)pH依赖性壳组合物,
其中所述填充材料包含至少一种药学活性成分,
其中所述pH依赖性壳组合物包含明胶、pH依赖性聚合物和右旋糖,并且
其中所述pH依赖性壳组合物在结肠环境中溶出/崩解/破裂。
49.将药物递送至患者结肠的方法,包括口服施用延迟释放软凝胶胶囊,所述胶囊包含:
(a)填充材料;和
(b)pH依赖性壳组合物,
其中所述填充材料包含至少一种药学活性成分,
其中所述pH依赖性壳组合物包含明胶、pH依赖性聚合物和右旋糖。
50.根据权利要求48所述的方法,其中至少80%的药学活性成分被递送至结肠。
51.根据权利要求48所述的方法,其中至少85%的药学活性成分被递送至结肠。
52.根据权利要求48所述的方法,其中至少90%的药学活性成分被递送至结肠。
53.根据权利要求48所述的方法,其中至少95%的药学活性成分被递送至结肠。
54.根据权利要求48所述的方法,其中至少99%的药学活性成分被递送至结肠。
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