CN1592612A - 有内核和外壳的剂型 - Google Patents
有内核和外壳的剂型 Download PDFInfo
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- CN1592612A CN1592612A CNA028233549A CN02823354A CN1592612A CN 1592612 A CN1592612 A CN 1592612A CN A028233549 A CNA028233549 A CN A028233549A CN 02823354 A CN02823354 A CN 02823354A CN 1592612 A CN1592612 A CN 1592612A
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Abstract
在一个实施方案中,本发明的剂型包括有外表面的核以及有外表面和内表面的壳,其特征在于该壳围绕着核,使壳的内表面与核的外表面上基本有相同形状,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,壳包含少于约50%的结晶糖,剂型中基本不含电荷控制剂。在另一个实施方案中,剂型包括有外表面的核以及有外表面和内表面的壳,该壳围绕着核,该剂型在40℃和相对湿度75%的环境中暴露60分钟,水分摄取少于约0.8%,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,剂型中基本不含电荷控制剂,壳也基本没有隆起的接缝。
Description
发明背景
1.技术领域
本发明涉及剂型。本发明尤其涉及壳围绕着核的剂型,如由壳围绕着核的药物组合物。
2.背景信息/发明背景
药物技术中已知有许多种剂型,如片剂、胶囊和胶囊片(gelcap)。片剂通常指把粉末相应地压制成不同的形状。胶囊通常用二个明胶壳制造,该明胶壳是用钢杆浸入明胶使明胶包被在杆的末端制成的。明胶变硬后成为二个半壳后抽出钢杆。变硬的半壳中充填粉剂,二个半壳合起来形成胶囊。(参见HOWARD C,ANSEL等人的《药物剂型和药物释放系统》(Pharmaceutical Dosage Forms and Drug DeliverySystems)(第7版,1999年)
包薄膜衣的片剂在美观上、稳定性上和吞咽性上对无包衣片剂是一种改进。一种长形的、胶囊形状的薄膜包衣片剂常被称为“囊片”。典型的薄膜包衣的厚度在约5至50微米,包含各种成膜聚合物如纤维素醚等等。这些聚合物通常是通过有机溶剂的溶液或水性分散体涂敷于片剂,它们是按照如美国专利4,973,480和美国专利6,113,945公开的常规喷雾方法进行的。常规的喷雾包衣方法不给剂型带来高水平的表面光泽,薄膜厚度也受到薄膜特性和加工成本的限制。而且,对片剂的二端使用不同颜色的喷雾包衣,在商业上是不可行的。
糖衣片剂,如美国专利2,925,365;3,420,931;4,456,629和3,361,631所公开的,尤其是那些经抛光处理的,例如,外层有巴西棕榈蜡包衣,通常比薄膜包衣片剂有更好的表面光泽和更厚的包衣,但是糖衣包衣加工是很消耗时间和成本的,而且制备的包衣会延迟剂型的溶出。虽然糖衣通常比薄膜包衣厚,而且有使片剂边缘变圆的效果,但糖衣片剂的整体形状取决于未加包衣的核,而且其形状与未加包衣的核是基本一致的。
明胶包衣片剂,常被称为凝胶片(geltab)和胶囊片(gelcap),是对明胶胶囊的改进,通常包括有光泽的胶状壳包衣的片剂。几种广为人知的胶囊片的例子是McNeil-PPC有限公司的以商品名Tylenol销售的基于醋氨酚的产品。生产上述凝胶片和胶囊片的一类方法包含把片剂浸入包衣溶液中,每次一半,该包衣溶液可以是二种不同的颜色,见如美国专利4,820,524;5,538,125;5,228,916;5,436,026;5,679,406;或把已有第一种颜色的片剂半途浸入第二种颜色的包衣溶液中,见如美国专利6,113,945;美国专利5,942,034和6,195,911描述的用于浸渍包衣片剂的其他方法和装置。另一类方法包括套合胶囊的各半到片剂上。见如美国专利5,415,868;6,126,767;6,080,426;5,460,824;5,464,631;5,795,588;5,511,361;5,609,010;6,245,350;和WO 97/37629。另一种生产胶囊片的方法是包被方法,该方法使用一对旋转模具把二片分离的胶状材料薄膜敷在片剂相对的两个面上,如美国专利5,146,730和5,459,983所公开的。
生产胶囊片的常规方法通常是分批生产的模式,该模式使用许多孤立的设备进行独立操作。上述分批生产过程常常包括制粒、干燥、混合、压制(如用压片机),薄膜包衣(如在包衣锅中喷雾),浸明胶、包囊或包被、干燥和记字的操作单元。
浸渍过的凝胶片和胶囊片受到包衣或包壳厚度变异的限制,也受到包衣或包壳色彩不一致的限制。
用于如美国专利5,146,730和5,459,983所公开的包被方法生产凝胶片和胶囊片的薄膜配方包括以水为基础的明胶制品,该制剂在重量上有约45%的明胶和约9%的增塑剂(甘油和/或山梨醇)。据报道增塑剂在上述配方中起重要作用。增塑剂与明胶比率低导致围绕片剂核的包衣易碎,而增塑剂与明胶比率高导致围绕片剂的明胶包衣柔软,会从片剂上脱落。如果明胶包衣要贴于产品核上,则明胶配方应考虑在重量上包含40%到60%的明胶,5%到12%的增塑剂,35%到50%的水,和0.1%到3%的着色剂和色素。甘油和山梨醇可单独使用或一起混合使用。而且,其他糖和多羟基化合物可用作添加剂和增塑剂。如果要求最终产品是能显示改换的明胶包衣的药物片剂,则明胶配方中增塑剂与明胶的比率应在约1∶5的范围。上述水平的增塑剂会给包被剂型带来限制,包括会吸收水分,这会危及产品的物理和化学稳定性,同时增加了配方的成本。
另一种生成核(或基质)外的壳(或包衣)的方法是WO01/57144所公开的应用静电沉积的原理生成包衣的方法。这个方法的局限在于核或壳至少有一个必须包括一种或多种“电荷控制剂”,如水杨酸金属盐,例如水杨酸锌、水杨酸镁、水杨酸钙;季铵盐;苯扎氯铵;萦氯铵;溴化三甲基十四烷基铵(西曲溴铵);以及环糊精和它们的加合物;占壳的重量的约1%到约10%。电荷控制剂常产生不佳的味觉,而且含有电荷控制剂的壳会增加氧化,这是不利的。因此希望有不含电荷控制剂的剂型。
常规的包囊和包被加工的局限在于其复杂性和高成本,壳或包衣的厚度有限,和在二片胶囊和/或包衣之间隆起的接缝。所以希望有不按照常规的包囊和包被加工方法制备的剂型。这些剂型可增加许多方面的应用,包括释放药物的剂型、营养剂和/或糖膏剂,其形式可以是凝胶片或胶囊片,包衣片剂,高强度剂型等等。而且,这些剂型拥有独特和舒适的美观特性,这在市场上是有价值的。
本发明的目的是提供一种剂型,该剂型包括核和壳,壳围绕着核并基本贴在核的外表面上,该剂型中基本不含电荷控制剂。
本发明的另一个目的是提供一种剂型,该剂型包括核和壳,壳围绕着核,壳也基本没有隆起的接缝。
由本文在此提供的详细描述,本发明的其他目的、特征和优点对本领域中的熟练技术人员将是显而易见的。
发明内容
在一个实施方案中,本发明的剂型包括有外表面的核以及有外表面和内表面的壳,其特征在于该壳围绕着核,壳的内表面基本与核的外表面有相同形状,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,壳包含少于约50%的结晶糖,剂型中基本不含电荷控制剂。
在另一个实施方案中,在核的外表面和壳的内表面之间的最大裂隙高度与最大裂隙处壳的总的理论厚度的比值小于约1∶7.5。
在另一个实施方案中,核有主面,核的外表面和壳的内表面之间的最大裂隙高度与主面中心处壳的厚度的比值小于约1∶7.5。
在另一个实施方案中,本发明的剂型包括有外表面的核以及有外表面和内表面的壳,其特征在于该壳围绕着核,该剂型在40℃和相对湿度75%的环境中暴露60分钟,水份摄取少于约0.8%,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,剂型中基本不含电荷控制剂,壳也基本没有隆起的接缝。
在另一个实施方案中,该壳在40℃和相对湿度75%的环境中暴露60分钟,水份摄取少于约0.65%。
在另一个实施方案中,核包括压制的片剂。
在另一个实施方案中,剂型有腹状突起,腹状突起的第一点的第一壳厚度与腹状突起的第二点的第二厚度之间的差不大于约二个厚度中较大者的约10%。
在另一个实施方案中,剂型有腹状突起,腹状突起的第一位置的第一壳厚度与腹状突起的第二位置的第二厚度之间的差不大于约50微米。
在另一个实施方案中,壳表面基本没有超过主面的壳厚度约1.25倍的隆起部分。
在另一个实施方案中,壳表面基本没有高度超过约50微米的隆起部分。
在另一个实施方案中,核有主面,剂型有腹状突起,腹状突起上任何一点的壳厚度不大于片剂主面中心的壳厚度。
在另一个实施方案中,核有主面,剂型有腹状突起,腹状突起上任何一点的壳厚度与主面中心的壳厚度之间的差不超过约50微米。
在另一个实施方案中,该壳基本不含湿润剂。
在另一个实施方案中,该核包含插入物。
在另一个实施方案中,该壳的表面光泽值至少约150光泽单位。
在另一个实施方案中,该壳的表面光泽值至少约175光泽单位。
在另一个实施方案中,该壳的表面光泽值至少约210光泽单位。
在另一个实施方案中,该壳是模制的。
在另一个实施方案中,该壳包含至少约50%的某物质,该物质选自成膜聚合物、胶凝化聚合物、低熔点疏水物质、非结晶糖和它们的混合物。
在另一个实施方案中,该壳包含活性成分。
在另一个实施方案中,该活性成分能溶出,该剂型的溶出与含活性成分的速释片剂的USP规格一致。
在另一个实施方案中,在核的外表面和壳的内表面之间没有底衣存在。
在另一个实施方案中,该壳包含第一壳部分和第二壳部分,二者在界面上粘连。
在另一个实施方案中,该第一壳部分和第二壳部分在视觉上可区分。
在另一个实施方案中,该核是有主面的片剂,在界面上的壳的总厚度不大于片剂主面中心最厚处的厚度。
在另一个实施方案中,该界面是对接形式。
在另一个实施方案中,该第一壳部分和第二壳部分在界面形成闭锁形态。
在另一个实施方案中,该第一壳部分比第二壳部分厚,并在界面形成突出。
在另一个实施方案中,该第一壳部分和第二壳部分相互重叠。
在另一个实施方案中,该壳没有高度超过该壳厚度相对标准偏差约25%的接缝。
在另一个实施方案中,该第一壳部分和第二壳部分的界面是平的接缝,在该接缝处第一壳部分沿单一水平线过渡到第二壳部分。
在另一个实施方案中,该壳的内表面有与该核外表面的凹迹和突出部分相对应的相反的凹迹和突出部分。
在另一个实施方案中,该凹迹和突出部分的长、宽、高或深不超过10微米。
在另一个实施方案中,该壳基本没有孔径在0.5到5.0微米的孔。
附图的概述
图1是本发明剂型某实施例的横截面图。
图2描述剂型和测定该壳厚度的相对标准偏差的测量位置。
图3A和图3B是商品化的现有技术凝胶片的显微照片。
图4是本发明的某一实施方案中的壳和核的显微照片。
图5是壳围绕的有主面的核的横截面图,该壳与核之间有裂隙。
图6是图5中壳与核的界面的分解图。
图7A是第一壳部分和第二壳部分所形成的没有突起的对接的横截面图。
图7B是第一壳部分和第二壳部分所形成的有突起的对接的横截面图。
图8A到8E是第一壳部分和第二壳部分在它们界面重叠的横截面图。
图9A到9F是第一壳部分和第二壳部分在它们界面重叠和形成闭锁形态的横截面图。
图10A到10F是第一壳部分和第二壳部分所形成的有突起的界面的横截面图。
图11A到11B是本发明的注塑剂型与现有技术剂型的比较。
图12A到12B显示本发明中有腹状突起的剂型的前视图与侧视图。
图13是样品重量随时间变化的图表,显示本文实施例6所描述的相对湿度数据。
发明的详细描述
本发明的剂型包括有外表面的核以及有外表面和内表面的壳,还包括本文描述的更多的特征。本文中使用的术语“剂型”应用于任何固体物体、半固体或液体组合物,它们用来容纳特别预先确定的数量(如剂量)的特定成分,例如下文中详述的活性成分。合适的剂型可以是药物释放系统,包括那些口服、颊部给药、直肠给药、局部、透皮或粘膜释放,或皮下植入,或其他植入的药物释放系统;或用于释放矿物质、维生素和其他营养品,口腔护理剂、调味剂等等的组合物。本发明的剂型较佳的是固体,然而它们可包含液体或半固体成分。在较佳实施例中,剂型是在人类胃肠道中释放药物活性成分的口服给药系统。在另一个较佳实施例中,剂型是包含药物非活性成分的口服“安慰剂”系统,剂型的外观设计成和某种药物活性剂型相同,可用于临床研究作为对照来测试,例如,某种药物活性成分的安全性和有效性。
本发明使用的合适的活性成分包括如药物、矿物质、维生素和其他营养药、口腔护理剂、调味剂和它们的混合物。合适的药物包括止痛药、抗炎剂、抗关节炎药、麻醉剂、抗组胺药、止咳药、抗生素、抗感染药、抗病毒药、抗凝剂、抗抑郁药、抗糖尿病药、止吐药、抗胀气药、抗真菌药、解痉药、食欲抑制剂、支气管扩张药、心血管药、中枢神经系统药、中枢神经系统兴奋剂、减充血剂、利尿剂、祛痰药、胃肠道药、偏头痛药、晕动病产品、粘液溶解剂、肌肉弛缓剂、骨质疏松症制剂、聚二甲基硅氧烷、呼吸制剂、助眠剂、泌尿道制剂和它们的混合物。
合适的口腔护剂包括呼吸清新剂、牙齿增白剂、抗微生物剂、牙齿矿化剂、牙齿腐蚀抑制剂、局部麻醉剂、粘膜保护剂等等。
合适的调味剂包括薄荷脑、薄荷、薄荷调味香料、水果调味香料、巧克力、香草、口香糖调味香料、咖啡调味香料、液体调味香料和复合物等等。
合适的胃肠道药物的例子包括抗酸药如碳酸钙、氢氧化镁、氧化镁、碳酸镁、氢氧化铝、碳酸氢钠、二羟化铝碳酸钠;轻泻药如比沙可啶、波希鼠李皮、丹蒽醌、番泻叶、酚酞、芦荟、蓖麻油、蓖麻油酸和去氢胆酸及它们的混合物;H2受体拮抗剂如法莫替丁、雷尼替丁、西米替丁、尼扎替丁;质子泵抑制剂如奥美拉唑或兰索拉唑;胃肠道细胞保护剂如硫糖铝和米索前列醇;胃肠道促动药如普卢卡必利,针对幽门螺杆菌的抗生素如克拉霉素、阿莫西林、四环素和甲硝唑;止泻药如地芬诺酯和洛哌丁胺;格隆溴铵;止吐药如昂丹司琼;止痛药如美沙拉秦。
本发明的一个实施方案中,活性药物可选自比沙可啶、法莫替丁、雷尼替丁、西米替丁、普卢卡必利、地芬诺酯、洛哌丁胺、乳糖酶、美沙拉秦、铋、抗酸药和药剂中可接受的盐、酯、异构体和它们的混合物。
在另一个实施方案中,活性药物可选自止痛药、抗炎剂和退热药,如非甾体抗炎药(NSAID),包括丙酸衍生物,如布洛芬、萘普生、酮洛芬等等;醋酸衍生物,如消炎痛、双氯芬酸、舒林酸、托美等等;芬那酸衍生物,如甲芬那酸,甲氯灭酸、氟芬那酸等等;联苯甲酸衍生物,如二氟尼柳,氟苯柳(flufenisal),等等;和昔康类药物,如吡罗昔康,舒多昔康(sudoxicam),伊索昔康,美洛昔康等等。在一个较佳实施方案中,在本发明的一个较佳实施例中,活性药物选自丙酸衍生物类NSAID,如布洛芬、萘普生、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬(indoprofen)、酮洛芬、氟洛芬(fluprofen)、吡洛芬、卡洛芬、奥沙普、普拉洛芬、舒洛芬和药剂中可接受的盐、衍生物和它们的复方。在本发明的一个较佳实施方案中,活性药物可选自醋氨酚、乙酰水杨酸、布洛芬、萘普生、酮洛芬、氟比洛芬、双氯芬酸、环苯扎林、美洛昔康、罗非考昔、塞来考昔和药剂中可接受的盐、酯、异构体和它们的混合物。
在本发明的另一个实施方案中,活性药物可选自伪麻黄碱、苯丙醇胺、氯苯那么敏、右美沙芬、苯海拉明、阿司咪唑、特非那定、非索非那定、氯雷他定、地洛他定、西替利嗪、它们的混合物和药剂中可接受的盐、酯、异构体和它们的混合物。
合适的聚二甲基硅氧烷的例子,包括但不限于二甲硅油和simethicone,由美国专利4,906,478;5,275,822;和6,103,260公开。本文中使用的术语“simethicone”指的是聚二甲基硅氧烷的大类,包括但不限于simethicone和二甲硅油。
剂型中可有一种或几种治疗有效量的活性成分,该量通过口服可获得所需要的治疗反应,此量易被本领域熟练技术人员确定。如本领域所知,为确定该量,应当考虑待使用的特定活性成分,该活性成分的生物利用度特征,给药方案,病人的年龄和体重和其他因素。在一个实施方案中,该核包括至少约85%的重量百分比的活性成分。在该实施方案中,该剂型包括至少约85%的重量百分比的活性成分。
如本领域所知,如果要求活性成分的释放有所改变,该活性成分可用改变释放的包衣包被。可以使用商品化的释放有所改变的活性成分。例如,本发明可使用通过凝聚法以可改变释放的聚合物包囊的醋氨酚颗粒。凝聚法包囊的醋氨酚可以从Eurand America有限公司(Vandalia,Ohio)或Circa有限公司(Dayton,Ohio)购买。
在该剂型用来被咀嚼或在吞咽前在口腔中崩解的实施方案中,该活性成分包以掩盖滋味的包衣较好,这在本领域是已知的。合适的掩盖滋味的包衣的例子已由美国专利4,851,226;5,075,114和5,489,436描述。也可使用商品化的掩盖滋味的活性成分。例如,本发明可按照上述使用通过凝聚法以掩盖滋味的聚合物包囊的醋氨酚颗粒。
合适的片剂赋形剂包括填充剂、粘合剂、崩解剂、润滑剂、助流剂等等。
合适的填充剂包括水溶性可压缩性碳水化合物如糖,包括葡萄糖、蔗糖、麦芽糖和乳糖;糖醇,包括甘露醇、山梨醇、麦芽糖醇、木糖醇;水解淀粉,包括糊精和麦芽糊精等等;不溶于水的塑性变形物质,如微晶纤维素或其他纤维素衍生物;水水溶性脆性破裂的物质,如磷酸二钙、磷酸三钙等等及它们的混合物。
合适的粘合剂包括干粘合剂如聚乙烯吡咯烷酮、羟丙甲基纤维素等等;湿粘合剂如水溶隆聚合物,包括水性胶体如藻酸盐、琼脂、瓜尔豆胶、角豆、角叉菜聚糖、tara、阿拉伯树胶、黄芪胶、果胶、黄原胶、gellan、麦芽糊精、半乳甘露聚糖、pusstulan、海带多糖、scleroglucan、阿拉伯树胶、菊粉、果胶、whelan、rhamsan、zooglan、methylan、壳多糖、环糊精、脱乙酰壳多糖、聚乙烯吡咯烷酮、纤维素类、淀粉等等;和衍生物及它们的混合物。
合适的崩解剂包括淀粉羟乙酸钠、交联聚乙烯吡咯烷酮、交联羧甲基纤维素、淀粉、微晶纤维素等等。
合适的润滑剂包括长链脂肪酸和它们的盐,如硬脂酸镁和硬脂酸、滑石粉和蜡。
合适的助流剂包括胶态二氧化硅等等。
本发明的剂型也可包含药学上可接受的助剂,包括,例如,防腐剂、高强度甜味剂如阿司帕坦、乙酰舒源钾、sucralose和糖精;调味剂,抗氧化剂,表面活性剂和着色剂。
在要求活性成分被动物的体循环吸收的实施方案中,一种或几种活性成分在接触体液如水、胃液、肠液等等能够溶出是较佳的。在一个实施方案中,活性成分的溶出特性符合USP对含有活性成分的即刻释放片剂的要求。例如,醋氨酚片剂,USP24要求在pH5.8的磷酸缓冲液中,使用USP装置2(浆法)在50rpm的情况下,在给药后30分钟内至少有剂型中包含的80%的醋氨酚被释放,而对布洛芬片剂,USP24要求在pH7.2的磷酸缓冲液中,使用USP装置2(浆法)在50rpm的情况下,在给药后60分钟内至少有剂型中包含的80%的布洛芬被释放。见USP24,2000版,19-20和856(1999)。在另一个实施方案中,活性成分的溶出特性得到改进:如控释的、持续的、长期的、减速的、延长的、迟延的等等。
对本发明的剂型的总体理解可参照图1。在图1中,剂型10包括壳18(可以是模制的壳),其形状围绕着核12的外表面(可以是模制的核或压制的剂型或硬或软胶囊,或任何基本上是固体可食用的形式),该核的形状与壳18不同。核12包括腹状突起14。图1中核和壳的形状可理解为仅用作说明,而不以任何形式限制本发明。
核或基质可以是任何固体形式。核可以是,例如,压制的剂型,或是模制的。在本文中使用的“基质”指一表面或放在下面的支持物,其他物质存在于它上面或与之作用,“核”是指某一物质至少部分地被其他物质包裹或围绕。核可任选地包括次级核(也可被称为“插入物”),该次级核可用任何方法制造,压制或模制,也可任选地包括一种或多种活性成分。例如,核可以是压制或模制的片剂、硬或软胶囊、栓剂,或糖膏剂形式如糖锭、牛轧糖、硬糖、软糖或脂质为基础的形式。在一个实施方案中,核可以包含微电子装置(如电子“芯片”),该微电子装置可用于任何目的,包括如作为有源元性部件或用来检测环境情况或控制,如剂型或装置中活性成分的释放。
核可以有许多不同的形状。例如,在一个实施方案中,核的形状可以是斜截锥。在另一个实施方案中,核的形状可以是多面体,如立方体、棱锥体、棱柱体等等;或可以有几个非平面的空间外形的几何形状,如圆锥体、圆柱体、球体、环面等等。可用作示范的核的形状包括如“Elizabeth Companies片剂设计培训手册”(The Elizabeth Companies Tablet Design Training Manual)(Elizabeth CarbideDie有限公司)第7页(McKeesport,Pa.)(本文引用作为参考)描述的压制工具制成的片剂形状,具体如下(片剂形状与压制工具的形状正好相反):
1.浅凹面
2.标准凹面
3.深凹面
4.特深凹面
5.改进的球凹面
6.标准凹面平分
7.标准凹面双重平分
8.标准凹面欧洲平分
9.标准凹面部分平分
10.双半径
11.斜面和凹面
12.平面
13.平面对斜边(F.F.B.E.)
14.平面对斜边(F.F.B.E.)平分
15.平面对斜边(F.F.B.E.)双重平分
16.环形
17.微凹
18.椭圆
19.卵形
20.囊状
21.矩形
22.正方形
23.三角形
24.六边形
25.五边形
26.八边形
27.菱形
28.箭头形
29.弹头形
30.筒形
31.半月形
32.盾形
33.心形
34.杏仁形
35.家用盘形
36.平行四边形
37.不规则四边形
38.8字形/杠铃形
39.蝶形领结形
40.不等边三角形
核或次级核可任选地至少部分被压制的、模制的、或用喷雾法形成的次级包衣复盖。但是,在一个较佳实施例中,核可以基本上没有次级包衣:即在核的外表面和壳的内表面之间没有次级包衣。
在另一个较佳实施例中,核是压制的剂型,如粉末压制成的片剂。该粉末包含活性成分较好,并可任选地包含各种各样的赋形剂,如常规的粘合剂、崩解剂、润滑剂、填充剂等等,或该粉末可包含其他药物或非药物的颗粒,如制片的无活性安慰剂混合物,糖膏剂混合物等等。一种较佳制剂包括活性成分、粉状蜡(如虫胶蜡、微晶蜡、聚乙二醇等等),可任选地包括崩解剂和润滑剂,具体可见美国专利申请序列号09/966,493的第4到11页,本文引用其公开文件作为参考。
本发明的一个实施方案中,本发明的各种剂型包含由粉末制成的核,该粉末的平均颗粒大小约在50微米到500微米。在一个实施方案中,活性成分的平均颗粒大小约在50微米到500微米。在另一个实施方案中,至少一种赋形剂的平均颗粒大小约在50微米到500微米。在上述实施方案中,一种主要的赋形剂,即构成核重量至少50%的赋形剂,其平均颗粒大小约在50微米到500微米。在这个大小范围内的颗粒对直接压片法特别有利。
在本发明的一个较佳实施例中,核可以通过直接压片法制备。通过这种技术,直接压实活性成分和其他合适的非活性成分如赋形剂的混合物制造各种压制的核。
任何用于制造固体剂型的常规压实方法可用于制造本发明的核。这些方法包括但不限于,干法制粒后压制,以及湿法制粒后干燥和压制。压制方法包括旋转压制,辊压技术,如chilsonator压片机或递墨辊,或模制、浇铸或挤压技术。这些方法在本领域是熟知的,详细记述于,如,Lachman等的《工业药剂学的理论和实践》(The Theory and Practice of Industrial Pharmacy),11章(第3版,1986)。
上述的一种方法把预定量的颗粒或成分放入旋转或压片机的模腔中,该压片机作为模盘的一部分从填充位置到压实位置持续旋转。在压实位置,颗粒在上下冲头之间被压实。模盘随后旋转至弹出位置,在该位置制成的片剂被下冲头推出模腔和被固定的卸除棒导入弹出斜槽。
本发明的另一个实施方案中,核是直接压制的片剂,该片剂由基本不含水溶性聚合物粘合剂和水化聚合物的粉末制成。该组合物有利于维持速释溶出特点,降低加工和材料成本,以及提供剂型以最佳的物理和化学稳定性。
在核是通过直接压制制备的多个实施方案中,该核的组成物质,如一种或多种活性成分和赋形剂,混合在一起,制成干粉较佳,并将其加到施压的设备中制成核。可以使用任何压实设备,包括如辊压机如chilsonator或递墨辊;或常规的压片机。通过本领域熟知的旋转或压片机压实制作该核较佳。在旋转式压片机中,计量好的粉剂填充入模腔,该压力机作为模盘的一部分从填充位置至压实位置进行旋转,在该压实位置粉末在上下冲头之间被压实,至弹出位置制成的片剂被下冲头推出模腔。直接压制法能最大程度减少或消除水溶性非糖类聚合物粘合剂如聚乙烯吡咯烷酮、藻酸盐、羟丙基纤维素、羟丙甲基纤维素、羟乙基纤维素等等,它们对溶出有不利影响。
在另一个实施方案中,通过湿法制粒制备该核,在该方法中活性成分、合适的赋形剂、湿粘合剂的溶液或分散体(如水煮淀粉糊或聚乙烯吡咯烷酮溶液)混合并被制成粒状。湿制粒法适用的设备包括低剪切,如行星式搅拌器、高剪切搅拌器和流化床,包括旋转式流化床。制成的粒状物质被干燥,并可任选地与其他成分干混合,如助剂和/或赋形剂如润滑剂、着色剂等等。最后的干混合物适合上述方法的压制。
直接压制法和湿制粒法是本领域熟知的,并详细记述于,如,Lachman等的《工业药剂学的理论和实践》(The Theory and Practice of IndustrialPharmacy),11章(第3版,1986)。
在另一个实施方案中,通过使用美国专利申请系列号09/966,509,第16-27页所述的压制方法和设备制备核,本文引用该公开文件作为参考。特别是,该核是使用旋转压制组件制造的,该组件包含如美国专利申请系列号09/966,509的图6的有双排模结构的单一设备中的填充区、插入区、压制区、弹出区和清洗区。压制组件的模以使用真空辅助填充较佳,其过滤器在每个模内或模附近。压制组件的清洗区包含任选的粉末回收系统以从过滤器中回收多余的粉末并把粉末返回模中。
也可以选择使用如美国专利申请系列号09/966,450,第57-63页所述的热凝固模制方法和设备制备核,本文引用该公开文件作为参考。在这个实施方案中,把流动形式的起始物质注入模腔来制造该核。该起始物质包括活性成分和热凝固物质则较佳,它们的温度在热凝固物质的熔点之上但在活性成分的分解温度之下。起始物质在模腔中冷却并固化成为成形的核(即有模的形状)。
按照这个方法,起始物质应当具流动形式。例如,它可以包含悬浮在熔化的基质,如聚合物基质中的固体颗粒。起始物质可以是完全熔化或处于糊状形式。起始物质可以包含溶解在熔化物质中的活性成分。可供选择的是,起始物质可通过在溶剂中溶解固体制备,该溶剂在起始物质熔化后从起始物质中蒸发。
该起始物质可以包含任何希望形成某一形状的可食用的物质,包括活性成分、营养剂、维生素、矿物质、调味剂、甜味剂等等。该起始物质包括活性成分和热凝固物质则较佳。该热凝固物质可以是在约37℃到120℃能流动,且在约0℃到35℃是固体的任何可食用的物质。较佳的热凝固物质包括水溶性聚合物如聚亚烷基二醇、聚环氧乙烷和衍生物和蔗糖酯;脂肪如可可油、氢化植物油如棕榈仁油、棉籽油、向日葵油和大豆油;甘油一酯、甘油二酯、甘油三酯、磷脂,蜡如巴西棕榈蜡、鲸蜡、蜂蜡、小烛树蜡、虫胶蜡、微晶蜡和固体石蜡;含脂肪混合物如巧克力;糖如用于制造硬糖形式的无定形玻璃形式的糖,如用于制造软糖形式的过饱和溶液中的糖;低湿度聚合物溶液如明胶和其他水状胶体的混合物,该混合物的水分达约30%,像用于制造“gummi”糖膏剂形式的混合物。在一个更佳实施方案中,热凝固物质是水溶性聚合物如聚乙二醇。
在另一个实施方案中,该核可以是中空的或抽真空的核。例如,该核可以是空的胶囊壳。或者,中空的核可以通过模制来制备。在上述方法中,流动物质被注入模腔中,并使该腔的温度达到核的外表面(与模相接触的)开始固化或凝固。随后可使用合适的装置把多余的流动物质从核的中心抽出,例如用活塞泵。另外,空胶囊可以用作次级核,在其上用本领域熟知的方法形成包衣层,这些方法如美国专利申请系列号09/966,497,第27-51页所述的喷雾包衣、浸渍包衣或热循环模制成形,本文引用该公开文件作为参考。
在美国专利申请系列号09/966,497中的热循环模制成形方法和设备,热循环模制成形组件有着如图3所示的大体外形。热循环模制成形组件200包含转子202,在转子202周围安置有多个铸模单元204。热循环模制成形组件包括用于放置制造核的流动物质的贮器206(见图4)。另外,热循环模制成形组件配备有快速加热和冷却铸模单元的温度控制系统。图55和56显示该温度控制系统600。
在这个实施方案中,该铸模单元包括如美国专利申请系列号09/966,497中图26C所示的中心铸模配件212和上铸模配件214较佳,上述配件配合形成所需核的形状的模腔。当转子202旋转时,相对的中心铸模配件和上铸模配件闭合。在贮库206加热到流动状态的核流动物质被注入到形成的模腔中。随后核流动物质的温度被降低,核流动物质硬化成为核。铸模配件打开,核被弹出。
本发明的另一个实施方案中,核是包含一种或多个插入物的压制剂型。插入物可被制成任何形状或大小。例如,可制成含不超过一个对称轴的不规则形状的插入物。也可制成圆柱形插入物。在一个较佳实施例中,可使用如美国专利申请系列号09/966,450,第57-63页所述的热凝固成型方法和设备制备插入物,本文引用该公开文件作为参考。
本发明的一个实施方案中,插入物的平均直径可在约100微米到约1000微米。本发明的另一个实施方案中,插入物的平均直径可以是核的直径或厚度的约10%到约90%。本发明的另一个实施方案中,核可以包含许多插入物。
在另一个实施方案中,插入物的平均直径、长度或厚度超过核的直径或厚度的约90%,例如,插入物的平均长度超过核的厚度的约100%。
本发明的壳(或包衣)可以包含任何能模制的物质,包括如成膜剂、低熔点疏水性物质、胶凝化聚合物、增稠剂、增塑剂、助剂和赋形剂。在一个实施方案中,壳包含至少约50%,至少约80%,更好至少约90%的选自成膜剂、胶凝化聚合物、低熔点疏水物质、非晶体糖或糖醇和它们的混合物的物质较佳。在另一个实施方案中,壳包含至少约50%的选自成膜剂、胶凝化聚合物、低熔点疏水物质和它们的混合物的物质,壳包含至少约80%的选自成膜剂、胶凝化聚合物、低熔点疏水物质和它们的混合物的物质较佳,壳包含至少约90%的选自成膜剂、胶凝化聚合物、低熔点疏水物质和它们的混合物的物质更佳。
用流动性物质制造壳较佳。该流动物质可以是在约37℃到120℃能流动,且在约0℃到35℃是固体或可形成凝胶的任何可食用的物质。当处于流体或流动状态时,流动物质可包含溶解的或熔化的成分,以及溶剂如水。该溶剂可以部分或基本通过干燥除去。合适的流动物质包括成膜剂、胶凝化聚合物、水状胶体、低熔点疏水物质如脂肪和蜡,非结晶糖等等。
本发明的一个实施方案中,流动物质包含明胶。明胶是一种天然的热胶凝化聚合物。它是通常可溶于温水的白蛋白类的衍化蛋白的无色无味混合物。经常使用的明胶有两种类型-A型和B型。A型明胶是经酸处理原料的衍生物。B型明胶是碱处理原料的衍生物。明胶的水分含量,和Bloom强度、成分与原始明胶加工条件,决定了它的液体和固体的转变温度。Bloom是明胶凝胶体强度的标准量度,它与分子量有粗略的相关性。Bloom被定义为以克为计量单位的用来在保持10℃达17小时的6.67%明胶凝胶体中移动直径为半英寸的塑料活塞4毫米所需的重量。在一个较佳实施例中,流动物质是包含20%275 Bloom的猪皮明胶,20%250 Bloom的骨明胶,和大约60%水的水溶液。
其他较佳的流动物质可包含蔗糖-脂肪酸酯;脂肪如可可油、氢化植物油如棕榈仁油、棉籽油、向日葵油和大豆油;甘油一酯、甘油二酯、甘油三酯、磷脂,蜡如巴西棕榈蜡、鲸蜡、蜂蜡、小烛树蜡、虫胶蜡、微晶蜡和固体石蜡;含脂肪的混合物如巧克力;糖如用于制造硬糖形式的无定形玻璃形式的糖,如用于制造软糖形式的过饱和溶液中的糖;碳水化合物如糖醇(例如山梨醇、麦芽糖醇、甘露醇、木糖醇),或热塑性淀粉;低湿度聚合物溶液如明胶和其他水状胶体的混合物,该混合物的水分达约30%,像用于制造“gummi”糖膏剂形式的混合物。
在本发明的一个较佳实施例中,流动物质包含成膜剂如纤维素醚,例如羟丙甲基纤维素或改性淀粉,例如含蜡玉米淀粉;可任选增量剂如多糖,例如麦芽糊精;可任选增稠剂如水性胶体,例如黄原胶或角叉菜聚糖,或糖,例如蔗糖;可任选增塑剂,例如聚乙二醇、丙二醇,植物油如蓖麻油、甘油,和它们的混合物。
本领域中熟知的任何成膜剂均适用于本发明的壳流动物质。合适的成膜剂的例子包括但不限于,聚乙烯醇(PVA)、聚乙烯吡咯烷酮(PVP)、羟丙基淀粉、羟乙基淀粉、pullulan、甲基乙基淀粉、羧甲基淀粉、甲基纤维素、羟丙基纤维素(HPC)、羟乙甲基纤维素(HEMC)、羟丙甲基纤维素(HPMC)、羟丁甲基纤维素(HBMC)、羟乙乙基纤维素(HEEC)、羟乙羟丙甲基纤维素(HEMPMC)、甲基丙烯酸和甲基丙烯酸酯共聚物、聚环氧乙烷和聚乙烯吡咯烷酮共聚物、明胶、蛋白质如乳清蛋白、可凝固蛋白质如白蛋白、酪蛋白和酪蛋白分离物、大豆蛋白和大豆蛋白分离物、预凝胶化淀粉,聚合物和衍生物及它们的混合物。
一种合适的羟丙甲基纤维素化合物是“HPMC2910”,其纤维素醚的取代度约1.9,羟丙基的摩尔取代度为0.23,按照化合物的总重量,该化合物含有约29%到约30%的甲氧基和约7%到12%的羟丙基。HPMC2910的商品化产品由Dow ChemicalCompany提供,其商品名METHOCEL E。METHOCEL E5是适用于本发明的HPMC2910的一个级别,在20℃的温度,2%的水溶液中用Ubbelohde粘度计测定其粘度约4到6cps(4到6毫帕斯卡秒)。相类似的,METHOCEL E6,适用于本发明的HPMC2910的另一个级别,在20℃的温度,2%的水溶液中用Ubbelohde粘度计测定其粘度约5到7cps(5到7毫帕斯卡秒)。METHOCEL E15,适用于本发明的HPMC2910的另一个级别,在20℃的温度,2%的水溶液中用Ubbelohde粘度计测定其粘度约15000cps(15毫帕斯卡秒)。本文中使用的“取换度”指连接在脱水葡萄糖环上的取代基的平均数目,而“羟丙基的摩尔取代度”指每摩尔脱水葡萄糖上的羟丙基的摩尔数。
本文中使用的“改性淀粉”包括为改进稳定性而交联,化学改性的淀粉,或为改进溶解特性而物理改性的淀粉。本文中使用的“预凝胶化淀粉”或“速溶化淀粉”指已经预先湿润,随后干燥以增加冷水溶解度的改性淀粉。合适的改性淀粉可以由许多供应商商业化提供,例如,A.E.Staley Manufacturing Company,和National Starch&Chemical Company。一种合适的改性淀粉包括预凝胶化的蜡状玉米衍生淀粉,该淀粉由National Starch&Chemical Company以商品名PURITYGUM和FILMSET进行商业化提供,和它的衍生物、共聚物和混合物。上述蜡状玉米淀粉通常包含,基于该淀粉总重量,约0%到约18%的直链淀粉和约100%到约82%的支链淀粉。
合适的木薯粉糊精包括National Starch&Chemical Company以商品名CRYSTAL GUM或K-4484提供的物质,和该物质的衍生物如衍生自木薯粉的改性食物淀粉,该淀粉由National Starch&Chemical以商品名PURITY GUM 40提供,以及该物质的共聚物和混合物。
本领域中熟知的任何增稠剂均可用于本发明的成膜成分。上述增稠剂的例子包括但不聚限于水性状胶体(本文中也指胶凝化聚合物)例如藻酸盐、琼脂、瓜尔豆胶、角豆、角叉菜糖、tara、阿拉伯树胶、黄芪胶、果胶、黄原胶、gellan、麦芽糊精、半乳甘露聚糖、pusstulan、海带多糖、scleroglucan、阿拉伯树胶、菊粉、果胶、whelan、rhamsan、zooglan、methylan、壳多糖、环糊精、脱乙酰壳多糖,和衍生物及它们的混合物。其他合适的增稠剂包括结晶糖,如葡萄糖(右旋糖)、果糖等等,和衍生物及它们的混合物。
合适的黄原胶包括由C.P.Kelco Company以商品名KELTROL 1000,XANTROL180,或K9B310提供的物质。
本制药领域中熟知的任何增塑剂均可适用于本发明,可以包括但不限于聚乙二醇;甘油;山梨糖醇;柠檬酸三乙酯;柠檬酸三丁酯;癸二酸二丁酯;植物油如蓖麻油;表面活性剂如聚山梨酯,十二烷基硫酸钠,和磺基丁二酸二辛酯钠;丙二醇;甘油单醋酸酯;甘油二醋酸酯;甘油三醋酸酯;天然树胶和它们的混合物。在含有纤维素醚成膜剂的溶液中,任选的增塑剂在量上可存在该溶液的总重量的约0%到约40%。
流动物质可任选包括助剂或赋形剂,可包含达到流动物质重量的约20%。合适的助剂或赋形剂例子包括脱粘剂(detackifiers)、湿润剂、表面活性剂、抗泡沫剂、着色剂、调味剂、甜味剂、遮光剂等等。在一个较佳实施例中,流动物质包含少于5%的保湿剂,或者基本上不含湿润剂,如甘油、山梨糖醇、麦芽糖醇、木糖醇或丙二醇。湿润剂常常被包括在用于包被法的预成形的薄膜中,如被转让给BannerGelatin Products公司的美国专利5,146,730和5,459,730所公开的,以保证在加工过程中薄膜有足够的柔韧性或可塑性和粘合性。湿润剂的作用是结合水分和在薄膜中保留水分。用于包被法的预成形薄膜常常包括多至45%的水。不利的是,湿润剂的存在会延长干燥过程,也会对制成的剂型的稳定性有不利影响。
在本发明的一个较佳实施例中,制成的剂型壳的至少约80%;如至少约90%的材料选自成膜剂、胶凝化聚合物(水性胶体)、低熔点疏水物质、非结晶糖和它们的混合物。本发明的壳可用注射模塑制造,有利于减少或消除直接压制中需要的填充剂-粘合剂如微晶纤维素、喷雾干燥乳糖、矿物盐如磷酸钙、结晶糖如蔗糖、dextrate等等。不利的是,这些物质会减低该壳的透明性和稳定性。本发明的壳包含少于约10%,如少于约1%,或少于约0.1%的直接压制中的填充剂-粘合剂较佳。所以本发明的各种壳是对压制包被的各种壳的改进,压制包被的各种壳常常包含至少约30%的直接压制中的填充剂-粘合剂。举例见WO 00/18447。
在一个实施方案中,该壳基本不含湿润剂,如甘油和/或山梨糖醇,即该壳包含少于约5%,如少于约1%,或少于约0.1%的湿润剂。在另一个实施方案中,该壳包含少于约5%,如少于约1%的选自结晶糖、糖醇和甘油的吸湿物质。在另一个实施方案中,该壳包含少于约5%的增塑剂。
在一个较佳实施例中,该壳的全部或部分是模制的。在该壳或壳的部分是模制的各种实施方案中,用模制的壳或壳的部分基本不含有直径在0.5到5.0微米的小孔较佳。本文中使用的“基本不含”指该壳的小孔在小孔直径在0.5到5.0微米范围内的体积小于约0.02cc/g,小于约0.01cc/g较佳,小于约0.005cc/g更佳。典型的压制物质在此小孔直径范围中的小孔体积大于约0.02cc/g。小孔的体积可用Quantachrome Instruments PoreMaster 60压汞孔度计和相关的计算机软件“Porowin”来测定。该测定步骤由Quantachrome Instruments PoreMaster操作手册记载。PoreMaster设备既测定固体或粉末的小孔体积,又测定固体或粉末的小孔直径,通过将不润湿的液体(汞)强制压入,这包括排净样品池(穿透计)中的样品,向池内填充汞使汞环绕样品,向样品池加压,用:(i)压缩空气(最高至50psi);和(ii)液压(油压)压力发生器(最高至60000psi)。通过汞在所加压力下从样品外面移入小孔中带来的容量变化来测量侵入体积。相应的发生侵入的小孔直径(d)通过所谓的“Washburn方程”直接计算:d=-(4γ(cosθ))/P其中γ是液体汞的表面张力,θ是汞与样品表面的接触角,P是所加的压力。
用于测量小孔体积的设备:
(1)Quantachrome Instruments PoreMaster 60
(2)能称重0.0001g的分析天平
(3)干燥器
用于测量的试剂:
(1)高纯度氮
(2)蒸馏三次的汞
(3)高压液体(Dila AX,由Shell Chemical公司提供)
(4)液氮(用于汞蒸汽冷阱)
(5)用于清洗样品池的异丙醇或甲醇
(6)用于池的清洗的液体清洁剂
步骤:
样品在分析前仍被密封包装或保存于干燥器中。接通真空泵,在汞蒸汽冷阱中充满液氮,提供的压缩气体调节在55psi,开启设备,加热时间至少30分钟。空的穿透计池按照设备手册的描述安装并记录其重量。该池被安置在低压站,在分析菜单上选择“仅可排净和充满”,并采用下列设置:
精密排净时间:1分钟
精密排净率:10
粗排净时间:5分钟
然后取出该池(已充满汞)并称重。向汞储器排空该池,每个样品取两片置于该池内,再装配该池。该池和样品的重量然后记录下来。该池然后安装在低压站,从菜单上选择低压选项,并设定下列参数:
模式:低压
精密排净率:10
精密排净到:200μHg
粗排净时间:10分钟
填充压力:接触+0.1
最大压力:50
方向:侵入和挤出
重复:0
汞接触角:140
汞表面张力;480
接着开始获取数据。关于压力与累计挤入体积的关系图显示在屏幕上。在低压分析结束后,该池从低压站取出并重新称重。汞以上的空间被注满液压油,然后该池被装配后安置在高压腔。使用下列参数:
模式;固定速率
发动机速度:5
起始压力:20
最终压力:60,000
方向:侵入和挤出
重复:0
油充满长度:5
汞接触角:140
汞表面张力;480
接着开始获取数据,关于压力与挤入体积的关系图显示在屏幕上。在高压运行结束后,同一样品的低压和高压数据文档被合并。
在本发明一个较佳实施例中,壳是以流动物质的形式涂敷到核上的,该流动物质使用如美国专利申请系列号09/966,497,第27-51页所述的热循环方法和设备制备,本文引用该公开文件作为参考。在该实施例中,使用有图3所示的总体外形的热循环铸模组件来敷贴壳。热循环铸模组件200包含转子202,它有多个铸模单元204安置在它的周围。热循环铸模组件包括用于放置制造核的流动物质的贮器206(见图4)。另外,热循环铸模组件配备有快速加热和冷却铸模单元的温度控制系统。图55和56显示了该温度控制系统600。
较佳的热循环铸模组件是美国专利申请系列号09/966,497的图28A所示的包含许多铸模单元204的类型。铸模单元204又包含如图28C所示的上铸模配件214、旋转中心铸模配件212和下铸模配件210。核被连续转移至铸模配件,随后铸模配件关闭核。在贮器206加热到流动状态的壳流动物质被注入到闭合的铸模配件形成的模腔中。随后壳流动物质的温度被降低,发生硬化。铸模配件打开,被包被的核被弹出。包被是通过两个步骤进行的,核的每一半分别通过中心铸模配件的旋转进行包被,如美国专利申请系列号09/966,497的图28B的流程图所示。
在一个实施方案中,更佳的是,本发明的壳有高度的表面光泽,该表面光泽是按照本文实施例5阐明的方法测定的反射光的量度。壳和/或制成的剂型的表面光泽至少约150光泽单位,如至少约175光泽单位,或至少约210光泽单位较佳。有高表面光泽的剂型由于美观雅致和感知的易吞咽性而受消费者喜爱。壳的表面光泽依赖许多因素,包括壳的成分,壳的制作方法,和,使用模子时的模的表面抛光。
本发明剂型的核、壳、插入物或它们的任何组合可以含有一种或多种活性成分。在本发明的一个实施方案中,只有核含有一种或多种活性成分。在本发明的另一个实施方案中,只有壳含有一种或多种活性成分。而在本发明的另一个实施方案中,只有插入物含有一种或多种活性成分。而在本发明的另一个实施方案中,核和壳都含有一种或多种活性成分。而在本发明的另一个实施方案中,核、壳或插入物中的一个或几个含有一种或多种活性成分。
在一个实施方案中,本发明的剂型包括有外表面的核以及有外表面和内表面的壳,其中该壳围绕着核,壳的内表面与核的外表面基本上有相同形状,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,壳包含少于约50%的结晶糖,剂型中基本不含(即基于壳重量,小于1%,小于约0.1%较佳)电荷控制。
本文中使用的术语“电荷控制药剂”指有电荷控制作用的物质,如在基质上生成包衣的静电沉积中使用的物质。该电荷控制剂包括水杨酸金属盐,例如水杨酸锌、水杨酸镁、水杨酸钙;季铵盐;苯扎氯铵;苄索氯铵;溴化三甲基十四烷基铵(西曲溴铵);以及环糊精和它们的加合物。
在本发明的这个实施方案中,壳包含少于约50%的结晶糖,壳包含少于约25%的结晶糖较佳,壳包含少于约5%的结晶糖更佳。
本文中使用的术语“基本上有相同形状”指壳的内表面有与核的外表面的峰和谷基本相应的相反的峰和谷或凹陷和突起。因此,该凹陷和突起的长、宽、高或深在尺寸上常常超过10微米,比方说超过20微米,且小于约30,000微米,小于约2000微米较佳。
在本发明的一个实施方案中,在核的外表面和壳的内表面之间的最大裂隙高度与最大裂隙处壳的总的理论厚度的比值小于约1∶7.5,小于约1∶10较佳,小于约1∶100最佳。
在另一个实施方案中,核的外表面和壳的内表面之间的最大裂隙高度与主面中心处壳的厚度的比值小于约1∶7.5,小于约1∶10较佳,小于约1∶100最佳。本文中使用的术语“主面”可应用于所有的核,包括但不限于那些压制片剂。在本发明的一个实施方案中,核有一个或多个主面。例如,核可以是多面体,如立方体、角锥体、棱柱体等等;或者核可以有几个非平面的空间外形的几何形状,如圆锥体、圆柱体、球体、环面等等。
壳的厚度可用显微镜测量,例如,环境扫描电子显微镜,型号XL 30 ESEMLaB6,Philips Electronic Instruments Company,Mahwah,WI。壳的厚度在一个剂型的6个不同位置上测量,如图2所示。相对标准偏差(RSD)的计算是样本标准偏差除以平均数,乘100,这是本领域熟知的(即RSD是用百分比表示的平均数的标准偏差)。壳厚度的RSD显示了一个剂型中壳厚度的变异。壳厚度的一致有利于提供美观的好处如色彩的一致,和基质覆盖层的一致;特别使壳具有功能上的优点,如对剂型内包含的活性成分的的改进释放实施方案有利。有利的是,本发明的剂型中壳厚度的相对标准偏差小于约40%,如小于约30%,或小于约20%较佳。
位置1:第一主面的中心,tc1
位置2和3:第一主面与侧面相交的边(接近冲头面刃口),tc2和tc3
位置4:第二主面的中心,tc4
位置5和6:第二主面与侧面相交的边(接近冲头面刃口),tc5和tc6
为了在多个剂型中测定总的剂型厚度的RSD,使用已校准的电子数字式测径器测定20个剂型的总的剂型厚度和直径。测径器放在跨过图2所示的t的位置来测量厚度。测径器放在图2所示的d的剂型侧面的最宽的点的中央部分来测量直径。
在本发明的一个更佳实施例中,总的剂型厚度的相对标准偏差小于约0.40%,例如小于约0.30%。产品特性的高度一致性,特别是总的尺寸,作为产品高质量和在制造过程中高度的可靠性、可重复性、可重现性和控制的指标,在制药领域被认为是有利的。产品尺寸的一致性还对下游操作的效率有利,这些操作如包装入泡罩包装,或用板条充填机装入瓶子中。
图3A是现有技术凝胶片的横截面显微照片,该凝胶片由CVS Pharmacie销售。如图3A所示,该凝胶片包含核300,该核有由两部分302和304组成的壳,这两部分302和304在306处交界和邻接。接近交界306的是在壳的302,304部分和核300的外表面之间的裂隙308。类似的,图3B是EXCEDRIN凝胶片现有技术的横截面显微照片(EXCEDRIN凝胶片是Bristol-Myers Squibb公司的产品)。如图3B所示,该凝胶片包含核350,该核有由两部分352和354组成的壳,这两部分352和354在356处交界和邻接。接近交界356的是在壳的352,354部分和核350的外表面之间的裂隙358。
图4是本发明的凝胶片剂型的横截面显微照片。如图4所示,该凝胶片包含核400,该核有由两部分402和404组成的壳,这两部分402和404在406处交界和邻接。但是,与图3A和图3B所示的凝胶片现有技术不同,如图4所示的本发明的凝胶片的壳的402和404部分基本与核400的外表面有相同形状,没有接近交界406的裂隙。
图5代表了剂型502的横截面图解,剂型502包含有主面503和505的核504及由壳独立的两部分508和510组成的壳506。如图5所示,“h”是在核的外表面和壳的内表面之间的最大的裂隙,“t”是主面中心的壳厚度。因此,上述本发明的实施方案中,h/t<1∶7.5,小于约1∶10较佳,小于约1∶100最佳。
图6是图5中壳与核的交界的分解图。特别的是,图6显示核504的外表面501与壳的508和510部分的交界。在外表面501和壳的内表面之间的最大裂隙503被显示为“h”。
在另一个实施方案中,本发明的剂型包括有外表面的核以及有外表面和内表面的壳,其中该壳围绕着核,该剂型在40℃和相对湿度(RH)75%的环境中暴露60分钟,水份摄取少于约0.8%,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,剂型中基本不含电荷控制剂,壳也基本没有隆起的接缝。
与美国专利5,146,730和5,459,983所述的常规包被过程制备各种剂型相比,本发明实施方案中的壳有其优势,该壳使用相对非吸湿物质制备,该物质在高湿度情况下有高稳定性。较佳的是,本发明的剂型在40℃/75%RH的环境中暴露10分钟,水份摄取少于约0.35%,少于约0.30%更佳。可选择的是,本发明的剂型在40℃/75%RH的环境中暴露20分钟,水份摄取少于约0.50%较佳,少于约0.40%更佳。可选择的是,本发明的剂型在40℃/75%RH的环境中暴露30分钟,水份摄取少于约0.60%较佳,少于约0.45%更佳。可选择的是,本发明的剂型在40℃/75%RH的环境中暴露60分钟,水份摄取少于约0.80%较佳,少于约0.65%更佳,其测量是按照本文实施例6提出的方法进行的。
在实施方案中,核包含压制的片剂,核和/或制成的剂型通常包含“腹状突起”,和两个相对的面,该面可以是平的或弯曲的,如图12A和12B所示。图12A显示了剂型10″的前视图,该剂型的轴向水平中心线16″是腹状突起22的正中央。剂型的长度(“l”)见图12A,剂型的宽度(10″)见图12B。
在一个较佳实施例中,如剂型有腹状突起,腹状突起的第一点的第一壳厚度与腹状突起的第二点的第二厚度之间的差不大于约二个厚度中较大者的约10%。
在另一个较佳实施例中,如剂型有腹状突起,腹状突起上任何一点的壳厚度不大于片剂主面中心的壳厚度。
在另一个较佳实施例中,壳基本没有超过主面的壳厚度约1.25倍的隆起部分。
在另一个较佳实施例中,剂型有腹状突起,腹状突起的第一位置的第一壳厚度与腹状突起的第二位置的第二厚度之间的差不大于约50微米。
在另一个较佳实施例中,壳表面基本没有高度超过约50微米的隆起部分。
在另一个较佳实施例中,核有主面,剂型有腹状突起,腹状突起上任何一点的壳厚度与主面中心的壳厚度之间的差不超过约50微米。
在本发明的另一个实施方案中,壳包含第一壳部分和第二壳部分。在上述实施方案中,第一壳部分和第二壳部分可以包含不同的壳材料。在另一个这样的实施方案,第一壳的材料。和第二壳的材料在视觉上可相互区分,例如在视觉上可区分的部分可以有不同的颜色、色调、光泽、反射特性、亮度、深度、阴影、色度、不透明度等等。例如,壳可以有红色部分和黄色部分,或无光的成品部分和有光泽部分,或不透明部分和透明部分。
本发明的一个优势是在一个核上安置一种以上的壳的材料的能力。在一个实施方案中,壳包含第一和第二部分,第一和第二壳部分在界面粘连。在一个上述实施方案中,界面可以是基本上平的(即,没有任何隆起)。在另一个上述实施方案中,界面可以是一种对接形式,即,第一和第二部分的边缘是相邻的和相互接触的,但不重叠,如图7A所示,或是相邻的但形成一个突起,如图7B所示。在另一个实施方案中,第一壳部分在交界处的厚度可以超过第二壳部分在交界处的厚度,以致于在界面形成一个突起,如图7B所示。
在一个特殊实施方案中,壳包含在交界处连结的第一和第二部分,交界处基本是平的(即,没有任何隆起)。在一个上述实施方案中,第一和第二壳厚度基本一致,在界面总的壳厚度与剂型主面中心的第一或第二壳部分的壳厚度基本没有不同。在另一个特殊实施方案中,壳包含在交界处连结的第一和第二部分,界面基本是平的(即,没有任何隆起),界面位置沿着剂型的腹状突起。在上述实施方案中,在界面处总的壳厚度与沿着剂型的腹状突起的任何点的第一或第二壳部分的壳厚度基本没有不同。
在另一个实施方案中,该第一壳部分和第二壳部分在界面相互重叠。重叠可以形成不同的形状,如尖的、斜行的、阶梯形的、舌形的和沟状的、或经切削的,如图8A到8E所示。
而在另一个实施方案中,该第一壳部分和第二壳部分在界面形成交错状态。该交错状态可以有不同的形态,如正方形交错、不同的锯齿“七巧板”形状、鸽尾形、Z字形、或任何数目的复杂不对称形态,如图9A到9E所示。
在一个特殊实施方案中,壳包含在界面相互重叠的第一部分和第二部分,在重叠处的总的壳厚度不超过每个单一壳部分的中位厚度,例如交界部分不包含隆起部分。在上述实施方案中,例如,界面总的壳厚度不超过在剂型主面中心第一或第二壳部分的壳厚度。在另一个特殊实施方案中,壳包含在界面相互重叠的第一部分和第二部分,界面总的壳厚度不超过沿剂型腹状突起的任何点的第一或第二壳部分的壳厚度。
而在另一个实施方案中,该第一壳部分和第二壳部分在界面相互连接并形成突出。该界面和突出可以形成不同的形状,如图10A到10F所示。
本发明的有利特性可通过图11A和11B进一步阐明。图11A是本发明的注射模塑剂型的分开的第一和第二壳部分1102和1104的显微照片。如图11A所示,壳部分1102和1104的界面是平接缝,在该接缝第一壳部分1102沿着单一的“水平线”(图11A所示的虚线)过渡到第二壳部分1104。相反,图11B显示了剂型现有技术,该剂型由预先制成的重叠薄膜形成如图所示的第一壳部分1152和第二壳部分1154。图11B清楚地显示,剂型现有技术在第一壳部分1152和第二壳部分1154的界面有一个“阶梯”,从而产生分离的“水平线”(图11B所示的虚线)。该阶梯是不利的,因为该阶梯在视觉上不如光滑表面精致,因为该阶梯可以被舌感觉到,可能会被消费者认为是粗糙的或不愉快的。而且,不平的表面或阶梯会在包装机械中钩住,降低生产能力/效率,或不平的表面或阶梯会作为一个开放点,在该处壳层能被有意或无意地移除,减少了剂型被改换的迹象。
在另一个实施方案中,本发明的壳没有高度超过壳厚度相对标准偏差的25%的接缝。
在另一个较佳实施例中,第一和第二壳部分的界面是平接缝,在该接缝第一壳部分沿着单一的“水平线”过渡到第二壳部分。
本发明将通过下列实施例进一步阐明,这些实施例并不意味着以任何形式限制本发明。
实施例1
有模制的明胶包衣的一系列片剂是按照本发明如下制造的:
A部分: 压制片
下列成分在塑料袋中充分混合:89.4份分的醋氨酚USP(590mg/片)和8.0份的合成蜡X-2068 T20(53mg/片)。接着,2.1份淀粉羟乙酸钠(EXPLOTAB)(13.9mg/片)和0.09份二氧化硅(0.6mg/片)被加入袋中并充分混合。随后0.36份的硬脂酸镁NF(2.4mg/片)被加入袋中,所有的成分再次混合。产生的干燥混合物在压制组件中被压制成片剂,按照美国专利申请序列号09/966,509的第16到27页(本文引用作为参考)所述使用7/16英寸特深凹面片剂冲头。该压制组件是一个双排旋转设备,包含填充区、插入区、压制区、弹出区和清洗区,如美国专利申请序列号09/966,509的图6所示。该压制组件的模的填充采用真空辅助,通过位于每个铸模的模壁开口的筛网过滤器。制成的片剂(核)的平均重量是660mg,厚度是0.306英寸,硬度是3.2kp。
B部分:片剂包衣
A部分制成的片剂通过如美国专利申请序列号09/966,414的第51到57页所述的传送设备,本文引用该公开文件作为参考,被传送至如美国专利申请序列号09/966,497的第27到51页(本文引用作为参考)所述的热循环铸模组件。片剂的一半被包被上红色明胶,它的另一半被包被上黄色明胶,从而形成壳。
把壳涂敷到片剂上的热循环铸模组件是如美国专利申请系列号09/966,939的图28A所示的类型。热循环铸模组件的铸模单元204包含如图28C所示的上铸模配件214、旋转中心铸模配件212和下铸模配件210。片剂被转移至铸模配件,随后铸模配件闭合。在贮器206加热到流动状态的壳流动物质被注入到闭合的铸模配件形成的模腔中。随后壳流动物质的温度被降低,发生硬化。铸模配件打开,被包被的核被弹出。包被是通过两个步骤进行的,片剂的每一半分别通过中心铸模配件的旋转进行包被,如美国专利申请系列号09/966,939的图28B的流程图所示。
红色明胶包衣按照下列步骤进行:净化水(450g),Opatint红DD-1761(4.4g),和Opatint黄DD-2125(1.8g)在室温下混合至均匀。275 Bloom猪皮明胶(150g)和250 Bloom骨明胶(150g)被一起加到一单独的容器中。干明胶颗粒被手工搅动混合。净化水/Opatint溶液被加到明胶颗粒中,混合约1分钟以使明胶颗粒完全湿润。明胶浆被放置到水浴中并加热到55℃以熔化和溶解明胶。明胶溶液被保持在55℃大约3小时(在这个温度的保持时间通常可在约2小时到约16小时范围)。随后该溶液被混合至均匀(约5到15分钟),并被转移至配备有桨式电动搅拌器的有夹套的供应槽。当明胶溶液在热循环铸模组件中使用时,明胶溶液被保持在55℃并不断混和。
黄色明胶包衣按照下列步骤进行:净化水(450g),和Opatint黄DD-2125(6.2g)在室温下混合至均匀。275 Bloom猪皮明胶(150g)和250 Bloom骨明胶(150g)被一起加到一单独的容器中。干明胶颗粒被手工搅动混合。净化水/Opatint溶液被加到明胶颗粒中,混合约1分钟以使明胶颗粒完全湿润。明胶浆被放置到水浴中并加热到55℃以熔化和溶解明胶。明胶溶液被保持在55℃大约3小时(在这个温度的保持时间通常可在约2小时到约16小时范围)。随后该溶液被混合至均匀(约5到15分钟),并被转移至配备有桨式电动搅拌器的夹套式供应槽。当明胶溶液在热循环铸模组件中使用时,明胶溶液被保持在55℃并不断混和。
实施例2
下列片剂样品的包衣厚度被测量:
A.超硬TYLENOL凝胶片(Extra Strength TYLENOL GelTab)(由McNeil-PPC提供)
B.EXCEDRIN偏头痛凝胶片(EXCEDRIN Migraine Geltab)(由Bristol-MyersSquibb提供)
C.按照实施例1生产的片剂
参考图2所示剂型上的位置(位置1:第一主面的中心,tc1;位置2和3:第一主面与侧面相交的边(接近冲头面刃口),tc2和tc3;位置4:第二主面的中心,tc4;以及位置5和6:第二主面与侧面相交的边(接近冲头面刃口),tc5和tc6),结果如下表1所示:
表1
A | B | C | |
6片的主面(位置1,4)平均包衣厚度 | 145.17微米 | 220.40微米 | 195.37微米 |
6片的主面(位置1,4)包衣厚度的变异性 | 10.12% | 5.01% | 8.79% |
平均包衣厚度(6片的位置1-6) | 85微米 | 244.83微米 | 209.62微米 |
包衣厚度的变异性(6片的位置1-6的RSD) | 52.71% | 12.64% | 18.49% |
各边的平均包衣厚度 | 54.92微米 | 257.05微米 | 216.74微米 |
各边包衣厚度变异性(6片的位置2,3,5,6的RSD) | 19.80 | 11.88 | 20.56 |
主面和边的包衣厚度的平均差值(位置1-位置2,位置4-位置5) | 63.25% | 16.99% | 15.93% |
主面和边的包衣厚度的最大差值(位置1-位置2,位置4-位置5) | 72% | 33.4% | 40.6% |
主面和边的包衣厚度的最小差值(位置1-位置2,位置4-位置5) | 54% | 7.1% | 4.1% |
测量了三个样品中每一个样品的20片包衣片剂的厚度和直径。结果如下总结表2:
表2
A | B | C | |
20片片剂主面(跨过位置1,4)平均包衣片剂厚度 | 7.67mm | 6.55mm | 7.99mm |
20片片剂主面(位置1,4)包衣片剂厚度的变异性 | 0.407% | 1.44% | 0.292% |
平均包衣片剂直径(跨过20片片剂的位置7,8) | 11.46mm | 12.58mm | 11.74mm |
包衣片剂直径的变异性(跨过20片片剂的位置7,8的RSD) | 0.183% | 0.476% | 0.275% |
实施例3
适合压制剂型的包衣的流动物质如下制备:
物质 | %w/w |
PEG 1450(部分1) | 30.0 |
PEG 1450(部分2) | 30-50% |
聚环氧乙烷300,000 | 15.0-25% |
甘油 | 0-10% |
红色溶液*(3%w/w) | 5 |
*红色溶液成分是4.85%w/w丙二醇和0.15%w/w红色#40染料
聚乙二醇(PEG)1450(部分1)和聚环氧乙烷(PEO)300,000在塑料袋中振摇直至粉末均匀混合。行星式搅拌器(Hobart公司,Dayton,OH)的槽(5qt)通过循环热水加热到80℃。PEG 1450(部分2)被注入槽中并熔化而形成液体。有色溶液,和任选的甘油在低速混合时被加入。该PEG/PEO粉末混合物被加入并混合15分钟。让产生的混合物在温度保持在80℃时停留在Hobart槽中2小时。使用不锈钢模(2″×5″×0.8mm)制备铸膜(大约0.8mm厚)。溶液被移入有夹套的烧杯(80℃)并用真空脱气6小时。第二张膜用相同的模制备。
把PEO从15%增加到25%(PEG相应地从85%减少到75%)增加屈服应力(在薄膜永久变形之前可施加的每单位面积上最大的力),和增加应变(在断裂点薄膜伸长的百分比)。
把甘油从10%减少到2%增加拉伸强度(破坏薄膜所需的每单位面积上的力)。在铸型前除去含甘油薄膜中的空气通常降低拉伸强度。
流动物质的涂敷可使用如美国专利申请序列号09/966,497的第27到51页所述的热循环铸模组件,本文引用公开文件作为参考。
实施例4
另一种适合压制剂型的包衣的流动物质如下制备:
物质 | %w/w |
PEG 1450颗粒 | 70-75% |
聚环氧乙烷600,000 | 15% |
白蜂蜡 | 5-10% |
红色溶液*(3%w/w) | 5 |
*红色溶液成分是4.85%w/w丙二醇和0.15%w/w红色#40染料
行星式搅拌器(Hobart公司,Dayton,OH)的槽(5qt)通过循环热水加热到80℃。PEG 3350颗粒被注入槽中并熔化而形成液体。白蜂蜡、有色溶液,和聚环氧乙烷在低速混合时被加入。产生的混合物一共混合12分钟,保持温度在80℃让混合物停留在Hobart槽中2小时。用一玻璃片制备铸型薄膜。溶液被移入有夹套的烧杯(80℃)并用真空脱气6小时。第二片薄膜用相同的模制备。
该白蜂蜡配方与甘油配方相比可增加拉伸强度。
实施例3和4阐明了流动物质的合适配方。有利的是,这些配方不含溶剂(包括水)。这消除了从按照这些配方制备的包衣中蒸发溶剂的需要,缩短和精简了干燥。因此,在本发明的一个实施方案中,流动物质基本不含溶剂,就是包含少于约1重量百分比的溶剂,包含溶剂较佳。
流动物质的涂敷可使用如美国专利申请系列号09/966,497的第27到51页所述的热循环铸模组件。
实施例5:包衣片剂的表面光泽测量
使用TriCor Systerms有限公司(Elgin,IL)以商品名TRI-COR MODEL805A/806H SURFACE ANALYSIS SYSTERM提供的设备来检测按照实施例1制备的剂型的表面光泽,通常依照“TriCor Systems WGLOSS 3.4 805A/806H型表面分析系统参考手册”(1996)(TriCor Systems WGLOSS 3.4 Model 805A/806H Surface AnalysisSystem Reference Manual),除下文中的改进内容外,本文引用作为参考。
该设备利用一个CCD照相检测器,使用一个无光泽散射光源,把片剂样品与参考标准品对比,来确定在60度入射角时的平均光泽值。在该设备运行中,它产生灰度色标图象,其中较亮象素的出现表明在特定位置有较多光泽出现。
该设备还带有使用分组方法以量化光泽的软件,也就是把近似亮度的象素归成组来求平均数。
“满刻度百分比”或“理想百分比”设定(也被称为“样品组百分比”设定),是使用者规定被认为是一组并在该组内计算平均数的在阈值以上的最亮的象素部分。本文使用的“阈值”,被定义为不被包括在平均光泽值计算中的最大光泽值。所以,背景,或一样品的无光泽区域被排除在平均光泽值计算之外。K.Fegley和C.Vesey的“片剂形状对高光泽薄膜包衣系统的感知的影响”(The Effect of TabletShape on the Perception of High Gloss Film Coating Systems)公开的方法,该方法在2002年3月18日的
www.colorcon.com获得并被本文引用作为参考,被用来把不同片剂形状的影响减到最小,并提供工业上可比的度量的报告。(选择50%样品组设定,作为片剂表面粗糙度测量的最近似的类似数据的设定。)
在最初使用校准参考盘(190-228;294度标准;无掩膜,旋转0,深度0)校准设备后,对由McNeil-PPC有限公司提供的商品名为“超硬TYLENOL胶囊片”(ExtraStrength TYLENOL Gelcap)的凝胶包衣囊片进行标准表面光泽测量。随后确定112片该凝胶包衣囊片的样品的平均光泽值,使用25mm全景掩膜(190-280),该设备采用以下设定:
旋转:0
深度:0.25英寸
光泽阈值:95
满刻度百分比:50%
折射率:1.57
参考标准品的平均表面光泽值经测定为269。
包衣片剂的每一个样品按照相同步骤进行独立检测。
按照实施例1的方法制备的50片样品的黄色面的平均表面光泽为241光泽单位,红色面的平均表面光泽为248光泽单位。
其他商品化的包衣片剂样品也按照相同步骤和与相同的标准品对比进行检测。结果总结如下表A;
表A:商品化的包衣片剂的光泽值
产品 | MOTRIN IB*囊片(白色) | EXCEDRIN**不含阿斯匹林的囊片(红色) | EXCEDRIN**偏头痛凝胶片(绿的侧面) | EXCEDRIN**偏头痛凝胶片(白的侧面) | 超硬TYLENOL凝胶片(黄的侧面) | 超硬TYLENOL凝胶片(红的侧面) |
包衣类型 | 喷雾薄膜 | 喷雾薄膜 | 明胶包被 | 明胶包被 | 浸渍 | 浸渍 |
测试的片剂数量 | 41 | 40 | 10 | 10 | 112 | 112 |
光泽值(光泽单位) | 125 | 119 | 270 | 264 | 268 | 268 |
*McNeil-PPC有限公司提供
**Bristol-Myers Squibb有限公司提供
本实施例显示本发明的剂型有高度的表面光泽值(例如本实施例的241-248光泽单位),与商品化的明胶包衣片剂的光泽值类似或优于商品化的明胶包衣片剂的光泽值。相反,本实施例中典型的喷雾薄膜有很低的表面光泽,如119到125光泽单位。
实施例6:水分摄取的对比
按照实施例1的方法制备的片剂与商品化的明胶包衣片剂就它们的水分摄取特性进行了比较。选出的用于比较的样品代表现有浸渍技术(McNeil-PPC有限公司的超硬TYLENOL胶囊片),和本文前文讨论的包被技术(所有其余样品,详见下表B)。
使用动态水汽吸附(DVS)分析设备(DVS-2000,Surface Measurenent SystemsLtd.,London,UK提供)来评估样品。DVC系统是配有精密微量天平的环境受到控制的室。样品在不同相对湿度中的重量变化随时间被记录下来。
每个产品检测时把三片明胶包衣片剂放入DVC系统,在40℃和75%RH的环境中保持1小时。记录重量变化。天平在检测条件下平衡并在样品检测前称取皮重。样品检测速度设定在每隔20秒种收集重量。图13显示详细结果。在40℃和75%RH的环境中于60分钟后的相对质量(用占起始质量的百分比来表示)在下表B中显示。
表B
样品 | 来源 | 相对量(%) |
实施例1 | - | 100.577 |
超硬TYLENOL胶囊片 | McNeil-PPC有限公司 | 100.557 |
CVS非阿斯匹林止痛凝胶片(CVS Non-Aspirin Pain Reliever Geltab) | CVS | 101.074 |
Safeway醋氨酚胶囊片(SafewayAcetaminophen Gelcap) | Safeway | 101.125 |
ADVIL胶囊片(ADVIL Gel Caplet)) | Wyeth | 101.347 |
EXCEDRIN偏头痛凝胶片 | Bristol-Myers Squibb | 100.851 |
超硬EXCEDRIN凝胶片 | Bristol-Myers Squibb | 101.134 |
在40℃/75%RH的环境中暴露1小时,实施例1的产品的水分摄取是约0.58%,对比的包被产品的水分摄取是约0.85%,浸渍产品的水分摄取是约0.56%。这些结果表明本发明的产品与现有技术包被方法的产品相比,随时间吸收的水分较少,而与明胶浸渍产品的水分吸收特性相近似。在长期暴露在相似的潮湿条件下,本发明的剂型显示出比包被剂型更好的物理稳定性。
虽然本发明通过特定的实施方案来阐明,本领域的熟练技术人员应当知道进行的多种改变和改进无疑是属于本发明的范围内的。
Claims (34)
1.一种剂型,包括有外表面的核以及有外表面和内表面的壳,其特征在于该壳围绕着核,壳的内表面与核的外表面上基本有相同形状,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,壳包含少于约50%的结晶糖,剂型中基本不含电荷控制剂。
2.如权利要求1所述的剂型,其特征在于在核的外表面和壳的内表面之间的最大裂隙高度与最大裂隙处壳的总的理论厚度的比值小于约1∶7.5。
3.如权利要求1所述的剂型,其特征在于核有主面,核的外表面和壳的内表面之间的最大裂隙高度与主面中心处壳的厚度的比值小于约1∶7.5。
4.一种剂型,包括有外表面的核以及有外表面和内表面的壳,其特征在于该壳围绕着核,该剂型在40℃和相对湿度75%的环境中暴露60分钟,水分摄取少于约0.8%,壳的厚度范围在约100-400微米,剂型中壳的厚度的相对标准偏差小于约30%,剂型中基本不含电荷控制剂,壳也基本没有隆起的接缝。
5.如权利要求4所述的剂型,其特征在于该壳在40℃和相对湿度75%的环境中暴露60分钟,水分摄取少于约0.65%。
6.如权利要求1或权利要求4所述的剂型,其特征在于核包括压制的片剂。
7.如权利要求4所述的剂型,其特征在于该剂型有腹状突起,腹状突起的第一点的第一壳厚度与腹状突起的第二点的第二厚度之间的差不大于约二个厚度中较大者的约10%。
8.如权利要求4所述的剂型,其特征在于该剂型有腹状突起,腹状突起的第一位置的第一壳厚度与腹状突起的第二位置的第二厚度之间的差不大于约50微米。
9.如权利要求4所述的剂型,其特征在于该壳表面基本没有超过主面的壳厚度约1.25倍的隆起部分。
10.如权利要求4所述的剂型,其特征在于该壳表面基本没有高度超过约50微米的隆起部分。
11.如权利要求4所述的剂型,其特征在于该核有主面,剂型有腹状突起,腹状突起上任何一点的壳厚度不大于片剂主面中心的壳厚度。
12.如权利要求4所述的剂型,其特征在于该核有主面,剂型有腹状突起,腹状突起上任何一点的壳厚度与主面中心的壳厚度之间的差不超过约50微米。
13.如权利要求1或权利要求4所述的剂型,其特征在于该壳基本不含湿润剂。
14.如权利要求1或权利要求4所述的剂型,其特征在于该核包含插入物。
15.如权利要求1或权利要求4所述的剂型,其特征在于该壳的表面光泽值至少约150光泽单位。
16.如权利要求15所述的剂型,其特征在于该壳的表面光泽值至少约175光泽单位。
17.如权利要求16所述的剂型,其特征在于该壳的表面光泽值至少约210光泽单位。
18.如权利要求1或权利要求4所述的剂型,其特征在于该壳是模制的。
19.如权利要求1或权利要求4所述的剂型,其特征在于该壳包含至少约50%的某物质,该物质选自成膜聚合物、胶凝化聚合物、低熔点疏水物质、非结晶糖和它们的混合物。
20.如权利要求1或权利要求4所述的剂型,其特征在于该核、壳或二者包含活性成分。
21.如权利要求20所述的剂型,其特征在于该活性成分能溶出,该剂型的溶出与USP中含活性成分的速释片剂的规格一致。
22.如权利要求1或权利要求4所述的剂型,其特征在于在核的外表面和壳的内表面之间没有底衣存在。
23.如权利要求1或权利要求4所述的剂型,其特征在于该壳包含第一壳部分和第二壳部分,二者在一个界面上粘连。
24.如权利要求23所述的剂型,其特征在于该第一壳部分和第二壳部分在视觉上可区分。
25.如权利要求23所述的剂型,其特征在于该核是有主面的片剂,在界面上的壳的总厚度不大于片剂主面中心最厚处的厚度。
26.如权利要求23所述的剂型,其特征在于该界面是对接形式。
27.如权利要求23所述的剂型,其特征在于该第一壳部分和第二壳部分在界面形成闭锁形态。
28.如权利要求23所述的剂型,其特征在于该第一壳部分比第二壳部分厚,并在界面形成突出。
29.如权利要求23所述的剂型,其特征在于该第一壳部分和第二壳部分相互重叠。
30.如权利要求1或权利要求4所述的剂型,其特征在于该壳高度没有超过该壳厚度相对标准偏差的约25%的接缝。
31.如权利要求23所述的剂型,其特征在于该第一壳部分和第二壳部分的界面是平的接缝,在该接缝处第一壳部分沿单一水平线过渡到第二壳部分。
32.如权利要求1或权利要求4所述的剂型,其特征在于该壳的内表面有与该核外表面的凹迹和突出部分相对应的相反的凹迹和突出部分。
33.如权利要求32所述的剂型,其特征在于该凹迹和突出部分的长、宽、高或深不超过10微米。
34.如权利要求1或权利要求4所述的剂型,其特征在于该壳基本没有孔径在0.5到5.0微米的孔。
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NZ (3) | NZ532097A (zh) |
PL (1) | PL369134A1 (zh) |
PT (1) | PT1429738E (zh) |
WO (12) | WO2003026625A1 (zh) |
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