CN105007899A - 用于提高生物利用度的口腔崩解片制剂 - Google Patents
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Abstract
本发明的一些方面涉及一种制剂,所述制剂包括难溶性药物和离子聚合物的固态分散体或均匀混合物,其令人惊讶地显示出片剂的快速崩解。
Description
相关申请的交叉引用
本申请要求于2012年12月20日提交的美国临时申请第61/739,813号的权益和于2013年1月4日提交的美国临时申请第61/749,040号的权益,其公开的内容在此引作参考。
技术领域
本发明主要涉及包含在水中具有低溶解性的活性药物成分的制剂。在一些方面,所述制剂为固体口服剂型。所述制剂的实施方案包括口腔崩解片。
背景技术
许多在治疗上有用的药品具有低水溶性和/或低肠道通透性。这些性质使得用于药品递送的剂型设计复杂化。已开发出生物药剂学分类系统(“BCS”),通过药品的溶解性及通透性来描述它们。
类别I-被很好吸收的高通透性、高溶解性药物。
类别II-生物利用度受限于溶解速率的高通透性、低溶解性药物。
类别III-生物利用度受限于渗透速率的低通透性、高溶解性药物。
类别IV-具有低生物利用度及高变异性的药代动力学参数(如,AUC和Cmax)的低通透性、低溶解性药物。
当一种药物的最高单位剂量强度是在1-7.5的pH范围内,可溶于250mL或更少的水介质中时,根据BCS规定所述药物被认为高度可溶。然而许多药品属于类别II和IV。配制剂型以递送这样的药物,特别地当每份剂量中必须要递送更大量的药物时,是非常具有挑战性的。绝对药物溶解度并不总是最重要的参数,因为口服给药后,药物在胃肠系统中不同部位的停留时间不同,并常常需要药物在其被运输通过特定部位时是溶液形式,使其能通过所述部位被全身吸收。具有低溶解度的药物的实例是与水所形成溶液的浓度不大于1mg/mL或不大于0.1mg/mL的那些。
已使用多种不同的方法改善药物的溶解度特性。对于许多物质,可通过减小颗粒尺寸来提高其溶解性;增大的颗粒表面积通常会产生更快的溶出速率。有时,不同的多晶形式,包括结晶形式、溶剂化物形式和无定形形式,都会具有不同的溶解性,可选择合适的形式以满足特殊需求。但是,这些方法并非没有困难,因为非常小的颗粒通常具有差流动性和操作特性,其可影响药物含量均匀性,且许多多晶形式不具有没有转化成不同形态的足够的物理稳定性去经历制剂加工过程以及去经历超过典型产品保质期的后续存储过程。
所述无定形颗粒可以通过克服晶格能而具有增强的溶解性。典型地,相比于物质的晶态,无定形药物颗粒是热力学亚稳定的,但具有显著提高的溶解性和生物利用度。溶解度可进一步被分类为平衡溶解度与过饱和度两类。“平衡溶解度”是指物质在特定液体环境中,没有助溶剂(solubilization aid)存在下的溶解度。“过饱和度”为物质在超过其平衡溶解度时的溶解状态,其特征在于该溶解度大于由物质在给定液体环境中的天然溶解度所定义的溶解度。通过将药物由结晶形式转化为无定形形式,可达到过饱和溶解度,这又可以提高生物利用度。但是,化学和物理学的药物不稳定性的巨大挑战仍然存在。无定形态可被看作是显示更高化学反应性的假溶液态,所述化学反应性体现在降低的物理和化学稳定性及保质期上。已有某些药物以无定形态被商业化,其中所述药品的无定形形式在产品的正常保质期内具有可接受的稳定性,或者可通过其他制剂组分得以稳定。此外,有些热力学亚稳定的晶态药物已成功地被商业化。
无定形固态分散体被用于稳定无定形材料。一种固态分散体至少由两个不同的组分形成,通常地为(a)一种可为晶态或无定形态的聚合物和(b)一种可进行分子级分散的,为无定形颗粒(簇)或结晶颗粒的疏水药物。聚合物可通过提高混相混合物的玻璃转化温度(Tg),从而降低分子在一般存储温度下的分子流动性,或者通过与药物的官能团发生特定的相互作用来改善固态分散体中无定形药物的物理稳定性。对于能有效阻止结晶的聚合物,其必须与药物是分子级混相的(molecularlymiscible)。但是,迄今为止,由于固态分散体系统的物理不稳定性而使固体分散体的发展受到显著制约。聚合物材料在它们的Tg温度下不处于热力学平衡中,所以固体聚合物达到了其更稳定的状态(更低的能量)。同时,湿度对无定形材料的存储稳定性的影响也非常重要,因为它可以增强药物的流动性并促进药物结晶。此外,固态分散体中所用的许多聚合物具有吸湿性,会在存储期间造成相分离、晶体生长或从非晶态转化为晶态或从亚稳结晶转化为更为稳定的结构,这些都可导致溶解度和溶出速率的降低。
对于某些患者,吞咽典型的固态药物剂型是困难的。这些患者可能是年老的、非常年幼的、遭受精神障碍的、具有口腔或食道功能障碍或畸形的人群等。当优选固体剂型时,例如要降低产生剂量误差的几率时,已开发出在口腔中保留时能快速崩解的产品。该崩解可能是药片基质分解为非常小的颗粒和/或基质在唾液中溶出,从而促进吞咽。
美国食品和药物管理局已将口腔崩解片(“ODT”)定义为一种包含药用物质的固体剂型,将所述固体剂型置于舌上时其可快速地,一般大约在几秒钟内崩解。通常,希望该剂型进入口腔后30秒内发生崩解。这样的剂型可用于治疗对吞咽药片、胶囊剂等有困难的儿科和老年患者,以及反感常规吞咽式固体剂型的精神病患者。唾液的作用足以达到预期的结果,而不需要机械粉碎(如咀嚼)。令人满意地,吞咽所述崩解剂型不需要外部液体来进行。ODT有时也被称作“口腔分散(orodispersible)”片。
为了病人的可接受性,除了需要合适的崩解时间外,ODT剂型具有某些重要的必要条件。经常地,由于许多物质具有苦的或其他不愉悦的味道,因而需要掩盖药品的味道。同样,崩解片的口感非常重要,因此应该避免吞咽后口中的砂砾感和残渣感。
当前有一些技术用于生产ODT产品,包括溶液或悬浮液的冷冻干燥或冻干、粉末掺混物的压缩、熔体或糊剂的塑型、熔融制粒以及其他技术。大多数技术将片剂制备成对水溶剂而言是相当多孔,从而促进基质在唾液中的快速崩解。
美国专利第4,758,598号中描述了一种早期制备口腔崩解片的方法,其中将药物物理地滞留于冷冻-干燥的基质中,所述基质包括填充剂(如:甘露醇)和聚合物(如:明胶)。所述产品是一个十分易碎的、低密度多孔的、包裹于塑料托盘中的干胶片(wafer),所述干胶片形成于冷冻干燥器中。最近,美国专利第5,763,476号中描述了以这种方式制备的马来酸阿塞那平;药物被释放到唾液中,并由于其适度的水溶性,通过口腔粘膜进行全身吸收。也有其他现有产品使用这种技术进行制造。
虽然,观念可能是快速崩解导致了快速的吸收速率和生物利用度,但是这通常无法在低溶解性的药物中观察到。伴随着剂型崩解,仍需要药物先溶解再能被吸收。在一个剂型中同时提供快速崩解性和增强的药物溶解性将是有利的。
有一种持续存在的需求是改善包含低溶解性药物的药学制剂,在其中提供口腔快速崩解和更高的药物溶解度的特点,从而针对某些治疗类型加快难溶性药物的起效时间,以改善患者依从性。
发明内容
本发明的一方面为一种口腔崩解片,其包括难溶性药物和离子聚合物的分散体,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中选择所述离子聚合物以使所述片剂在约30秒内崩解,其中所述片剂进一步包括至少一种添加剂、赋形剂或载体。在一些实施方案中,所述药物是甲地孕酮或其药学上可接受的盐。
本发明的一方面为一种制剂,其包括难溶性药物和离子聚合物的固态分散体或均匀混合物,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中所述离子聚合物以所述制剂的重量的至少45%的量存在。在一些实施方案中,所述离子聚合物以所述制剂的重量的至少约50%的量存在。在一些实施方案中,所述离子聚合物以所述制剂的重量的至少约65%的量存在。在一些实施方案中,所述离子聚合物以所述制剂的重量的约50%至约75%的范围的量存在。
在一些实施方案中,所述聚合物是阴离子聚合物。在一些实施方案中,所述阴离子聚合物是甲基丙烯酸和丙烯酸酯的共聚物,所述丙烯酸酯选自由丙烯酸乙酯、甲基丙烯酸酯和甲基丙烯酸甲酯组成的组。
在一些实施方案中,所述聚合物是阳离子聚合物。在一些实施方案中,所述阳离子聚合物基于甲基丙烯酸二甲胺乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的共聚物。
在一些实施方案中,所述聚合物是乙酸和羟丙基甲基纤维素的单琥珀酸酯的混合物。
在一些实施方案中,所述难溶性药物以所述制剂的重量的大约5%到大约75%的范围的量存在。在一些实施方案中,所述难溶性药物以所述制剂的重量的大约20%到大约50%的范围的量存在。在一些实施方案中,所述难溶性药物以所述制剂的重量的大约30%到大约50%的范围的量存在。在一些实施方案中,所述难溶性药物选自由镇痛药、安眠药、用于治疗双相型障碍的药剂、用于治疗精神分裂症的药剂和用于治疗中枢神经系统的药剂组成的组。在一些实施方案中,所述难溶性药物选自由甲地孕酮、齐拉西酮、右旋佐匹克隆和舒马曲坦或它们的药学上可接受的酸、盐或水合物组成的组。
在一些实施方案中,选择所述离子聚合物以使所述分散体的玻璃转化温度维持在约50℃到约150℃之间。在一些实施方案中,选择所述离子聚合物以使所述分散体的玻璃转化温度维持在约50℃到约120℃之间。在一些实施方案中,组合物进一步包括至少一种添加剂、赋形剂或载体。在一些实施方案中,所述至少一种添加剂、赋形剂或载体选自由稀释剂、粘合剂、药物稳定剂、崩解剂、助流剂、润滑剂、释放率调节剂、抗氧化剂、包衣、着色剂、甜味剂和香料组成的组。
本发明的另一方面为一种口腔崩解片制剂,其包括难溶性药物和离子聚合物的分散体,以及至少一种药学可接受的添加剂、赋形剂或载体,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中所述离子聚合物以所述制剂的重量的至少45%的量存在。在一些实施方案中,所述分散体的平均颗粒尺寸为约100μm到约350μm。
在一些实施方案中,提供了一种治疗个体的方法,其包括施用一种制剂,所述制剂包含难溶性药物和离子聚合物的分散体,以及至少一种药学可接受的添加剂、赋形剂或载体,其中所述离子聚合物以维持所述难溶性药物处于实质上无定形形式的量存在,且其中所述离子聚合物以所述制剂的重量的至少45%的量存在。
本发明的另一方面为一种制剂,其包括甲地孕酮和一种离子聚合物,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中所述离子聚合物以所述制剂的重量的65%的量存在。
在本发明的一些实施方案中,所述口腔崩解片令人惊奇地展现出快速崩解和提高的溶出度以及生物利用度。在一些实施方案中,选择离子聚合物以提供前文所述的快速崩解和提高的溶出度/生物利用度。
本发明另一方面为一种药物制剂,其包含一种具有低水溶性无定形药物和至少一种难溶性离子聚合物的均匀混合物。在一些实施方案中,从所述药物和聚合物的熔融结合物中得到所述均匀混合物。在一些实施方案中,从包含药物和聚合物的溶液的沉淀中得到所述均匀混合物。在一些实施方案中,所述混合物为口腔崩解片的形式。在一些实施方案中,所述药物是甲地孕酮或及其盐。在一些实施方案中,所述药物是醋酸甲地孕酮。
本发明的另一方面为一种包括具有低水溶性药物的组合物。
本发明的另一方面为口腔崩解片药物制剂,其包括具有低水溶性的无定形药物和至少一种阳离子聚合物的均匀混合物。
本发明的另一方面为一种口腔崩解片药物制剂,其包括具有低水溶性无定形药物和至少一种阴离子聚合物的均匀混合物。在一些实施方案中,从所述药物和聚合物的熔融结合物中得到所述均匀混合物。在一些实施方案中,从包含所述药物和聚合物的溶液的沉淀中得到所述均匀混合物。在一些实施方案中,所述聚合物是一种氨基甲基丙烯酸酯共聚物。在一些实施方案中,所述聚合物是一种甲基丙烯酸共聚物,类型A。在一些实施方案中,所述聚合物是一种甲基丙烯酸共聚物,类型B。在一些实施方案中,所述聚合物是一种甲基丙烯酸共聚物,类型C。在一些实施方案中,所述聚合物是羟丙甲纤维素醋酸琥珀酸酯。
不希望被任何特定的理论限制,现已发现,当将与离子聚合物制备的难溶性药物的无定形固态分散体被压缩成片剂时,其显示快速崩解,因此所述固态分散体适用于制备具有快速作用时间的ODT剂型。
附图说明
图1阐明了实施例1中组合物1A的初始和存储样品的对比的X-射线粉末衍射(“XRPD”)图。
图2阐明了实施例1中组合物1D的初始和存储样品的对比的XRPD图。
图3阐明了实施例2中组合物2E中不同的药物对聚合物比率的对比的XRPD图。
图4是实施例3中组合物的溶解度数据的图解表示。
图5是ODT组合物的溶解度数据的图解表示。
发明详述
本发明的一些方面为一种制剂,其包括一种难溶性药物和离子聚合物的分散体或均匀混合物。本发明的其他方面涉及一种制剂,其包括一种难溶性药物和离子聚合物的分散体或均匀混合物,其中所述离子聚合物以维持所述难溶性药物处于实质上无定形形式的量存在。本发明的又一方面为一种制剂,其包括难溶性药物和离子聚合物的分散体或均匀混合物,其中所述离子聚合物以维持所述难溶性药物处于实质上无定形形式的量存在,且所述离子聚合物以所述制剂的重量的至少50%的量存在。
如在此所使用的,术语“基本上”的意思是一定程度上达到标准,这样的程度是指本领域普通技术人员将理解,达到了要获得的利益、或条件或预期属性值。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少80%。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少85%。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少90%。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少92.5%。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少95%。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少97.5%。在一些实施方案中,处于无定形形式的活性试剂的量通常为所存在活性试剂总重量的至少99%。
本公开的一些方面涉及具有低水溶性的药物的药学制剂。可以例如使用United States Pharmacopeia 24(美国药典24)(美国药典委员会有限公司,罗克维尔市,马里兰,1999)(USP)中的测试711“溶出”来测试它们的药物溶出度。可使用多种流体用作溶出介质(dissolution media),其包括酸、缓冲剂、消化道模拟液等等,USP的不同专刊中定义了许多所述溶解介质。操作的一个实例是使用“装置2”,其包括一个含有介质的容器,用旋转叶片搅拌所述介质。典型地,将单位剂量浸没于介质中,间歇地取出介质的样本用于药物含量分析,时常使用的是高效液相色谱(“HPLC”)技术。
可使用USP中测试701“崩解”来确定药物剂型的崩解时间。
目前有多种方法用于确定药物的肠道通透性参数,其同时包括体外和体内技术。D.Volpe的“Application of Method Suitability for DrugPermeability Classification”(《美国药剂学家协会杂志》(The AAPS Journal),2010年12月第12卷第4期第670-678页)中综述了部分所述技术。
如本文所使用,术语“药物”、“活性药剂”和“活性药物成分”可相互替换使用。
用于制备制剂的合适药物包括但不限于治疗学分类的下述成员:镇痛药、抗炎药、驱虫药、抗心律失常药、抗菌剂、抗病毒剂、抗凝剂、抗抑郁药、抗糖尿病药、抗癫痫药、抗真菌药、抗痛风药、抗高血压药、抗疟药、抗偏头痛药、抗毒蕈碱药、抗肿瘤药、勃起功能障碍改善剂、免疫抑制剂、抗原虫药、抗甲状腺剂、抗焦虑药、镇静剂、安眠药、神经松弛剂、β-阻滞剂、心肌收缩药、皮质类固醇、利尿剂、抗帕金森剂、胃肠道剂(gastrointestinal agents)、组胺受体拮抗剂、角质剥脱剂、脂质调节剂、抗心绞痛药、环氧合酶-2抑制剂(cox-2inhibitors)、白三烯抑制剂、大环内酯类、肌肉松弛药、营养油(nutritional oil)、抗良性前列腺肥大剂(anti-benign prostate hypertrophy agent)、必需脂肪酸、非必需脂肪酸及其中任意两种或多种的组合。
合适活性药物成分的具体实例包括,但不仅限于:阿比特龙、依曲替酸(acutretin)、阿苯达唑、沙丁胺醇、氨鲁米特(aminogluthemide)、胺碘酮、氨氯地平、安非他明、两性霉素B、阿托伐他汀、阿托伐醌、阿奇霉素、氯苯氨丁酸、倍氯米松(beclomethsone)、贝那普利(benezepril)、苯佐那酯、倍他米松、比卡鲁胺(bicalutanide)、波普瑞韦(boceprevir)、布地奈德、丁胺苯丙酮、白消安、布替萘芬、骨化二醇、卡泊三烯(calciprotiene)、骨化三醇、喜树碱、坎地沙坦、辣椒素、卡马西平(carbamezepine)、胡萝卜素、塞来考昔、西伐他汀(cerivistatin)、塞替利嗪、氯苯那敏、胆钙化醇、西洛他唑、西咪替丁、桂利嗪、环丙沙星、西沙必利、克拉霉素、氯马斯汀、氯米芬、氯米帕明、氯吡格雷(clopidrogel)、可待因、辅酶Q10、环苯扎林、环孢霉素、达那唑、丹曲林、右氯苯那敏(dexchlopheniramine)、双氯芬酸、双香豆素、地高辛、双氢表雄甾酮、双氢麦角胺、双氢速甾醇、地红霉素、多奈哌齐、依法韦仑、依普沙坦(eposartan)、麦角钙化醇、麦角胺、必需脂肪酸来源、右旋佐匹克隆、依托度酸、依托泊苷、法莫替丁、非诺贝特、芬太尼、非索非那定、非那雄胺、氟康唑(flucanazole)、氟比洛芬、氟伐他汀、磷苯妥英(fosphenytion)、夫罗曲普坦、呋喃唑酮、加巴喷丁、吉非罗齐、格列本脲、格列吡嗪、格列本脲、格列美脲(glymepride)、灰黄霉素、卤泛群、布洛芬、厄贝沙坦、伊立替康、异山梨醇、异维A酸(isotreinoin)、伊曲康唑、伊维菌素、酮康唑、酮咯酸、拉莫三嗪、兰索拉唑(lanosprazole)、来氟米特、赖诺普利、洛哌丁胺、氯雷他定、洛伐他汀、L-甲状腺素(L-thryroxine)、叶黄素、番茄红素、甲羟孕酮、米非司酮(mefepristone)、甲氟喹、甲地孕酮(megesterol)、美他沙酮、美沙酮、甲氧沙林、甲硝唑、甲硝唑、咪康唑、咪达唑仑、米格列醇、米诺地尔、米托蒽醌、孟鲁司特、萘丁美酮、纳布啡、那拉曲坦(naratiptan)、那非那韦、硝苯地平、尼索地平(nilsolidipine)、尼鲁米特(nilutanide)、呋喃妥因、尼扎替丁、奥美拉唑、奥普瑞白介素(oprevelkin)、雌二醇(osteradiol)、奥沙普嗪、紫杉醇、帕立骨化醇、帕罗西汀、喷他佐辛、吡格列酮、pizofetin、普伐他汀、泼尼松龙、普罗布考、孕酮、伪麻黄碱、吡啶斯的明、雷贝拉唑、雷洛昔芬、罗非考昔(refocoxib)、瑞格列奈、利福平(rifabutine)、利福喷丁、利福昔明(rifaximine)、利美索龙、利托那韦(ritanovir)、利扎曲普坦、罗格列酮、沙奎那韦、舍曲林、西布曲明、西地那非、辛伐他汀、西罗莫司、螺内酯、舒马普坦、他克林、他克莫司、他莫昔芬、坦洛新、塔革雷汀(targretin)、他扎罗汀、特拉匹韦(telaprevir)、替米沙坦、替尼泊苷、特比萘芬、特拉唑嗪(terzosin)、四氢大麻酚、噻加宾、噻氯匹定(ticlidopine)、替罗非班(tirofibran)、替扎尼定、托吡酯、托泊替康、托瑞米芬、曲马多、维甲酸、曲格列酮、曲伐沙星、泛癸利酮、缬沙坦、文拉法辛、维替泊芬(vertoporfin)、氨己烯酸、维生素A、维生素D、维生素E、维生素K、扎鲁司特、齐留通、齐拉西酮、佐米曲坦、唑吡坦和佐匹克隆。该列表并非意在穷举,因为也可以使用许多其他药物。同样,也可使用能递送任意药物的药学可接受的盐、酯、溶剂合物、水合物和其他衍生物,以任何多晶型形式,可与任意两种或多种活性药物成分相结合以制备制剂。尽管许多药物通常使用它们的药学可接受的衍生物(如盐和酯)来配制,但是为了简洁,上述列表仅给出了基础药物。
某些类别的药物如镇痛药、安眠药、用于治疗双相型障碍和精神分裂症的药物以及其他作用于中枢神经系统的药物将令人期望地具有快速作用时间以提供更有效的治疗。当所述药物具有低溶解性时,如在BCS分类II和IV中的那些药物,则增强其吸收速率尤为重要。在实施方案中,本文公开的技术将增强药物在生理液中的溶出速率。
通常,本发明的所述组合物或制剂中的药物的量为所述制剂的总重量的大约5%到大约75%。在一些实施方案中,在制剂中的药物的量为所述制剂的总重量的大约20%到大约50%。在其他实施方案中,在制剂中的药物的量为所述制剂的总重量的大约25%到大约40%。在进一步的实施方案中,在制剂中的药物的量为所述制剂的总重量的大约25%到大约30%。
本公开的一方面包括至少一种无定形药品和至少一种聚合物的均匀混合物。术语“均匀混合物”表明组分是分散的,当使用例如光学显微术技术时,无法区分个体的组分,因而不可能是粉末组分的简单混合物。在实施方案中,分散体可认为是组分的固态分散体、分子分散体或固溶体。
用于形成均匀混合物的合适聚合物包括但不限于,离子聚合物,例如:丙烯酸酯类,比如由德国的Evonik Industries生产的,作为EUDRAGITTM共聚物销售的多种产品;聚醋酸乙烯酞酸酯;及更疏水的纤维素醚衍生物,比如醋酸纤维素酞酸酯、羟丙甲纤维素醋酸琥珀酸酯和羟丙甲纤维素酞酸酯(例如,HP-50和HP-55级的)。典型地,尽管取决于聚合物,所述聚合物能在具有弱酸性、中性或碱性pH的液体中降解,但它们仍被认为是难溶于水或甚至不溶于水的。
不期望受任何特定理论的限制,认为所述离子聚合物以帮助维持所述药物或活性剂以基本上无定形形式存在,在本文中所定义的该术语。也认为,同样不期望受任何特定理论的限制,所述药物和离子聚合物的分散体或均匀混合物提供的玻璃转化温度为大约50℃到大约150℃。在其他实施方案中,所述分散体的玻璃转化温度可维持在大约50℃到大约100℃。还认为使用离子聚合物,而不用例如非离子聚合物,使所述制剂具有相对更快的崩解时间,因而使所述组合物可被配制成口腔崩解片。
商品EUDRAGIT E 100是一种基于甲基丙烯酸二甲胺乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的阳离子共聚物,其化学名称是“聚(甲基丙烯酸丁酯-共-甲基丙烯酸(2-二甲基氨基乙基)酯-共-甲基丙烯酸甲酯)1:2:1”,在美国药典(USP)中将其归类为“氨基甲基丙烯酸酯共聚物”。
EUDRAGIT L 100-55是一种基于甲基丙烯酸和丙烯酸乙酯的阴离子共聚物,其化学名称是“聚(甲基丙烯酸-共-丙烯酸乙酯)1:1”,在美国药典(USP)将其归类于“甲基丙烯酸共聚物,类型C”。
EUDRAGIT L 100是一种基于甲基丙烯酸和甲基丙烯酸甲酯的共聚物,其化学名称是“聚(甲基丙烯酸-共-甲基丙烯酸甲酯)1:1”,在美国药典(USP)将其归类于“甲基丙烯酸共聚物,类型A”。
EUDRAGIT S 100是一种基于甲基丙烯酸和甲基丙烯酸甲酯的阴离子共聚物,其化学名称是“聚(甲基丙烯酸-共-甲基丙烯酸甲酯)1:2”,在美国药典(USP)将其归类于“甲基丙烯酸共聚物,类型B”。
丙烯酸产品可按多种物理形式提供,例如:EUDRAGIT E PO为EUDRAGIT E 100的粉末形式。类似于EUDRAGIT产品的聚合物产品也可从其他商业来源得到。
羟甲基纤维素醋酸琥珀酸酯可由Shin-Etsu Chemical Co.公司作为AQOATTM产品提供,同样也可从其他来源获得。它们是羟甲基纤维素的醋酸酯和单琥珀酸酯的混合物。美国药典(USP)说明书要求其基于干基计算时,含有12.0-28.0%的甲氧基、4.0-23.0%的羟丙基、2.0-16.0%的乙酰基、4.0-28.0的琥珀酰基。例如,可商购的AQOAT AS-LF产品包含8%的乙酰基和15%的琥珀酰基,AQOAT AS-MF产品包含9%的乙酰基和11%的琥珀酰基,AQOAT AS-HF产品含有12%的乙酰基和7%的琥珀酰基。离子聚合物已被广泛用于肠溶或缓释的包衣应用,以及无定形固态分散体的稳定化。目前发现使用下述方法加入离子聚合物,可制备具有增强的生物利用度的难溶性药物的口腔快速崩解片(ODT)。
可使用多种方法制备均匀混合物,其包括将药物与聚合物混合并融化混合物。另一有用的方法涉及处理药物和聚合物的溶液以形成固体混合物,例如通过移除溶剂或另外沉淀所述固体混合物来实现。可使用技术如蒸发例如在旋转蒸发仪或薄膜干燥器中,或通过喷雾干燥,在真空中移除溶剂。沉淀也可包括将所述溶剂与反溶剂(anti-solvent)或与另一试剂相混合以降低溶质的溶解度,如酸的水溶液。下文讨论了这些及其他溶解度提升的技术。
已开发并持续在开发用于改善难溶性药物的溶出性质的技术,其包括但不限于如下的技术:成盐,使用更可溶的“前药”化合物,使其在体内通过酶或其他化学反应形成所需药物、使用研磨法减小颗粒尺寸、溶解的制剂、脂质类制剂、乳剂系统、分子络合、共结晶和固体分散。每一个所述技术的目的都是通过加快溶出速率和/或提高溶解度来改善难溶性药物的口腔递送。
药学文献中已反复证明减小颗粒尺寸以显著改善难溶性药物的溶出速率,相应地产生改善的吸收和潜在的改善药物治疗的效果。减少颗粒尺寸的方法可分为“自顶向下”或“自底向上”法。可应用于难溶性药物以通过自顶向下方法减小颗粒尺寸的技术实例有微粉化、湿磨法和纳米磨法。通过自底向上方法制备药物颗粒的方法的实例有可控的沉淀、水溶液中的蒸发沉淀及微沉淀。
在一些实施方案中,所述颗粒具有从约100μm至约350μm的尺寸。在其他实施方案中,所述颗粒具有从约100μm至约250μm的尺寸。
固体分散技术是用于改善难溶性药物的溶出特性并从而改善口服生物利用度的一种策略。固体分散技术涉及将难溶性药物分散于固体聚合物基质中。药物在混合物中可按无定形形式或结晶形式存在,在胃液和肠液中提供了增大的溶出速率和/或表观溶解度。已开发出一些制备固态分散体的技术,其包括共沉淀、熔融、喷雾干燥以及热熔体挤出。固体分散系统提供增大的可湿性的药物颗粒表面积,使得溶出速率显著提高。因此,如果肠通透性不是限制性因素(即:BSC分类II中化合物),则作为固体分散系统的制剂可改善这些化合物的吸收。
在热熔体挤出中,将热塑性载体聚合物与药物及任选药理学惰性的赋形剂相结合。将所述混合物引入至旋转螺杆(rotating screw)中,使粉末传输至加热区域,在那里给予所述混合物剪力,混合所述材料直至产生熔融体。热熔体挤出设备包括挤出机、用于挤出机的辅助设备、下游处理设备以及其他用于性能和产品质量评估的监测工具。所述挤出机典型地由进料斗、桶、单或双螺杆以及冲模和螺杆传动单元组成。用于挤出机的辅助设备主要由桶的加热/冷却装置、冷却产品用的传输带和溶剂递送泵组成。设备中的监测装置包括温度计、螺杆转速控制器,挤出扭矩监测器和压力计。
使用不同形状的冲模和合适下游处理使得热熔体挤出成为制造大量不同剂型的高度通用的技术。可通过裂隙状模具将材料挤压至冷却的轧辊上以制备薄膜,所述轧辊将薄膜拉伸至预期的厚度。可将挤出线料(strand)切割成片剂,或在短圆筒中丸化,其可接着被球化以获得球状颗粒。切割可在传输带上的线料冷却后(线料造粒机),或直接在挤出机中,线料处于软状态时(模面造粒机)进行。除切割操作外,整体基质可通过在片型空腔中注塑成型或在软状态时于两个反向旋转的轧光辊(calendar roll)间压延来得到。研磨热熔体挤出物得到粉末,其可被直接压缩成片剂或应用于干燥粉末包衣。
在喷雾干燥法中,首先将聚合物和药物溶解在有机溶剂中,而后将其转化为粉末状固体,转化方法为将溶液雾化成小液滴,并使用热的干燥气体蒸发溶剂。在溶剂蒸发之后,用过滤器或旋风分离器将干燥的粉末颗粒从气体中分离。由于液滴所带来的大的比表面积,所述溶剂快速蒸发,并很快形成固态分散体,所述过程可以足够快以阻止相分离。用喷雾干燥法制备的固态分散体由颗粒组成,所述颗粒的尺寸可通过改变液滴的尺寸来调节,以满足后续处理或应用的需求(例如:自由流动的颗粒或用于吸入的颗粒)。喷雾干燥法相关的挑战涉及到的事实是聚合物和药物都必须溶解在有机溶剂中,达到保持可喷射的较高固体含量。同样,必须调节加工条件以避免产品的热应力,并生产具有低的溶剂残留水平的产品。使用喷雾干燥法的优势涉及从液体到粉末形式的一步处理、快速干燥、药品的低热应力,以及高吞吐速率。
对通过喷雾干燥法制备的材料进行下游处理,可涉及将所得材料与一种或多种赋形剂掺混,然后压缩为片剂。直接压缩法受到所使用的赋形剂的性质影响,如表面能和变形。此外,为保证坚固及成功加工而选择的适当赋形剂的物理机械性能包括:良好的流动性、良好的粘合功能、良好的可压缩性、低润滑敏感性、以及在具有甚至减少的停留时间的高速制片机中良好的可加工性(machineability)。
pH-控制的离子沉淀(PCIP)依赖于酸性或碱性水溶液中溶剂-控制沉淀,因此只有离子聚合物(而非水溶性聚合物)适宜应用。PCIP法包括如下:(a)将药物和离子聚合物溶解于合适的非水溶剂中;及(b)将(a)溶液与水溶液接触,以产生一个所述聚合物难以溶解在其中的pH环境,从而药学活性化合物和离子聚合物作为化合物/聚合物复合物的微量沉淀,由粉末X-射线衍射确定其中存在于水不溶性复合物中的药学活性化合物主要处于无定形形式,且其在所述化合物/聚合物复合物中以重量计不少于约10wt%,所述化合物/聚合物复合物中的离子聚合物以重量计小于约20wt%。在一些实施方案中,对于阴离子聚合物,水溶液的pH范围是大约1至大约4。在其他实施方案中,对于阴离子聚合物,水溶液的pH范围是大约1至大约3.5。在一些实施方案中,对于阳离子聚合物,水溶液的pH范围是大约7至大约11。使用PCIP方法制备的材料的下游加工可包括:(a)使用重击或碾压法将所得材料密实化;(b)碾磨(a)中材料,以得到所需的颗粒尺寸;(c)将(b)中碾磨的材料与一种和多种合适的赋形剂掺混;并(d)压缩为片剂。
流化床包衣使用一种流化床包衣系统,其中将包含药物和载体的溶液喷射到赋形剂的颗粒上,如糖或纤维素球,以便一步生产可用于制片的粒料或用于胶囊化的药物包衣小球。该技术基于去除散装液体的溶剂,同时固体沉淀,并同时沉积于颗粒的表面。包衣法非常高效,且易于按比例放大。该方法既可用于控释-固态分散体也可用于速释-固态分散体。
所述固体剂型的组分包括,但不限于:一种或多种药品以及任意所需数目的赋形剂,如稀释剂、粘合剂、药物稳定剂、崩解剂、助流剂、润滑剂、释放速率调节剂、抗氧化剂、包衣剂、着色剂、甜味剂、香料等。
基于本发明的多种有用的填料和稀释剂包括但不限于:淀粉、乳糖、纤维素衍生物、糖粉等。不同等级的乳糖包括但不限于:乳糖一水合物、乳糖DT(直接压片)、无水乳糖及其他。不同的淀粉包括但不限于:玉米淀粉、马铃薯淀粉、大米淀粉、小麦淀粉、预胶凝淀粉及其他。可使用的不同纤维素包括晶态纤维素类(crystalline celluloses),如微晶纤维素和粉状纤维素。其他有用的稀释剂包括但不限于:羧甲醚纤维素、糖醇类如甘露醇、山梨糖醇和木糖醇、碳酸钙、碳酸镁、磷酸氢钙和磷酸钙。
根据本发明的多种有用的粘合剂包括但不限于:各种等级的羟丙基纤维素、各种等级的羟丙基甲基纤维素、各种等级的聚乙烯吡咯烷酮、共聚维酮(copovidones)、阿拉伯胶粉、明胶、瓜尔胶、卡波姆、甲基纤维素,聚甲基丙烯酸酯和淀粉。
多种有用的崩解剂包括但不限于:羟甲基纤维素钙、羧甲基淀粉钠、交联羧甲基纤维素钠、交聚维酮(交联的N-乙烯基-2-吡咯烷酮均聚物)和低取代的羟丙基纤维素。其他有用的崩解剂包括羧甲基淀粉钠、胶体二氧化硅、海藻酸和海藻酸酯、丙烯酸衍生物及各种淀粉。
在实施方案中,本申请的制剂可包含至少一种用于增强药物稳定性的抗氧化剂。所述抗氧化剂可以作为制剂的一部分或者作为封装组分(packaging component)存在。抗氧化剂可以按有效延迟对氧化敏感的药物的分解的量存在。在实施方案中,所述制剂中抗氧化剂的含量为约0.001-10重量%(相对于活性剂含量)。抗氧化剂的非限制性实例包括一种或多种抗坏血酸及其盐、生育酚、亚硫酸盐如焦亚硫酸钠或亚硫酸钠、硫化钠、丁羟茴醚、丁羟甲苯、抗坏血酸棕榈酸酯和没食子酸丙酯。本领域技术人员能容易地识别出其他合适的抗氧化剂。
有用的润滑剂包括硬脂酸镁、单硬脂酸甘油酯、棕榈酸、滑石、巴西棕榈蜡、硬脂酸钙钠、十二烷基硫酸钠或十二烷基硫酸镁、钙皂、硬脂酸锌、聚氧乙烯单硬脂酸盐、硅酸钙、二氧化硅、氢化植物油和脂肪、硬脂酸和它们的任意组合。
可使用一种或多种助流剂材料,其能改善粉末掺混物、小丸等的流动,并帮助使剂型质量的变化最小化。有用的助流剂包括但不限于:二氧化硅、滑石、高岭土,及它们的任意组合。
可使用的甜味剂包括蔗糖、三氯蔗糖、阿斯巴甜等。
有用的香料包括药学可接受的天然油类、天然香料及人工香料。代表性的香料包括但不限于:薄荷醇、薄荷、冬青、柑橘、樱桃及其他水果,香草、杏仁及其他坚果等。常使用两种或更多种香料的混合物。
着色剂可用于色码(color code)组合物,例如,用于指示其中治疗剂的类型和剂量。还可以使用着色剂去区分包含在单位剂型(如胶囊剂)中的多微粒的不同成分。合适的着色剂包括但不限于:一种或多种天然色素和/或人工色素例如FD&C着色剂、天然果汁浓缩剂,色素如氧化钛、二氧化硅、氧化铁、氧化锌等。
可用于制备本公开的药学制剂的多种溶剂包括但不限于:水、甲醇、乙醇、丙酮、乙酰丙酮、多元醇类、聚醚类、油类、酯类、烷基酮类、二氯甲烷、异丙醇、丁醇、乙酸甲酯、乙酸乙酯、乙酸异丙酯、蓖麻油、乙二醇单乙醚、二乙二醇单丁醚、二乙二醇单乙醚、二甲亚砜、N,N-二甲基甲酰胺、四氢呋喃及它们的任意混合物。
前述罗列的赋形剂物质和助加工剂非意在穷举,而只是不同分类的代表性成员。本领域普通技术人员会知道到许多其他有用的物质,以及它们的用途是明确涵盖在本文中的。同样,熟知许多赋形剂可以在药物制剂中发挥超过一种的功能。
下述实施例进一步描述了本公开的某些特定的方面和实施方案,但不得以任何方式解释为限制本公开的范围。在实施例中,难溶性药物的代表是醋酸甲地孕酮,但对于本领域普通技术人员显而易见的是本公开的技术对许多其他药品也是有用的。
具体实施方式
实施例1
使用下表所列成分及温度制备组合物,其中成分中圆括号内数字为重量百分数。
*例如,EUDRAGIT L 100。
**例如,EUDRAGIT L 100-55。
***例如,AQOAT AS-LF。
****例如,EUDRAGIT E PO。
将成分于高剪切混合器中混合,并使用Leistritz NANO 16活塞馈双螺杆挤出机(piston-fed twin screw extruder)(Leistritz ExtrusionstechnikGmbH,Nuremberg,德国)通过2mm冲模,在指定温度下以底部进料模式对所述成分进行挤出。然后使用由The Fitzpatrick Company(Elmhurst,Illinois,U.S.A.)出售的FitzMill Comminutor造粒机(孔筛#1521-0040,中速,刀口向前)将所述挤出物进行研磨,并用下述方法进行进一步的表征。
为了评估挤出物的物理学稳定性,以及所提出的将晶态醋酸甲地孕酮转化为无定形形式方法的有效性,将挤出物的样品放置于20mL的棕色玻璃容器中,并在40℃及75%的相对湿度(“RH”)下于开放的气氛中维持一周。使用X-射线粉末衍射测定原始挤出物中药物及存储后的样品的物理形态,结果示于图1和图2中。
图1和图2的图示中,x轴为2θ角度,y轴为强度单位。曲线A和D是初始的醋酸甲地孕酮成分的图示。曲线B针对组合物1A,其为敞开于40℃及75%的相对湿度(RH)的气氛储存一周后的图示。曲线C针对初始合成的组合物1A。曲线E针对组合物1D,其为敞开于40℃及75%的相对湿度(RH)的气氛中储存一周后的图示。曲线F针对初始制备的组合物1D。这里所提供的所有X-射线数据,均使用铜Kα辐射得到。
实施例2
使用pH-控制离子沉淀(PCIP)法制备含有醋酸甲地孕酮(以重量计40%)和一种聚合物(以重量计60%)的组合物。将所述药物和阴离子聚合物溶解于N,N-二甲基乙酰胺中,以形成含有20wt%溶质的溶液,加入冷的0.1N盐酸直至固体沉淀。分离所得固体,用0.1N的HCl洗涤,然后以冷水洗涤两次,并于室温下干燥过夜(25℃)。将所得粉末通过40目筛,并包装留作后用。
*例如,EUDRAGIT L 100。
**例如,EUDRAGIT L 100-55。
***例如,AQOAT AS-LF。
图3显示了初始醋酸甲地孕酮(“A”)和样品的X-射线衍射图,所述样品的制备类似组合物2A,其中不同的药物对聚合物重量比为50:50(“B”);40:60(“C”);35:65(“D”)及30:70(“E”)。x轴单位为2θ角度,y轴值为强度单元。不希望被任何特定的理论限制,认为当组合物中至少含有约65wt%的聚合物时,药物的晶态峰消失,但不同的药物能使用更低或更高量的聚合物成为无定形态。
实施例3
使用下表中成分,制备口腔崩解片制剂3A-3H。
步骤:
1.将醋酸甲地孕酮与列表中所需的其后五种成分混合,并用与实施例1中相类似的方法进行挤出。将冷却的挤出物通过60目筛孔的FitzmillTM造粒机。
2.将研磨后的挤出物与交聚维酮、甘露醇、微晶纤维素、三氯蔗糖和香料(若需要)混合,然后加入硬脂酸镁并混合。
3.使用大约8.9kN(2000磅)的力将混合后的材料压缩为片剂。
也可根据实施例2中的操作制备组合物制备片剂,将那些组合物替换为上述步骤2中的研磨挤出物。
使用美国药典(USP)中的操作,测试根据上述制剂3A、3D、3E和3H制备的片剂在水中的崩解时间。结果如下表所示。
包含具有离子聚合物如甲基丙烯酸共聚物,类型A(如EUDRAGITL100)或羟丙甲纤维素醋酸琥珀酸酯(如AQOAT AS-LF)的固态分散体的片剂在水中快速崩解,即:小于30秒。通过最优化片剂重量和某些赋形剂组分,可进一步改善使用离子聚合物制备的片剂的崩解时间,提供20秒到5秒的崩解时间。但是,如组合物3D的25分钟的崩解时间所证明,包含由水溶性非离子聚合物(如共聚维酮)制备的固态分散体的片剂崩解极为缓慢。
虽然本发明所公开内容不应该被任何特定的操作理论所限制,但是由于离子聚合物在水中缓慢水合的性质,包含嵌入水难溶性离子聚合物的无定形药物的片剂在水中有可能会快速崩解。由于非离子聚合物在水中快速水合的特性,其阻碍了崩解从而延迟药物的释放,使得用水溶性非离子聚合物(如共聚维酮)制备的固态分散体崩解更为缓慢。
使用美国药典(USP)装置2和900mL 10mM的磷酸缓冲液(pH 6.8),以50rpm的转速测试组合物3D和3H的溶出。结果示于图4中,其中x轴为分钟,y轴为所含有的溶解的药物的累积百分数。曲线A针对组合物3H,曲线B针对组合物3D。如图4所示,包含分散于难溶性离子聚合物的固体药物分散体的组合物(组合物3H),其溶出曲线展示出快速的药物释放,这可归因为快速的剂型崩解。包含由水溶性非离子聚合物(组合物30)制备的固体药物分散体的组合物(组合物3D),表现出更缓慢的药物释放,这可能归因于该剂型相对缓慢的崩解性质。
溶解性测试的实施方式为,将200mg含药物的未压缩最终掺混组合物与100mL的50mM磷酸缓冲液(pH 7.5)相混合,并将所得混合物放于振荡器上的封闭容器内。间隔取样(每次2mL),并使用紫外光谱分析样品中溶解的醋酸甲地孕酮浓度。结果示于图5中,其中x轴是分钟,y轴是单位为mg/mL的药物浓度。曲线A针对组合物3H,曲线B针对组合物3A,曲线C针对组合物3G,曲线D针对初始醋酸甲地孕酮成分。
实施例4
使用实施例3中描述的操作制备口腔崩解片,成分如下表所示。
使用美国药典(USP)中的操作,测试片剂在水中的崩解时间,结果如下所示。
如表中所示,含难溶性离子聚合物(如羟丙甲纤维素醋酸琥珀酸酯(AQOAT AS-LF))的固态分散体,在水中的崩解显著地快于包含水溶性非离子聚合物(如共聚维酮(KOLLIDON VA64))的崩解。
实施例5
使用下述方法制备口腔崩解片,成分如下表所示。
步骤:
1.将药物和丙烯酸树脂EPO在PK混合器中混合,并使用类似于实施例1中的方式对其进行挤出。使冷却后的挤出物通过具有60筛目的FitzMillTM造粒机。
2.将碾磨后的挤出物与交聚维酮、甘露醇、微晶纤维素、三氯蔗糖和香料混合,然后加入硬脂酸镁并混合。
3.将混合后的材料压缩成片剂。
Claims (27)
1.一种制剂,其包括难溶性药物和离子聚合物的固态分散体,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中所述离子聚合物以所述制剂的重量的至少45%的量存在。
2.权利要求1所述的制剂,其中所述离子聚合物以所述制剂的重量的至少约50%的量存在。
3.权利要求1所述的制剂,其中所述离子聚合物以所述制剂的重量的至少约65%的量存在。
4.权利要求1所述的制剂,其中所述离子聚合物以所述制剂的重量的大约55%至大约75%的范围的量存在。
5.权利要求1所述的制剂,其中所述聚合物是阴离子聚合物。
6.权利要求5所述的制剂,其中所述阴离子聚合物是甲基丙烯酸和丙烯酸酯的共聚物,所述丙烯酸酯选自由丙烯酸乙酯、甲基丙烯酸酯和甲基丙烯酸甲酯组成的组。
7.权利要求1所述的制剂,其中所述聚合物是阳离子聚合物。
8.权利要求7所述的制剂,其中所述阳离子聚合物是基于甲基丙烯酸二甲胺乙酯、甲基丙烯酸丁酯和甲基丙烯酸甲酯的共聚物。
9.权利要求1所述的制剂,其中所述聚合物是羟丙基甲基纤维素的醋酸酯和单琥珀酸酯的混合物。
10.权利要求1所述的制剂,其中所述难溶性药物以所述制剂的重量的大约5%到大约75%的范围的量存在。
11.权利要求1所述的制剂,其中所述难溶性药物以所述制剂的重量的大约20%到大约50%的范围的量存在。
12.权利要求1所述的制剂,其中所述难溶性药物以所述制剂的重量的大约30%到大约50%的范围的量存在。
13.权利要求1所述的制剂,其中所述难溶性药物选自由镇痛药、安眠药、用于治疗双相型障碍的药物、用于治疗精神分裂症的药物和用于治疗中枢神经系统药物组成的组。
14.权利要求1所述的制剂,其中所述难溶性药物选自由甲地孕酮、齐拉西酮、右旋佐匹克隆和舒马曲坦或它们的药学可接受的酸、盐或水合物组成的组。
15.权利要求1所述的制剂,其中选择所述离子聚合物以使所述分散体的玻璃转化温度维持在大约50℃到大约150℃。
16.权利要求1所述的制剂,其中选择所述离子聚合物以使所述分散体的玻璃转化温度维持在大约50℃到大约120℃。
17.权利要求1所述的制剂,其进一步包括至少一种添加剂、赋形剂或载体。
18.权利要求17所述的制剂,其中所述至少一种添加剂、赋形剂或载体选自由稀释剂、粘合剂、药物稳定剂、崩解剂、助流剂、润滑剂、释放速率调节剂、抗氧化剂、包衣剂、着色剂、甜味剂和香料组成的组。
19.一种口腔崩解片,其包括权利要求1所述的制剂和至少一种药学可接受的添加剂、赋形剂或载体。
20.权利要求19所述的口腔崩解片,其中所述分散体的平均颗粒范围为大约100μm到大约350μm。
21.一种治疗个体的方法,其包括施用权利要求1所述的制剂,其中将所述制剂与至少一种药学可接受的添加剂、赋形剂或载体相结合。
22.一种治疗个体的方法,其包括施用权利要求19所述的口腔崩解片。
23.一种制剂,其包括甲地孕酮和离子聚合物的固态分散体,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中所述离子聚合物以所述制剂重量的至少约65%的量存在。
24.一种口腔崩解剂,其包括难溶性药物和离子聚合物的固态分散体,其中所述离子聚合物以维持所述难溶性药物处于基本上无定形形式的量存在,且其中选择所述离子聚合物以使所述片剂崩解时间在大约30秒之内,其中所述片剂进一步包含至少一种添加剂、赋形剂或载体。
25.权利要求24所述的口腔崩解片,其中所述难溶性药物是甲地孕酮或其药学可接受的盐。
26.权利要求24所述的口腔崩解片,其中所述离子聚合物的量为所述分散体的重量的至少约55%。
27.权利要求24所述的口腔崩解片,其中所述离子聚合物的量为所述分散体的重量的至少约65%。
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CN107669647A (zh) * | 2017-10-30 | 2018-02-09 | 湖南中医药高等专科学校 | 一种右佐匹克隆口崩片及其制备方法 |
CN108926541A (zh) * | 2017-05-26 | 2018-12-04 | 万全万特制药(厦门)有限公司 | 齐拉西酮口崩片及其制备方法 |
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EP2934486A2 (en) | 2015-10-28 |
CA2895534A1 (en) | 2014-06-26 |
CA2895534C (en) | 2019-10-22 |
WO2014100418A3 (en) | 2014-08-28 |
WO2014100418A2 (en) | 2014-06-26 |
AU2013361307A1 (en) | 2015-07-09 |
US20190083403A1 (en) | 2019-03-21 |
US20160120809A1 (en) | 2016-05-05 |
CA3053189A1 (en) | 2014-06-26 |
US10195150B2 (en) | 2019-02-05 |
BR112015014775A2 (pt) | 2017-07-11 |
RU2015128794A (ru) | 2017-01-25 |
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