CN1193740C - 基本上不含哺乳动物明胶的快速分散剂型 - Google Patents
基本上不含哺乳动物明胶的快速分散剂型 Download PDFInfo
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- CN1193740C CN1193740C CNB008031592A CN00803159A CN1193740C CN 1193740 C CN1193740 C CN 1193740C CN B008031592 A CNB008031592 A CN B008031592A CN 00803159 A CN00803159 A CN 00803159A CN 1193740 C CN1193740 C CN 1193740C
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Abstract
本发明涉及快速分散固体剂型,该剂型优选在60,更优选在30,最优选在10秒内溶于口腔。本发明的固体剂型的一种新特征基于该组合物基本上不含有或绝对不含有哺乳动物明胶的事实。已发现采用浓度为该固体剂型重量的20-90%的某种改性淀粉制得具有机械和化学稳定性并能比迄今所用的基于明胶的快速分散固体剂型携带更高浓度活性成分的剂型。而且,本发明的固体剂型可以通过冷冻干燥除去含有活性成分、改性淀粉和基质形成试剂的混合物中的溶剂如水而得到。
Description
相关申请
本申请要求题目为药物组合物的1999年1月27日提交的英国专利申请号9901819.4的优先权。
技术领域
本发明涉及一种以快速分散剂型的形式进行口腔给药的药物组合物。该新剂型基本上不含有哺乳动物明胶,并含有至少一种基质形成试剂和乳糖改性淀粉。
发明背景
最为常见的药物剂型为片剂。片剂的主要局限包括由于难以吞咽而不易被患者接受和由于片剂没有有效溶解而缺乏活性物质的生物利用性。因此,在医药领域需要快速溶解的剂型。已使用多种方法以克服片剂的缺陷,包括泡腾片剂、可咀嚼片剂、崩解剂和毛细试剂。
最近,已采用快速溶解的基于明胶的基质制得用于在口腔中释放活性成分的快速分散剂型。这些剂型是已知的并可以用于传送宽范围的药物。最快的分散剂型采用明胶作为载体或结构形成试剂。通常,明胶用于赋予该剂型充足的强度以防止从包装取出时破裂,但是一旦将其放在口中,该明胶使该剂型立即溶解。
在这种制剂中常规应用的明胶B.P规定为由动物的胶原组织如皮肤、腱、韧带和骨部分水解而得到的蛋白质。但是,这种来源于哺乳动物的明胶是乏味的,因此有必要在该快速分散剂型中应用甜味剂和调味品以掩盖活性成分的口味。在这种快速分散剂型产物中使用常规的来源于哺乳动物的明胶时,有必要加热该明胶溶液以影响溶液。该加热步骤增加了处理时间并带来加热成本,由此增加了这种处理的总成本。
常规的处理要求持续时间达48小时。已发现经过这段时间会增大明胶基混合物的粘度,导致处理的困难。而且,使用哺乳动物明胶产生容易吸收水的剂型并由此导致在正常的储存期间发生该剂型的皱缩。
另一种已知的与明胶基的快速溶解剂型有关的问题在于缺乏均匀性并且在处理持续期间某些混合物结合作为悬浮颗粒的活性物质而发生液体混合物的沉积。采用来源于哺乳动物的明胶造成活性成分的沉积的原因在于哺乳动物明胶的低粘度。本发明的一个优点是本文所公开的改性淀粉基本上克服了与哺乳动物明胶有关的均匀性和沉积的问题。
在快速溶解剂型的制备中采用改性淀粉的另一优点在于发现改性淀粉剂型具有较高药物装载量。其有益之处在于对于给定剂量的活性成分,改性淀粉剂型基本上可以比常规的明胶剂型小。
已尝试用其它物质代替快速分散剂型中的明胶,但是它们可能形成强健产物(降低了崩解和破碎的性能),因而它们在口中一般缓慢地分散或形成树胶块。现已发现可以用改性淀粉代替来源于哺乳动物的明胶来制备快速分散剂型。
因此本发明提供了一种快速分散剂型形式的用于口服的药物组合物,设计这种剂型用于在口腔中快速释放活性成分,该剂型的特征在于这种基本上不含有明胶的组合物包括改性淀粉和至少一种基质形成试剂。
本发明提供了从快速分散剂型(FDDF)中减少或优选除去明胶的可能性。改性的淀粉可以用作FDDF的基本结构形成试剂以形成物理性强健产物但同时保持了期望的该产物的快速分散特征。通过适宜选择改性淀粉有可能得到具体的期望性能:冷水可溶性、溶液的粘度不随时间而变化和改进的该剂型稳定性和物理强度。采用改性淀粉使原先用于改善该剂型口味的甜味剂/矫味剂的浓度降低或消除。采用来源于植物的物质与采用来源于动物的物质还具有免除与BSE等试剂接触的优点。
可以认为淀粉是葡萄糖的缩合聚合物。这些葡萄糖组分以葡糖酐单元(AGU)的形式存在。如果用酸或某种酶处理淀粉,则它会通过甙键水解成它的组分葡萄糖单元而完全降解。大部分的淀粉由两种类型的葡萄糖聚合物组成,每一种具有广泛的分子大小:
(i)称为直链淀粉的直链分子,它可以含有高达6,000个被1-4个键连接的葡萄糖单元;和
(ii)称为支链淀粉的高度支化聚合物,它由被μ-1,6-键连接的短链(10-60个葡萄糖单元)组成。
该淀粉分子的葡萄糖单元在碳-6上具有伯羟基而在碳-2和碳-3上具有仲羟基。淀粉分子具有多个羟基,它们赋予该淀粉亲水性能并导致在用水加热时淀粉的分散能力。但是,这些羟基还趋于相互吸引,在相邻的淀粉分子之间形成氢键并防止在冷水中溶解。
可以通过物理、化学或酶处理法或赋予其新的性质或改变它们的性质。这些改性淀粉的性质包括与固体粘性的关系、胶凝和烹饪特征、对由酸、热和/或机械剪切力引起的粘度损失的耐受性、离子特征和亲水特征。
一定范围的改性淀粉是可以商购得到的,并可用在本发明中,它包括:
预凝胶化的淀粉,它是通过转筒干燥或挤出而制得;
低粘度淀粉,它是通过调节甙键的水解而制得;
糊精,它是通过在存在少量酸的情况下旋转干燥淀粉而制得;
酸改性淀粉,它是通过在稀酸中悬浮至达到所需的粘度而制得;
氧化淀粉,氧化剂导致引入羰基或羧基,其中发生的解聚造成退化和胶凝能力的减小;
酶改性淀粉,它是通过调节酶降解至获得所需的物理化学属性而制得;
交联淀粉,二或多官能反应剂与羟基反应以形成交联,特定的反应剂包括氯氧化磷、三偏鳞酸钠和环氧氯丙烷;和
稳定化的淀粉,淀粉在存在碱催化的情况下与醚化或酯化反应剂反应以得到宽范围的产物。
背景技术
美国专利号5,120,549公开了了一种通过以下方法制得的快速分散剂型:首先将分散于第一溶剂中的基质形成体系凝固,然后让该凝固的基质与第二溶剂接触,该第二溶剂在低于第一溶剂的凝固点的温度处基本上与第一溶剂混溶,该基质形成成分和活性成分基本上不溶于第二溶剂,借此基本上除去第一溶剂而形成快速分散剂型。
美国专利号5,079,018公开了一种包括水溶性、可水化的明胶或泡沫形成物质的多孔骨架结构的快速分散剂型,该骨架已经进行过如下处理:用水水化、在水化状态下用硬化试剂硬化并在大约0℃或0℃以下的温度用液体有机溶剂脱氢以留下空间代替水化液体。
国际申请公布号WO 93/12769(PCT/JP93/01631)描述了通过采用琼脂、含有基质形成成分和活性成分的含水体系胶凝,然后通过加压空气或真空干燥除去水而形成的低密度快速分散剂型。
美国专利号5,298,261公开了包括已在该基质的分解温度以上进行过真空干燥的部分分解的基质网状物的快速分散剂型。但是,该基质优选至少在该基质的平衡凝固点以下部分干燥。
国际申请公布号WO 91/04757(PCT/US90/05206)公开了快速分散剂型,它含有设计用于与唾液接触时冒泡的泡腾崩解剂以使该剂型快速崩解和使活性成分快速分散在口腔中。
美国专利号5,595,761公开了具体的用于制备快速溶解片剂的载体基质,它包括:
在溶液中具有净电荷的第一多肽组分如未水解的明胶;
在溶液中具有与第一多肽组分相同符号净电荷的第二多肽组分如水解的明胶;和
膨胀剂,其中第一多肽组分和第二多肽组分共同包括约2%-20wt%的特定载体基质,而该膨胀剂包括约60%-96wt%的特定载体基质;和
其中第二多肽组分在水溶液中具有比第一多肽组分更大的溶解度且质量(第一多肽组分对第二多肽组分的质量比)约为2∶1-1∶14;和
其中当往含水环境中引入载体基质时,该载体基质在小于约20秒之内崩解。
EP-B-0690747描述了含有形成基质的赋形剂和至少一种均匀分布在该基质物质中的活性成分的颗粒,该颗粒是由包括以下步骤的方法制得的:从至少一种活性成分、生理学上可接受的亲水赋形剂和水中制备室温(15-20℃)下测得粘度小于1Pa.s的均匀的糊状混合物;挤出所得的均匀混合物并切断挤出物得到潮湿的颗粒;在0℃以下的温度通过惰性气流将所得的颗粒在重力作用下下落时冷冻;通过冷冻干燥将该颗粒干燥。
澳大利亚专利号666666公开了具有被包衣的微晶体或可选择的被包衣的微粒形式的活性物质的赋形剂混合物的多微粒片剂。这种片剂在口中在极短的时间内,一般小于60秒的时间内崩解。
美国专利号5,382,437公开了一种具有用于转运和给予能够被唾液快速溶解的活性物质足够强度的多孔载体物质,它是通过以下方法形成的:冷冻含有液体氨、溶于氨的液体明胶或发泡物质和选自单糖、多糖及其组合的明胶或发泡物质的硬化剂的液化氨溶液,将如此得到的冷冻的物质通过造成氨从冷冻状态到气体状态的物质转移而脱氨,借此在该载体物质上留下代替该冷冻氨的空间。
国际申请公布号WO93/13758(PCT/US92/07497)描述了物理强度增大的片剂,它是通过以下方法制备的:在片剂内组合和压缩可溶的粘合剂、赋形剂和药学活性成分,熔解该片剂中的粘合剂,然后将该粘合剂凝固。在一个实施方案中,采用崩解剂以增加片剂在口服以后的崩解状态。在另一个实施方案中,采用挥发性组分形成多孔片剂。某些实施方案在口中崩解的时间少于10秒。
美国专利号3,885,026和4,134,943还公开了快速分散多孔片剂和增加其物理强度的方法,该方法首先通过压缩片剂,然后挥发该片剂中引入的易挥发佐剂以获得期望的多孔性。
国际申请公布号WO94/14422描述了一种干燥冷冻分散单元的方法,其中使溶剂在固体中从液相到气相蒸发而不是如在冷冻干燥中的从固相到气相的升华的条件下除去溶剂。它是通过在低于溶剂(如水)的位相发生变化的组合物平衡凝固点以下温度进行真空干燥而实现的。
Lilly S.A.的EP-0693281涉及通过直接压缩而将其置于可分散片剂中的fluoxetine或其酸加成盐的药物制剂。该参考资料公开了采用羟乙酸淀粉钠作为崩解剂。该参考资料中的羟乙酸淀粉钠使用的浓度超过5wt%,优选浓度在9.5%和17%之间。该参考资料没有公开含有至少20wt%的至少一种改性淀粉的快速分散固体剂型和从含有活性成分、改性淀粉和基质形成试剂的混合物中除去溶剂而制备该剂型的方法。
EP-0599767涉及一种制备可分散二氯苯胺苯乙酸片剂的方法。该方法的特征在压缩由含有亲水润滑剂和崩解剂的颗粒、活性成分和其它赋形剂组成的混合物。这些赋形剂包括微晶纤维素、玉米淀粉和乳糖。实施例还说明了羧甲基淀粉的应用。该参考资料并没有提示或公开含有至少一种活性成分、至少一种浓度为该固体剂型重量的20%-90%的改性淀粉和至少一种固体基质形成试剂的快速分散固体剂型。而且,该参考资料相反地教导不采用本发明的通过冷冻干燥从混合物中除去溶剂而形成该固体剂型的方法。
国家淀粉和化学公司(National Starch & Chemical Corporation)的EP-0159631涉及作为片剂或胶囊的粘合剂的可压缩淀粉。该参考资料公开了许多适用于制片操作,特别是直接压缩和类似地用作胶囊装填操作的粘合剂、稀释剂等的化学改性淀粉。该参考资料并没有提示或公开这种改性淀粉在可以通过从含有活性成分、改性淀粉和基质形试剂的混合物中除去溶剂而得到的固体剂型中的应用。
GB-2172006涉及用在片剂的压模中的赋形剂。该参考资料公开了通过将纤维素粉末和羟丙基淀粉粉末分散于水溶液中,然后喷雾干燥该分散体而制得的赋形剂。该公开的制备用于片剂的模压。它没有提示或公开含有至少一种浓度为该剂型重量的20%-90%改性淀粉,且可以通过从包含活性成分、改性淀粉和基质形成试剂的混合物中除去溶剂而得到的快速分散固体剂型。
Horstmann等人的美国专利号5,629,003涉及含有20%-60%的至少一种成膜试剂即甘露糖醇,2%-40wt%的至少一种凝胶形成试剂即改性淀粉,活性成分和至多40wt%的至少一种惰性填充剂的快速崩解片状制剂。该参考资料的产品散布在硅化纸上和在80℃下干燥15分钟。该参考资料没有提示或公开含有至少一种浓度为该剂型重量的20%-90%改性淀粉,且可以通过从包含活性成分、改性淀粉和基质形成试剂的混合物中除去溶剂而得到的快速分散固体剂型。
标题为″用于药品、化妆品和食品中的乳化剂的制备方法″的化学文摘文章,Vol.110,No.10,文摘号82495,公开了将改性淀粉作为乳化剂用于药剂中。该参考资料没有提示或公开含有至少一种浓度为该剂型重量的20%-90%改性淀粉,且可以通过从包含活性成分、改性淀粉和基质形成试剂的混合物中除去溶剂而得到的快速分散固体剂型。
发明概述
公开了一种设计用于在口腔内快速释放活性成分的快速分散固体剂型,其特征在于该剂型基本上不含有哺乳动物明胶并且包括:
至少一种活性成分;
至少一种浓度为所述固体剂型20-90wt%的改性淀粉;和
至少一种基质形成试剂;
其中,该固体剂型可以通过从含有该活性成分、该改性淀粉和该基质形成试剂的混合物中除去溶剂而得到。
在本发明的一个实施方案中,该固体剂型包括至少一种选自羟基已被酯化的淀粉、羟丙基二淀粉磷酸酯、酶改性的淀粉、预凝胶化二淀粉磷酸酯、羟基乙基淀粉、预凝胶化的乙酰化二淀粉磷酸酯和预凝胶化的精制淀粉的改性淀粉。
在一个优选的实施方案中,本发明的固体剂型包括50-90wt%的改性淀粉。
虽然提供了许多关于有用的改性淀粉的特定实施例,但在本发明的快速分散固体剂型中的有用的改性淀粉的一般特征是它们在室温下易于溶解或分散于水中。与本发明所用的改性淀粉有关的另一优点是该活性成分、改性淀粉和基质形成试剂的混合物在大约24小时期间表现出相当一致的粘性。本发明优选的溶剂为水。优选的基质形成试剂为甘露糖醇。
本发明的快速分散固体剂型还含有着色剂、矫味剂、赋形剂、多种治疗剂等等。在本发明的一个优选的实施方案中,优选通过冷冻干燥除去混合物中的溶剂。
发明详述
本文和权利要求所用的术语“快速分散剂型(FDDF)”指放置于口腔内时在1-60秒,优选1-30秒,更优选1-10秒,尤其是2-8秒内崩解/分散的组合物。本发明的剂型类似于英国专利号1548022所述的剂型,即含有活性成分和对该活性成分惰性的水溶性或水分散性载体的网状物的固体快速分散剂型。已通过从固态组合物中升华溶剂而得到该网状物,该组合物含有活性成分和处在某种溶剂中的载体的溶液。区别点在于采用改性淀粉作为代替常规哺乳动物明胶的载体。
除了活性成分和改性淀粉以外,本发明的快速分散剂型还含有其它基质形成试剂和第二组分。适用于本发明的基质形成试剂包括来源于动物或植物蛋白的物质,如非哺乳动物明胶,糊精和黄豆、小麦以及欧车前种子蛋白;树胶如阿拉伯胶、瓜尔胶、琼脂和黄原胶;多糖;藻酸酯;羧甲基纤维素;角叉菜胶;葡聚糖;果胶;合成聚合物如聚乙烯吡咯烷酮;和多肽/蛋白质或多糖配合物如明胶-阿拉伯胶配合物。
适用于本发明的基质形成试剂包括糖如甘露糖醇、右旋糖、乳糖和海藻糖;环糖如环糊精;无机盐如磷酸钠、氯化钠和硅酸铝;和具有2-12碳原子的氨基酸如甘氨酸、L-丙氨酸、L-天门冬氨酸、L-谷氨酸、L-羟基脯氨酸、L-异亮氨酸、L-亮氨酸和L-苯丙氨酸。
可以在凝固之前将一种或多种基质形成试剂引入溶液或悬浮液中。该基质形成试剂可以包含表面活性剂或不包含表面活性剂。除了形成基质以外,该基质形成试剂可帮助保持溶液、悬浮液或混合物内活性成分的分散。这在由于活性成分未充分溶于水而必须悬浮而不是溶解的情况下特别有帮助。
还可以往该组合物中引入第二组分如防腐剂、抗氧化剂、表面活性剂、粘度增强剂、着色剂、矫味剂、pH改性剂、甜味剂或味觉掩盖剂。适宜的着色剂包括红、黑和黄氧化铁和FD&C染料如FD&C蓝2号和FD&C红40号。适宜的矫味剂包括薄荷、红莓、甘草、橙、柠檬、葡萄柚、焦糖、香草、樱桃和葡萄矫味剂及它们的组合。适宜的pH改性剂包括柠檬酸、酒石酸、磷酸、盐酸、马来酸和氢氧化钠。适宜的甜味剂包括天冬甜素、双氧噁噻嗪K和非洲竹芋甜素。适宜的味觉掩盖试剂包括碳酸氢钠、离子交换树脂、环糊精包埋化合物、吸附物或微囊包封的活性成分。
一般来说,改性淀粉包括5%-99.5wt%的FDDF固体,一般为20%-90%,通常为50-90%。
任何药物可以用作本发明组合物的活性成分。适宜的药物的实施例包括但不限于以下:
镇痛剂和抗炎剂:阿洛普令、金诺芬、阿扎丙宗、贝诺酯、二氟尼柳、依托度酸、芬布芬、非诺洛芬、卡西霉素、氟比洛芬、布洛芬、消炎痛、酮洛芬、甲氯芬那酸、甲芬那酸、萘丁美酮、萘普生、奥沙普秦、羟布宗、保泰松、吡罗昔康、舒林酸。
驱虫药:阿苯达唑、苄酚宁羟萘甲酸酯、坎苯达唑、二氯甲烷、伊维菌素、甲苯咪唑、奥沙尼奎、奥芬达唑、奥克太尔扑酸酯、吡喹酮、噻嘧啶扑酸酯、噻苯达唑。
抗心律失常试剂:盐酸胺碘酮、丙吡胺、乙酸氟卡尼、硫酸奎尼丁。
抗菌剂:苄乙胺青霉素、西诺沙星、盐酸环丙沙星、克拉霉素、氯法齐明、氯唑西林、地美环素、多西环素、红霉素、乙硫异烟胺、亚胺培南、萘啶酸、呋喃妥因、利福平、螺旋霉素、磺胺苯甲酰胺、磺胺羟基喹啉、磺胺甲基嘧啶、硫代乙酰胺、磺胺二嗪、磺胺呋喃唑、磺胺甲氧唑、磺胺吡啶、四环素、甲氧苄啶。
抗凝血剂:双香豆素、双嘧达莫、醋硝香豆素、苯茚二酮。
抗抑郁剂:阿莫沙平、环拉亲哚(ciclazindol)、盐酸马普替林、盐酸米安色林、盐酸去甲替林、盐酸曲唑酮、马来酸曲米帕明。
抗糖尿病剂:醋磺己脲、氯磺丙脲、格列本脲、格列齐特、格列吡嗪、妥拉磺脲、甲苯磺丁脲。
抗癫痫药:贝克拉胺、卡马西平、氯硝西泮、乙苯妥英、美芬妥因、甲琥胺、甲基苯巴比妥、奥卡西平、甲乙双酮、苯乙酰脲、苯巴比通、苯妥英、苯琥胺、扑米酮、舒噻嗪、丙戊酸。
抗真菌剂:两性霉素、硝酸布康唑、克霉唑、硝酸益康唑、氟康唑、氟胞嘧啶、灰黄霉素、伊曲康唑、酮康唑、咪康唑、那他霉素、制霉菌素、硝酸硫康唑、盐酸特比萘芬、特康唑、噻康唑、十一碳烯酸。
抗痛风药:别嘌醇、丙磺舒、硫化吡唑酮
抗高血压药:氨氯地平、贝尼地平、达罗地平、盐酸地尔硫卓、二氮嗪、非洛地平、乙酸胍那苄、吲哚拉明、伊拉地平、米诺地尔、盐酸尼卡地平、硝苯地平、尼莫地平、盐酸苯氧苄胺、盐酸哌唑嗪、利血平、盐酸特拉唑嗪。
抗疟疾药:阿莫地喹、氯喹、盐酸氯丙胍、盐酸卤泛群、盐酸甲氟喹、盐酸氯胍、乙胺嘧啶、硫酸奎宁。
抗偏头痛试剂:甲磺酰双氢麦角胺、酒石酸麦角胺、马来酸美西麦角、马来酸苯噻啶、琥珀酸舒马普坦。
抗毒蕈硷试剂:阿托品、盐酸苯海索、比哌立登、盐酸普罗吩胺、丁基溴化东莨菪碱、莨菪碱、溴美喷酯、奥芬那君、盐酸羟苄利明、托吡卡胺。
抗肿瘤试剂和免疫抑制剂:氨鲁米特、安吖啶、硫唑嘌呤、白消安、苯丁酸氮芥、环孢菌素、达卡巴嗪、雌莫司汀、依托泊苷、罗氮芥、美法仑、巯基嘌呤、甲氨蝶呤、丝裂霉素、米托坦、米托桑酮(mitozantrone)、盐酸丙卡巴肼、柠檬酸他莫昔芬、睾内酯。
抗原虫试剂:苄硝唑、氯碘羟喹、地考喹酯、二碘羟基喹啉、糠酸二氯尼特、二硝托胺、furzolidone、甲硝唑、尼莫唑、硝呋醛、奥硝唑、替硝唑。
抗甲状腺剂:甲亢平、丙基硫氧嘧啶。
抗焦虑药、镇静剂、催眠药和精神抑制药:阿普唑仑、异戊巴比妥、巴比妥、苯他西洋、溴西泮、溴哌利多、溴替唑仑、丁巴比妥、卡溴脲、甲氨二氮草、氟美噻唑、氯丙嗪、氯巴占、氯噻西泮、氯氮平、地西泮、氟哌利多、炔己蚁胺、flunanisone、氟硝西泮、三氟丙嗪、癸酸氟哌噻吨、癸酸氟奋乃静、氟西泮、氟哌啶醇、劳拉西泮、氯甲西泮、美达西泮、甲丙氨酯、甲喹酮、咪达唑仑、硝西泮、奥沙西泮、戊巴比通、奋乃静、匹莫齐特、普鲁氯嗪、舒必利、替马西泮、硫利达嗪、三唑仑、佐匹克隆。
β-阻断剂:醋丁洛尔、阿普洛尔、阿替洛尔、拉贝洛尔、美托洛尔、纳多洛尔、氧烯洛尔、吲哚洛尔、普萘洛尔。
强心试剂::氨力农、洋地黄毒甙、依诺昔酮、毛花苷C、甲地高辛。
皮质类固醇:丙酸倍氯米松、倍他米松、布地奈德、醋酸可的松、去氧米松、地塞米松、醋酸氟氢可的松、9-去氟肤轻松、氟尼缩松(flucortolone)、丙酸氟地松、皮质甾醇、甲泼尼龙、氢化泼尼松、泼尼松、曲安西龙。
利尿剂:乙酰唑胺、阿米洛利、苄氟噻嗪、布美他尼、氯噻嗪、氯噻酮、依他尼酸、呋塞米、美扎拉宗、螺内酯、氨苯蝶啶。
酶:
抗帕金森氏病试剂:甲磺酸溴隐亭、马来酸二苯甲酰胺。
胃肠试剂:比沙可啶、西米地丁、西沙必利、盐酸地芬诺酯、多潘立酮、法奈替丁、洛派丁胺、美沙勃龙、尼扎替丁、盐酸奥美拉唑、盐酸雷尼替丁、sulphasalazine。
组胺H-受体拮抗剂:阿伐斯汀、阿司咪唑、桂利嗪、赛克利嗪、盐酸赛庚啶、茶苯海明、盐酸氟桂利嗪、氯雷他定、盐酸甲氯环素、奥沙米特、特非那定、曲普利啶。
脂类调节试剂:苯扎贝特、氯贝特、非诺贝特、吉非贝齐、普罗布考。
局部麻醉剂:
神经-肌肉试剂:麦斯提龙
硝酸酯和其它抗绞痛试剂:硝酸戊酯、三硝酸甘油酯、二硝酸异山梨醇酯、一硝酸异山梨醇酯、四硝酸季戊四醇酯。
营养试剂:倍他胡萝卜素、维生素A、维生素B2、维生素D、维生素E、维生素K。
类阿片镇痛剂:可卡因、右丙氧芬、二乙酰吗啡、双氢可待因、美普他酚、美沙酮、吗啡、纳布啡、喷他佐辛。
口服疫苗:设计用于预防或减少以下代表性但不是排他性列表的疾病症状的疫苗:
流行性感冒、肺结核、脑膜炎、肝炎、百日咳、脊髓灰质炎、破伤风、白喉、疟疾、霍乱、疱疹、伤寒、HIV、AIDS、麻疹、莱姆病、旅行者腹泻、A、B和C型肝炎、中耳炎、登革热、狂犬病、副流感、黄热病、痢疾、军团病、弓形体病、Q热、出血热、阿根廷出血热、骨疽、恰加斯病、由大肠埃希杆菌杆菌导致的尿道感染、肺炎球菌疾病、流行性腮腺炎和基孔肯雅病。
用于预防或减少以下代表性但不是排它性的致病有机体列表的疾病症状的疫苗:
弧菌属的种类、沙门氏菌属的种类、博代氏杆菌属的种类、嗜血杆菌属的种类、鼠弓形体、巨细胞病毒、衣原体的种类、链球菌的种类、诺活克病毒、大肠埃希杆菌、幽门螺旋杆菌、轮状病毒属、脑膜炎奈瑟氏球菌、腺病毒、非洲淋巴细胞瘤病毒、日本脑炎病毒、卡氏肺囊虫、单纯疱疹、梭状芽胞杆菌种类、呼吸的合胞体病毒、克雷伯杆菌种类、志贺氏菌属的种类、铜绿假单胞菌属、细小病毒属、弯曲菌属的种类、立克次氏体种类、带状疱疹、耶尔森菌属的种类、罗斯河病毒、J.C.病毒、等红球菌(RhodococcuS equi)、卡他性鼻炎摩拉克氏菌、Borrelia burgdorferi和溶血性巴斯德氏菌。
针对非感染性免疫调节病症例如局部和全身过敏症状如海氏热(Hayfever)、哮喘、类风湿性关节炎和癌的疫苗
兽医用的疫苗包括针对球虫病、鸡的病毒性肺炎及脑脊髓炎地方性兽病肺炎、猫白血病、萎缩性鼻炎、丹毒、脚和口疾病、猪肺炎和其它病症及其它影响同伴和农场动物的感染与自体免疫病症。
蛋白质、多肽和重组药物:胰岛素(六聚/二聚/单体形式)、高血糖素、生长激素(growth hormone(somatotropin))、多肽或其衍生物(优选分子量为1000-300,000)、降钙素及其合成变型、脑啡肽、干扰素(尤其是治疗常见的感冒的α-2干扰素)、LHRH和类似物(那法瑞林、布舍瑞林、zolidex),GHRH(生长激素释放激素)、促胰液素、缓激肽拮抗剂、GRF(生长释放因子)、THF,、TRH(促甲状腺素释放激素)、ACTH类似物、IGF(胰岛素样生长因子)、CGRP(降钙素基因相关肽)、前房利钠肽、后叶加压素和类似物(DDAVP、赖氨加压素)、因子VII、G-CSF(粒细胞菌落刺激因子)、EPO(红细胞生成素)。
性激素:柠檬酸氯米芬、达那唑、乙炔基雌二醇、乙酸甲羟孕酮、美雌醇、甲睾酮、炔诺酮、炔诺孕酮、雌二醇、结合的雌二醇、孕酮、司坦唑、己烯雌酚、睾丸激素、替勃龙。
杀精子剂:壬苯醇醚9。
兴奋剂:苯丙胺、地塞苯他敏(dexamphetamine)、右芬氟拉明、芬氟拉明、马吲哚、匹莫林。
活性成分的精确用量取决于所选择的药物。但是,该活性成分一般用量为0.2-95%,正常为该干燥剂型组合物重量的1-20%。
通过以下实施例进一步说明本发明,这些实施例的意在举例而不限定。在以下的实施例中,在不存在活性成分的情况下制备和测试FDDF。
实施例1
制备以下制剂:
组分 | 量(g) | 重量% |
Amylogum CLS | 5 | 10 |
甘露糖醇 | 1.5 | 3 |
纯化水 | 43.5 | 87 |
Amylogum CLS为一种羟基已被酯化的淀粉。它可以从英格兰南Huberside的Avebe U.K.,Ltd.商购得到。甘露糖醇由英格兰Roquette Ltd.of Kent提供。
将淀粉加到纯化水中并边搅拌边加热至60℃。将所得的混合物于60℃下保存10分钟以作用于溶液,然后冷却至环境温度。当混合物已充分冷却时,加入甘露糖醇并搅拌直至全部溶解。将该混合物以500mg装填重量配制PVC/PVdC囊泡中。在冷氮气流下将单元冷却然后在0.5mbar的压力下从-10℃爬升到+20℃进行冷却干燥。
实施例2
采用实施例1的方法制备以下的制剂。
组分 | 量(g) | 重量% |
Perfectagel MPT | 5 | 10 |
甘露糖醇 | 1.5 | 3 |
纯化水 | 43.5 | 87 |
Perfectagel MPT为磷酸羟丙基二淀粉,它可以从Avebe U.K.,Ltd.商购得到。
实施例3
制备以下制剂:
组分 | 量(g) | 重量% |
Paselli MD 10 | 10 | 10 |
甘露糖醇 | 3 | 3 |
纯化水 | 87 | 87 |
Paselli MD 10为酶改性淀粉,它可以从Avebe U.K.,Ltd.商购得到。
用带手柄的电搅拌器搅拌水,并搅拌加入淀粉和甘露糖醇。该淀粉不需要加热。搅拌该溶液1.5小时至平衡。
该剂型平和而快速地分散在口中,并具有甜味。
实施例4
采用实施例3的方法制备以下的制剂。
组分 | 量(g) | W重量% |
Avebe MD20 | 10 | 10 |
甘露糖醇 | 3 | 3 |
纯化水 | 87 | 87 |
Avebe MD20为酶改性淀粉,它可以从Avebe U.K.,Ltd.商购得到。
实施例1-4所制得的剂型在口中都以在少于10秒的时间快速地崩解。
实施例5
多种改性淀粉粘度曲线的研究
制备具有以下组合物的制剂。
组分 | 量(g) | 重量% |
改性淀粉 | 3 | 3 |
甘露糖醇 | 3 | 3 |
纯化水 | 94 | 94 |
所用的改性淀粉为:
预凝胶化的二淀粉磷酸酯Paselli Easygel。
预凝胶化的乙酰化二淀粉磷酸酯Paselli BC。
预凝胶化的精制淀粉Paselli WA4。
所有这些改性淀粉可以从Avebe,U.K.,Ltd.商购得到。
将粉末干混合并加到纯化水涡流中。然后将该混合物加热到50℃,接着用Silverson L4R(小头接管)匀化。将配料冷却到环境温度,同时连续搅拌。在混合1-3小时和22小时以后采用Haake粘度计在500xs-1下测定粘度。
结果:
配料组分 | 粘度@500xs-1(mPa.s) | |
最初 | 24小时混合之后 | |
Easygel 3%甘露糖醇3% | 48.49 | 51.98 |
Paselli BC3%甘露糖醇3% | 35.18 | 36.06 |
Paselli WA4 3%甘露糖醇3% | 34.17 | 33.87 |
在22小时期间内观察粘度没有发生显著变化。这是在FDDF’s的制备中的高度期望的性能。这种性能改进了产物的效能并减少了由于浪费而造成的损耗。
实施例6
Paselli BC和明胶之间的稳定性对比研究
明胶制剂 | 量(g) | 重量% |
明胶 | 8.75 | 3.5 |
甘露糖醇 | 7.50 | 3 |
纯化水 | 233.75 | 93.5 |
改性淀粉制剂 | 量(g) | 重量% |
Paselli BC | 8.75 | 3.5 |
甘露糖醇 | 7.50 | 3 |
纯化水 | 233.75 | 93.5 |
Paselli BC为预凝胶化的乙酰化二淀粉磷酸酯,它可以从英格兰Cheshire的Croda Colloids,Ltd.商购得到。
明胶制剂
往纯化水涡流中加入明胶和甘露糖醇,加热到60℃以作用于溶液。然后将该混合物在给药前冷却至25℃。
改性淀粉制剂
干燥混合甘露糖醇和Paselli BC,然后在环境温度下将其缓慢加到纯化水的涡流中。接着用Silverson L4R(小头接管)将所得的混合物匀化大约1分钟。
采用可编程的Hamilton Microlab M分配器将混合物料配制于PVC/PVdC中,直径16mm,500mg装填重量囊泡。在0.5mbar的压力下从-10℃爬升至20℃温度之前在冷氮气流下冷冻囊泡。
在40℃和75%的相对湿度下在未密封的稳定的小室内放置20小时,在此时间之后测定该单元的直径。
结果:
制剂 | 抗拉强度N/mm% | %20小时@40℃/75%RH之后的皱缩量 | |
2小时冰库储藏 | >24小时冰库储藏 | ||
改性淀粉 | 0.013 | 0.123 | 5.6% |
明胶 | 0.151 | 0.163 | 10.2% |
可以看出,采用改性淀粉的FDDF在皱缩量方面比常规的含有明胶的FDDF降低了50%。这是一个意外而令人惊奇的结果。
实施例7
明胶与改性淀粉FDDF的比较
H.Seagers等人的标题为″药物传送产品和Zydis快速溶解剂型″的文章,J.Pharm Pharmacol.1998,讨论了在FDDF中与高水溶性药物有关的问题。Zydis是R.P.Scherer Corporation,BaskingRidge,N.J.,USA.的注册商标。Seagers等人认识到水溶性药物的剂量一般上限值限于约60mg每个剂型。该剂量受药物在冷冻过程的表现和其干燥特征支配。低共熔混合物可在未充分冷冻时形成或在高于冷冻干燥方法的温度时熔解。还有可能的是溶解的药物可以在冷冻时形成无定形的固体并且这种固体可在干燥方法过程中由于冰的升华和载体结构的损失而瓦解。
已知通过引入晶体形成赋形剂减小水溶性药物形成结构的瓦解。已知这些物质有时还作为基质形成试剂。这些物质导致结晶度并因此导到无定形产物的刚度系数。另一种方法是将水溶性化合物结合到离子交换树脂上形成水不溶性配合物。进一步的技术是将该活性成分的非水溶液配制在预先形成的安慰剂FDDF单元中。然后将有机溶剂蒸发而再结晶的药物沉积在该Zydis基质的孔上。
另一种已知克服高水溶性活性成分问题的技术是减少药物与赋形剂的比率,借此增加囊泡的装填重量。通过使相同剂量的药物含有更大量赋形剂而有效地稀释了该可溶活性成分的作用。这种可能的溶液的明显缺陷在于它要求更大量的赋形剂,更大的“对患者较不友好”的剂型,并且由于受大小的限制而减少了制造的产量。
还已知通过PH操作可以改变药物的溶解度。已知溶解度降低有利于在FDDF中结合更高剂量的活性成分。本发明的一方面在于发现基本不含明胶而采用改性淀粉物质的FDDF与常规的明胶体系相比可以结合更高浓度的水溶性药物。提出该实施例用来证明这种意外的结果。
在该实施例中,将三(3)种高水溶性的活性成分制成FDDF。这些活性成分的水溶性表示如下:
双氯酚酸钠-1∶30水
普伐他汀钠-1∶3水
盐酸苯丙醇胺-1∶2.5水
根据表1制备以下的样品。
表I
(所有的值为重量%)
样品# | 明胶 | 淀粉(Prejel) | 甘露糖醇 | 活性成分/数量 | 水 |
1 | 4% | 0 | 3% | 双氯酚酸钠2.5%* | 90.5% |
2 | 0 | 4% | 3% | 双氯酚酸钠2.5% | 90.5% |
3 | 4% | 0 | 3% | 普伐他汀钠2.0%+ | 91.0% |
4 | 0 | 4% | 3% | 普伐他汀钠2.0%+ | 91.0% |
5 | 4% | 0 | 3% | 盐酸苯丙醇胺2.5%# | 91.0% |
6 | 0 | 4% | 3% | 盐酸苯丙醇胺2.5%# | 91.0% |
*设计在500mg的填充中有12.5mg的活性物质
+设计在500mg的填充中有10.0mg的活性物质
#设计在500mg的填充中有12.5mg的活性物质
通过以下方法制得样品1、3和5(含有样品的明胶):往搅拌的纯化水涡流加入明胶和甘露糖醇,然后将该混合物加热至60℃(±1℃)以往溶液中放入明胶和甘露糖醇。接着将溶液冷却到24℃(±1℃),然后加入所需数量的活性物质。各份配料在被配制于囊泡包装前至少保持1小时。样品2、4和6(改性淀粉样品)是通过以方法制得的:往清洁、干燥的烧杯中加入淀粉和甘露糖醇,用刮刀干燥混合这些物质。然后将纯化水加到该混合物中,并采用Silverson L4R匀化。
匀浆器-小头接管在两分钟时间内处于半速。然后将列举的活性物质加到该溶液中并在配制之前放置最小1小时。这些配料无需加热或进行加热。
采用Hamilton Microlab将每种样品配制在20囊泡包装中,其将500mg的混合物(2%)进入铝囊泡料袋中。然后采用液氮在-110℃温度下冷冻3.2分钟。接着将冷冻的样品在冷冻干燥前在-25℃下储存。在0.5mbar处应用-10℃至10℃的温度周期完成冷冻干燥。将样品在制造的同一天干燥过夜。
在冷冻干燥之后,取出并检查各包装。检查各样品囊泡的裂纹。根据FDDF的检查这种裂纹是视觉明显的,并且测得90%的样品1出现裂纹而0%的样品2(含有对比物的改性淀粉)出现。含有明胶的样品3出现了45-50%的裂纹率,而基于淀粉的配方样品4没有出现裂纹。
含有2.5重量%苯丙醇胺和4重量%明胶的样品5裂纹出现率为60-70%。这意味着60-70%的该样品的20囊泡填充出现裂纹并在尝试从该囊泡包装中取出时崩裂。作为对比,样品6中使用的淀粉只出现10-20%的裂纹率。
本实验显然表明在FDDF中使用改性淀粉在FDDF中结合了高浓度的高水溶性活性物质同时没有出现在常规明胶制剂上可见的物理稳定性的崩裂和降解。
实施例8
对比
根据实施例7所进行的工作表明在FDDF中使用改性淀粉使该剂型具有更高的荷载量但又不致出现崩裂和/物理损失。尝试确定制备每个剂型含有相同数量的活性成分的基于明胶的FDDF所需的额外物质的数量。实际上,进行本实验以确定是否可制得水具有熔回(水蒸汽的吸收和物理稳定性的降解)和崩裂问题的含有高水溶性活性物质的基于明胶的配方。制备以下的制剂:
表II
(所有的值为重量%)
样品# | 明胶 | 甘露糖醇 | 活性成分/数量 | 水 |
7 | 4% | 3% | 双氯酚酸钠1.67% | 91.33% |
8 | 4% | 3% | 普伐他汀钠1.33% | 91.67% |
9 | 4% | 3% | 盐酸苯丙醇胺1.67% | 91.33% |
如实施例7所述制得这些样品除了使用750ml的填充量。在从冷冻干燥中取出样品时,视察检查的结果是样品不含有裂纹。该实施例表明如果在制备快速溶解剂型中使用明胶则需要更高的剂量单元。该意外的结果的优点在于该采用改性淀粉的更小剂型将提高患者的接受性并减少了制造的成本。
工业实用性
本发明涉及用于口服给药的快速溶解剂型。快速分散剂型的优点包括舌、舌下或口腔传送药物。目前商业上最流行的形式是通过将治疗剂浆液、溶剂、明胶和其它赋形剂等分进入预先形成的凹槽中而制得的快速溶解剂型。然后将该液体冷冻并通过升华,一般通过冷冻干燥除去溶剂。所得的片剂具有与唾液接触时快速溶解的开口多孔基质。
使用常规FDDF’s具有某些缺陷,例如:1)使用来源于动物的明胶;2)FDDF中有限的高水溶性活性物质荷载量;3)缺乏机械强度;4)不适的味觉;5)不能提供均匀的混合物;6)不能防止活性颗料的沉积;和7)最小的冷水溶解。本发明通过以下的发现而领先于FDDF现有技术的状态:某些改性淀粉可以用于制备具有以下性质的FDDFs:改进的物理稳定性、意外的包含更高荷载的高水溶性药物能力、改进的味觉、改进的物理稳定性(与明胶基质体系相比对吸湿量的耐受性及随后的皱缩)、混合物中活性颗粒沉积率的物质减少。
应认识到说明书和实施例是对本发明的列举而不是限定,本领域技术人员将想到其它的在本发明精神和范围之内的实施方案。
Claims (7)
1.一种设计用于在口腔内快速释放活性成分的快速分散固体剂型,其特征在于该剂型不含有哺乳动物明胶而包含:
a)至少一种活性成分;
b)至少一种浓度为50-90重量%的改性淀粉,该改性淀粉选自羟基已被酯化的淀粉、羟丙基二淀粉磷酸酯、酶改性的淀粉、预凝胶化二淀粉磷酸酯、羟基乙基淀粉、预凝胶化的乙酰化二淀粉磷酸酯和预凝胶化的精制淀粉;和
c)至少一种基质形成试剂;
其中,所述的固体剂量形式的崩解/分散时间为1-60秒,并且该固体剂型可以通过从含有该活性成分、该改性淀粉和该基质形成试剂的混合物中除去溶剂而得到。
2.根据权利要求1的快速分散固体剂型,其中,该改性淀粉在环境温度下易于溶解或分散于水中。
3.根据权利要求1的快速分散固体剂型,其中,该活性成分、改性淀粉和基质形成试剂的混合物在24小时的时间内表现出相当一致的粘性。
4.根据权利要求1的快速分散固体剂型,其中所述溶剂为水。
5.根据权利要求1的快速分散固体剂型,其中的基质形成试剂为甘露糖醇。
6.根据权利要求1的快速分散固体剂型,可进一步含有着色剂、矫味剂或赋形剂。
7.根据权利要求1的快速分散固体剂型,其中通过冷冻干燥除去该混合物中的溶剂。
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