CN100408029C - 有镶嵌部分的组合剂型 - Google Patents
有镶嵌部分的组合剂型 Download PDFInfo
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- CN100408029C CN100408029C CNB028234308A CN02823430A CN100408029C CN 100408029 C CN100408029 C CN 100408029C CN B028234308 A CNB028234308 A CN B028234308A CN 02823430 A CN02823430 A CN 02823430A CN 100408029 C CN100408029 C CN 100408029C
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Abstract
一种剂型包含至少一种活性成分,第一部分包含一个外表面和一个或多个腔,腔有至少一个带凹口的内表面和一个外表面,第二模塑部分镶嵌在第一部分的腔内和有一个外表面。第一和第二部分在界面上接触,第二部分包含凝固的热塑性物质,第二部分大体上正形地在第一部分的凹口上。在另一个实施方案中,剂型包含至少一种活性成分,片心有一个外表面,壳在片心外表面的至少一部分上存在,其特征在于,壳包含第一壳部分和镶嵌在第一壳部分的第二模塑壳部分。在另一个实施方案中,剂型包含至少一种活性成分,片心,和有不连续的第一模塑壳部分的壳,及连续的第二模塑壳部分,第一壳部分的不连续是由于第二模塑壳部分的存在,第一和第二壳部分在成分上是不同的。
Description
发明背景
1.技术领域
本发明涉及组合剂型如药物组合物。更特别地,本发明涉及的组合剂型包含至少一种活性成分和第一部分及镶嵌在其中的模塑第二部分。
2.背景信息
包衣片剂,如薄膜包衣片剂、糖包衣片剂、胶囊片(gelcap)和凝胶片(geltab)被用作固体口服剂型,与无包衣片剂相比,在美观性、稳定性和易吞咽性上都有改进。特别有用的是,对固体剂型提供了独特的美观特性,以支持它们在市场上的识别与区分。薄膜包衣和糖包衣一般通过在旋转盘中喷雾获得,而它们可以各种颜色调配,通常只有一种颜色可用于围绕片心的全部,胶囊片和凝胶片可通过浸渍包衣、涂糖衣和胶囊壳收缩贴在片心的表面来制备。这些方法能使用多种颜色,但受到其它限制。
通过涂糖衣方法制备胶囊片和凝胶片的薄膜制剂,该方法如美国专利5,146,730和5,459,983所公开的内容,通常包含基于水的明胶制品,该制品包含占重量约45%明胶和约9%增塑剂(甘油和/或山梨糖醇)。据报道增塑剂在该制剂中起重要作用。增塑剂与明胶的比率低导致围绕片心的包衣易碎,而增塑剂与明胶的比率高导致围绕片剂的明胶包衣有柔性和可从片剂上剥落。如果需要附着产品片心的明胶包衣,则应考虑明胶制剂成分中占重量40%到60%明胶,5%到12%增塑剂,35%到50%水,和在0.1%到3%范围的着色剂和色素。甘油和山梨糖醇可以单独用作增塑剂或联合使用。另外,其他糖和多羟基化合物可用作添加剂和增塑剂。如果需要的终产品是防拆封的明胶包衣药物片剂,则明胶制剂中增塑剂与明胶的比率应在约1∶5的范围。该水平的增塑剂的要求对涂糖衣的剂型会带来限制,包括吸收水分的倾向,该倾向会危及产品的物理和化学稳定性,也增加制剂的成本。
现在另一种在片心(或基质)上形成壳(或包衣)的方法是WO01/57144所公开的利用静电沉积的原理形成包衣的方法。这个方法的局限在于片心或壳中至少有一个必须掺合一种或多种“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;四价铵盐;苯扎氯铵;氯化苄乙氧铵;三甲基十四烷基溴化铵(溴化十六烷基三甲铵);和环糊精和它们的加合物;其量占壳的重量约1%到约10%。电荷控制剂常产生不舒服的味觉,另外会不利地增加在采用的电荷控制剂中的壳的氧化。
常规的包囊和涂糖衣加工的其它局限性在于其复杂性和高成本,壳或包衣厚度的限制,和在一半胶囊和/或包衣之间产生隆起的接缝。因此希望有本发明的剂型。这些剂型对许多应用增加了多用性,包括释放药物、营养剂和/或糖膏剂的剂型,其形式可以是凝胶片或胶囊片,包衣片剂,高效剂型等等。而且,这些剂型具有独特和舒适的美观特性,这在市场上是有价值的。
用压制(方法)产生片剂包衣是已知的,产生多堆叠层,或是片心或壳的外形。该包衣的形状与片心的形状大体上无关,如WO 00/18447所公开的内容。商品化的压制包衣设备可由例如Korsch美国公司(Korsch AG的一个子公司)提供,在WO89/11968中有描述。通过压制制备的改进释放剂型在美国专利5,738,874和6,294,200,和WO 99/51209中有例子。通过压制包衣来生产二部分的壳是可能的,该壳可以作为屏障或释放延迟包衣,但是压制包衣系统受到壳的厚度和壳的成分以及加工成本的限制。例如,Gunsel等的“压制包衣的片剂和层片剂”(Compression-coated and layer tablets),在H.A.Lieberman,L.Lachman,J.B.Schwartz编的《药物剂型-片剂》(Pharmaceutical Dosage Forms-Tablets)中(修订第2版,Marcel Dekker有限公司),第247-284页,公开了压制包衣壳的厚度通常在800到1200微米之间。而且这些作者指出“薄膜包衣的出现消除了干性包衣的许多优点,因为大量片剂可以在短时间内用溶解于有机或水性溶剂的薄膜形成剂包被。”通常,压制包衣必须包含大量的可压制物质。例如,WO 00/18447中的压制的壳使用了约30%的微晶纤维素。
有二种或更多不同部分的剂型在药学领域中可用于克服许多通常遇见的困难,包括分离不相容的活性成分,获得低剂量/高效活性成分的可接受的内容物一致性,以脉动形式传递一种或多种活性成分,对剂型的识别提供独特的美观特征。获得多部分的药物剂型的已知方法包括微粒包衣、多层片剂、压制包衣和喷雾包衣技术。例如在家用产品行业也知道用上述方法装配二种或多种不同部分的固体形式用来分离活性成分或在不同时间传递不同的活性成分。
包含包衣微粒的剂型如美国专利5,593,696描述的用于治疗胃疾患的口服剂型。该剂型包含的活性成分有法莫替丁和硫糖铝。在该剂型中,法莫替丁在组合物中以微粒(颗粒)形式存在,该微粒法莫替丁有保护屏障层以防止组合物中法莫替丁和硫糖铝相互反应。该屏障层是聚合物包衣较佳,该聚合物包衣在体内胃中部分溶解释放有包衣的法莫替丁。美国专利5,980,944描述了一种用于治疗胃肠道疾患的固体口服剂型,包括有效治疗剂量的适合治疗胃疾患的药物,该药物选自地芬诺酯、咯哌丁胺、咯哌丁胺-N-氧化物的颗粒,及它们药学上可接受的盐和它们的组合物,和治疗有效量的聚二甲基硅氧烷,其中药物和聚二甲基硅氧烷被颗粒上的对聚二甲基硅氧烷大体上不通透的屏障包衣所隔离。
所述的多层片剂,例如美国专利5,20,0193所描述的多层药物活性片剂,该片剂包含即时刻释放层和包含侵蚀促进剂的均一压制的持续释放层,使用时产生药物活性成分的持久续、缓慢和相对有规律增加的释放。美国专利6,372,252描述了一种药物持续释放制剂,该制剂能在人受试者给药后至少12小时提供治疗上有效的生物利用度的愈创木酚甘油醚。公开的改进释放愈创木酚甘油醚双层片剂有包含即时释放愈创木酚甘油醚制剂的第一部分和包含持续释放愈创木酚甘油醚制剂的第二部分。美国专利4,999,226公开了一种多层片剂,该片剂包含布洛芬层,吡啶基烷醇抗组胺层,和包含一层或多层的常规的药物赋形剂,该赋形剂散布在布洛芬和吡啶基烷醇层之间,用来在物理上分隔这两层。该多层片剂解决了与布洛芬和piperidino-alkanol抗组胺物之间物理上和化学不相容有关的问题。美国专利4,198,390描述了一种包含至少二种分离和不连续体积部分的片剂,其中一种包含聚二甲基硅氧烷,另一种包含抗酸剂。一个屏障分离二个体积部分以保持聚二甲基硅氧烷不与抗酸剂接触,防止聚二甲基硅氧烷从其片剂的体积部分移动到含有抗酸剂的体积部分,反之亦然。美国专利5,133,892描述了一个多层洗涤剂片剂,该片剂包含外层,屏障层和内层。该片剂有顺序地释放外层中包含的成分和内层中包含的成分。释放外层的成分和释放内层的成分之间的时间间隔是通过对屏障层成分的特殊选择和内层、屏障层和外层的相对厚度来控制的。该片剂能够随着不相容成分如酶和含氯漂白剂的分解而及时分离。该片剂还提供洗碟成分和漂洗助剂成分的有顺序的释放,使清洁在漂洗助剂释放之前完成。
压制包衣片剂用于分离不相容活性成分,和一种或多种活性成分的脉动释放。压制包衣的形状可以与片心的形状大体上不同,如WO 00/18447所公开的内容。商品化的压制包衣设备可由例如Korsch美国公司提供,它是Korsch AG的一个子公司,在WO 89/11968中有描述。通过压制制备的改进释放剂型在美国专利5,738,874和6,294,200,和WO 99/51209中有例子。通过压制包衣生产二部分的壳是可能的,该壳可以作为屏障或释放延迟包衣,但是压制包衣系统受到壳的厚度和壳的成分以及加工成本的限制。例如,Gunsel等的“压制包衣的片剂和层片剂”(Compression-coated and layer tablets),在H.A.Lieberman,L.Lachman,J.B.Schwartz编的《药物剂型-片剂》(Pharmaceutical Dosage Forms-Tablets)中(修订第二版,Marcel Dekker有限公司),第247-284页,公开了压制包衣壳的厚度通常在800到1200微米之间。而且这些作者指出“薄膜包衣的出现消除了干性包衣的许多优点,因为大量片剂可以在短时间内用溶解于有机或水性溶剂的薄膜形成剂包被。”通常,压制包衣必须包含大量的可压制物质。例如,WO 00/18447中的压制的壳使用了约30%的微晶纤维素。
一种解决低剂量/高效活性成分问题的方法在例如美国专利4,322,449和U.S.RE 31764所述,这些文件公开了制备药物的载体方法,该方法包含使用压电计量系统将液体的、溶解的或悬浮的活性物质在药物载体上打点。该公开方法使活性药物成分在药物载体上精确计量成为可能。打点是通过,例如,使用管状的或盘状的压电计量系统来实现的。然而,液体的、溶解的或悬浮的活性物质在通过使用高压的小喷嘴后,还可以被分成不连续的特定体积的小滴,由此各个小滴被依次施以电荷并断续地静电偏转向药物屏障。
把模塑部分掺入传递系统已用于家用产品行业,以获得更多的多功能性。组装形式包括已知如用于洗涤剂的传递的压制和模塑部分的混合物。WO 01/49815描述了一个用于洗碗机的组合物,该组合物的特征是片剂形式的基础组合物,该组合物在主要洗涤循环中大体上有活性,还有至少在片剂上有一个由洗碗机的漂洗循环中大体上有活性的物质组成的分离区。该组合形式的例子包括在主面上有半球状凹口的压制片剂部分,和与该压制片剂部分相配并附着于凹口的模塑球形部分。由于附着不恰当和二者间接触面极小而使两部分有分离倾向是该组装的一个缺点。在该组装中,模塑部分可比压制部分中的凹口小,例如,模塑部分的直径比压制部分中的开口直径至少小约20微米。另一方面,类似形式可用压配方法组装。在这些形式中,模塑部分的大小和压制部分中的凹口可以是相似的。这些组装还受到可能在界面上的几何学类型的限制。在压配的组装,模塑部分的在界面最深部分的宽度可以大体上不大于该模塑部分必须配合的开口宽度。换言之,压制部分的内外表面之间的锥度可以不是负数。而且,二部分接触的界面或区域可不形成交锁。
在设计药物剂型中另一个重要机会是产品的识别和区分。无论从消费者安全观点还是商业观点,有易于认识和识别的独特外形对剂型来说是有用的。
提供独特剂型识别的现有技术包括凹雕的使用。凹雕通常是通过蚀刻或印记图示来印下标记的,例如图形、标记、符号如字母、名称、标识图案、图示,等等,或它们的任何组合物,在片剂或其他固体剂型中,使用冲压步骤较佳。例如,美国专利5,827,535描述的软明胶胶囊有印记的图示在其外表面上。美国专利5,405,642公开了一种在白色或有色彩包衣片剂上突出凹雕的方法,通过在上述片剂上喷涂包含有不同色彩、蜡状物质和溶剂的充填物质的悬浮液,和除去溶剂和过量的充填物质和蜡状物质来实现。美国专利5,405,642的悬浮液包含蜡状物质和充填物质的临界重量比约1∶3到约1∶12。太少的蜡状物质会导致充填物质的结合不充分;太多的蜡状物质会使充填物质与片剂表面结合太牢,因而难以在以后除去。美国专利5,405,642的悬浮液的合适溶剂,其中充填物质,如果有的话,与染料不溶解。例如,非染色淀粉和纤维素可在酒精,如乙醇、异丙醇等等,卤化烃,如二氯甲烷、三氯甲烷等等中悬浮。
EP 060,023公开了一种在色彩(即,非白色)的固体物,在特殊片剂上强调凹雕的方法,通过对片剂表面包衣和用含有光学各向异性物质的包衣薄膜充填凹雕。获得了片剂表面和凹雕之间的光反差,可能是由于在片剂表面和凹雕的光学向异性物质的不同方向所致。该技术受到色彩物的限制,只能使用光学各向异性充填物质。仅基于不同反差获得的光学效果不是特别清楚。
EP 088,556涉及一种在白色或有色彩的片剂上强调凹雕的方法,通过将片剂表面颜色不同的干粉状物质与所述的片剂接触,除去没有沉积在凹雕中的过量粉状物质。粉状物质被认为在包衣片剂上凹雕的附着要好于在无包衣片剂上凹雕的附着。为了进一步增加附着,可使用蜡与粉状物质的混合物作为沉积物质并把充填的片剂加热到40℃到90℃以融化蜡。最后,可将外层包衣用到充填的片剂上。但是,EP 088,556公开的方法有许多问题。首先,粉状物质与凹雕的附着并不满意,因为该物质有松动和脱落的倾向。在将外层包衣用到充填的片剂上和松动的物质固定在外层包衣薄膜上,产生有斑点的片剂时此问题特别明显。另一方面,在粉状物质中添加蜡以提高附着性,使粉状物质更多的粘附在片剂表面而不利地影响粉状物质的分布和难以除去。在干粉状物质中使用蜡还带来其他一些缺点。特别是需要加热充填有蜡和粉状物质的片剂以熔化蜡带来了几乎不能接受的风险,因为许多药物是不耐热的,在过程中可能明显变坏。而且,在蜡和粉状物质的干混合物上均匀地染色也是困难的,这对有效的可能色彩组合物会有限制。
美国专利4,139,589描述了一种镶嵌片剂的制造过程,包括将持续释放的活性成分掺入到塑性口香糖物质中;将大体上即时释放药物活性成分掺入到非塑性片剂物质中;分别将口香糖物质和片剂物质转化成镶嵌片剂的片心和外层。一个较佳实施例包括将片剂物质转化为凹口的预制部件,将口香糖物质转化成片心,将片心插入到预制部件的凹口,将预制部件和片心导入片剂模具中,再对模具中的预制部件和片心进行压制。
上述产生有一个或多个分离部分的剂型的所有方法都比较昂贵、复杂和花费时间。而且,已知的生产充填凹雕的方法在合适的物质和作为结果而产生的剂型可获得的表面构型和外观受到限制。除了上述对充填物质本身的限制,片剂的包底衣必须是非粘着的,足以使充填物质在热包衣盘中翻动时被消除。这些方法不能产生充填物质高于片剂表面的充填凹雕,或甚至与片剂表面完全齐平的充填凹雕。现有技术产品只能提供相对于片剂表面轻微压低的、磨损的或凹陷的充填物质表面。
对医药工业来说,另一个明显的挑战是通过标准化最低限度降低生产和包装成本的机会。许多药物是几种不同强度的片剂,以方便有不同用药需要的不同患者。通常,较高强度片剂与含较少是活性成分的片剂相比更重和更大。通过设计多功能的剂型以在相同大小的片剂中容纳多个不同剂量的药物,可降低操作成本和包装成本,而患者和医学保健专业人士在同一性和强度方面容易识别。
因此,本发明的目的之一是提供一种组合形式,该形式包含至少一种活性成分,第一部分和第二模塑部分包含第二种物质,其中该第二种物质是镶嵌的与第一种物质在成分上不同。
由本文详细描述提供的本发明的其他目的、特征和优点对本领域中的熟练技术人员是明显的。
发明概要
在一个实施方案中,本发明的剂型包含至少一种活性成分,第一部分包含一个外表面和一个或多个定义为至少一个有凹口的内表面的腔,和外表面,和镶嵌在第一部分的腔内和有外表面的第二模塑部分。第一和第二部分在界面上相接触,第二部分包括凝固的热塑性物质,第二部分大体上共形地存在于凹口上。
在另一个实施方案中,第二模塑部分大体上没有直径在0.5到5.0微米的孔。
在另一个实施方案中,第一和第二部分在界面上紧密接触。
在另一个实施方案中,第一部分是压制的片剂。
在另一个实施方案中,第一部分是模塑的片剂。
在另一个实施方案中,第一部分包含凹雕,第二部分在凹雕中。
在另一个实施方案中,第二部分的外表面与第一部分的外表面齐平。
在另一个实施方案中,第二部分的外表面相对于第一部分的外表面是升高的。
在另一个实施方案中,第一部分基本上由单一均质层组成。
在另一个实施方案中,第二模塑部分包括至少一种活性成分。
在另一个实施方案中,第一部分有第一种颜色,镶嵌的第二部分有第二种颜色。
在另一个实施方案中,第一部分包含第一活性成分和镶嵌的第二部分包含与第一活性成分相同或不同的第二活性成分。
在另一个实施方案中,第一和第二部分一起构成预先安排的式样。
在另一个实施方案中,第一部分包含微电子装置。
在另一个实施方案中,第一部分中一个或多个腔的内表面的锥度值小于零。
在另一个实施方案中,界面与内表面大体上同等延伸。
在另一个实施方案中,第一部分是不连续的,第二部分是连续的。
在本发明的另一个实施方案中,剂型包含至少一种活性成分,片心有外表面,壳至少在片心外表面的一部分上。壳包含第一壳部分和第二壳部分,第二模塑壳部分镶嵌入第一模塑壳部分,第一和第二壳部分在界面上接触。
在另一个实施方案中,壳有外表面,第二模塑壳部分从片心的外表面延伸到壳的外表面。
在另一个实施方案中,第一和第二壳部分都是不连续的。
在另一个实施方案中,第一壳部分是不连续的,第二壳部分是连续的。
在另一个实施方案中,第一壳部分有第一色彩,第二壳部分有第二色彩。
在另一个实施方案中,片心包含压缩的粉剂。
在另一个实施方案中,片心包含插入物。
在另一个实施方案中,插入物包含一种活性成分。
在另一个实施方案中,一个或多个片心、镶嵌部分或插入物包含一种活性成分。
在另一个实施方案中,片心包含微电子装置。
在另一个实施方案中,插入物包含微电子装置。
在另一个实施方案中,第一壳部分、第二壳部分,或两者有带纹理的外表面。
在另一个实施方案中,壳的外表面包含预先安排的式样。
在另一个实施方案中,壳包含在其中的一个或多个开口。
在另一个实施方案中,壳的外表面大体上光滑。
在另一个实施方案中,壳包括凹口、字母、符号或图案。
在另一个实施方案中,第一壳部分包括凹口、字母、符号或图案。
在另一个实施方案中,第二壳部分包括凹口、字母、符号或图案。
在另一个实施方案中,第一壳部分、第二壳部分,或两者包含以字母、符号或图案形式的突起部分。
在另一个实施方案中,镶嵌部分大体上没有直径0.5到5.0微米的孔。
在另一个实施方案中,第二壳部分有界面的锥度值小于零的部分。
在本发明的另一个实施方案中,剂型包含至少一种活性成分、片心、和有不连续的第一模塑壳部分的壳,和连续的第二模塑壳部分,第一壳部分的不连续是由于第二模塑壳部分的存在,第一和第二壳部分在成分上不同。
在另一个实施方案中,第一和第二壳部分包括凝固的热塑性物质。
在另一个实施方案中,第一和第二壳部分的外表面是共线性的。
在另一个实施方案中,第二模塑部分有锥度值小于零的部分。
在另一个实施方案中,腔确定为许多用于容纳镶嵌部分的侧壁,该侧壁有小于零的锥度值。
在另一个实施方案中,第一壳部分、第二壳部分,或是两者包含活性成分。
附图的简要说明
图1A和1B显示了本发明的剂型的一个实施例。
图2A和2B显示了本发明的剂型的另一个实施例,其中片心有包含镶嵌部分的壳。
图3A和3B显示了现有技术组合物的锥度和本发明的一个实施方案。
发明的详细描述
在本发明的一个实施方案中,剂型包含至少一种活性成分,第一部分包含一个或多个腔和凹口和一个外表面,第二模塑部分镶嵌入第一部分的腔内和有一个外表面。第一和第二部分在界面上接触,第二部分包括凝固的热塑性物质,第二部分大体上共形地在第一部分的凹口上。
本文中使用的,一个部分的“外表面”是指包含完成的剂型的外表面部分的表面。
本文中使用的术语“大体上共形地”是指第一部分的腔由具峰和谷的表面确定,第二部分在腔内,第二部分的表面也有峰和谷,第二部分的表面的峰和谷与腔确定的表面的主要峰和谷大体上相反。
在本发明的另一个实施方案中,剂型包含至少一种活性成分,片心有外表面,壳至少在片心外表面的一部分上,其中壳包含第一壳部分和第二壳部分,第二模塑壳部分镶嵌入第一模塑壳部分中。
在本发明的另一个实施方案中,剂型包含至少一种活性成分、片心、和有不连续的第一模塑壳部分的壳,和连续的第二模塑壳部分,第一壳部分的不连续是由于第二模塑壳部分的存在,第一和第二壳部分在成分上不同。
本文中使用的术语“成分上不同”是指通过定性或定量化学分析、物理测试或视觉观察易于区分的特征。例如,第一和第二物质可包含不同的成分,或不同水平的相同成分,或第一和第二物质可有不同的物理或化学特性、不同的功能特性或在视觉上可区分。可不同的物理或化学特性的例子包括亲水性、疏水性、吸湿性、弹性、塑性、抗拉强度、结晶性和密度。可不同的功能特性的例子包括物质本身或其中活性成分溶出的速度和/或程度,物质崩解的速度,活性成分的渗透性,对水或液体介质的渗透性,等等。视觉上区分的例子包括大小、形状、地形或其他几何特征、色彩、色调、不透明性和光泽。
在某些实施方案中,第一部分基本上由单一均质层组成。换句话说,可以是单一模塑组合物或单一压制片剂。若该部分被分成几个部分,每个部分有相同的密度、多孔性、色彩、结晶性等。
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,设计含有某些成分的特别预先确定量(即剂量),例如下文中确定的活性成分。合适的剂型可以是给药系统,包括口服、含服给药、直肠给药、局部、透皮或粘膜传递,或皮下植入,或其他植入的给药系统;或用于传递矿物质、维生素和其他营养食品,口腔护理制剂、食用香料等等的成分。本发明的剂型被认为是固体较佳,虽然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”给药系统,剂型的设计成如特定药物活性剂型相同的外观,如可用于临床研究中的对照来测试,例如,特定药物活性成分的安全性和功效。
本发明使用的合适的活性成分包括如药物、矿物质、维生素和其他营养食品、口腔护理制剂、食用香料和它们的混合物。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、镇咳药、抗生素、抗感染药、抗病毒药、抗凝剂、抗抑郁药、抗糖尿病药、镇吐药、抗气胀药、抗真菌药、解痉药、食欲抑制剂、支气管扩张药、心血管制剂、中枢神经系统制剂、中枢神经系统兴奋剂、减轻充血剂、利尿剂、祛痰药、胃肠道制剂、偏头痛制剂、晕动病产品、粘液溶解剂、肌肉松驰剂、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。
合适的口腔护理制剂包括呼吸清新剂、牙齿增白剂、抗微生物剂、牙齿矿化剂、龋齿抑制剂、局部麻醉剂、粘膜保护剂等等。
合适的食用香料包括薄荷脑、薄荷、薄荷香料、水果香料、巧克力、香草、口香糖香料、咖啡香料、液体香料和组合物等等。
合适的胃肠道制剂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、二羟铝碳酸钠;刺激性轻泻药如吡沙可啶、波希鼠李皮、二羟蒽醌、番泻叶、酚酞、芦荟、蓖麻油、蓖麻油酸和脱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;胃肠道促动药如普卡比利,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;葡萄糖吡咯;镇吐药如昂丹司琼;镇痛药如美沙拉明。
本发明的一个实施方案中,活性剂可选自吡沙可啶、法莫替丁、雷尼替丁、西米替丁、普卡比利、地芬诺酯、洛哌丁胺、乳糖酶、美沙拉明、铋、抗酸药和药学上可接受的盐、酯、异构体和它们的混合物。
在另一个实施方案中,活性剂可选自镇痛药、抗炎剂和解热药,如非甾体类抗炎药(NSAIDs),包括丙酸衍生物,如布洛芬、萘普生、酮洛芬等等;醋酸衍生物,如吲哚美辛、双氯芬酸、舒林酸、托美汀等等;芬那酸衍生物,如甲芬那酸,甲氯灭酸、氟芬那酸等等;二苯基酸酸衍生物,如二氟尼柳,氟苯柳,等等;和昔康类制剂,如吡罗昔康,舒多昔康,伊索昔康,美洛昔康等等。在一个较佳实施方案中,活性剂可选自丙酸衍生物NSAID,如布洛芬、萘普生、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬、酮洛芬、氟洛芬、吡洛芬、卡洛芬、奥沙普嗪、普拉洛芬、噻丙芬和药学上可接受的盐、衍生物和它们的组合物。在本发明的另一个实施方案中,活性剂可选自对乙酰氨基酚、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、罗非昔布、塞来昔布和药学上可接受的盐、酯、异构体和它们的混合物。
在本发明的另一个实施方案中,活性剂可选自假麻黄碱、去甲麻黄碱、氯苯那敏、右美沙芬、苯海拉明、艾司咪唑、特非那定、非索非那定、洛罗塔丁、地氯雷他定、doxilamine、去甲阿司咪唑、西替利嗪、它们的混合物和药学上可接受的盐、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西甲硅油,由美国专利4,906,478;5,275,822;和6,103,260公开,每个文件的内容被本文清楚的纳入作为参考。本文中使用的术语“二甲基硅油”指的是聚二甲基硅氧烷的大类,包括但不限于二甲硅油和二甲基硅油。
有效治疗量的剂型中可有一种或几种活性成分,该量通过口服获得需要的治疗反应,易被本领域熟练技术人员确定。如本领域所知,为确定该量,必须考虑使用的特定活性成分,该活性成分的生物利用度特征,剂量方案,病人的年龄和体重和其他因素。在一个实施方案中,该剂型包括至少约85重量百分比的活性成分。
在某些实施方案中,需要活性成分的改进释放,如本领域所知,该活性成分可任选地用释放改进包衣包被。这对改进剂型中活性成分的释放曲线有利的提供了另外的工具。例如,如本领域所知,剂型可包含一种或多种活性成分的包衣微粒,其中微粒包衣起释放改进功能。对微粒合适的释放改进包衣的例子在美国专利4,173,626;4,863,742;4,980,170;4,984,240;5,286,497;5,912,013;6,270,805;和6,322,819中有描述。
可以使用商品化的改进释放活性成分。例如,本发明可通过凝聚加工用释放改进聚合物包裹对乙酰氨基酚颗粒。凝聚包裹的乙酰氨基酚可以从Eurand美国公司(Vandalia,Ohio)或Circa有限公司(Dayton,Ohio)商业购买。
如果活性成分有讨厌的味道,和该剂型被用来咀嚼或在吞咽前在口腔中崩解的,该活性成分可用味觉掩蔽包衣法包被,这在本领域是已知的。合适的味觉掩蔽包衣法的例子在美国专利4,851,226;5,075,114和5,489,436中描述。也可使用商品化的味觉掩蔽的活性成分。例如,本发明可通过凝聚加工用乙茎纤维素和其他聚合物包裹对乙酰氨基酚颗粒。凝聚包裹的乙酰氨基酚可以从Eurand美国公司(Vandalia,Ohio)或Circa有限公司(Dayton,Ohio)商业购买。
在第一部分是通过压制制备的实施方案中,合适的赋形剂包括充填剂、粘合剂、崩解剂、润滑剂、助流剂等等。
在第一部分是通过压制制备的实施方案中,合适的充填剂包括水溶性可压的碳水化合物如糖,包括葡萄糖、蔗糖、异麦芽果糖、果糖、麦芽糖和乳糖;聚葡萄糖,糖醇类,包括甘露醇、山梨醇、异麦芽、麦芽糖醇、木糖醇、赤藓糖醇、淀粉水解物,包括糊精和麦芽糖糊精等等;不溶水塑性变形物质,如微晶纤维素或其他纤维素衍生物;水不溶性脆性破裂物质,如磷酸二钙、磷酸三钙等等及它们的混合物。
在第一部分是通过压制制备的实施方案中,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;湿粘合剂如水溶性聚合物,包括水胶体如藻酸盐、琼脂、瓜尔胶、剌槐豆、角叉菜胶、他拉胶、阿拉伯树胶、黄芪胶、果胶、黄原胶、吉兰糖胶、麦芽糊精、半乳糖甘露聚糖、pusstulan、昆布多糖、硬葡聚糖、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、淀粉等等;及它们的衍生物和混合物。
在第一部分是通过压制制备的实施方案中,合适的崩解剂包括羟基乙酸淀粉钠、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。
在第一部分是通过压制制备的实施方案中,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。
在第一部分是通过压制制备的实施方案中,合适的助流剂包括胶体二氧化硅等等。
在第一部分是通过压制制备的实施方案中,本发明的剂型也可掺入药学上可接受的辅剂,包括,例如,防腐剂、高强度甜味剂如阿斯巴坦、乙酰舒洗钾、环磺酸盐、糖精、三氯半乳蔗糖等等;其他甜味剂如dihydroalcones、甘草甜素、MonellinTM、甜菊苷、TalinTM等等;调味剂,抗氧化剂,表面活性剂和着色剂。
当与液体如水、胃酸、肠液或等等接触时,活性成分或成分最好能够溶出。在一个较佳实施方案中,活性成分的溶出特性符合USP对含有活性成分的即时释放片剂的技术要求。在需要活性成分被吸收入动物的体循环的实施方案中,活性成分或成分在接触液体如水、胃液、肠液等等时最好能够溶出。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时释放片剂的技术要求。例如,对乙酰氨基酚片剂,USP24要求在PH5.8磷酸缓冲液中,使用USP装置2(桨式)在50rpm下,在给药后30分钟内至少有剂型中包含的80%对乙酰氨基酚被释放,而对布洛芬片剂,USP24要求在PH7.2磷酸缓冲液中,使用USP装置2(桨式)在50rpm下,在给药后60分钟内至少有剂型中包含的80%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被改进:如控制的、持续的、延长的、延迟的、长期的、时延的等等。
对本发明的剂型的总体理解可参照图1A,1B,2A和2B。图1A和1B显示了本发明的剂型的一个实施方案。在图1A中,显示包括第一部分4的剂型2。第一部分包含许多凹陷,依次包含镶嵌的第二部分6。在这个实施方案中,第一活性成分位于第一部分4内,第二活性成分位于镶嵌的第二部分6内。图1B是图1A的剂型2的截面图。如图1B所示,在这个实施方案中,模塑的镶嵌第二部分6从第一表面8和第二表面10部分延伸到第一部分4。在这个实施方案中,第一活性成分位于镶嵌的第二部分6内,第二活性成分(可与第一活性成分相同或不同)位于第一部分4内,虽然在其他实施方案中只有在镶嵌的第二部分6或第一部分4中的一个包含活性成分。
在图1A和1B所示的其他实施方案中,清楚或半透明的包衣可在第一表面8和第二表面10上。
图2A和2B显示了本发明的另一个实施方案。图2A显示包含片心104的剂型102。该片心的壳105至少在片心104的外表面的一部分上。壳105在图2B中有详细显示,该图是图2A的剂型的截面图。如图2B所示,壳105在片心104的外表面108和110上,该壳包含有腔的第一壳部分107,模塑的镶嵌的第二壳部分106在腔内。在这个实施方案中,第一活性成分位于壳部分107内,第二活性成分位于镶嵌的第二壳部分106内,虽然在其他实施方案中只有在第一壳部分107或镶嵌的第二壳部分106中的一个可包含活性成分。片心104也可任选地包含一种活性成分,该活性成分可以与第一壳部分107和镶嵌的第二壳部分106所包含的活性成分相同或不同。如图2B所示,壳105可沿着片心104的侧面部分112和114延伸,镶嵌部分116和118可在壳105的凹口内。在这个实施方案中,腔通过第一壳部分延伸到片心的表面;但是,在其他实施方案中腔只通过第一壳部分的一部分延伸。
片心(或基质)可以是任何固体或半固体形式。片心可通过任何合适的方法制备,例如和可以是压制的剂型,或是模塑的。本文中使用的“基质”指一个表面或下面的支持物,其他物质位于它上面或与它作用,“片心”是指至少被其他物质部分包裹或围绕的物质。为了本发明的目的,术语可以互换:即术语“片心”也可用来指“基质”。片心由固体组成较佳,例如,片心可以是压制或用模塑的片剂、硬或软胶囊、栓剂,或糖膏剂形式如糖锭、牛轧糖、焦糖、软糖或脂基成分。在某些其他实施方案中,在完成的剂型中片心可以是半固体或液体形式。
片心可以是许多不同的形状。例如,在一个实施方案中,片心的形状可以是截短的锥体。在另一个实施方案中,片心的形状可以是多面体,如立方体、角锥体、棱柱体等等;或可以有一些非平面的空间构形的几何形状,如圆锥体、圆柱体、球体、圆枕体等等。可使用的示范性片心形状包括如“伊丽莎白公司片剂设计培训手册”(The Elizabeth Companies Tablet Design Training Manual)(ElizabethCarbide Die Co.,Inc.,)第7页(McKeesport,Pa.)(本文引入作为参考)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.修饰的球凹面
6.标准凹面平分
7.标准凹面双倍平分
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.)双倍平分
16.环形
17.小凹
18.椭圆
19.卵形
20.囊状
21.矩形
22.正方形
23.三角形
24.六角形
25.五角形
26.八角形
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.图形8/杠铃形
39.蝶形领结形
40.不等边三角形
片心或底片心(Subcore)可任选地至少部分被压制的、模塑的、或喷雾的包底衣覆盖。但是,在一个较佳实施例中,片心可以大体上没有包底衣:即在片心的外表面和壳的内表面之间没有包底衣。
在本发明的另一个实施例中,片心是压制的剂型,如粉剂压制成的片剂。该粉剂包含活性成分较好,可任性地包含各种赋形剂,如常规的粘合剂、崩解剂、润滑剂、填充剂等等,或该粉剂可包含其他药物或非药物性质的颗粒,如压片的非活性安慰剂混合物,糖膏剂混合物等等。一种特别制剂包括活性成分、粉末蜡(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,详细可见未定的美国专利申请序列号09/966,493的第4到11页,本文引入作为参考。
片心可任选地包括底片心(也可被称为“插入物”),片心可用任何方法制造,例如,压制或模塑,也可任选地包括一种或多种活性成分。
本发明的一个实施方案中,本发明的各种剂型包含由粉剂混合制成的片心,该粉剂的平均粒径约50微米到500微米。在一个实施方案中,活性成分的平均粒径约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粒径约50微米到500微米。在上述实施方案中,一种主要的赋形剂,即包含片心重量至少50%的赋形剂,其平均粒径约50微米到500微米,例如约100微米到约500微米在这个大小范围内的微粒对直接压制加工特别有用。在本发明的一个较佳实施方案中,片心可以通过直接压制过程制备。
在本发明的一个这种实施方案中,片心是直接压制的片剂,该片剂由大体上不含水溶性聚合物粘合剂和水合的聚合物的粉剂制成。该组合物有利于维持即时释放溶出曲线,最低程度降低加工和材料成本和提供剂型最佳的物理和化学稳定性。
在片心是通过直接压制制备的实施方案中,该包含片心的物质,如活性成分或成分和赋形剂混合在一起,作为干粉剂较佳,加到应用压力的设备中制成片心。可以使用任何合适的压制设备,包括如辊式压实机如chilsonator或落下辊;或常规的压片机。通过本领域已知的旋转压片机压实形成该片心较佳。在旋转压片机中,计量体积的粉剂填入模腔中,该压片机作为“压模辊道”的一部分在充填位置和压实位置之间旋转,在该压实位置粉剂在上下冲头之间被压实,至弹出位置制成的片剂被下冲头从模腔推出。直接压制加工能最低程度地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。
在一个较佳实施方案中,通过使用待批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片心,本文引入作为参考。特别地,该片心是使用旋转压制模件制造的,该模件包含充填区、插入区、压制区、弹出区和清除区在如美国专利申请系列号09/966,509的图6所示的有双排模具结构的单一设备中。压制模中的模具使用真空辅助充填较佳,其过滤器位于或靠近每个模具。压制模件的清除区包含任选的粉剂回收系统以从过滤器中回收多余粉剂并将粉剂还回模具中。
在另一个实施方案中,通过湿制粒法制备该片心,在该方法中活性成分或成分、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床,如行星搅拌器、高剪床搅拌器和液体床,包括旋转流化床。制成的粒状物质被烘干,任选地与其他成分干混合,如辅剂和/或赋形剂如润滑剂、着色剂等等。最后的干混合适合用前述段落描述的方法压制。
直接压制和湿制粒法加工是本领域已知的,详细记述于,如,Lachman等的《工业制药的理论和实践》(The Theory and Practice of Industrial Pharmacy),11章(第3版,1986)。
在一个实施方案中,第一部分和片心可以用如待批的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,本文引入作为参考。在这个实施方案中,将流动形式的始料注入成型室形成该第一部分和片心。该始料包括活性成分和热凝固物质较佳,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。始料在成型室中冷却并凝固成为有形状的片心(即有模具的形状)。
在另一个实施方案中,第一部分和片心可以用如待批的美国专利申请系列号09/966,497,第27-51页所述的热循环成型方法和设备制备,本文引入作为参考。在这个实施方案中,将流动形式的始料注入加热的成型室形成该第一部分和片心。该始料包括活性成分和热塑性物质较佳,温度在热塑性物质的固定温度之上但在活性成分的分解温度之下。始料在成型室中冷却并凝固成为有形状的片心(即有模具的形状)。
按照这个方法,始料必须是流动形式。例如,它可以包含悬浮在熔化基质中的固体微粒,如聚合物基质。始料可以是完全熔化或处于糊状形式。始料可以包含溶解在熔化物质中的活性成分。另一方面,始料可通过在溶剂中溶解固体制备,该溶剂在始料熔化后从始料中蒸发。
该始料可以包含任何需要掺入有形状形式的可食用物质,包括活性成分如上述关于片心、营养剂、维生素、矿物质、调味剂、甜味剂等等的活性物质。该始料包含活性成分和热凝固物质较佳。该热凝固物质可以是在约37℃到约250℃温度间能流动的任何可食用物质,和在约-10℃到约35℃温度间是固体或半固体的物质。该能流动的物质可以是在约37℃到约250℃温度间任何可食用物质,和在约-10℃到约35℃温度间是固体、半固体或可形成凝胶的物质。当处于液体或流动状态时,流动物质可包含溶解或熔化的成分,和任选地包含溶剂例如水或有机溶剂,或它们的组合物。该溶剂可通过烘干被部分或大体上除去。合适的流动物质包括那些包含热凝固物质、薄膜形成聚合物、胶凝聚合物、水胶体、低熔点疏水物质如脂肪和蜡、非结晶碳水化合物等等。较佳的热凝固物质包括水溶性聚合物如聚二醇、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;游离脂肪酸和它们的盐;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状的糖,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胶体的混合物,该混合物的水分达约30%,如用于制造“gummi”糖膏剂形式一样。在一个较佳实施方案中,热凝固物质是脂肪和甘油一酯、甘油二酯的混合物。
在另一个实施方案中,该片心可以是中空的或抽空的片心。例如,该片心可以是空的胶囊壳。两者择一地,中空片心可以通过用模塑制备。在这种方法中,流动物质被注入模腔中,该腔的温度达到片心的外表面(与模具相接触)开始变硬或凝固。然后使用合适的装置把多余的流动物质从片心的中心抽取,例如用活塞泵。在另一个方法中,空胶囊用作底片心,在其上用本领域已知的方法形成包衣层,如喷雾包衣、浸渍包衣或热循环成形方法,如待批的美国专利申请系列号09/966,497,第27-51页所述,本文引入作为参考。
在本发明的某些实施方案中,片心还可包含用任何方法获得的包底衣,例如喷雾、压制或模塑。在本发明的某些其他实施方案中,片心可以大体上没有包底衣。
本发明的另一个实施方案中,片心至少部分包含一种或多种插入物。插入物可被制成任何形状或大小。例如,可制成不超过一个对称轴的不规则形状插入物。也可制成圆柱形插入物。插入物可使用常规的技术如用盘制(Panning)、压制或模塑制备。在一个实施方案中,插入物可使用本文所述的热凝固方法和设备制备。
本发明的一个实施方案中,插入物的平均直径约100微米到约1000微米。本发明的另一个实施方案中,插入物的平均直径或厚度可以是片心的直径或厚度的约10%到约90%。本发明的另一个实施方案中,片心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、长度或厚度大于片心的直径或厚度约90%,例如,插入物的平均长度大于片心的厚度约100%。
在本发明的另一个实施方案中,片心、插入物(如果使用的话)、镶嵌部分或它们的任何组合物可以包含微电子装置(如电子“芯片”),该微电子装置可用作活性部件或用来控制,例如,对输入信号响应的片心或插入物内活性成分的释放速度。该微电子装置的例子如下:
(1)整体的,自身调节响应的治疗装置包括生物传感器,电子反馈和完全整体的药物/对抗释放装置。这些装置排除遥测试和人为干涉,例如在www.chiprx.com/products.html所公开的内容,本文引入作为参考。
(2)小型化诊断成像系统包含可吞咽的含有视频照相机的胶囊,例如在www.givenimaging.com/usa/default.asp所公开的内容,本文引入作为参考。
(3)皮下葡萄糖监控器包括植入式或插入式传感器装置,该装置检测肠液内葡萄糖浓度变化,并与外部的探测器和数据储存设备连通。例如,该装置在www.applied-medical.co.uk/glucose.htm公开,本文引入作为参考。
(4)密封在人工眼内晶状体的微显示视觉辅助装置。该装置包括用于能量供应的接收器、数据和时钟恢复,和连接于硅CMOS驱动电路和微光学设备上的小型化LED阵列倒装芯片,例如,在http://ios.oe.uni-duisberg.de/e/公开,本文引入作为参考。该微显示装置从放置在眼外的高动力范围CMOS照相机接收位流+能量无线信号,该照相机产生数字黑白图象并通过数字信号处理单元(DAP)用接近1Mbit/s的数据速度转换成一系列位流。该图象被投射到视网膜上。
(5)微芯片用于刺激受损的视网膜细胞,使它们对黄斑变性或其他视网膜疾患的患者的大脑发送视觉信号。该芯片为2毫米x 25微米,含有近5,000个极小的太阳能电池(“微光二极管”),每个都有自己的刺激电极。这些微光二极管把图象的光能量转换成电化学脉冲,刺激AMD和RP患者中视网膜残存的功能性细胞。该微芯片在www.optobionics.com/artificialretina.htm公开,本文引入作为参考。
(6)一次性“灵敏针头”用于乳房活组织检查,能实时显示结果。该装置装入连接到电子计算机的20到21规格的一次性针头,随针头插入到可疑的病变部位。该装置测量氧部分压力、电阻抗、温度,和光散射和吸收特性包括脱氧血红蛋白、血管化和组织密度。由于来自六路同时测量的准确性,和该装置的实时特性,该装置有希望超过片心心针头活组织检查步骤的准确性水平和接近外科手术活组织检查的高精确水平。而且,如果发现癌症,可配置该装置以进行不同的治疗如癌症标记、激光加热、低温、药物、和放射性籽壳。该装置在www.biolnminate.com/description.html公开,本文引入作为参考。
(7)个人UV-B记录器,用于测量和记录UV-B暴露的分级装置,可配置在腕表面上。该装置也可作用做眼罩佩戴。
在本发明的一个实施方案中,壳与镶嵌部分或二者由流动性物质制成。
镶嵌部分必须是模塑的。在本发明的一个较佳实施实施方案中,镶嵌部分是使用上述的热凝固成型或热循环成型方法制备的。
本发明的镶嵌部分可包含任何可模塑的物质,包括例如,膜形成剂、低熔点疏水物质、胶凝聚合物、增稠剂、增塑剂、辅剂和赋形剂。
在一个实施方案中,镶嵌部分最好包含至少约50%,较佳至少约80%,最佳至少约90%的物质,选自膜形成剂、胶凝聚合物、低熔点疏水物质、非结晶性糖或糖类醇,和它们的混合物。在另一个实施方案中,镶嵌部分包含至少约50%,较佳至少约80%,最佳至少约90%的物质,选自膜形成剂、胶凝聚合物、低熔点疏水物质,和它们的混合物。
在本发明的一个实施方案中,流动物质包含作为胶凝聚合物的明胶。明胶是一种天然的热胶凝聚合物。它是通常溶于温水的白蛋白类的衍生蛋白的无色无味混合物。通常使用的明胶有两种类型-A型和B型。A型明胶是酸处理的原料的衍生物。B型明胶是碱处理的原料的衍生物。明胶的水分含量,和Bloom强度、成分与原始明胶加工条件,决定了它在液体和固体之间的转换温度。Bloom是明胶凝胶体强度的标准量度,它与分子量有粗略的关系。Bloom被定义为以克为重量单位的用来在保持10℃、17小时的6.67%明胶凝胶中移动直径为半英寸的塑料活塞4毫米所需的力。在一个较佳实施例中,流动物质包含20%275Bloom猪皮明胶,20%250Bloom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;游离脂肪酸和它们的盐;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杯中的糖,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、木糖醇和赤藓糖醇),或热塑性淀粉;低湿度聚合物溶液如明胶和其他水胶体的混合物,该混合物的水分达约30%,如用于制造“gummi”糖膏剂形式一样。
在本发明的一个较佳实施例中,流动物质可包含薄膜形成剂如纤维素酯,例如羟丙甲基纤维素或改性淀粉,例如蜡状玉米淀粉;任选的膨胀剂如多聚碳水化合物,例如麦芽糊精;任选的增稠剂如水胶体,例如黄原胶或角叉菜胶,或糖,例如蔗糖;任选的增塑剂,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。
本领域中已知的任何薄膜形成剂适合用于流动物质。合适的薄膜形成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、支链淀粉、甲乙基淀粉、羧甲基淀粉、甲基纤维素、羟丙基纤维素(HPC)、羟乙甲基纤维素(HMEC)、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(HBMPMC)、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、预胶凝化淀粉,及它们的聚合物和衍生物和混合物。
一种合适的羟丙甲基纤维素化合物是“HPMC2910”,其纤维素醚的置换度约1.9,羟丙基的摩尔置换度为0.23,按照化合物的总重量,该化合物含有约29%到约30%的甲氧基团和约7%到约12%的羟丙基团。HPMC2910的商品化产品由DowChemical Company提供,其商品名METHOCELE。METHOCEL E 5是适用于本发明的HPMC2910的一个级别,在20℃,2%的水溶液中用Ubbelohde粘度计确定其粘度约4到6cps(4到6豪帕斯卡秒)。类似地,METHOCEL E 6适用于本发明的HPMC2910的另一个级别,在20℃,2%的水溶液中用Ubbelohde粘度计确定其粘度约5到7cps(5到7豪帕斯卡秒)。METHOCEL E 15适用于本发明的HPMC2910的另一个级别,在20℃,2%的水溶液中用Ubbelohde粘度计确定其粘度约15000cps(15豪帕斯卡秒)。本文中使用的“置换度”指附在无水葡萄糖环上的置换基团的平均数目,而“羟丙基摩尔置换度”指每摩尔无水葡萄糖羟丙基的摩尔数。
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“预胶凝化淀粉”或“预配制淀粉”指已经预先润湿,然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胶凝化的蜡状玉米衍生淀粉,该淀粉由Nat ional Starch & Chemical Company提供的商品名PURITY GUM和FILMSET和它的衍生物、共聚物和混合物。这种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。
合适的木薯糊精包括由National Starch & Chemical Company提供的商品名CRYSTAL GUM或K-4484,和该物质的衍生物如衍生自木薯的改性食物淀粉,该淀粉由National Starch & Chemical以商品名PURITY GUM 40提供,以及该它物的共聚物和混合物。
本领域中已知的任何增稠剂可适用于流通物质。增稠剂的例子包括但不限于水胶体(本文中也指胶凝聚合物)例如藻酸盐、琼脂、瓜尔胶、刺槐豆、角叉菜胶、他拉胶、阿拉伯树胶、黄芪胶、果胶、黄原胶、吉兰糖、麦芽糊精、半乳糖甘露聚糖、pusstulan、昆布多糖、硬葡聚糖、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,及它们的衍生物和混合物。其它合适的增稠剂包括可结晶碳水化合物等,和它们的衍生物和组合物。合适的可结晶碳水化合物包括单糖和寡糖。单糖中优选己醛糖如阿洛糖、阿卓糖、葡萄糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖的D和L异构体,和己酮糖如果糖和山梨糖的D和L异构体以及它们的氢化类似物:如山梨糖醇和甘露糖醇。寡糖中优选1,2-二糖蔗糖和海藻糖,1,4-二糖麦芽糖、乳糖、纤维二糖、1,6-二糖龙胆二糖、蜜二糖、三糖棉子糖、以及蔗糖的异构形式称为异麦芽糖和它的氢化类似物异麦芽糖。优选还原性二糖(如麦芽糖和乳糖)的其它氢化形式,例如麦芽糖醇(maltitol)和乳梨醇(lactitil)。此外,优选戊醛糖的氢化形式:例如,D和L核糖、阿拉伯糖、木糖、和丁醛糖的氢化形式:例如,D和L赤藓糖,且分别以木糖醇和赤藓醇作为例子。
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。
合适的热塑性物质在加热时可模塑和成形,包括水溶性聚合物和不溶于水的聚合物,这些聚合物通常是线性的,不是交联的,没有强氢与邻近的聚合物链连结。合适的热塑性物质的例子包括:化学改良的纤维素衍生物如羟丙基纤维素(HPC)、羟丙甲基纤维素(HPMC)、甲基纤维素(MC)、醋酸纤维素(CA)、乙基纤维素(EC)、醋酸丁酸纤维素(CAB)、丙酸纤维素;乙烯聚合物如聚乙烯醇(PVA)和聚乙烯吡咯烷酮(PVP);热塑性淀粉、天然或化学改良蛋白质如明胶、大豆蛋白质分离物、乳清蛋白质、肌原纤维蛋白质,和来自乳的酪蛋白;和它们的衍生物和组合物。
制药领域中已知的任何增塑剂可适用于本发明,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醇酯,十二烷基硫酸钠,和二辛基磺基琥珀酸钠;丙二醇;甘油单醋酸盐;甘油二醋酸盐;甘油三醋酸盐;天然胶和它们的混合物。在含有纤维素醚薄膜形成剂的溶液中,任选的增塑剂可以基于该溶液的总重量的约0%到约40%的量存在。
流动物质可任选包括辅剂或赋形剂,可包含流动物质重量的约20%。合适的辅剂或赋形剂例子包括防粘剂、致湿剂、表面活性剂、消泡沫剂、着色剂、食用香料、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%致湿剂,或者可选择地大体上不含致湿剂,如甘油、山梨糖醇、麦芽糖醇、木糖醇或丙二醇。致湿剂常常被包括在用于涂糖衣加工的预形成薄膜中,如美国专利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性或可塑性和粘合性。致湿剂的作用是结合水分和在薄膜中保留水分。用于涂糖衣加工的预形成薄膜通常包括多至45%的水。不利的是,致湿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,剂型的镶嵌部分包含至少约80%优选约90%的材料选自薄膜形成剂、胶凝聚合物(水胶体)、热塑性物质、低熔点疏水物质、非结晶糖和它们的混合物。镶嵌部分可用注射模塑形成,有利于最低程度减少或排除直接压制需要的充填剂-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、糊精等等。不利的是,这些物质会降低该镶嵌部分的透明性和稳定性。本发明的镶嵌部分包含少于约10%,如少于约1%,或少于约0.1%的直接压制充填剂-粘合剂较佳。所以用于本发明的镶嵌部分是对压制包衣的壳的改进,压制包衣的壳通常包含至少约30%的直接压制充填剂-粘合剂。见举例WO 00/18477。
镶嵌部分可以通过模塑制备,如上文所述。
在本发明的一个实施方案中,镶嵌部分包含改进释放组合物如美国专利申请系列号00000000000(WO/0000000000)[MCP320],本文引入作为参考。
在本发明的另一个实施方案中,镶嵌部分包含任何改进释放组合物如美国专利申请系列号00000000000或000000000000000(WO/0000000000或WO/0000000000)[MCP322和323],本文引入作为参考。
在一个较佳实施方案中,镶嵌部分大体上不含有直径0.5到5.0微米的小孔。本文中使用的“大体上不含”指该镶嵌部分的小孔在小孔直径范围为0.5到5.0微米时体积小于约0.02cc/g,小于约0.01cc/g较佳,小于约0.005cc/g更佳。在此小孔直径范围中,典型的压制物质的小孔体积大于约0.02cc/g。小孔的体积、小孔的直径和密度可用Quantachrome Instruments PoreMaster 60汞挤入孔率计和相关的计算机软件程序“Porowin”来测定。该测定步骤由QuantachromeInstruments PoreMaster操作手册记载。PoreMaster设备确定固体或粉剂的小孔体积和小孔直径,通过非湿性液体(汞)加压挤入,包括排空样品池(穿透计)中的样品,向池内注入汞使样品周围环绕汞,向样品池提供压力,用:(I)压缩空气(最高至50psi);和(ii)水压(油压)压力发生器(最高至60000psi)。在提供的压力下,通过汞从样品外面移入小孔中带来的容量变化来测量挤入体积。挤入发生时相应的小孔大小直径通过所谓的“Washburn等式”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度,P是提供的压力。
用于测量小孔体积的设备:
1.Quantachrome Instruments PoreMaster 60
2.能称0.0001g的分析天平
3.干燥器
用于测量的试剂:
1.高纯度氮
2.三重蒸馏的汞
3.高压液体(Dila AX,由Shell Chemical Co.提供)
4.液氮(用于汞蒸汽冷阱)
5.用于清洗样本池的异丙醇或甲醇
6.用于池清洗的液体洗涤剂
步骤:
样品在分析前被密封包装或安放在干燥器中。接通真空泵,汞蒸汽冷阱注入液氮,提供的压缩气体调节在55psi,开启设备,预热时间至少30分钟。空的穿透计池按照设备手册中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“只排空和充注”,并使用下列数值:
精细排空时间:1分钟
精细排空率:10
粗排空时间:5分钟
该池(已充注了汞)被移出和称重。然后在汞储存器中清空该池,每个样品的两小片被置于该池内,该池被重新装配。然后记录该池和样品的重量。该池被安置在低压站,从菜单上选择低压选项,并设定下列参数:
模式:低压
精细排空率:10
精细排空到:200μHg
粗排空时间:10分钟
充注压力:接触+0.1
最大压力:50
方向:挤入和挤出
重复:0
汞接触角度:140
汞表面张力;480
然后开始获取数据。关于压力与累计挤入体积关系的图显示在屏幕上。在低压分析结束后,该池从低压站移出并重新称重。汞以上的空间被充注液压油,该池被装配,并安装在高压腔中。使用下列参数:
模式;固定速率
发动机速度:5
起始压力:20
结束压力:60,000
方向:挤入和挤出
重复:0
油充注长度:5
汞接触角度:140
汞表面张力;480
开始获取数据,关于压力与挤入体积关系的图显示在屏幕上。在高压运行结束后,同一样品的低压和高压数据文件被合并。
在本发明的一个实施方案中,只有片心包含一种或多种活性成分。在本发明的另一个实施方案中,只有镶嵌部分包含一种或多种活性成分。而在本发明的另一个实施方案中,只有插入物包含一种或多种活性成分。而在本发明的另一个实施方案中,片心和镶嵌部分包含一种或多种活性成分。而在本发明的另一个实施方案中,一个或多个片心、镶嵌部分、或插入物包含一种或多种活性成分。
本发明的优点之一是镶嵌部分可以有复杂的几何形状或图案。例如,以前在现有技术中公开的插入物或镶嵌部分限于简单的形状,如圆形的横截面形状。使用现有技术,极难恰当地压制出复杂的标识图案,例如凹雕导致或需要在基底、片心表面中的不连线性或它在第一部分中必须镶嵌。但是,由于本发明的插入物或镶嵌部分是使用流动性物质获得的,或如果使用多个喷嘴可以用来充填任何形状或连续图案的任何抽空部分,乃至一种不连续的图案。
本发明的一个特殊优点是插入物或镶嵌部分在横截面上(至少是一部分)可比包含插入物或镶嵌部分的腔大。例如,在第二模塑部分镶嵌在剂型的第一部分的外表面中的一个或多个腔内的实施方案中,第二模塑镶嵌部分的至少一个横截面面积比第一部分的表面的腔的横截面面积大。相反,现有技术中插入物的横截面面积必须不大于容纳插入物的腔的开口。这也可用插入物或镶嵌部分的“锥度”来表示。本文中使用的术语“锥度”指腔的侧壁和与第一部分的面垂直线限定的角度,例如Rosato等,《注射成型手册》(Injection Molding Handbook)第601-04页,(第2版1995),本文引入作为参考。本文用图3A和3b说明。在图3A中,显示现有技术插入物300插入片心304的腔302中。锥度θ由垂直线306和侧壁307确定,θ必须有零或正值。但是,本发明中θ可以有小于零的值。
相反,在图3B中显示的本发明的插入物或镶嵌部分500插入片心504的腔502中。锥度θ由腔502和片心504的交叉点射出的垂直线506和插入物500的侧面508确定,如图所示小于0。。这是由于插入物500的第一末端509比腔502宽。但是,由于插入物是由流动性物质组成,插入物500可充填腔502。所以,插入物500可被“锁”或交锁在腔502内。
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
本发明的剂型是使用包含压制模制和两个热循环成型模制,通过第一和第二传递装置连接成系列的设备进行连续加工制备的,如待批的美国专利申请系列号09/966,939的第14-16页所述,本文引入作为参考。该剂型包含压制的片心,片心上有壳,壳包含形成镶嵌图案的第一壳部分和第二壳部分。
片心由下列成分的混合物制备:对乙酰氨基酚USP(590mg/片)、合成蜡X-2068T20(53mg/片)、羟基乙酸淀粉钠(EXPLOTAB)(13.9mg/片)、二氧化硅(0.6mg/片)、硬脂酸镁NF(2.4mg/片)。这些成分被进行干混合,就是在压制模件上被压制成片心,按照待批的美国专利申请序列号09/966,509的第16到27页(本文引入作为参考)所述使用7/16英寸特深凹片剂加工。该压制模件是一个双排,旋转设备,包含充填区、插入区、压制区、射出区和清除区,如美国专利申请序列号09/966,509的图6所示。该压制模件的模具用真空辅助充填,通过位于每个模具的模壁口的网眼筛过滤器。制成的片剂的平均重量是660mg,厚度是0.306英寸,和硬度是3.2kp。
片心通过如待批的美国专利申请序列号09/966,414的第51到57页所述的第一传递装置,被转移至如待批的美国专利申请序列号09/966,497的第27到51页所述的第一热循环成型模件,本文引作为参考。第一和第二传递装置的结构如待批的美国专利申请系列号09/966,414中图3的300所示,分别将片心从压制模件转移到第一热循环成型模件和从第一热循环成型模件转移到第二热循环成型模件。传递装置包含许多以悬臂形式连接到带子312上的传递单元304,如待批的美国专利申请系列号09/966,414的图68和69所示。第一传递装置与相连接的压制模件和第一热循环成型模件同步旋转和运行。第二传递装置与相连接的第一热循环成型模件和第二热循环成型模件同步旋转和运行。传递单元304包含定位器330,该定位器用于放置围绕传递装置移动的片心。
片剂在第一热循环成型模件中被包含红色明胶的第一壳部分包被。如待批的美国专利申请序列号09/966,939的图28A所示的类型。热循环成型共同待定的模具单元204包含如图28C所示的上模具组合件214、可旋转中心模具组合件212和下模具组合件210。片心被转移至模具组合件,然后模具组合件关闭,片心上的镶嵌图案被模具组合件的内表面遮蔽,留下镜图象镶嵌图案暴露在片心的表面。第一壳流动物质,如下文所述,在贮主206加热到流动状态,被注入到关闭的模具组合件形成的模腔中。由于遮蔽,流动物质只能用于片心的暴露部分。然后第一壳流动物质的温度被降低,硬化。模具组合件打开,且被部分包被的片心弹出到第二传递装置,该装置把片心传递到第二热循环成型模件。
包含红色明胶包衣的第一壳部分,由下列成分制备:净化水,Opatint红DD-1761,Opatint黄DD-2125,275 Bloom猪皮明胶和250 Bloom骨明胶(150g)一起作为干明胶颗粒的混合物。明胶浆由这些成分形成并加热到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)。然后该溶液被混合至均匀(约5到15分钟)。当明胶溶液在第一热循环成型模件中使用时,明胶溶液被保持在55℃连续混合。
第二热循环成型模件也是如待批的美国专利申请序列号09/966,497的图26A所示的类型。第二壳部分(由净化水(450g),Opatint黄DD-2125(6.2g),275Bloom猪皮明胶(150g)和250 Bloom骨明胶(150g)以与第一壳部分相同的方法制备)可应用到片心。第二热循环成型模件的上和中模具组合件配合,使前述的片心的暴露部分(现包被了第一壳部分)被遮蔽。这使先前遮蔽的尚未包被的片心部分暴露出来。第二流动物质在贮主206加热到流动状态,被注入到配合的上和中模具组合件中。然后第二流动物质的温度被降低,硬化,使第二流动物质形成镶嵌图案。模具组合件打开,弹出完成的剂型。
虽然本发明通过特定的实施方案作了阐明,本领域的熟练技术人员应当明白进行的各种改变和改进无疑属于本发明的范围内。
Claims (27)
1. 一种剂型,所述剂型包含至少一种药物活性成分,第一部分包含一个外表面和一个或多个定义为至少一个有凹口的内表面的腔,和镶嵌在第一部分的腔内和有外表面的第二模塑部分,其中,第一部分是压制的片剂,第二模塑部分没有直径0.5到5.0微米的孔,第一和第二部分在界面上接触,第二部分包括凝固的热塑性物质,第二部分正形地在凹口上;所述热塑性物质选自羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、醋酸纤维素、乙基纤维素、醋酸丁酸纤维素、丙酸纤维素、聚乙烯醇、聚乙烯吡咯烷酮、热塑性淀粉、明胶、大豆蛋白质分离物、乳清蛋白质、肌原纤维蛋白质、来自乳的酪蛋白、或它们的组合物。
2. 权利要求1所述的剂型,其特征在于,第一和第二部分在界面上紧密接触。
3. 权利要求1所述的剂型,其特征在于,第一部分包含凹雕,第二部分在凹雕中。
4. 权利要求1所述的剂型,其特征在于,第二部分的外表面与第一部分的外表面齐平。
5. 权利要求1所述的剂型,其特征在于,第二部分的外表面高于第一部分的外表面。
6. 权利要求1所述的剂型,其特征在于,第一部分由单一均质层组成。
7. 权利要求1所述的剂型,其特征在于,第二模塑部分包含至少一种药物活性成分。
8. 权利要求1所述的剂型,其特征在于,第一部分有第一种颜色,镶嵌的第二部分有第二种颜色。
9. 权利要求1所述的剂型,其特征在于,第一部分包含第一药物活性成分和镶嵌的第二部分包含与第一药物活性成分相同或不同的第二药物活性成分。
10. 权利要求1所述的剂型,其特征在于,第一和第二部分一起构成预先安排的式样。
11. 权利要求1所述的剂型,其特征在于,第一部分包含微电子装置。
12. 权利要求1所述的剂型,其特征在于,第一部分是不连续的,第二部分是连续的。
13. 一种剂型,所述剂型包含至少一种药物活性成分,片心有外表面,壳至少在片心外表面的一部分上,其中,壳包含第一壳部分和第二模塑壳部分,第一部分中的一个或多个腔的内表面的锥度值小于零,第二模塑壳部分镶嵌在第一模塑壳部分中,第一和第二壳部分在界面上接触;所述壳包括凝固的热塑性物质,它选自羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、醋酸纤维素、乙基纤维素、醋酸丁酸纤维素、丙酸纤维素、聚乙烯醇、聚乙烯吡咯烷酮、热塑性淀粉、明胶、大豆蛋白质分离物、乳清蛋白质、肌原纤维蛋白质、来自乳的酪蛋白、或它们的组合物。
14. 权利要求13所述的剂型,其特征在于,第一和第二壳部分都是不连续的。
15. 权利要求13所述的剂型,其特征在于,第一壳部分有第一颜色,第二壳部分有第二颜色。
16. 权利要求13所述的剂型,其特征在于,片心包含压缩的粉剂。
17. 权利要求13所述的剂型,其特征在于,第一壳部分、第二壳部分,或两者有带织纹的外表面。
18. 权利要求13所述的剂型,其特征在于,壳的外表面包含预先安排的图案。
19. 权利要求13所述的剂型,其特征在于,壳的外表面光滑。
20. 权利要求13所述的剂型,其特征在于,壳含有凹口、字母、符号或图案。
21. 权利要求13所述的剂型,其特征在于,第一壳部分含有凹口、字母、符号或图案。
22. 权利要求13所述的剂型,其特征在于,第二壳部分含有凹口、字母、符号或图案。
23. 权利要求13所述的剂型,其特征在于,第一壳部分、第二壳部分,或两者含有以字母、符号或图案形式的突出部分。
24. 权利要求13所述的剂型,其特征在于,镶嵌部分没有直径0.5到5.0微米的孔。
25. 一种剂型,所述剂型包含至少一种药物活性成分、片心、和有不连续的第一模塑壳部分和连续的第二模塑壳部分的壳,其中,所述第一模塑壳部分确定为许多用于容纳镶嵌部分的侧壁,该侧壁有小于零的锥度值,第一壳部分的不连续是由于第二模塑壳部分的存在,第一和第二壳部分在成分上不同;所述壳包括凝固的热塑性物质,它选自羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、醋酸纤维素、乙基纤维素、醋酸丁酸纤维素、丙酸纤维素、聚乙烯醇、聚乙烯吡咯烷酮、热塑性淀粉、明胶、大豆蛋白质分离物、乳清蛋白质、肌原纤维蛋白质、来自乳的酪蛋白、或它们的组合物。
26. 权利要求13所述的剂型,其特征在于,第一和第二壳部分包括凝固的热塑性物质;所述热塑性物质选自羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、醋酸纤维素、乙基纤维素、醋酸丁酸纤维素、丙酸纤维素、聚乙烯醇、聚乙烯吡咯烷酮、热塑性淀粉、明胶、大豆蛋白质分离物、乳清蛋白质、肌原纤维蛋白质、来自乳的酪蛋白、或它们的组合物。
27. 权利要求13所述的剂型,其特征在于,第一和第二壳部分的外表面是共面的。
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Application Number | Priority Date | Filing Date | Title |
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US09/966,509 US6767200B2 (en) | 2001-09-28 | 2001-09-28 | Systems, methods and apparatuses for manufacturing dosage forms |
US09/966,509 | 2001-09-28 | ||
US09/966,450 | 2001-09-28 | ||
US09/966,497 | 2001-09-28 | ||
US09/966,497 US7122143B2 (en) | 2001-09-28 | 2001-09-28 | Methods for manufacturing dosage forms |
US09/967,414 US6742646B2 (en) | 2001-09-28 | 2001-09-28 | Systems, methods and apparatuses for manufacturing dosage forms |
US09/966,939 US6837696B2 (en) | 2001-09-28 | 2001-09-28 | Apparatus for manufacturing dosage forms |
US09/966,450 US6982094B2 (en) | 2001-09-28 | 2001-09-28 | Systems, methods and apparatuses for manufacturing dosage forms |
US09/967,414 | 2001-09-28 | ||
US09/966,939 | 2001-09-28 |
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2003
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2004
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2005
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2008
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