CN1458862A - 药物颗粒的连续生产 - Google Patents
药物颗粒的连续生产 Download PDFInfo
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- CN1458862A CN1458862A CN01811310A CN01811310A CN1458862A CN 1458862 A CN1458862 A CN 1458862A CN 01811310 A CN01811310 A CN 01811310A CN 01811310 A CN01811310 A CN 01811310A CN 1458862 A CN1458862 A CN 1458862A
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Images
Classifications
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
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- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/20—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by expressing the material, e.g. through sieves and fragmenting the extruded length
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- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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- B29K2105/0005—Condition, form or state of moulded material or of the material to be shaped containing compounding ingredients
Abstract
一种用于生产一种药物颗粒的单程、连续、自动化系统,它包括用于粉末和液体进料的多个进料器、一个用于制粒的双螺杆处理器、一种用于干燥此颗粒的基于射频或微波的干燥装置、以及至少一个将干燥后的颗粒处理至所需颗粒大小的磨。该系统结合了在线上监测关键处理参数的手段。所生产的颗粒可以被压片或装入胶囊,此活性成分在片或胶囊中分布均匀。此系统可以生产具有统一特性的产品,甚至是当生产规模进行以生产商业数量的片剂时。一种用于生产来源于低密度活性物质的高剂量的药物颗粒的单程、连续、自动化系统,包括用于粉末和液体进料的多个进料器、用于制粒的双螺杆处理器、用于干燥此颗粒的基于射频或微波的干燥装置、以及至少一个将干燥后的颗粒处理至所需颗粒大小的磨。此系统可以生产具有统一特性的产品,甚至是当规模生产商业数量的片剂时。此双螺杆处理器具有第一和第二传送元件,在传送元件之间具有一个混合元件,而且第二传送元件具有至少一个螺距,该螺距小于第一传送元件的至少一个的螺距。此系统还可以优化许多其他的设计参数,例如一种定位和侧填料器和液体进料器的进料速度、制粒机本身的旋转速度、以及最终颗粒的大小。此系统特别适宜于生产一种用于高剂量产品的奈菲那维甲磺酸盐和赋形剂(包括硅酸钙)的颗粒。
Description
本发明的技术领域
本发明涉及一种用于生产典型地被压成片剂或者被装入硬胶囊的药物颗粒产品的方法和装置。尤其特别的是,本发明涉及一种单程自动化系统和一种用于连续生产一种药物颗粒的装置,此连续生产结合了湿制粒法、干燥和碾磨。
本发明还涉及一种生产高剂量(大于200mg强度活性组分)的可压成片剂或者装入硬胶囊的药物颗粒产品的方法。
本发明的背景技术
制粒是固体口服剂型生产中的一个关键元件操作。甚至随着用于自动化生产和提高产品产量的压片设备的不断改进,粉末制粒还必须具有特殊的物理特性,以确保下游操作的顺利进行。因此,一致的产品质量经常是指导制粒技术改进最重要的动机。其它重要的目标是保持规定的顺应性、缩短循环时间、提高操作效率以及降低产品成本。
湿制粒技术中的改进包括高剪切混合制粒机、带高剪切混合制粒机和微波干燥的单罐操作,以及与一个流化床干燥器结合的高剪切制粒机,例如半连续多室装置。在这些技术与先前应用的制粒方法相比具有某些优势的同时,它们各自也存在特殊缺点,而且最重要的是,没有一种方法提供了一种以单个组分或粉末掺合物为起始的真正的连续制粒方法。
例如,在一个应用高剪切混合器的单罐微波制粒机中,通过一种高速搅拌机完成掺合和附聚,同时一种切碎机对组分掺合物进行高机械搅拌。即使这种制粒机在相同的设备中操作时间短,并可对干燥方法进行选择,但这种制粒机仍不能有效地使粘合原料制粒;生产出形状和大小不均匀的颗粒;使易碎颗粒的质量下降;使不受控制的颗粒增长;并且生产出孔隙率低的颗粒。
另外,Glatt GmbH(Binzen德国)公开了一种半连续系统(″GlattMulticell GMC″)的应用,在此系统中以连续成批的方式,将小批量原料传送至入将原料混合并制粒的高剪切混合制粒机中。相继将这种湿颗粒通过一系列的三个流化床干燥器真空传送以干燥。当微小批量通过此系统时,相继进行每个元件操作。
与上面所述高剪切和流化床制粒方法相比,本发明可容易地按比例增加。由于这种方法是连续的,应用同一种设备可生产不同大小的批量。因此,可以断定:本方法从一个批量可以按比例增加到一个较大的批量。
应用传统高剪切混合器和流化床制粒机,进行高剂量和/或低堆积密度活性物质的制粒是非常困难的,而且经常是不可能的。在这种制粒方法中,原料易于停留在球形混合器的边上,需要间断手工进行刮落。甚至,不能确保活性物质在颗粒中的均匀分布。更特别的是,对于低密度活性成分例如奈菲那维甲磺酸盐(nelfinavir mesylate)来说,在此制粒方法中增加药物的装载量将导致具有不利的“太妃糖样”稠度的湿颗粒的产生。另外,尝试对比例为3∶1的奈菲那维甲磺酸盐和硅酸钙的掺合物使用高剪切湿制粒,结果分别造成溶解度和崩解度的提高,但它们与市售产品不具有生物等效性。这种制剂的流化床制粒也低于理想的制粒。作为这些粉末的流化方式较差的结果,这种附聚方法不能确保赋形剂包被活性物质。当处理非常粘性的原料时,这种情况是特别严峻的。应用本发明的双螺杆制粒机可克服这些缺点。
对于在药用产品的生产过程中干燥组分,传导和对流是两种最常用的加热方法。为了干燥药用固体,对流的使用优于传导的使用,这是因为传导性热传递需要温度,这种温度将潜在地导致产品降解。然而,在对流干燥中,需要大量的气流,或者需要较长的停留时间,以便得到所需要的湿度水平的下降。在某些例子中,应用真空环境以进一步增强去除蒸发的水分。对流干燥的大量气流或长时间停留可降解或者损害由此制造的药用产品。为了到一个较低的程度,还应用了微波能,但是仅仅是批量的方式。目前,没有一种常规干燥系统可提供一种真正的符合先进先出原则的单程干燥方法。
因此,需要一种制粒方法,一种干燥方法和一种单程、全自动、连续的系统,这种系统可生产具有一致物理特性的药物颗粒。
还需要一种制粒方法、一种干燥方法和一种单程、全自动、连续的系统,该系统可生产出具有一致物理特性的低密度活性组分的高剂量药物颗粒。
本发明的总结
本发明提供了一种用于生产颗粒产品的单程连续全自动方法,该颗粒产品可以被进一步加工制成一种固体口服剂型,例如片剂或胶囊。
在一个实施方式中,本发明包括一个双螺杆湿制粒机-切碎机(TSWGC),将活性组分和固体与液体添加剂进料至其中,它将这些成分混合、制粒并湿碾磨,形成一种颗粒产品。
在另一个实施方式中,本发明包括一个干燥装置,它应用介电能例如射频能、低频(常规)微波能或高频(毫米波)微波能,以连续单程的方式,还可以任选地结合一种产品隔离通道,来干燥颗粒。
在另一个实施方式中,本发明包括系统组件的整体性自动加工控制,以便在整个系统过程中监测关键的加工参数和产品特性;例如流水线上监测颗粒的水分含量和活性组分分布的均匀性。
本发明的另一个方面是一个生产高剂量药物颗粒的连续加工系统。此系统包括双螺杆湿制粒机-切碎机、一个粉末进料器,它适于将一种粉末进料至这种双螺杆湿制粒机-切碎机中;以及一个液体进料器,它适于将一种液体进料至这种双螺杆湿制粒机-切碎机中。将粉末进料器和液体进料器都连接在这种双螺杆湿制粒机-切碎机上,并适于将粉末和液体在这种双螺杆湿制粒机-切碎机的一个进口进行进料。
这种双螺杆湿制粒机-切碎机包括第一和第二传送元件,每个均含有至少一个传送元件螺距,而且第一混合元件位于传送元件之间。另外,这种双螺杆湿制粒机-切碎机包括至少一个切碎元件,定位在传送元件后面以接触药物活性组分。对于传送元件,第二传送元件的至少一个螺距小于第一传送元件的至少一个螺距。
本发明的另一个方面是一种生产高剂量药物颗粒的方法,它包括将一种含有药物活性组分的粉末进料至双螺杆湿制粒机-切碎机,并使液体和粉末接触这种双螺杆湿制粒机-切碎机的第一传送元件。然后使此液体和粉末与第一混合元件混合,形成一种湿团块,它与这种双螺杆湿制粒机-切碎机的第二传送元件接触。最后,这种湿团块与这种双螺杆湿制粒机-切碎机的切碎元件接触,并将它切碎为一种颗粒。
本发明提供了一种单程连续自动化方法,生产低密度活性组分的一种高剂量(强度大于200mg)颗粒产品,然后可进一步将其加工为一种固体口服剂型,例如片剂或胶囊。
在另一个实施方式中,本发明包括一种双螺杆湿制粒机-切碎机,将活性组分和固体与液体添加剂进料至其中,它将这些成分混合、制粒并湿碾磨,形成一种高剂量颗粒产品。
应当理解的是:前面一般的描述和下面的详细描述均是举例说明性的,而不是对本发明进行的限制。
附图的简要说明
当读到相关附图时,通过下面的详细说明可更好的理解本发明。需要强调的是,按照通常的惯例,附图的各种特征不是按比例缩小的。相反,为了清楚起见,将各种特征的尺寸进行了任意地扩大或缩小。附图包括下面各图:
附图1是按照本发明的程序和装置的方块示意图;
附图2是按照本发明的双螺杆湿制粒机-切碎机的示意图;
附图3A是按照本发明的双螺杆湿制粒机-切碎机的一个实施方式;
附图3B是按照本发明的双螺杆湿制粒机-切碎机的另一个实施方式;
附图4是按照本发明的双螺杆制粒机-切碎机进料系统的等比例视图;
附图5是按照本发明的干燥装置的示意图;以及
附图6是用于本发明干燥装置的电极结构的示意图。
本发明的详细说明
本发明包括一个用于药物颗粒连续生产的自动、单程系统,该系统包括程序和装置,这些药物颗粒还可被进一步加工制成固体口服剂型。整个系统包括一个双螺杆湿制粒机-切碎机(TSWGC);一个单程干燥装置,它可应用介电能,例如射频(RF)、微波能,或者两者均用。这些组件生产一种颗粒,当这种颗粒加入药物产品中时,它可具有良好的特性。可将TSWGC与介电能干燥装置联合应用,或者,可代替的,它可与例如流化床或连续桨式干燥器等的常用组件分开应用。另外,介电能干燥装置可与TSWGC联合应用,或者,可代替的,它可与例如高剪切制粒机等的常用组件分开应用。
装置TSWGC克服了常规湿制粒设备的局限性。TSWGC包括传送、混合、制粒和切碎元件,以获得分布和分散混合(当需要时)。可改变螺杆元件的设计和组合,以处理活性组分和不同堆积密度的添加剂,以便生产一种均匀的颗粒产品。这种TSWGC所提供产品的致密性和均匀性超过高剪切制粒机的能力,并且当与本发明的介电干燥装置联合应用时,其干燥速度相当于或优于流化床制粒机/干燥器的干燥速度。
TSWGC与常规挤压机在几个方面不同。在常规挤压机中当出口点对着模板是开口的;它具有扩展柄,可任意从开口中伸出;而且切碎元件位于输出端。它具有一个或多个粉末和液体进料区,其中一个惯常设计的进料区用于液体和粉末的同时进料。TSWGC的附加特征是轴护圈封条,它可防止操作过程中螺杆轴的向前运动。
按照这样将活性组分和添加剂(例如赋形剂、粘合剂、增塑剂等)进料至TWWGC中:(1)固体组分的进料是应用多失重型进料器,它可连续监测进料固体组分的重量;(2)液体组分的进料是应用结合质量流量计或失重型进料箱的多个泵。可沿着TSWGC长度的一处或多处,对进料筒进行修改,以适合液体和粉末的同时进料。
TSWGC应用一种双螺杆处理器将活性组分和添加剂混合并制粒。排列螺杆元件的螺纹,以优化混合和制粒,从而获得进行制粒的活性组分和添加剂所需的颗粒结构。这种排列使湿碾磨可在TSWGC范围中进行,这样可以不需要单独湿碾磨步骤。将活性组分和添加剂直接进料至TSWGC中。另外,传送元件和通风装置在进料点的设置可除去带入的空气,并使产品产量最大化。TSWGC应用液体加热和冷却颗粒,而且可提供更一致的温度,并且可在制粒所用的温度下提供更佳的温度控制。
湿颗粒以分散颗粒的形式,通过开口端排出双螺杆处理器,可任选通过一种筛子,此筛子在下面进行描述。然后,应用一种装载/平整设备,将这些颗粒弄平,均匀地堆积在干燥单元的传送带上。干燥单元利用例如RF或微波能等的介电能,在一种单程连续的机械中除去颗粒中的水分。另外,对此干燥单元进行设计,使其具有利于水分除去的适宜气流,并且设计干燥单元中所用的电极,使它们在需要时可以是偏置和倾斜的,这样,在将颗粒保持在所需要的温度范围中的同时除去水分。一旦进行了干燥,即通过传送系统将颗粒传送至碾磨组件。在碾磨组件中,用一种适宜的碾磨机将干燥颗粒的粒径变小,此碾磨机例如为锤磨机、锥形磨、菲茨磨、针形磨,或者其它适宜的筛选设备。
可用一种主控制器控制生产颗粒产品的系统组件,此主控制器可调节系统中的参数,以适应生产条件,这些条件在系统中各点/各组件处测定。对这些参数和条件进行在线测定,以使该系统是连续的,同时使每个元件所生产的原料均具有相同的处理/剪切历史。例如,在线监测颗粒的水分含量和活性组分分布的均匀性,对单个组件提供反馈,使操作者可对条件进行调节。更特别的是,例如,在它脱离TSWGC后,或者在它干燥以后,可测定颗粒产品中的水分含量,并且如果其测定值是在容许范围(例如干燥后0%-10%)之外时,可对条件进行适当地调节。
此所得颗粒的组合物比常规生产的颗粒更同质,更均匀。另外,本发明的技术转化为市售产品比应用常规的非连续处理技术更快,这是因为本发明系统中按比例增加的步骤更少。
如附图1所示,本系统包括一种TSWGC,它具有两个或多个螺杆,它们在制粒阶段7.4的旋转方向相同或相对。在7.1-7.3进料阶段中,将一种或多种固体和/或液体原料进料至这个TSWGC中,典型地至少包括一种药物活性组分。将活性组分与赋形剂、水和可能的其它添加剂结合,在沿着TSWGC长度的一个或多个点连续地将它们引入。可替代的是,在一种高剂量产品的生产中在被引入TSWGC中之前,优选地以一种已知的方式,例如在一种双壳或双仓混合器中,将干燥组分预掺合。
在TSWGC 1中,如附图2、3A、3B和4所示,固体组分是通过一个或多个旁或顶粉末进料器2进料,液体组分是通过一个顶或底进料器4进料,所有这些均接近TSWGC 1的上游端。通过一个泵3将液体组分注射入TSWGC 1中,此泵3与一个液体储蓄器5连接。当液体和固体组分沿着TSWGC 1的长度运行时,将它们混合为一种相对同质的湿混合物。
更特别的是,如附图3A和3B所示,在本发明TSWGC 1中所用的双螺杆元件的典型安排包括一种外壳9,它包含传送元件6、混合(制粒)元件8和切碎元件10,这些可以完成分布,并且当需要时可以完成分散的混合。这些元件生产一种均匀的,具有所要求的致密性的颗粒,以使下一步生产所需固体口服剂型的处理更容易。本发明的TSWGC可处理不同堆积密度的活性组分和添加剂,而生产出一种同质均匀的颗粒。
本发明的TSWGC的特征在于其基于螺杆元件的直径。例如,螺杆直径为18mm的TSWGC被称作18mm TSWGC。通常螺杆直径约在16mm至135mm之间。将单个筒(外壳)9的长度,即整个制粒区的长度,设计为螺杆直径的倍数。通常,外壳的长度与螺杆直径的比例约在20∶1和60∶1之间。然而,可改变这个比例,以适应制粒加工中任何特殊的需要。
外壳中单个元件的长度通常为15mm的倍数。根据机器的大小和特殊制粒加工的要求,传送元件6的螺距通常约在15mm至180mm之间。例如,对于50mm螺杆,传送元件的螺距通常约在20mm至72mm之间。下面将对本发明中所用的各种传送元件的螺距进行更详细的描述。
对于双叶(bilobal)元件,螺距是传送元件两个相邻偶数或奇数螺纹之间的螺杆轴的距离。
对于混合和切碎功能,根据所制粒的组分,可应用各种不同的设计,包括但并不限于捏合盘、梳刷混合器、齿轮混合器、针型混合器和压延间隙混合器。另外,传送元件和混合元件6和8可包括短距的反向线、捏合元件和/或传动元件8,以提高混合过程。
尽管温度可以升高,以提高溶解差的活性组分的溶解度(为了可控释放的目的),以辅助干燥处理,或者是为了其它可以影响产品特性的原因,但是一般情况下,TSWGC中的湿制粒阶段7.4是在室温下进行。TSWGC内部的温度可用一种热交换液体保持,此液体在包绕TSWGC1的外壳9的外套管中循环,也可应用电加热。
在本发明的一个实施方式中,如附图3A和3B所示,TSWGC 1中的梳状切碎机8和10用于混合和切碎,其TSWGC中的螺杆直径为34mm或27mm,其外壳长度/螺杆直径比为28∶1。在每个梳状混合器8中,有5排叶片19,在每排内有8个通道。叶片19是环状结构中的突起,在每个叶片19之间存在间隙。相邻两排叶片之间的间隙是交替的,这样两排之间的间隙利于颗粒的混合。在一个实施方式中,叶片对着TSWGC输出端的螺距角度为120°,它可使颗粒挤着通过TSWGC。根据制粒的组分,也可应用呈平面的螺距或其它螺距角度。
螺杆大小、螺纹、螺距以及与外壳9和颗粒接触的角度可根据混合入颗粒产品中的活性组分和赋形剂以及生产的程度的不同而改变。但无论如何,TSWGC中可结合常规使用的挤压机螺杆。
双螺杆湿制粒机-切碎机螺杆设计包括第一和第二传送元件组,每组均含有至少一组传送元件螺距,并且含有位于传送元件之间的第一混合元件。关于传送元件,第二传送元件的至少一个螺距小于第一传送元件的至少一个螺距。这样,传送元件的螺距沿着传送元件的长度逐渐减小。随着颗粒通过此机器的长度,这种设置(逐渐减小)使除去空气和致密化同时进行。例如,一种含有低密度活性组分例如奈菲那维甲磺酸盐的粉末,在它进入本发明的TSWGC时,可以具有约为0.2g/mL的密度;当它从TSWGC中出来时,其颗粒的密度约为0.5g/mL或以上。
重要的是,每个后面传送元件的螺距可优选小于或者等于前面传送元件的螺距。如上所述,这种设置可使致密性渐增,同时可防止原料的聚集,并使这种处理具有一个稳定的产率。将低密度活性组分引入TSWGC的优选方法是应用一种常规的侧填料器。
本领域普通技术人员可以理解:此设备的大小确定可应用的螺距。
附图3A和3B中所示的切碎元件10位于TSWGC 1的末端12,它用以消除颗粒中的结块,并保持颗粒的结构。另外,可以将柄的长度延长,以便末端12的切碎元件10与筒的出口平齐,或者伸出更远,达1至60mm,优选约为1至30mm,这样可进一步促进分散颗粒的形成。而且,这种TSWGC 1包括一个任选的防护装置和斜槽12,如附图3A和3B所示,以协助维持进一步处理湿颗粒的通道,以及一个任选的用于接受抛弃废料的卸料箱17。
如附图3A和3B的示例TSWGC 1所示,TSWGC 1包括一个减压排气口11、一个留置密封物13和一个使双螺杆旋转的组合动力马达和齿轮减速元件15。与常规双螺杆挤压机不同,本发明的TSWGC在其输出端不包括模板。而且,外壳19在双螺杆挤压机的输出端是开放的,而且制粒产品可由此处自由地送出。
控制此湿颗粒处理变量,例如挤压机筒温度曲线、螺杆速度、螺杆设计和加入不同混合成分的速率,以适应各种下游需要(变量),例如颗粒堆积密度、水分含量、活性组分分布的均匀性、产品溶解度、混合程度、温度以及混合、制粒和切碎后任意阶段产品原料的存量。尤其是,在线监测干燥颗粒含水量和活性组分分布的均匀性,以获得最佳的产品组合物。另外,此控制系统可包括报警或警告信号,以显示各种处理参数或事件,例如错误条件系统过载或不可接受的产品特征。
一旦从TSWGC中出来,即用一个装载/平整设备在干燥带上将湿颗粒堆积并平整(附图1中7.6阶段)至适宜的高度和厚度。然后用此装载/平整设备将颗粒传送至干燥阶段(附图1的7.7),进行干燥,优选是由介电能例如RF或微波能诱导的干燥。任选的是,在将此湿颗粒传送至干燥器之前,可在湿碾磨机中对其进行进一步处理(附图1的7.5阶段)。也可用其它方法和设备对此颗粒进行干燥,例如搅拌、流化床或应用真空或不用真空的红外线干燥。
如附图5和6所示,干燥阶段7.7可包括一种RF发生器22,它在两个电极24之间产生一种交流电场。按照国际ISM(工业、科学、医学)标准,对于RF源,其所用频率为27.12MHz和40.56MHz。用于微波干燥器的频率是915MHz和2450MHz作为低频,毫米波条件下的几千兆赫作为高频。在电极之间传送将要干燥的原料。这种设计可使单程连续的干燥系统成为可能。
从干燥带上除去干燥颗粒,将其传送至一个在线碾磨机,例如锥形碾磨机中(附图1的7.9阶段),经过另一个设备/传送机械,将此颗粒碾磨为药用剂型中典型使用的大小。根据产品原料的反应性,此过程可在氮气或其它惰性气体下进行。从干燥碾磨机中出来后,在将干燥颗粒压成片剂或将它们装入硬胶囊中之前,任选将它们与其它常用的赋形剂混合。
如附图5和6所示,干燥设备20应用RF能,它加入一个RF发生器22,此发生器在两个电极24之间产生一种交流电场。这两个电极24位于设备20的相对侧。将被干燥的原料在干燥设备20的入口端进入此设备,并用一个马达44驱动的干燥带28进行传送。一个装载/平整设备将干燥带28上的湿颗粒原料整平至需要的高度。平整设备产生一层颗粒原料,此原料与干燥带28一起以预定的速度通过干燥区。一种干燥带清理机械48可连续地清理干燥带28。
在颗粒进入配置有电极24的干燥设备20部分的同时,电极24产生的交流电场对这些将被干燥的原料起作用,将此原料加热。可插入一个任选的内部通道46,以便在不妨碍RF能分布的情况下进一步隔离产品。电极24与接地电极25一起用以产生电场。用一种特殊的方式安排电极24,对颗粒层进行可控地加热。可使用不同的电极结构,例如平行板电极(如附图5所示)、交错棒电极等。可根据干燥特定原料的能量需要增加电极的数量。
在电极24之间的交流电场的影响下,由水分子恒定的再定位所产生的摩擦力,导致原料中的水分快速升温,并蒸发。在颗粒产品在传送带上传送的同时,用同向(相同方向)或反向(相反方向)流动的处理气体,将水蒸气从传送带28表面的顶部和/或底部除去。这种处理气流通过传送加热的调节气流34和冷却的调节气流36产生。带有调节器40的冷却系统38,通过调节围绕RF发生器22流动的循环气流42的温度来调节RF发生器22的温度。控制器40也可控制其它参数和其它条件,以优化颗粒产品的干燥。在入口26和输出端30的衰减器32可防止射线从通道20中泄漏。
因此,当需要干燥的原料(颗粒层)通过干燥设备/通道时,原料的水分含量逐渐下降。将原料保持在较窄的温度范围中可使水分得到最大程度的排除。
在干燥过程中,可将颗粒层保持在一个可通过产品的性质测定的温度范围中,通常是在大约30°的范围内,例如约75℃至105℃。而且,应用RF能,在如室温一样低的温度下理论上可能获得所需要的水分的排除。如果需制粒的活性组分和赋形剂容许,也可应用105℃以上的温度。根据所需的入口/出口的水分水平、产品的性质和需要的产品产量,典型的在通道中的停留时间可为几分钟至几小时。
通过介电能的频率、电极上应用的电压平方、将要干燥原料的面积和将要干燥原料的介质损耗因素(此代表可用这种方法将原料加热的容易程度)测定RF干燥设备中产生的热量。介电加热在性质上是容积性的。由于给定了极性,当置于本发明的干燥设备中时,水被选择性地和容积性地加热。这种选择性和容积性加热与常规加热/干燥系统相比,增加了热传递的速率,并缩短了在干燥设备中的停留时间,这样可更好地保护在升高的温度下可降解的原料。水的选择性加热和水分在原地蒸发大大地消除了干燥原料中温度和水分的变化,由此可提高产品质量和/或进一步改善干燥原料的处理。
将介电能(即RF或微波能)用于干燥,可避免为了要把原料充分干燥而将欲干燥的原料多次通过干燥区。
用传送带28将干燥原料通过干燥设备20的输出端30传送出干燥设备20。从干燥设备20出来后,传送干燥原料,并用一种碾磨设备将其进一步处理为适宜压成片剂或装入硬胶囊或小药囊中的粒径。
本发明也包括一种用于连续生产一种高剂量(活性组分强度大于200mg)药用颗粒的自动、单程系统,该系统包含一种方法和设备,这种密度较低(例如此掺合物的堆积密度约为0.2g/ml或更低)的活性组分/赋形剂掺合物的颗粒,可以被进一步处理以形成固体口服剂型。
此系统包括一种双螺杆湿制粒机-切碎机(TSWGC),它适于将低密度组分/赋形剂掺合物制粒为一种适于加工成一种高剂量产品的形式。因此,当将这些组件产生的颗粒加入一种药用产品时,该颗粒具有优良的特性。如上所述,当片剂是由本发明的颗粒生产的时,该片剂每日典型的给药数量可明显地减小,通常可减小40-60%左右。该系统可与基于介电能的干燥设备联合应用,或者,可替代地,可与常规应用的组件分开应用,这些常规组件例如为流化床或连续桨式干燥器。
在申请人的发明之前,没有商业上可行的用于生产一种高强度剂型的奈菲那维甲磺酸盐的技术或系统。因为双螺杆湿制粒切碎机所产生的混合和剪切程度远高于常规湿制粒设备所产生的混合和剪切程度,由此大大地增加了颗粒的密度,所以申请人用于高剂量产品生产的双螺杆湿颗粒技术的开发是可能的。因此,含有例如奈菲那维甲磺酸盐的低密度活性组分的粉末,当进入本发明的TSWGC时,其密度可约为0.2g/mL,而当其成为颗粒从TSWGC中出来时,其密度变成约0.5g/mL或更大。
这种TSWGC克服了常规湿制粒设备的局限性。这种TSWGC包括传送、混合、制粒和切碎元件,以完成分布,并且当需要时,可完成分散的混合。可改变这种螺杆元件的设计和排列,以处理不同堆积密度的活性组分和添加剂,从而生产一种均匀的颗粒产品。此TSWGC提供产品致密性和均匀性的能力超过高剪切制粒机。
为了生产一种用于高剂量产品的颗粒,温度可以在约25℃至50℃之间变化,典型地为约25℃。但是,含有一种例如奈菲那维甲磺酸盐的低密度活性组分,当温度约为50℃时,在此系统中产生的颗粒更大更硬。但是,温度的变化并不影响颗粒的整体溶解性能。
可调节湿制粒方法的变量。已发现通过调节参数,可生产一种低密度活性组分(即奈菲那维甲磺酸盐)的一种高剂量产品,由此减少必须每日给药的片剂总数量。在这个发现之前,商业上没有可行的技术或系统用于生产奈菲那维甲磺酸盐的高强度剂型。因为双螺杆湿制粒切碎机所产生的混合和剪切程度远高于常规湿制粒设备所产生的混合和剪切程度,由此大大地增加了颗粒活性组分的密度,所以申请人用于高剂量产品生产的双螺杆湿颗粒技术的开发是可能的。
除了例如奈菲那维甲磺酸盐的低密度活性组分外,可配制为固体剂型的任何适宜活性组分均可应用本发明的方法、设备和系统。但是,上面描述的参数是特别用于一种低密度活性组分的一种高强度颗粒的生产的,尤其是用于奈菲那维甲磺酸盐。治疗的适应症和特殊的活性组分的实例列举如下:
1、解热剂、止痛剂和抗炎剂,例如消炎痛、阿斯匹林、双氯酚酸钠、酮洛芬、布洛芬、甲芬那酸、地塞米松、氢化可的松、泼尼松龙、对乙酰氨基酚、保泰松、氟芬那酸、水杨酸钠、盐酸曲马多片、奥沙普秦、和依托度酸。
2、抗溃疡剂,例如奥美拉唑、西咪替丁、兰索拉唑、尼扎替丁胶囊USP、盐酸雷尼替丁、法莫替丁、和尼扎替丁。
3、冠状血管舒张剂,例如硝苯地平、硝酸异山梨酯、盐酸地尔硫、双嘧达莫、单硝酸异山梨酯、维拉帕米、尼卡地平、硝苯地平、和硝酸甘油片。
4、周围血管舒张剂,例如柠檬酸sildenafil、马来酸桂哌齐特、环扁桃酯、和己酮可可碱。
5、抗生素,例如氨苄西林、阿莫西林、头孢氨苄、克拉霉素片、头孢呋辛酯片、cefropzil、琥乙红霉素、盐酸巴氨西林、盐酸米诺环素、氯霉素、四环素、和红霉素。
6、合成抗菌剂,例如萘啶酸、依诺沙星、西诺沙星、左氧氟沙星片、氧氟沙星、诺氟沙星、盐酸环丙沙星、和磺胺甲噁唑-甲氧苄啶。
7、解痉剂,例如溴丙胺太林、硫酸阿托品、和东莨菪碱。
8、镇咳剂和止喘剂,例如茶碱、氨茶碱、磷酸可待因、右美沙芬氢溴化物、盐酸麻黄碱、和那可汀。
9、支气管扩张药,例如硫酸沙丁胺醇、盐酸吡布特罗、双甲苯喘定甲磺酸盐、盐酸克仑特罗、硫酸特布他林、盐酸马布特罗、非诺特罗溴化物、和盐酸甲氧苯丙胺。
10、利尿药,例如呋塞米、乙酰唑胺、三氯噻嗪、环噻嗪、氢氯噻嗪、氢氟噻嗪、螺内酯、和氨苯蝶啶。
11、肌肉松弛剂,例如盐酸托哌酮、盐酸乙哌立松、盐酸替扎尼定、美芬新、氯唑沙宗、苯丙醇氨酯、美索巴莫、巴氯芬、和丹曲林钠。
12、大脑代谢促进剂,例如盐酸甲氯芬酯。
13、安定剂,例如奥沙唑仑、地西泮、替马西泮、甲丙氨酯、硝西泮、和氯氮、舒必利、盐酸氯卡帕明、左替平、氯丙嗪、和卤哌地特。
14、β-阻滞剂,例如吲哚洛尔、盐酸普萘洛尔、酒石酸美托洛尔、盐酸拉贝洛尔、盐酸氧烯洛尔、盐酸醋丁洛尔、琥珀酸美托洛尔、盐酸布非洛尔、盐酸阿普洛尔、和纳多洛尔。
15、抗心律失常剂,例如盐酸普鲁卡因胺、丙吡胺、硫酸奎尼丁、盐酸普罗帕酮、和盐酸美西律。
16、抗痛风剂,例如别嘌呤醇、丙磺舒、秋水仙碱、丙酮苄羟香豆素钠片USP和磺吡酮。
17、抗凝剂,例如盐酸噻氯匹定、双香豆素和丙酮苄羟香豆素钾。
18、抗癫痫剂,例如加巴喷丁胶囊、gaphenytoin、双丙戊酸钠、丙戊酸钠和甲巴比妥。
19、抗组胺药,例如氯雷他定、盐酸西替利嗪、马来酸氯苯吡胺、盐酸fexofenade、延胡索酸氯马斯汀、和盐酸赛庚啶。
20、止吐药,例如盐酸地芬尼多、甲氧氯普胺、和马来酸曲美布汀。
21、抗高血压剂,例如甲基多巴、盐酸哌唑嗪、盐酸布那唑嗪、盐酸可乐定、布屈嗪、延胡索酸比索洛尔、和氢氯噻嗪、盐酸特拉唑嗪、和乌拉地尔。
22、拟交感神经药,例如甲磺双氢麦角胺、盐酸异丙肾上腺素、和盐酸依替福林。
23、祛痰药,例如盐酸溴己新、羧甲司坦、和盐酸半胱氨酸甲酯。
24、口服抗糖尿病剂,例如格列苯脲、glumepiride片、格列吡嗪、盐酸二甲双胍片、曲格列酮、甲苯磺丁脲、和格列嘧啶钠。
25、铁制剂,例如硫酸亚铁和干燥的硫酸亚铁。
26、维生素类,例如维生素B12、维生素B6、维生素C、和叶酸。
27、尿频治疗剂,例如盐酸黄酮哌酯、盐酸奥西布宁、和盐酸特罗地林。
28、血管紧张素转化酶抑制剂,例如马来酸依那普利、依那普利垃USP、福辛普利钠片、阿拉普利、赖诺普利、盐酸喹那普利片、雷米普利、和盐酸地拉普利。
29、其它类型活性组分,例如醋磺己脲、阿义马林、阿仑膦酸钠、氨氯地平苯磺酸盐、异戊巴比妥、阿托伐他汀钙、苄氟噻嗪、苯溴马隆、苯佐那酯、苯甲酸苄酯、倍他米松(betametharzone),商标盐酸帕罗西汀、盐酸安非他酮、盐酸丁螺环酮USP、氯霉素、氯磺丙脲、氯噻酮、氯贝丁酯、共轭雌激素片USP、皮质类固醇、安定、双香豆素、洋地黄毒甙、地高辛、双羟丙茶碱、盐酸地尔硫、多沙唑嗪甲磺酰酯、麦角生物碱、乙苯妥英、非洛地平、盐酸氟西汀、氟康唑、氟伐他汀钠、呋塞米、格鲁米特、灰黄霉素、双氢克尿噻、氢化可的松、氢氟噻嗪、对苯二酚、羟烷基黄嘌呤、消炎痛、盐酸苯氧丙酚胺、酮洛芬、凯林、左甲状腺素钠USP、氯沙坦钾片、洛伐他汀USP、甲丙氨酯、大麻隆、奈菲那维甲磺酸盐、盐酸奈法唑酮、烟酰胺、心痛定、呋喃妥因、安乃近、制霉菌素、罂粟碱、对乙酰氨基酚、保泰松、苯巴比妥、帕伐他汀(pravastin)钠、强的松龙、强的松、primadonel利血平、利培酮、romglizone、水杨酸、沙美特罗xinafoate、盐酸舍曲林、辛伐他汀、安体舒通、磺胺苯酰、sulphadiamadine、磺胺对甲氧嘧啶、磺胺甲基嘧啶、琥珀磺胺噻唑、磺胺甲噻二唑、磺胺甲基异噁唑、磺胺噻唑、磺胺异噁唑、琥珀酸舒马曲坦、睾酮、托拉佐林、甲苯磺丁脲、三氟吡啦嗪、甲氧苄啶、缬沙坦胶囊、酒石酸唑吡坦和其它水不溶性活性组分。
可在本发明中应用的赋形剂(聚合物、小分子、以及有机和无机化合物)可为任意的、可在药物产品的生产中用作原料的天然或合成物质。这些赋形剂的实例包括:羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、羧甲基乙基纤维素、纤维素乙酸邻苯二甲酸酯、丙烯酸树脂丙烯酸共聚物、异丁烯酸共聚物LD、异丁烯酸共聚物S、氨烷基异丁烯酸共聚物E、聚(乙烯基乙缩醛)二乙氨基乙酸酯、聚乙烯吡咯烷酮、乙基纤维素、异丁烯酸共聚物RS、聚乙烯醇、高分子量聚乙二醇、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、糊精、普鲁兰、阿拉伯胶、黄芪胶、藻酸钠、丙二醇藻酸酯、琼脂粉末、明胶、淀粉、加工淀粉、磷脂(例如卵磷脂)、葡甘露聚糖、十六烷醇、中链甘油三酯、聚氧乙烯一聚氧化丙二醇(Pluronic)、聚乙二醇(200、300、400、600、1000、1500、1540、4000、6000、20000)、聚乙二醇(例如PEG 200、PEG 300、PEG 400和PEG 600)、甘油三乙酸酯和柠檬酸三乙酯(Citroflex)、吐温20、60和80、Span 20、Span 40、Pluronics、聚氧乙烯山梨醇酯、甘油单酯、聚氧乙烯酸、聚氧乙烯醇及其混合物、碳酸钙、磷酸二钙二水合物、硫酸钙、微晶纤维素、乳糖、碳酸镁、氧化镁、麦芽糖糊精、甘露醇、蔗糖、可压缩糖、交联羧甲纤维素、交聚维酮、羟基乙酸淀粉钠、预胶化淀粉、瓜耳树胶、藻酸、抗坏血酸、柠檬酸、环糊精、dextrates、胶态二氧化硅、苯甲酸钠、碳酸氢钠和滑石。
可单独使用这些赋形剂,或者如果需要,可联合应用两种或多种类型的赋形剂。在其它的条件中,处理参数,例如压力、温度、原料的进料速度、本发明生产过程中所用的水和其它赋形剂的量和进料速度,根据活性组分的类型和赋形剂而定。而且,必须设定本系统操作参数的组合,以便将活性组分和赋形剂的温度保持在它们的分解点之下,并且获得所需要的药物产品的特性。
下面的实施例将举例说明本发明的某些方面。在下面的实施例中,通过生产一种含有所研究药物产品的片剂来评价连续湿制粒、干燥和碾磨,这种研究的药物产品应用了本发明的TSWGC,尤其是应用了共旋转TSWGC,如附图2所示。在实施例2中,应用介电能,尤其是应用射频能(如附图5和6所示),在一种干燥设备/通道中干燥通过TSWGC生产的颗粒(应用常规方法干燥实施例1中生产的颗粒)。在下面的实施例中,通过生产一种含有奈菲那维甲磺酸盐的颗粒来评价连续湿制粒、干燥和碾磨,这种颗粒应用了本发明的TSWGC,尤其是应用了共旋转TSWGC。实施例3和4举例说明由一种低密度活性组分生产一种高剂量产品。这些实施例仅仅是为了举例说明,并不是要限制本发明的范围。
实施例1所研究的300-mg片剂的生产
通过在一种16qt(夸脱)V型混合器中混合称重的各组分而制备所研究药物和赋形剂的一种预掺合物。从一种失重型固体进料器中将这种干燥组分的掺合物进料至TSWGC中,此TSWGC带有一种侧填充机构。调节进料器,使进料速率为11.4kg/小时。把含有一种表面活性剂的水溶液用作制粒液体,并用一种活塞泵以8.64kg/小时的速率将其注射至TSWGC中。这种产品所用此液体的总量为6.8升。将TSWGC的温度保持在26℃,并将螺杆速度保持在177rpm,最大扭力为19%。
通过TSWGC制备此颗粒,产量为18.2kg/小时。在一种盘架干燥器中,在50℃下将此颗粒干燥9小时,使水分水平由13.6%变为1.0%。
在一种锤磨机中碾磨这种干燥颗粒,并在一个V型混合器中将碾磨的颗粒产品与列举的外赋形剂混合,从而制备最终的掺合物产品。将填充物和崩解剂加入碾磨的颗粒产品,并以20rpm将其混合10分钟。然后,将润滑剂加入所得产品,并以20rpm将其再混合5分钟。
用一种六边压片机进行压片。应用标准凹形椭圆形工具对最终的掺合物进行压片,尺寸为0.645″×0.3295″×0.0465″,压片速率为30rpm。在所用力的范围,通过对此掺合物压片产生一种压片的数据图(如表1所示)。
所研究药物制剂的物理试验结果也概括在表1中:(1)此制剂表现出良好的压缩性和崩解性,片剂核心在6分钟内崩解;以及(2)溶解试验的结果(表1中未显示)表明所研究药物在20分钟之内从完全单个片剂中全部释放。
表1研究药物的片剂-物理试验
压缩力 硬度 崩解性 脆性(%)
(kN/kg) (kPa) (分钟) (n=20)
(n=10) (n=3) 时间=10分钟5.16/526.3 9.1±0.5 2.0 0.887.17/731.3 14.2±0.8 3.0 0.358.07/823.1 16.3±0.9 3.7 0.329.27/945.5 19.3±1.3 4.7 0.1811.77/1200.5 24.2±1.4 5.3 0.18
实施例2所研究的600-mg片剂(较高强度)的生产
通过在一个42升的仓式混合器中,将称重的各组分以25rpm混合20分钟,制备一种研究药物和赋形剂的预掺合物,所研究药物的强度高于实施例1的。然后通过一个侧填充进料机构将粉末掺合物引入本发明的TSWGC(如附图2-4所示)。三对混合元件与大小不同的传送元件联合应用。
从一个失重型固体进料器将干燥组分进行进料,此进料器具有一个侧填充机械,它与可容纳固体组分的料斗连接。应用一个垂直搅拌机,混合料斗的内容物。粉末进料的进料速率为10.5kg/小时。把含有一种表面活性剂的水溶液用作制粒液体,并用一种活塞泵以3.2kg/小时的速率将其注射至TSWGC中。这种产品所用此液体的总量为2.5升。将TSWGC的温度保持在26℃,并将螺杆速度保持在200rpm,最大扭力为35%。通过TSWGC制备这种颗粒,产量为14.5-15.1kg/小时。在一种干燥通道中,应用射频能干燥此颗粒,使水分水平由22.9%变为低于2.0%。将颗粒放置在24英寸的宽传送带上。颗粒层为22英寸宽,1英寸深,传送带的速度为0.26英尺/分钟。
在一种锤磨机中碾磨这种干燥颗粒,并在一个V型混合器中将碾磨的颗粒产品与外赋形剂混合,从而制备最终的掺合物产品。将填充物和崩解剂加入碾磨的颗粒产品,并以20rpm将其混合10分钟。然后,将润滑剂加入所得产品,并以20rpm将其再混合5分钟。
用一种六边压片机进行压片。应用标准凹形椭圆形工具对最终的掺合物进行压片,尺寸为0.7″×0.355″×0.07″,压片速率为30rpm。在所用力的范围内,对此掺合物压片而产生一种压片数据图表。
所研究的高强度药物制剂的物理试验结果也概括在表2中:(1)此制剂表现出良好的压缩性和崩解性,片剂核心在7分钟内崩解;以及(2)溶解试验的结果表明药物在20分钟之内从在整个硬度范围内所压制的片剂中完全释放。
表2高强度所研究药物的片剂-物理试验
压缩力 硬度 崩解性 脆性(%)(n=20)
(kN/kg) (kPa)(n=10) (分钟)(n=3) 时间=10分钟4.66/475.5 8.5±0.9 4.2 2.766.03/614.7 12.0±0.9 5.5 1.386.58/671.0 13.7±1.1 5.3 0.828.54/870.8 18.9±1.2 6.0 0.399.93/1012.5 22.3±1.7 6.9 0.49
实施例3奈菲那维甲磺酸盐颗粒和高剂量片剂的生产A.预掺合
在一个双壳混合器中进行预混合单元的操作。将每部分的奈菲那维甲磺酸盐和硅酸钙混合15分钟。每种原料的密度为0.1至0.15g/cc。然后将预掺合物卸进衬里为聚乙烯袋的纤维圆筒中。B.双螺杆湿制粒
将低密度预掺合物进料至双螺杆湿制粒机(改进的34mmLeistritz),经过侧填充器单元进入第二筒。此制粒机设定为350rpm,侧填充器设定为207rpm。干燥的预掺合物的进料速率为3.0至3.2kg/小时。液体的注射速率为16至25mL/分钟。在第一个筒中进行交换气体的通气。将液体注射入第二个和第三个筒中。随着原料通过此制粒系统被进一步处理,这些元件的螺距减小,因而减小其容积。观察到高密度湿颗粒的产量为3.9至4.2kg/小时。然后在一个流化床中干燥这种颗粒。应用所得的这种颗粒制备一种高剂量片剂。应用本领域中熟知的设备和技术进行压片。
尽管对本发明的特殊实施方式进行了描述,但这并不是要将其限制于此。在通常的情况下,本发明包括一种用于生产药物颗粒的双螺杆制粒机-切碎机和/或射频或微波干燥器,以及一种单程的连续系统,此系统与制粒机-切碎机、干燥器或者两者结合,用于生产这种产品。提供的实施例是举例说明由一种低密度活性组分生产一种高剂量产品。并不是将本发明限制在这些实施例中。相反,在不背离本发明的精神和范围的情况下,可对本发明的细节,以及所描述和例证的各种实施方式进行不同的修改。下面的权利要求应当作相应的理解。
Claims (41)
1、一种生产药物颗粒的单程连续处理系统,包括:
(a)粉末和液体进料器,以提供至少一种药物活性组分和添加剂;
(b)一种双螺杆湿制粒机-切碎机设备,用于将从粉末和液体进料器收到的活性组分和添加剂制粒为一种湿颗粒产品,所述双螺杆湿制粒机-切碎机包括一种包绕所述设备的外壳,所述外壳包括一个位于出口的非挤压开口;
(c)传送、装载和整平装置,用于传送从所述双螺杆湿制粒机-切碎机的出口出来的湿颗粒,将此湿颗粒装载在一个干燥带上,并将此湿颗粒整平至所要的高度;
(d)一种干燥装置,用于接受来自干燥带的湿颗粒,并使用介电能干燥这种湿颗粒;
(e)传送装置,用于传送干燥颗粒,这些干燥颗粒来自用于减少大小的干燥通道;
(f)一种碾磨机,用于将干燥颗粒减小为一种所需大小的颗粒;以及
(g)控制装置,用于对粉末和液体进料器、双螺杆湿制粒机-切碎机、传送、装载和整平装置、干燥装置、传送装置、以及碾磨机中的至少一种的处理变量进行控制,以优化药物颗粒的生产。
2、权利要求1的系统,其中粉末通过一种侧填充器单元进料,而液体进料至一种液体注射器中,用于加入双螺杆湿制粒机-切碎机中。
3、权利要求1的系统,其中双螺杆湿制粒机-切碎机包括一种将此颗粒切碎为分散的颗粒的机械。
4、权利要求1的系统,其中传送元件的螺距沿着传送元件的长度而逐渐减小。
5、权利要求1的系统,其中粉末在同一位置进料至此设备中,其中至少一部分液体注射至此设备中。
6、权利要求1的系统,其中控制装置包括用于监测本系统条件和对粉末和液体进料器、双螺杆湿制粒机-切碎机、传送、装载和整平装置、干燥装置、传送装置、以及碾磨机中的至少一种的处理变量进行控制的装置。
7、权利要求6的系统,其中颗粒的水分含量被在线监测,而且控制液体进料器以调节水分含量。
8、权利要求6的系统,其中对活性组分分布的均匀性进行在线监测,并对粉末和液体进料器、双螺杆湿制粒机-切碎机、传送、装载和整平装置、干燥装置、传送装置、以及碾磨机中的至少一种进行控制,以调节分布的均匀性。
9、权利要求1的系统,其中双螺杆湿制粒机-切碎机包括具有相互连接的螺纹以适应同向或反向旋转和活性组分及添加剂的制粒的两个或多个螺杆。
10、权利要求1的系统,在步骤(b)后还包括将这种湿颗粒碾磨成所需大小的颗粒的步骤。
11、一种生产可压缩的药物颗粒的方法,此药物颗粒是通过将至少一种药物活性组分与赋形剂、粘合剂和液体混合,形成一种湿混合物,将所述湿混合物切碎为一种湿颗粒,并干燥所述湿颗粒而生产的,其中的改进包括:
通过在沿着其长度的预定位置,将至少一种药物活性组分、赋形剂、粘合剂和液体进料至所述制粒机-切碎机中,在一种双螺杆湿制粒机-切碎机中形成所述湿颗粒;在所述制粒机-切碎机的一个末端连续地不进行挤压地除去所述颗粒;以及干燥所述颗粒。
12、权利要求11的方法,其中螺杆的螺距逐渐减小。
13、权利要求11的方法,其中通过所述制粒机-切碎机双螺杆的旋转对所述湿混合物进行制粒,所述螺杆具有相互连接的螺纹,以适应同向或反向旋转以及将所述混合物进行制粒。
14、权利要求13的方法,其中通过所述螺杆的无螺纹区将所述湿混合物进行制粒,并切碎所述制粒的混合物,以形成分散的颗粒。
15、权利要求14的方法,其中无螺纹区包括揉合盘、梳式混合器、齿轮混合器、针式混合器和压延缝隙混合器中的至少一种。
16、一种生产可压缩药物颗粒的方法,此药物颗粒是通过将一种药物活性化合物与赋形剂、粘合剂和液体混合,形成一种湿混合物,然后将此湿化合物制粒并干燥而生产的,其中的改进包括:以一个单程连续的方式,应用介电能干燥所述颗粒。
17、权利要求16的方法,其中在一个干燥装置中,应用射频(RF)、低频微波或高频微波能干燥所述颗粒,所述干燥装置具有一种梯度,随着所述颗粒沿所述干燥装置移动,所述颗粒中的水分含量逐渐下降。
18、权利要求1 7的方法,其中通过一种交流电场干燥所述颗粒,此交流电场是由一种RF能发生器产生的。
19、一种干燥药物颗粒的装置,包括:
传送带,用于接受和传送待干燥的颗粒;
用于接受此颗粒的干燥通道,所述通道含有一种介电能源和电极,以产生加热此颗粒的交流电场;
热和冷空气源;
用于控制通道中热和冷空气的流动的气流控制机械,此气流控制机械除去通道中的水分;以及
用于控制通道中的能量和气流的控制装置。
20、权利要求19的装置,其中介电能为射频能。
21、权利要求19的装置,其中介电能为低频或高频微波能。
22、权利要求19的装置,其中通道中热和冷空气的气流方向与干燥带上所传送颗粒的方向是同向或反向的。
23、一种用于活性组分和添加剂制粒的双螺杆湿制粒机-切碎机,包括:
外壳,包括固体和液体的进料点,此固体和液体至少含有一种活性组分和添加剂;
在外壳内的双螺杆,这些螺杆具有相互连接的螺纹,以适应同向或反向的旋转;
驱动双螺杆的马达,以将固体和液体混合为一种颗粒;
一个卸载此颗粒的开口端;以及
将颗粒切碎为分散颗粒的装置。
24、权利要求23的双螺杆湿制粒机-切碎机,它还包括反螺纹和无螺纹区中的一种或两种,以对固体和液体进行制粒。
25、权利要求23的双螺杆湿制粒机-切碎机,它还包括揉合盘、梳式混合器、齿轮混合器、针式混合器和压延缝隙混合器中的至少一种,以对固体和液体进行制粒。
26、权利要求23的双螺杆湿制粒机-切碎机,其中切碎装置与双螺杆湿制粒机-切碎机的开口端平齐,或者超出其开口端。
27、一种生产高剂量药物颗粒的连续处理系统,包括:
双螺杆湿制粒机-切碎机;
粉末进料器,它适于将一种粉末进料至所述双螺杆湿制粒机-切碎机中,所述粉末包含一种药物活性组分;
第一液体进料器,它适于将液体进料至所述双螺杆湿制粒机-切碎机中;
其中所述粉末进料器和所述液体进料器连接在所述双螺杆湿制粒机-切碎机上,并适于所述粉末和所述液体在所述双螺杆湿制粒机-切碎机的一个入口进料;以及
其中所述粉末和所述液体经由从所述双螺杆湿制粒机-切碎机的所述入口至其一个出口通过所述双螺杆湿制粒机-切碎机;
所述双螺杆湿制粒机-切碎机包括:
a)第一传送元件,它具有至少一个传送元件螺距;
b)第二传送元件,它具有至少一个传送元件螺距,并被定位以在所述第一传送元件之后与所述药物活性组分接触,其中所述第二传送元件的至少一个螺距小于所述第一传送元件的至少一个螺距;
c)第一混合元件,它位于所述第一和所述第二传送元件之间;
d)至少一个切碎元件,它被定位使其在所述第二传送元件之后与所述药物活性组分接触;以及
包绕这些元件的外壳,所述外壳确定了所述入口和一个位于所述出口上的非挤压开口。
28、权利要求27的连续处理系统,它还包括:
第三传送元件,它具有至少一个传送元件螺距,所述第三传送元件被定位以在所述第二传送元件之后和所述切碎元件之前与所述药物活性组分接触,其中所述第三传送元件的至少一个螺距小于所述第二传送元件的至少一个螺距;以及
第二混合元件,它位于所述第二和所述第三传送元件之间。
29、权利要求27的连续处理系统,它还包括一个第二液体进料器。
30、权利要求27的连续处理系统,其中所述粉末进料器和所述第一液体进料器连接在所述双螺杆湿制粒机-切碎机上的位置都是所述第一传送元件位于所述外壳中的位置。
31、权利要求30的连续处理系统,其中所述第二液体进料器连接在所述双螺杆湿制粒机-切碎机上的位置位于所述第一传送元件和所述第一混合元件处于所述外壳中的位置。
32、权利要求27的连续处理系统,其中所述活性药物组分包括奈菲那维甲磺酸盐。
33、权利要求33的连续处理系统,其中所述粉末还包括硅酸钙。
34、权利要求34的连续处理系统,其中奈菲那维甲磺酸盐与硅酸钙的比例在3∶1至5∶1之间。
35、权利要求34的连续处理系统,其中奈菲那维甲磺酸盐与硅酸钙的比例为4∶1。
36、权利要求27的连续处理系统,其中所述液体包括水。
37、权利要求27的连续处理系统,其中所述第一混合元件紧贴着所述第一传送元件和所述第二传送元件。
38、一种用于生产高剂量药物颗粒的方法,它包括:
(a)将一种包含药物活性组分的粉末进料至所述双螺杆湿制粒机-切碎机中,所述粉末的密度小于0.2g/mL;
(b)将液体进料至所述双螺杆湿制粒机-切碎机中;
(c)将所述液体和所述粉末与所述双螺杆湿制粒机-切碎机的第一传送元件接触,所述第一传送元件具有至少一个螺距;
(d)将所述液体和所述粉末与所述双螺杆湿制粒机-切碎机的第一混合元件接触,以形成一个湿团块;
(e)将所述湿团块与所述双螺杆湿制粒机-切碎机的第二传送元件接触,所述第二传送元件具有至少一个螺距,其中所述第二传送元件的至少一个螺距小于所述第一传送元件的至少一个螺距;以及
(f)将所述湿团块与所述双螺杆湿制粒机-切碎机的一个切碎元件接触,并将所述湿团块切成颗粒。
39、权利要求42的方法,还包括下列步骤:
(a)将所述湿团块与所述双螺杆湿制粒机-切碎机的第三传送元件接触,所述第三传送元件具有至少一个螺距,其中所述第三传送元件的至少一个螺距小于所述第二传送元件的至少一个螺距;以及
(b)将所述湿颗粒与第二混合元件接触;其中所述湿团块与所述第三传送元件接触的步骤,以及所述湿颗粒与所述第二混合元件接触的步骤,是在所述湿团块与所述第二传送元件接触的步骤之后,并在所述湿团块与所述切碎元件接触的步骤之前进行。
40、权利要求42的方法,其中所述双螺杆湿制粒机-切碎机的温度保持在15℃至90℃之间。
41、一种药物制剂,含有按照权利要求11的方法生产的药物颗粒。
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CN101668583B (zh) * | 2007-02-27 | 2013-06-05 | Gea制药系统公司 | 包括测量单元的连续成粒及干燥设备和连续成粒及干燥方法 |
CN102014846A (zh) * | 2008-04-30 | 2011-04-13 | 诺瓦提斯公司 | 制备药物组合物的连续方法 |
CN104274318A (zh) * | 2014-09-23 | 2015-01-14 | 苏州仁捷瑞自动化科技有限公司 | 一种医用薄板整平机 |
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CN106860009A (zh) * | 2015-02-14 | 2017-06-20 | 充爱军 | 安全高效的中药配制车 |
CN109310960A (zh) * | 2016-04-22 | 2019-02-05 | 斯提尔生命印度私人有限公司 | 对粉末进行造粒的加工机及工艺 |
CN109310960B (zh) * | 2016-04-22 | 2022-02-22 | 斯提尔生命印度私人有限公司 | 分数叶式加工机及造粒方法 |
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CN111194211A (zh) * | 2017-08-31 | 2020-05-22 | 诺华股份有限公司 | 用于制备颗粒剂的方法 |
CN108421497A (zh) * | 2018-04-03 | 2018-08-21 | 杨高品 | 药物连续化制粒的生产工艺和设备 |
CN110926118A (zh) * | 2018-09-20 | 2020-03-27 | 天津金耀集团有限公司 | 一种通过微波的甾体类化合物固体物料的干燥方法 |
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CN110926117A (zh) * | 2018-09-20 | 2020-03-27 | 天津金耀集团有限公司 | 一种孕甾类化合物固体物料的干燥方法 |
CN110051685A (zh) * | 2019-03-13 | 2019-07-26 | 安庆瑄宇医药科技有限公司 | 一种维达列汀降糖咀嚼片及其制备方法 |
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EE200200651A (et) | 2004-06-15 |
MXPA02011556A (es) | 2003-04-25 |
CA2409777A1 (en) | 2001-11-29 |
NO20025592D0 (no) | 2002-11-21 |
AP2002002696A0 (en) | 2002-12-31 |
HUP0302312A2 (hu) | 2003-11-28 |
WO2001089679A3 (en) | 2003-07-31 |
NO20025592L (no) | 2003-01-22 |
NZ522722A (en) | 2004-06-25 |
SK16252002A3 (sk) | 2003-09-11 |
JP2004501679A (ja) | 2004-01-22 |
US20030090039A1 (en) | 2003-05-15 |
WO2001089679A2 (en) | 2001-11-29 |
AU2001261588A1 (en) | 2001-12-03 |
OA12266A (en) | 2004-03-18 |
US6499984B1 (en) | 2002-12-31 |
EA200201159A1 (ru) | 2003-06-26 |
IS6624A (is) | 2002-11-18 |
BG107297A (en) | 2003-06-30 |
ZA200209283B (en) | 2003-09-02 |
PL359532A1 (en) | 2004-08-23 |
HRP20021014A2 (en) | 2004-02-29 |
EA004777B1 (ru) | 2004-08-26 |
HUP0302312A3 (en) | 2005-03-29 |
CZ20023764A3 (cs) | 2003-06-18 |
BR0111001A (pt) | 2003-04-08 |
IL152991A0 (en) | 2003-06-24 |
KR20030011340A (ko) | 2003-02-07 |
EP1351760A2 (en) | 2003-10-15 |
MA26903A1 (fr) | 2004-12-20 |
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