CN105687167A - 用于递送生物活性剂的可挤出的和挤出的组合物、其制造方法及其使用方法 - Google Patents
用于递送生物活性剂的可挤出的和挤出的组合物、其制造方法及其使用方法 Download PDFInfo
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- CN105687167A CN105687167A CN201610204563.1A CN201610204563A CN105687167A CN 105687167 A CN105687167 A CN 105687167A CN 201610204563 A CN201610204563 A CN 201610204563A CN 105687167 A CN105687167 A CN 105687167A
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Abstract
一种非水性的、可挤压的组合物包含超过总组合物的20wt%的量的至少一种热塑性聚合物和烟草。一种薄片形式的挤出的生物活性产品可以通过将包含至少一种热塑性聚合物和生物活性剂的非水性组合物挤出或热熔成型而制成,该薄片可溶于使用者口中并导致生物活性剂控释给该使用者。该薄片可以为可与使用者的粘膜接触地放置的形式,并且具有5至50分钟的平均溶解时间来将生物活性剂递送给该使用者。
Description
本分案申请是基于申请号为200880118176.X,申请日为2009年4月16日,发明名称为“用于递送生物活性剂的可挤出的和挤出的组合物、其制造方法及其使用方法”的原始中国专利申请的分案申请。
技术领域
本发明涉及生物活性产品、可挤出的生物活性组合物、用于制造生物活性产品的方法以及用于将该产品中所含的生物活性剂递送给使用者的方法等。该生物活性剂可以是但不限于药物。
背景技术
固体药物剂型的历史是简单明了的。它从生物活性粉末开始,它们演变成压片。压片发展到胶囊和胶囊形片剂和最终的它们的变型,后者发展到液体核凝胶(liquidcoregel)等。控释片剂,例如由Zaffaroni博士在Alza开发的渗透泵体系,遵循并允许在胃肠道中的控释。接下来的进步是口腔溶解片(ODT),它已用于对具有常规片剂和胶囊吞咽困难的患者的容易的给药;以及ODT基口腔输送产品,例如Cephalon的—一种用于芬太尼的口腔给药的ODT体系。教导了制造这些ODT的各种新的方法,例如冻干快速溶解形式()、泡腾快速溶解体系(CIMA)和基于棉花糖基体的ODT(由本发明人发明,见例如4,855,326)。然后销售了次级ODT产品Copycat,它很大程度上基于使用低达因压力下的压片工艺,导致提出FDA规定来保证ODT产品真正快速溶解(见2007年4月的FDADraftGuidance,http://www.fda.gov/CDER/guidance/5909dft.htm)。
下一个发展是快速溶解薄膜(部分地由本发明人发明)。薄膜通常使用湿法流延制造工艺制造,并且的确是膜,因为它们仅可以最高达10密耳的最大厚度,通常认为当它们超过10密耳的厚度时,类似基体的产品变成“薄片”。湿法流延膜的制造和产品记载于本发明人发明的、最近授予的美国专利No.7,425,292:“膜可以最初具有约500μm至约1,500μm或约20密耳至约60密耳的厚度,并且干燥后具有约3μm至约250μm或约0.1密耳至约10密耳的厚度。可取的是,干燥的膜将具有约2密耳至约8密耳的厚度,更可取约3密耳至约6密耳的厚度”。另外参见美国专利No.5,948,430,其中公开了湿法流延薄膜组合物,并且指出“膜的厚度应当不超过2.7密耳,以防止不好的口感”。测量了市售的湿法流延药物膜产品的厚度,发现范围为3密耳—标明由MonoSolRx生产的GSK的BreathRightSnoreRelief;4密耳—标明由MonoSolRx生产的Fleet的番泻叶产品;和6密耳—据信由宾夕法尼亚GlenRock的AdhesivesLabs为Novartis生产的Novartis的右美沙芬7.5mg。
对湿法流延膜厚度的限制部分地反映为需要干燥高度水性的膜组合物,它对这些膜的厚度产生了实际限制;并反映为难以在涂敷工艺自身中获得某些湿厚度,这在本文中讨论并且涉及这样的挑战:将具有足够粘度的较高分子量聚合物流延以获得较高的涂层厚度。水也起到降低粘度的作用。湿法流延工艺实际上不能处理很高的粘度,因为这样的粘度不能够用已知的流延系统可靠地流延。这样的限制表明了本申请中所示的新的独创性步骤的功用。
与湿法流延膜有关的厚度限制倾向于限制装载,因为得到的剂型缺乏负荷承载能力。如果需要掩味,情况尤其如此(当然,很多高值药物靶点仍然处在湿法流延膜的装载能力内)。厚度限制也使得膜能够快速溶解。例如,MonoSolRx在其网站上指出它“专注于快速溶解薄膜药物产品”并且在其向美国证券交易委员会在有价证券申请上市登记表S-1表中陈述“与快速溶解片技术相比,我们的条带崩解得更快”。其它具有湿法流延膜制造能力的公司,例如AdhesivesResearch、LohmannTherapeuticSystems、瑞士的AppliedPharmaceuticalResearch、德国的Labtec和希腊的Lavipharm类似地说明了它们的产品和技术。
如上所述,可食用薄膜通常采用湿法流延工艺生产。在讨论该技术时,申请人强调使用术语“薄片”而不是“膜”。这是因为湿法流延生产工艺的固有特性—按照目前的理解—不能生产较厚的薄片(我们也用专有名称“板材(slab)”来指代“薄片”)。厚度往往可以关系到溶解时间,特别是如果使用某些配方。湿法流延的可食用薄膜通常是快速溶解的产品,并且从业者努力—但并不成功—延长湿法流延的可食用薄膜产品的崩解时间,较慢溶解的产品将更适合于预期用途。主要问题之一是聚合物分子量经常与粘度正相关而湿法流延不能处理高粘度。
用于各种食物和其他应用的湿法流延可食用包装薄膜的发展开始于至少五十年以前(见http://www.watson-inc.com/about_history.php)。其他历史先例可以参见亚洲的果肉和稻米基薄膜的湿法流延生产。
用于药物和维生素递送的湿法流延单分子膜组合物在Fuchs等人的颁布于1979年1月23日的US4,136,162中公开。在颁布于1989年7月18日的US4,849,246中Schmidt公开了用于药物和食品用途的双层薄膜组合物。
发明人HorstZerbe被授予了用于治疗剂和口气清新剂的薄膜组合物的专利5,948,430。正如Zerbe指出的,薄膜厚度不应超过2.7密耳以便防止不良口感。这项专利的受让人LohmannTherapeuticSystems(“LTS”)被认为是第一个在生产可食用薄膜上获得商业成功—即2001年的支链淀粉基Listerine口气清新贴(BreathStrips)投放市场(一种在Leung等人的6596298“快速溶解口服可消耗薄膜”和Leung等人的6923981中更全面地描述的产品)。
该Listerine薄膜是一种非常快速溶解的薄膜。它十秒之内溶解并且仅有33mg的重量。该产品含有高水分含量,并用水来帮助赋予该产品柔性(通过将Listerine清新贴干燥容易证明的特征—那时它变得很脆并且弯曲时会开裂和破碎)。
湿法流延薄膜技术已经从口气清新转移到了非处方药物产品。重点仍然在于实现在口中迅速崩解。著名薄膜药物递送公司MonoSolRxLLC在其网站上这样描述其薄膜技术:“MonoSolRx已开发出一种比其它常规给药形式更稳定、更持久并且更快溶解的薄膜药物递送技术。与邮票的尺寸、形状和厚度相仿的该薄膜,有能力携带非常低剂量的高度均一的处方产品,最高达80mg的较大剂量。”本领域技术人员技术人员将会理解,某些装载成就是独特的。市售薄膜产品对于“常规”活性成分的最高装载量是的25毫克二苯基醇胺。Novartis也以的商标上市了62.5毫克二甲硅油产品,但是这样的装载量是由于二甲硅油的独特特性。
其它药物薄膜开发商,如LTS、Labtec、AdhesivesResearch、Lavipharm和AppliedPharmaResearch以类似的方式描述了它们的薄膜技术。应该指出的是,这些湿法流延产品的描述没有论述活性物质是水可溶性的还是不溶性的以及是需要掩味还是不需要掩味。这些因素可能对如上所述的活性成分的载入有重大影响。
薄膜药品递送过渡到药物产品需要致力于满足药品标准,如在湿法流延生产过程期间实现和保持药物含量一致。湿法流延组合物薄膜技术发展到可以加载越来越多的药物量并继续强调该薄膜的快速崩解。(参见例如Yang等人的7,357,891和7,425,292,两者均包括本发明人)。
湿法流延技术的一个局限是难以(实际上是不能)在一定厚度(或负载)范围之外进行薄膜的湿法流延。这是因为粘度与涂层厚度和干燥之间的关系,其产生对超过一定厚度水平进行涂布的能力的实际限制,以及从超出一定厚度水平的薄膜中去除水分的困难,即使它们被成功地流延。
厚度的局限转化为薄膜能够承载的生物活性成分的量的限制以及是否可以承载吸收改性剂例如离子交换树脂。如上所述,市面上有售的薄膜递送的固体有效成分最大量为辉瑞的快速溶解带中的25毫克苯海拉明。同样地,厚度的局限也限制了薄膜基体的溶解时间的延长。延长单层湿法流延介质中的溶解时间的挑战明显存在于Fankhauser等人的US2007/0202057A1中,这是一个针对含有烟碱药物的湿法流延薄膜的案件。这一案件使用实验室规模的包括冰水浴(以胶化聚合物)的配方技巧以使单层湿法流延薄膜达到所主张的15分钟崩解时间。显而易见这种做法在–放大到商业规模生产时会面临巨大的挑战,可以说是不可能的。
也有人提出多重流延膜迭片来减缓剂型的溶解(参见例如LTS的网站)。这种方法无疑是比Fankhauser提出的解决方案从生产前景上更加切实可行,但是太昂贵而不能实施—特别是在制药领域。因此,不出所料,还没有在市场上看到作为商品的这种多重薄膜迭片。
即使单层湿法流延也可能相对昂贵。商业设备包括长的烘干炉并且太重而不能移动,需要专门和专用的生产套间。烘干需要大量的过滤空气(这需要专门设备)和大量的热能以去除水分。这些成本可能能被药物产品承受,但在成本竞争的全球烟草领域中可能是个挑战。随着能源成本的提高,这在水性流延膜中越来越重要。
另外必须提到两点,即湿法流延薄膜的物理强度和物理稳定性。湿法流延薄膜通常流延在基板或背纸上。除其他事项外,基板在工艺中给薄膜增加物理强度,直到该薄膜从基板上脱层。但是,在使用基板衬垫的情况下,涉及额外的成本和工艺步骤。另外,在基板上的流延材料的均匀分布方面,衬垫会是个问题。
如果这类薄膜缺乏必要的柔韧性和抗拉强度,它们往往会在包装过程中破裂,造成成品率的巨大损失。这种破裂问题很可能导致Novartis的薄膜粘接的方法的专利(Slominski等人的20060207721A1)的申请。MonoSolRx用其聚氧化乙烯(PEO)基组合物做出了最柔韧的、牢固的湿法流延薄膜(见Yang等人的US2005/0037055A1)。这些薄膜的强度导致随后在Novartis在商业上出售的配制剂中使用PEO。现实情况是物理强度和造成的破损和成品率问题已经成为许多非PEO湿法流延膜的重要问题。
湿法流延膜的干燥要求干燥空气的精确定向,以避免形成表皮层,并且还要求足够的热空气流以弄干水含量。然而,再一次,在水性湿法流延膜中,空气可以主要指向干燥膜的顶部或底部,与现代干燥器中允许的流型一致(参见7,425,292)。
物理稳定性的相关问题也是许多湿法流延膜的问题—昂贵的隔离包装经常是必须使用的。不过,物理稳定性并不总是已知的。BootsChemists推出了由佛罗里达州坦帕的BioProgress生产的必须下架的维生素C带,因为它在包装中碎裂了—获得了“碎片而不是带”的名字。这个故事不是唯一的—许多项目由于物理稳定性问题都未能从开发转入商业化。
此外,用于流延的湿基组合物的混合本身产生了一定的挑战。首先,溶剂本身增加了混合物的体积。湿组合物可能趋向于粘附在混合容器和任何输送管道上,导致产量损失。它们也可能在向流延头的运送中涉及复杂的流动问题。
泡沫可能是个问题。湿法混合物必须脱气以避免可能降低内容物均匀性的气泡。此外,当水性混合物通过混合工艺形成时,流延水性膜组合物可能倾向于充气。因而这需要脱气以便产生不均匀问题。流延膜的脱气包括在湿混合物上抽真空,并且包括多种类型的脱气剂,例如二甲硅烷等。简单地说,在流延膜中,混合过程可能在流延膜中的水性混合物中引入空气,并且可以使用真空和脱气剂来将其去除并保持均匀性。见Fuisz等人的US20080075825A1。在我们的挤出的非水性膜中,不存在这样的问题。
以上关于水性湿法流延的很多论述同样适用于使用非水溶剂的湿法流延。
挤出的可食用产品具有很长历史—在1920年代糖果被挤出(见P.B.LaskeyUS1,492,600)。挤出最近已经更多用于医疗设备制造和透皮给药系统的形成—当然,这些都是非食用和不溶性的。总体上参见PharmaceuticalExtrusionTechnology,IssacGhebre-Sellassie和CharlesMartin编辑(2007),其全部内容纳入本文。
在透皮给药系统的成功的鼓舞下,开始研究挤出药品递送用途的可溶性的可食用薄片和薄膜。
Schiraldi等人(USRE33,093)公开了生物粘附的单层挤出薄膜,它不足10密耳,主要由聚氧化乙烯连同较少量的HPC、水不可溶的聚合物、增塑剂和药剂共同组成。又见Mooney和Schiraldi的US6,072,100,它公开了包含PEO或HPC、羧酸衍生出的水聚合物、30-80%的增塑剂和最多达10%的药剂的挤出的薄膜和薄片组合物。
MichaelRepka和JamesMcGinnity公开了厚度为10-13密耳的热熔挤出薄片,其使用50-50比例的PEO和HPC连同3%的维生素ETPGS(见"InfluenceofVitaminETPGSonthepropertiesofhydrophilicfilmsproducedbyhotmeltextrusion,"InternationalJournalofPharmaceutics202(2000)63-70.)
Repka等人的颁布于2002年4月23日的US6,375,963公开了一种热熔挤出薄膜及其制备方法。发明人指出“包含纯的羟丙基纤维素(HPC)和其它水溶性或水溶涨性聚合物的薄膜不能够容易地通过热熔挤出来生产,这是因为在挤出机上所表现出的高应力。因此将增塑剂加入HPC和其它聚合物中”,并且“现有技术没有公开包含高比例HPC和其它水溶性或水溶涨性聚合物的薄膜能够在不存在增塑剂的情况下通过热熔挤出而生产”。为解决该问题,Repka等人提出使用生物粘附聚合物来代替增塑剂。Repka等人的薄膜由含有至少一种水溶性或水溶涨性热塑性聚合物(优选HPC和/或PEO)的生物粘附聚合物的前体组合物制得。该膜也可以含有治疗剂、防腐剂、缓冲剂、抗氧剂、超级崩解剂或吸收剂、食用香料、着色剂、水不溶性聚合物、有机酸、表面活性剂、薄膜改性剂和/或交联剂。该薄膜不含常规增塑剂或在本领域中通常被视为挤出薄膜的增塑剂的材料。Repka等人尤其要求保护包含一种或多种水溶性或水溶涨性热塑性聚合物、治疗剂和生物粘附聚合物的热熔挤出薄膜。生物粘附聚合物选自聚卡波非、卡波姆、一种或多种丙烯酸类聚合物、一种或多种聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐、它们的组合以及它们的盐。
橙皮书的回顾表明,上述挤出专利都没有用于FDA批准的药物产品,也没有任何非处方产品参考了任何这样的专利。
作为技术示范,从业者们必须努力获得热熔挤出药物薄膜所需的柔韧性,并依靠PEO、聚卡波非或极端水平的增塑剂来获得薄片或薄膜的这种柔韧性。PEO和聚卡波非两者都没有在美国以外被批准用于食品。此外,PEO是一种从成本角度不适合的非常昂贵的聚合物,并且对于很多应用往往溶解得太快。因此,挤出薄膜和薄片的制药技术没有对本发明的组合物提供指引。
可见与含有活性成分的薄片和/或薄膜的热熔挤出相关的制药技术包含必须克服的真正的挑战,正如本发明所做的。
因此,仍然需要提供生产含生物活性剂的薄片的更有效的途径,以便可以进行生物活性剂的吸收。这通过使用下述板材或薄片剂型而实现。
发明内容
本发明涉及一种非水性的、可挤出的组合物,其包含至少一种超过总组合物20wt%的量的热塑性聚合物和生物活性剂。
本发明还涉及一种药物产品,其包含由包含至少一种热塑性聚合物和一种或多种生物活性成分的非水性组合物通过挤出或热熔成型制成的薄片,该薄片包含基体,该基体包含该至少一种热塑性聚合物和分布于该基体中的一种或多种生物活性成分,该基体可溶于使用者口中并导致生物活性剂控释给使用者。
本发明还涉及一种包含非水性组合物的药物产品,该组合物包含至少一种热塑性聚合物和一种或多种生物活性成分,该产品为可以放在使用者的任何粘膜上,例如口腔(颊、齿龈、舌下或颚上)、鼻、直肠或阴道粘膜上的形式并且具有5至50分钟的平均溶解时间以完全溶解在使用者的口腔中,所述平均溶解时间针对具有大约0.25-1.5平方英寸的表面积和大约10-70密耳的厚度的薄片形式的组合物而测量。
本发明还涉及一种药物产品,其包含具有小于1000毫克、优选小于500毫克、更优选小于100毫克的量的一种或多种生物活性成分的基体。本发明还涉及一种制造药物产品的方法,其包括通过挤出机挤出包含大于总组成的20wt%的量的至少一种热塑性聚合物和一种或多种生物活性成分的非水性组合物以形成该非水性组合物的挤出板材或薄片。
本发明还涉及一种将超级生物利用度的生物活性剂从含有一种或多种生物活性剂的药物产品递送给使用者的方法,其包括提供包含挤出的非水性组合物的薄片,所述组合物包含至少一种热塑性聚合物和该生物活性成分;并将该薄片放在使用者的颊腔粘膜中或腭上或口腔中的舌下粘膜中。
本发明还涉及一种将超级生物利用度的生物活性剂从含有一种或多种生物活性剂的药物产品递送给使用者的方法,其包括提供包含挤出的非水性组合物的薄片,所述组合物包含至少一种热塑性聚合物和与生物活性成分联用的离子交换树脂;并将该薄片放在使用者的任何粘膜,例如口腔(颊、齿龈、舌下或颚上)、鼻、直肠或阴道粘膜上或伤口上或伤口中。
附图说明
图1是显示一种可以用于本发明的药物产品的生产方法的混合工艺的实例的示意图。
图2是显示一种可以用于本发明的药物产品的生产方法的挤出工艺的实例的示意图。
图3是显示一种可以用于本发明的药物产品的生产方法的小型挤出工艺的实例的示意图。
图4是显示一种可以用于本发明的药物产品的生产方法的中型挤出工艺的实例的示意图。
图5是显示一种可以用于本发明的药物产品的生产方法的大型挤出工艺的实例的示意图。
图6是显示一种可以用于本发明的药物产品的生产方法的带有可选的压辊的挤出工艺的实例的示意图。
图7是显示根据Gothiatek引用的Lunell的研究的消费四种不同的鼻烟品牌和一种2毫克烟碱口香糖所得到的烟碱血浆浓度对时间的曲线图。
图8是根据本发明的含有烟草中天然存在的烟碱的薄片与根据实施例Q的2毫克口香糖相比的烟碱血浆浓度对时间曲线图。
具体实施方式
在本发明的一方面,本发明涉及一种包含至少一种热塑性聚合物和一种或多种生物活性成分的非水性的、可挤出的组合物。
申请人已意外发现,与上述Repka等人的专利中的教导相反,包含至少一种超过总组合物20wt%的量的热塑性聚合物和生物活性剂的非水性组合物可以容易地挤出以形成薄片,尽管该组合物不一定含有PEO、聚卡波非或其它生物粘附材料(聚卡波非、卡波姆、一种或多种丙烯酸类聚合物、一种或多种聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐、它们的组合以及它们的盐)或增塑剂。
申请人用术语“非水性的”指的是该组合物包括多种材料但是除了可存在于该组合物其他材料中的任何水、水分或水性溶液之外没有添加水或其他水性溶剂。例如,该组合物可含有可有少量残留水分含量的生物活性成分和/或本身可能为水性的调味剂,但该组合物除生物活性成分中的残留水分含量和/或调味剂中的任何水之外不含有任何水;因此,这样的组合物仍被认为是如本文所定义的术语“非水性的”。优选地,本发明的非水性组合物在挤出之前含有小于20wt%,更优选小于12.5wt%,并且更优选小于10wt%的水,在挤出或热熔之后含有优选小于6wt%,并且更优选小于4wt%的水。作为热塑性聚合物,优选可热加工的聚合物和基体形成剂。该热塑性聚合物可包括至少一种选自纤维素醚、聚氧化乙烯、聚甲基丙烯酸酯、泊洛沙姆、可挤出的碳水化合物、聚乙二醇(PEG)、PVP、聚乙烯醇、丙烯酸酯、乙基纤维素、醋酸丁酸纤维素、共聚物例如聚(乙烯-共聚-醋酸乙烯酯)共聚物和聚(甲基乙烯基醚/马来酸酐)共聚物、聚醋酸乙烯酯、支链淀粉、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、无定性多糖和聚卡波非的聚合物。优选地,该热塑性聚合物为可水溶的。
在本发明的一个实施方案中,优选诸如羟丙基纤维素(HPC)的纤维素醚。市面上有售的可使用的HPC的例子包括特拉华州Wilmington的Hercules公司(HerculesIncorporated)的Aqualon部门销售的EF、ELF和LF羟丙基纤维素(HPC)(在下文中分别表示为HPCEF、HPCELF和HPCLF)。
如果使用PEO,优选PEO的分子量为100,000或更大并且小于1,000,000。PEO也可与其它聚合物结合使用。如果使用PEO,优选将维生素E和维生素E的衍生物用作应力裂纹消除剂。1至15%的维生素E或维生素E的衍生物,优选地5至10%并且最优选5%,起到消除这样的应力裂纹的作用。
某些不溶性聚合物可以与水溶性聚合物结合使用以延长溶解时间。它们有时可以以离子交换树脂/药物的组合的形式存在。希望颗粒尺寸小于500微米,优选小于200微米并且最优选小于150微米。
该非水性的、可挤出的组合物包含超过总组合物的20wt%的至少一种这样的热塑性聚合物。优选地,该组合物包含少于总组合物重量的50wt%,更优选少于40wt%、最优选少于30重量%的至少一种这样的热塑性聚合物。
本发明的生物活性剂优选为药物,但是可以是任何生物制品、抗原、植物制品、食品或营养保健品、药用化妆品或其它活性剂。
药物生物活性剂的实例包括但不限于痤疮抑制剂,例如贝那普利,卡托普利,依那普利,赖诺普利,莫昔普利,培哚普利,喹那普利,雷米普利和群多普利;痤疮治疗剂,例如阿达帕林,壬二酸,BenzaClin,必麦森,过氧化苯甲酰,克林霉素,Duac,红霉素,羟基乙酸,异维A酸,磺胺醋酰和硫,他扎罗汀和维A酸;光线性角化病,例如双氯芬酸,氟尿嘧啶;戒瘾药,例如丁丙诺啡,双硫仑,纳曲酮,Suboxone和伐仑克林;醛固酮拮抗药,例如依普利酮和螺内酯;α-1类肾上腺素阻断剂,例如阿夫唑嗪,多沙唑嗪,哌唑嗪,坦洛新和特拉唑嗪;肌萎缩性侧索硬化治疗剂,例如利鲁唑;阿尔兹海默病药物,例如多奈哌齐,加兰他敏,利斯的明,他克林和美金刚;麻醉剂,例如右美托咪定,依托咪酯,氯胺酮,美索比妥,戊巴比妥,丙泊酚和硫喷妥;血管紧张素Il受体阻断剂,例如坎地沙坦,甲磺酸依普罗沙坦,厄贝沙坦,氯沙坦,奥美沙坦,替米沙坦和缬沙坦;解酸剂,例如氢氧化铝,AIOH和三硅酸镁;抗心律失常药,例如腺苷,胺碘酮,阿托品,溴苄铵,地高辛免疫抗原结合片段,丙吡胺,多非利特,肾上腺素,艾司洛尔,氟卡尼,伊布利特,异丙肾上腺素,利多卡因,美西律,莫雷西嗪,普鲁卡因胺,普罗帕酮,奎尼丁,索他洛尔,妥卡尼和维拉帕米;抗生素,例如氨曲南,TMP/SMX,氯霉素,克林霉素,氨苯砜,达托霉素,厄他培南,亚胺培南/西司他丁,利奈唑胺,美罗培南,甲硝唑,呋喃妥因,奎奴普丁/达福普汀,利福昔明,替加环素,泰利霉素和替硝唑;抗胆碱能酸,例如双环维林,Donnatal,黄酮哌酯,格隆溴铵,莨菪碱,奥昔布宁,丙胺太林和托特罗定;抗痉挛药,例如卡马西平,氯硝西泮,地西泮,乙琥胺,非尔氨酯,磷苯妥英,加巴喷丁,左乙拉西坦,拉莫三嗪,劳拉西泮,奥卡西平,苯巴比妥,苯妥英,普瑞巴林,扑米酮,噻加宾,托吡酯和丙戊酸;抗抑郁药,例如阿米替林,安非他酮,西酞普兰,地昔帕明,多塞平,度洛西汀,依地普仑,氟西汀,氟伏沙明,丙米嗪,米氮平,奈法唑酮,去甲替林,去甲替林,舍曲林,曲唑酮和文拉法辛;止泻药,例如地芬诺酯+阿托品,易蒙停和碱式水杨酸铋;镇吐药,例如阿瑞吡坦,多拉司琼,氟哌利多,格拉司琼,甲氧氯普胺,昂丹司琼,丙氯拉嗪,东莨菪碱和甲美苄胺;抗真菌剂,例如AmphoB,AmphoB脂,阿尼芬净,卡泊芬净,克霉唑氟康唑,氟胞嘧啶,灰黄霉素,伊曲康唑,酮康唑,米卡芬净,制霉菌素,泊沙康唑,特比萘芬,伏立康唑,布替萘芬,环吡酮,克霉唑,益康唑,酮康唑,咪康唑,萘替芬,制霉菌素,奥昔康唑特比萘芬和托萘酯;抗肝炎药,例如阿德福韦,恩替卡韦,拉米夫定,聚乙二醇化干扰素α-2a,聚乙二醇化干扰素α-2b,Rebetron和利巴韦林;抗疱疹剂,例如阿昔洛韦,泛昔洛韦,伐昔洛韦,阿昔洛韦,二十二烷醇和喷昔洛韦;抗组胺剂,例如西替立嗪,脱羧氯雷他定,非索非那定,氯雷他定,扑尔敏,氯马斯汀,赛庚啶,茶苯海明,苯海拉明,安太乐和异丙嗪;抗高血压药,例如贝那普利&HCTZ,卡托普利&HCTZ,依那普利&HCTZ,赖诺普利&HCTZ,莫昔普利&HCTZ,氯沙坦&HCTZ,缬沙坦&HCTZ,阿替洛尔&氯噻酮,比索洛尔&HCTZ,美托洛尔&HCTZ,纳多洛尔&苄氟噻嗪(bendroflumethazide),普萘洛尔&HCTZ,噻吗洛尔&HCTZ,氨氯地平&贝那普利,维拉帕米&群多普利,阿米洛利&HCTZ,螺内酯&HCTZ,氨苯喋啶&HCTZ,可乐定&氯噻酮,肼屈嗪&HCTZ,甲基多巴&HCTZ和哌唑嗪&泊利噻嗪;抗高血压药,例如阿利克仑,阿利克仑,依前列醇,非诺多泮,肼屈嗪,米诺地尔,硝普钠,酚妥拉明和曲前列素;抗流感剂,例如金刚烷胺,磷酸奥塞米韦,金刚乙胺和扎那米韦;抗疟药/抗原生动物药/抗阿米巴药,例如阿托伐醌,氯喹,双碘喹啉,甲氟喹,伯氨喹,乙胺嘧啶,乙胺嘧啶-磺胺多辛和硫酸奎宁;抗血小板剂,例如阿昔单抗,双嘧达莫/ASA,阿那格雷,西洛他唑,氯吡格雷,双嘧达莫,依非巴特,噻氯匹定和替罗非班;安定药,例如阿立哌唑,氯丙嗪,氯氮平,氟奋乃静,氟哌啶醇,洛沙平,吗茚酮,奥氮平,奋乃静,匹莫齐特,喹硫平,利培酮,硫利达嗪,thiothixine,三氟拉嗪,齐拉西酮和锂;解痉孪药,例如双环维林,DonnatalExtentabs,丙胺太林,二甲硅油,莨菪碱,利眠宁,替加色罗和Bellergal-S;镇咳药/祛痰药,例如苯佐那酯和愈创甘油醚;特应性皮炎药物,例如吡美莫司和他克莫司;苯二氮卓类和非苯二氮卓类镇静药,例如阿普唑仑,丁螺环酮,氯氮卓,氯氮卓,氯硝西泮,地西泮,艾司唑仑,右佐匹克隆(eszcpiclone),氟西泮,劳拉西泮,咪达唑仑,奥沙西泮,雷美替胺,替马西泮,三唑仑,扎来普隆和唑吡坦;β-受体阻滞药,例如阿替洛尔,倍他洛尔,比索洛尔,卡维地洛,艾司洛尔,拉贝洛尔,美托洛尔,纳多洛尔,吲哚洛尔,普萘洛尔,索他洛尔和噻吗洛尔;胆汁酸螯合剂,例如消胆胺,考来维仑和考来替泊;二膦酸盐,例如阿仑膦酸盐,依替膦酸,帕米膦酸二钠,利塞膦酸盐,替鲁膦酸钠和唑来膦酸,雷洛昔芬和特立帕肽;膀胱痉挛药,例如黄酮哌酯,莨菪碱,达非那新,奥昔布宁,索非那新,托特罗定和曲司氯铵;良性前列腺肥大药,例如阿夫唑嗪,多沙唑嗪,度他雄胺,非那雄胺,坦洛新和特拉唑嗪;烧伤制剂,例如醋酸磺胺米隆和磺胺嘧啶银盐;钙通道阻滞药,例如氨氯地平,苄普地尔,地尔硫卓,非洛地平,伊拉地平,尼卡地平,硝苯地平和尼索地平;补钙剂,例如钙和低钙血症;头孢菌素,例如头孢羟氨苄,头孢唑林,头孢拉定,头孢氨苄,头孢克洛,头孢替坦,头孢西丁,头孢丙烯,头孢呋辛,头孢呋辛,氯碳头孢,头孢地尼,头孢克肟,头孢哌酮,头孢噻肟,头孢泊肟,头孢他啶,头孢布烯,头孢唑肟和头孢吡肟;集落刺激因子,例如达依泊汀α,红细胞生成素,非格司亭,重组人白介素-11,聚乙二醇化非格司和沙格司亭;皮质甾类,例如布地奈德,醋酸可的松,地塞米松,氟氢可的松,氢化可的松,甲泼尼龙和泼尼松;关节内皮质甾类,例如甲基氢化泼尼松和曲安奈德;膀胱炎药,例如木聚硫酸盐,氯贝胆碱和明矾溶液;减充血剂,例如苯肾上腺素和伪麻黄碱;抗糖尿病药,例如阿卡波糖,米格列醇和二甲双胍,,Glucovance,Metaglip,Metaglip,罗格列酮,罗格列酮,瑞格列奈,氯磺丙脲,格列美脲,格列本脲,格列吡嗪,妥拉磺脲,甲苯磺丁脲,高血糖素,extenatide和普兰林肽;直接凝血酶抑制剂,例如阿加曲班,比伐卢定和来匹卢定;疾病修饰药物,例如,阿达木单抗,阿那白滞素,金诺芬,硫唑嘌呤,依那西普,羟基氯喹,英利昔单抗,来氟米特,甲氨喋呤和柳氮磺吡啶;利尿剂,例如乙酰唑胺,阿米洛利,阿米洛利和HCTZ苄氟噻嗪,布美他尼,氯噻嗪,氯噻酮,双氯非那胺,依普利酮,利尿酸,呋塞米,双氢氯噻嗪,HCTZ/氨苯蝶啶,氢氟噻嗪,吲达帕胺,醋甲唑胺,甲氯噻嗪,甲氯噻嗪,美托拉宗,泊利噻嗪,螺内酯,螺内酯,HCTZ托拉塞米,三氯噻嗪和氨苯喋啶;内分泌剂,例如溴代肉桂醛,西那卡塞,替可克肽,riptine,卡麦角林,降钙素,去氨加压素,亮丙立德,奥曲肽和加压素;勃起功能障碍药,例如西地那非,他达拉非,伐地那非;发热药,例如别嘌醇,抗组胺剂,硫唑嘌呤,巴比妥酸盐,卡马西平,头孢菌素,西咪替丁,叶酸,肼苯哒嗪,羟基脲,布洛芬,异烟肼,甲基多巴,呋喃妥因,青霉素类,苯妥英,苯妥英,普鲁卡因胺,丙硫氧嘧啶,奎尼丁,链霉素磺酰胺类,舒林酸,氨苯喋啶和万古霉素;贝特类,例如氯苯丁酯,非诺贝特和吉非贝齐;氟喹啉酮,例如环丙沙星,加替沙星,左氧氟沙星,莫西沙星,诺氟沙星和氧氟沙星;肠胃病药,例如阿洛司琼,英利昔单抗,氨基水杨酸,米索前列醇,新霉素,octreotidev,奥沙拉嗪,奥利司他,硫糖铝,柳氮磺吡啶和加压素;痛风治疗药,例如别嘌醇,秋水仙碱,丙磺舒,拉布立酶和磺吡酮;H2受体阻断剂,例如西米替丁,法莫替丁,尼扎替丁和雷尼替丁;抗疱疹剂,例如阿昔洛韦,泛昔洛韦,伐昔洛韦,阿昔洛韦,二十二烷醇和喷昔洛韦;高血压紧急状态药,例如卡托普利,可乐定和拉贝洛尔;高血压急症药,例如依那普利,艾司洛尔,甲磺酸非诺多泮,肼屈嗪,拉贝洛尔,尼卡地平,硝酸甘油和硝普钠;痔疮制剂,例如AnusolHC,AnusolSuppository,辛可卡因,1%普莫卡因,Proctofoam-HC和Analpram-HC;炎性肠病药,例如巴柳氮,布地奈德,英利昔单抗,氨基水杨酸,奥沙拉秦和柳氮磺吡啶;干扰素,例如干扰素α-2A,干扰素α-2b,干扰素α-2b和RibavirincomboPack,干扰素α-N3,干扰素β-1A,干扰素β-1B(Betaseron);间歇性跛行药,例如西洛他唑和己酮可可碱;免疫药,例如Comvax,白喉-破伤风类毒素,肝炎A疫苗,肝炎B疫苗,流感疫苗,Fluzone,莱姆(Lyme)病疫苗,PNEUMOVAX*23;轻泻药,例如比沙可啶,鼠李皮提取物,多库酯,FleetPhospho-Soda,甘油,Lacalutose,鲁比前列素,柠檬酸镁,氢氧化镁-MOM,矿物油,Pericolace,洋车前子和番泻叶;低分子量肝素,例如达肝素,达那肝素,依诺肝素,亭扎肝素,磺达肝素;大环内酯,例如阿奇霉素,克拉霉素和红霉素;镁,例如镁盐;偏头痛治疗药,例如阿莫曲坦,依来曲坦,夫罗曲坦,那拉曲坦,利扎曲坦,舒马普坦,佐米曲,,,双氢麦角胺和;嘴和唇处理药,例如氨来呫诺,苯佐卡因,尿素,过氧化物,Kenalogin,苯酚,洗必太,克霉唑,制霉菌素,喷昔洛韦,二十二烷醇,Gelclair,lidocaineviscous,BMXCocktail,毛果芸香碱和人工唾液;多发性硬化治疗药,例如格拉替雷,干扰素β-1A和干扰素β-1B;肌肉松弛药,例如巴氯芬,carisprodol,环苯扎林,环苯扎林,地西泮,美他沙酮,美索巴莫,奥芬那君;鼻用制剂,例如氮卓斯丁,倍氯米松,布地奈德,色甘酸,链锁加压素醋酸盐,氟尼缩松,氟替卡松,异丙托溴铵,莫米松,羟甲唑啉,去氧肾上腺素,鼻用盐水喷剂,舒马普坦,曲安西龙和佐米曲;泌尿治疗药,例如颠茄制剂和鸦片,黄酮哌酯,天仙子胺,天仙子胺,奥昔布宁,索非那新,托特罗定和曲司铵;神经肌肉阻断剂,例如阿曲库铵,顺阿曲库铵,杜什库铵,米库铵,泮库铵,罗库铵,琥珀酰胆碱,维库铵,咪伐库铵,瑞帕库铵(Rapacuronium),罗库铵,琥珀酰胆碱,阿曲库铵,顺阿曲库铵,泮库铵,维库铵,杜什库铵,哌库铵和筒箭毒碱;硝酸盐,例如硝酸异山梨酯,单硝酸异山梨酯,硝化甘油软膏,Nitrobid和硝化甘油透皮剂;非类固醇抗发炎剂,例如奥湿克,双氯芬酸,依托度酸,吲哚美辛,酮咯酸,舒林酸,托美丁二氟尼柳双水杨酯美洛昔康,吡罗昔康,萘丁美酮氟比洛芬,布洛芬,酮洛芬,萘普生,奥沙普秦,塞来考昔,罗非考昔和伐地考昔;眼药,例如丙美卡因,丁卡因,环丙沙星,红霉素,庆大霉素,左氧氟沙星,左氧氟沙星,诺氟沙星,氧氟沙星,,Polytrim,磺胺醋酰,妥布霉素,,,,Pred和,地塞米松,氟米龙,氯替泼诺,泼尼松,利美索龙,氮卓斯汀,色甘酸钠,依美斯汀,依匹斯汀,酮替芬延胡索酸盐眼用溶液0.025%,左卡巴斯汀,洛度沙胺氨丁三醇,萘甲唑啉,Naphcon-,奈多罗米,奥洛他定,吡嘧司特,倍他洛尔,倍他洛尔,左布诺洛尔,噻吗洛尔,布林唑胺,多佐胺,毛果芸香碱,比马前列素,拉坦前列素,曲伏前列素,乌诺前列酮,阿可乐定,溴莫尼定,和,阿托品,环喷托酯,后马托品,去氧肾上腺素,去氧肾上腺素,双氯芬酸,氟比洛芬和酮咯酸;耳用制剂,例如,过氧化脲,,环丙沙星和氢化可的松,Cort,氧氟沙星,三乙醇胺和Vosol;鸦片制剂,例如可待因芬太尼氢可酮氢可酮,麦啶美沙酮,吗啡,羟考酮(xycodone),右丙氧芬,,Fioricet,Fiorinal,Somacompound,曲马朵,Anexsia,Darvocet,DarvonCompound,Lorcet,Lortab,Percocet,Percodan,Roxicet,TylenolwithCodeine,泰勒宁(Tylox),Vicodin,Wygesic,Buprenorphene,布托啡诺,地佐辛,纳布啡,喷他佐辛,纳美芬纳洛酮,和齐考诺肽;帕金森氏病治疗药,例如金刚烷胺,苯扎托品,溴隐亭,恩他卡朋,培高利特,普拉克索,罗匹尼罗,司来吉兰,,托卡朋和苯海索;PCA—患者自控镇痛药,例如芬太尼,氢吗啡酮,麦啶和吗啡;青霉素,例如氨苄青霉素,氨苄西林/舒巴坦,阿莫西林,阿莫西林/克拉维酸盐,氯唑西林,双氯西林,萘夫西林,青霉素G,青霉素VK,哌拉西林,哌拉西林/他唑巴坦,替卡西林,和替卡西林/克拉维酸盐;磷酸盐补充剂,例如中性片剂,ORIGINAL,;补钾剂,例如K-LOR,,Potassiumdepletion;前列腺癌药物,例如比卡鲁胺,氟他胺,戈舍瑞林,亮丙立德和尼鲁米特;质子泵抑制剂,例如埃索美拉唑,兰索拉唑,奥美拉唑,泮托拉唑和雷贝拉唑钠;牛皮癣药,例如阿曲汀,阿法赛特,地蒽酚,卡泊三醇,依法利珠和他扎罗汀;肾衰竭药,例如氢氧化铝,乙酸钙,骨化三醇,多西骨化醇,葡萄糖酸铁钠,帕立骨化醇和司维拉姆;肺药,例如异丙托铵,噻托铵,沙丁胺醇,比托特罗,左旋沙丁胺醇,吡布特罗,奥西那林,福莫特罗,沙美特罗,,,倍氯米松,布地奈德,氟尼缩松,氟替卡松,糠酸莫米他松,曲安西龙,孟鲁司特钠,扎鲁司特,色甘酸钠,奈多罗米,乙酰半胱氨酸和氨茶碱/茶碱;疾病修饰药物,例如阿达木单抗,阿那白滞素,金诺芬,硫唑嘌呤,依那西普,羟基氯喹,英利昔单抗,来氟米特,甲氨喋呤和柳氮磺吡啶;HMGCOA还原酶抑制剂,例如阿伐他汀,氟伐他汀,洛伐他汀,普伐他汀,罗苏伐他汀,辛伐他汀,,和依折麦布;兴奋剂,例如阿托西汀,苄非他明,咖啡因,右哌甲酯,右旋苯丙胺,安非拉酮,哌甲酯,莫达非尼,匹莫林,苯甲曲秦,芬特明和西布曲明;四环素,例如多西环素,米诺环素和四环素;血栓溶解剂,例如阿替普酶;抗甲状腺剂,例如甲巯咪唑和丙硫氧嘧啶;毒物学相关药物,例如乙酰半胱氨酸,炭,去铁胺,地高辛免疫抗原结合片段,氟马西尼,甲吡唑,亚甲基蓝,纳洛酮,聚磺苯乙烯钠和山梨醇;抗结核药,例如乙胺丁醇,异烟肼,吡嗪酰胺,利福布汀,Rifamate,利福平,利福喷汀和卫非特;局部产品,例如阿利维A酸,贝卡普勒明,炉甘石,辣椒碱,多塞平,利多卡因/丙胺卡因,氟尿嘧啶,马索罗酚,吡美莫司,硫化硒和他克莫司;局部抗病毒药,例如阿昔洛韦,二十二烷醇,咪喹莫特,喷昔洛韦,普达非洛和鬼臼素;局部抗细菌药,例如杆菌肽,甲硝唑,莫匹罗星,杆菌肽/新霉素/多粘菌素,杆菌肽/多粘菌素和磺胺嘧啶银盐;局部抗真菌药,例如布替萘酚,环吡酮,克霉唑,益康唑,酮康唑,,咪康唑,萘替芬,制霉菌素,奥昔康唑,特比萘芬和托萘酯;局部抗寄生虫药,例如克罗米通,林旦,扑灭司林,除虫菊酯和胡椒基丁醚;局部烧伤制剂,例如醋酸磺胺米隆和磺胺嘧啶银盐;局部用皮质甾类,例如Aclometasonediproprionate,地奈德,醋酸肤轻松,氢化可的松,二丙酸倍他米松,戊酸倍他米松,三甲基乙酸氯可托龙,去羟米松,氟轻松,氟氢缩松,丙醋氟替卡松,Chydrocortisonebutyrate,戊酸氢化可的松,糠酸莫米松,泼尼卡酯,曲安西龙,安西奈德,强化的倍他米松二丙酸盐,倍他米松二丙酸盐,去羟米松,双氟拉松二醋酸盐,氟轻松,醋酸氟轻松,哈西奈德,氯倍他索丙酸盐,双氟拉松二醋酸盐和丙酸乌倍他索;泌尿药物,例如木聚硫酸盐,贝胆碱和非那吡啶;阴道制剂,例如克林霉素,甲硝唑,布康唑,克霉唑,咪康唑,特康唑和噻康唑;血管扩张药甲磺酸非诺多泮,肼屈嗪,奈西立肽,尼卡地平,硝酸甘油,和硝普钠;以及血管加压药和强心剂,例如多巴酚丁胺,多巴胺,肾上腺素,氨力农,米力农,去甲肾上腺素,苯肾上腺素和血管加压素。
食品或营养保健生物活性剂的实例包括但不限于食品或食品添加物中的负责改变健康状态的组分,例如植物的组分,尤其是水果和蔬菜,例如含有异黄酮和植物雌激素的大豆,含有可具有抗癌性能的番茄红素的番茄,含有可充当抗氧剂的类黄酮如花青素的浆果例如蓝莓和悬钩子,含有可具有抗癌性能的表没食子儿茶素没食子酸酯(EGCG)的绿茶,来自红葡萄产品的作为抗氧剂的白藜芦醇,可溶性膳食纤维产品,例如用于降低血胆脂醇过多的亚麻籽壳,作为防癌剂的椰菜(萝卜硫烷),以及改善动脉健康的大豆或三叶草(异黄酮类)。类黄酮、抗氧剂、来自亚麻籽的α-亚油酸、提取物如人参、大蒜油等。生物学生物活性剂的实例包括但不限于具有证实的(例如植物甾醇类的胆固醇降低作用)或潜在的对健康的有益效果的植物中的生物活性物质,即植物性化学物质或植物性营养物,特别是叶子、茎、根、块茎、芽、果实、种子和花中的植物性化学物质,以及来自于植物的食品和饮料(例如茶、咖啡、酒精饮料),例如存在于很多来自于植物的食品中(包括茶、葡萄酒、洋葱、苹果和浆果)的类黄酮,来自于十字花科植物的芥子油苷,例如茶和咖啡中的酚酸,以及普遍存在于红色、绿色和橙色水果和蔬菜中的类胡萝卜素(其中一些是维生素A的前体)。
抗原生物活性剂的实例包括但不限于外源抗原、内源抗原、自体抗原和肿瘤抗原。外源抗原是从外部通过例如吸入、摄食或注射而进入体内的抗原。通过胞吞作用或吞噬作用,这些抗原被摄入抗原呈递细胞(APCs)中并被加工成片段。然后APC通过使用其表面上的II类组织相容性分子将这些片段呈递给T辅助细胞(CD4+)。一些T辅助细胞对于肽是特异的:MHC复合物。它们变得活化并开始分泌细胞因子。细胞因子是可以激活细胞毒性T淋巴细胞(CTL)、抗体分泌B细胞、巨噬细胞和其它颗粒的物质。内源抗体是作为正常细胞代谢的结果或者因为病毒或细胞内细菌感染而在细胞内生成的抗体。然后这些片段呈递于细胞表面上与MHCI类分子的复合物中。如果激活的细胞毒性CD8+T细胞将它们识别,则T细胞开始分泌导致这些受感染细胞溶解或凋亡的多种毒素。为了避免细胞毒性细胞仅仅为了呈递自身蛋白而杀死细胞,自反应性T细胞作为耐受性(也称为负选择)的结果从所有组成成分中去除。它们包括异种的(异源的)、自体的和特应的或异源的(同源的)抗原。自体抗原通常是正常蛋白或蛋白的复合物(有时为DNA或RNA),它们由经受特异性自体免疫疾病的患者的免疫系统识别。在正常条件下,这些抗原不应当是免疫系统的目标,但是,主要由于遗传和环境因素,对这样的抗原的免疫耐受在这些患者中丧失。肿瘤抗原或新抗原是由肿瘤细胞表面上的MHCI或MHCII分子呈递的那些抗原。这些抗原有时可以由肿瘤细胞呈递,但是从来不由正常细胞呈递。在这种情况下,它们被称为肿瘤特异性抗原(TSAs),并且通常由肿瘤特异性突变产生。更通常的是由肿瘤细胞和正常细胞呈递的抗原,并且它们通常被称为肿瘤相关抗原(TAAs)。识别这些抗原的细胞毒性T淋巴细胞可能能够在它们增生或转移之前破坏肿瘤细胞。肿瘤抗原也可以以例如突变受体的形式存在于肿瘤细胞表面上,在这种情况下它们将被B细胞识别。
植物性生物活性剂的实例包括但不限于PMI-004(用于II型糖尿病的高级植物制剂-代表多机理生物活性剂,它1)在脂肪细胞中提高脂连蛋白分泌,2)在肝脏中降低PEPCK表达,并且3)在肌细胞中通过胰岛素受体途径提高细胞信号,提高葡萄糖摄取、糖原合酶和糖原积聚)、PMI-005(来源于普通植物的植物性生物活性剂,它抑制多种促炎细胞因子(包括a-TNF、i-NOS、IL-1b和COX-2)的表达。目前正在进行骨关节炎的人体临床试验。也可以用于处置严重/危及生命的发炎病症,例如处置败血病患者)、PMI-006(来源于香料的植物性生物活性剂,它抑制一些发炎相关的酶(包括a-TNF和COX-2)。也具有与脂质和葡萄糖代谢相关的新的生物活性(RXR受体)。)、PMI-007(强效的中枢作用植物性食欲抑制剂,它经由营养感觉下丘脑神经元中的单一中枢途径通过提高ATP含量/生产而起作用。它具有强效的厌食活性,没有通常的CNS食欲抑制剂的副作用。临床前数据表明该药剂抑制食欲并降低动物模型的体重,同时存在人体功效的支持性临床证据。)、PMI-008(来源于农业废料加工物流的植物性生物活性剂,它通过与多种脂肪酶(包括PL、LPL和HSL)的相互作用而阻断脂肪积累/吸收并促进重量减轻)以及PMI-016(来源于植物的强效的合成代谢/机能增进(ergogenic)剂,没有雄激素副所用;能够用于多种人类肌肉消瘦障碍,包括与癌症和AIDS相关的,以及一般的老化(肌肉减少症)。已表明该药剂诱导肌细胞中的蛋白合成(类似于IGF)并促进蛋白降解的降低,同时也表明它提高生长激素基因转录并降低泛素蛋白连接酶基因转录。与合成代谢类固醇不同,PMI-016不表现出与睾丸激素受体的结合。)。
FDA将药物定义为“治愈、治疗、减轻或防止疾病或影响人体的结构或功能”的产品。FDA将化妆品定义为“拟用于擦拭、倾注、喷洒或喷射于人体上,引入人体中,或以其它方式施用于人体…用于清洁、美化、提高吸引力或改变外表”的制品。尽管药用化妆品具有两者的性质,但是FDA将它们归结于化妆品的定义下,并且它们不被认为是独立的一类。由于药用化妆品不包括在FDA的药物的定义中,因此它们不受制于相同的规定、限制和测试。
本发明的组合物不要求存在PEO、增塑剂或聚卡波非。
该非水性的、可挤出的组合物还可以包括粘膜吸收增强剂,即增强通过粘膜、粘膜涂层以及上皮的吸收的物质(或称为(见美国专利申请公开第2006/0257463号)“促渗剂”或“渗透增强剂”)。该粘膜吸收增强剂可以包括但不限于聚乙二醇(PEG)、二乙二醇单乙醚(Transcutol)、23-十二烷基醚、抑肽酶、氮酮、苯扎氯铵、西吡氯铵、十六烷基甲基溴化铵、硫酸葡聚糖、月桂酸、月桂酸/丙二醇、溶血磷脂酰胆碱、薄荷醇、水杨酸甲酯,油酸、磷脂酰胆碱、聚氧乙烯、聚山梨酯-80、乙二胺四乙酸钠、甘氨胆酸钠(sodiumglycholated)、甘氨脱氧胆酸钠(sodiumglycodeoxycholate)、十二烷基硫酸钠、水杨酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠、亚砜以及各种烷基苷类或如美国专利申请公开第2006/0257463号中所述的诸如脱氧胆酸钠、甘氨脱氧胆酸钠、牛磺胆酸钠和甘氨胆酸钠的胆汁盐,诸如十二烷基硫酸钠、聚山梨酯-80和月桂醇聚醚-9、苯扎氯铵、西吡氯铵的表面活性剂和诸如和系列的聚氧乙烯单烷基醚,诸如水杨酸钠和水杨酸甲酯的苯甲酸类,诸如月桂酸、油酸、十一酸和油酸甲酯的脂肪酸,诸如辛醇、壬醇、月桂氮卓酮、多羟基化合物、丙二醇和甘油、环糊精的脂肪醇,诸如二甲基亚砜和十二烷甲基砜的亚砜,诸如薄荷醇、麝香草酚、柠檬油精、尿素、壳聚糖的萜烯类和其他天然及合成聚合物。优选地,该粘膜吸收增强剂为多羟基化合物,例如聚乙二醇(PEG)、甘油、麦芽糖醇、山梨醇等,或二乙二醇单乙醚(Transcutol)。
另外,需要时可以将0.1至10%,优选0.1至5%,更优选0.1至3%的PEG添加到这一混合物中以助于粘膜层渗透。
为了提高使用者对生物活性成分的吸收,优选该非水性的、可挤出的组合物具有针对给定的生物活性成分的吸收进行了优化的pH值。缓冲剂可用于控制pH值,不带限制地包括碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、碳酸钙、磷酸氢二钾、柠檬酸钾、磷酸钠以及任何其他这样的缓冲体系。考虑到在使用过程中的唾液影响,该缓冲体系可以设计为动态控制产品的pH值,即动态缓冲体系。获得优选的pH值的缓冲体系的例子包括磷酸氢二钠和磷酸二氢钠。两者都是FDA认可的缓冲材料,并被列在非活性成份清单中。一个实例是烟碱吸收,它在7至8的pH值得到强化。例如,对于7的pH值,二氢盐/氢二盐的比例可以是4.6/8.6;对于7.5的pH值,二氢盐/氢二盐的比例可以是1.9/11.9;而对于8.0的pH值,二氢盐/氢二盐的比例可以是0.6/13.4。这些是数学计算的缓冲数并且会需要根据加入配方中的其他成分来调整。它们还需要针对板材剂型在颊粘膜上的指定溶解时间长度进行调整,因为唾液可以为约6.8的pH值,但是随着它在口中的量更大,唾液有时可以变得更加偏碱性。因此,在板材剂型中通过缓冲体系的量调整该动态缓冲范围,因为唾液是在口中随时更新的。
该非水性、可挤出的组合物还可以任选性地包括甜味剂例如蔗糖素,和/或调味剂例如薄荷、樱桃、波旁酒、朗姆酒、烟熏玫瑰(smokeyrose)、甜棕和辣(sweetbrown&spicy)、冬青、冰凉薄荷、佛手柑、citramint和甘草。合适的调味添加剂可以从Ungerer&Companyor或从马里兰州Eldersburg的烟草技术公司(TobaccoTechnology,Inc.)购得。大多数调味剂优选地使用乙醇作溶剂,或无溶剂。
尽管该非水性的、可挤出的组合物不要求使用增塑剂,但是也可以包含增塑剂。增塑剂可以以基于热塑性聚合物重量的最高达30%的量存在。或者以低到不存在的范围存在。该增塑剂可以非限制性地为聚氧化乙烯、聚丙二醇、聚乙二醇、甘油、可食用多羟基化合物、丙三醇、多羟基化合物、麦芽糖醇、异麦芽酮糖醇和还原糖的至少之一。某些增塑剂的使用可以起增强粘膜粘附的作用(例如聚丙二醇或甘油),并可以用于该目的。可以使用壳聚糖。高装载量的该材料可以用于伤口中以通过导致红血球形成凝块而止血。这代表了挤出的薄片材料的局部使用。
可以任选性地添加着色剂。最高达百分之五重量的二氧化钛的使用得到白色或浅色产品。可以使用其他可食用色素,例如ColorconRed#40。
此外,可以使用最高达10%,优选3-5%的可接受的硅酸盐,特别是如果该生物活性成分具有显著的水分含量以提高组合物的流动性和均匀的加工。
本发明的意图不仅在于制造方便的剂型,而且在于制造由于更高的药物吸收(即改善的药代动力学)而附加了临床益处的剂型。这样的改善可以呈现以下形式:更快的起效、更慢的起效、控释、与其它递送载体相比对于给定的剂量更好的药物吸收、更低的剂量、降低的副作用等。实现这一点的一种方式是使用口腔粘膜来吸收药物,其中剂型的表面积抵靠该粘膜。另外,为控制药物的释放,剂型的溶解速率也是重要的。与常规剂型如舌下片剂的相比,用于粘膜递送的薄片剂型的使用提高了药物的接触面积。粘膜递送使得活性剂可以避免正常的活性剂从胃肠道中的首过(从而避免与药物在胃肠道中释放相关的肝代谢)。通过制造厚度为10至100密耳的非水性的、非湿法流延的挤出产品,我们提供了活性药物的控释。将会看到,通过改变该产品的这些厚度并将其与多种聚合物结合,可以控制吸收的时间长度(控释)。另外,通过使用某些聚合物和其它赋形剂,使得该产品具有很高的粘膜粘附性并且容易地根据情况粘着到使用者的颊腔或舌下。此外,通过向这些生物活性剂中掺入离子交换盐,可以对任何不好的药物味道进行掩味。离子交换树脂/药物的组合可以附加地或替代地用于导致活性剂的分子分散或导致活性剂的纳米颗粒分散或帮助药物的控释。
重要的是,离子交换树脂在快速溶解薄膜剂型中的使用限于掩味和薄膜,如美国专利No.7,067,116中所讨论。尽管这些树脂的小颗粒尺寸对于薄膜应用可能特别需要,但是对于给定量的树脂材料它们的相对低的药物含量使得难以在薄膜中使用树脂技术,这是因为本文中所讨论的薄膜固有的药物装载限制。这是为什么在薄膜用途中美国专利No.7,067,116要求保护3比1至1比3的药物/树脂比例关系的原因。他们没有能力达到3倍以上。
存在两种对溶解于口中的味道不好的药物进行掩味的途径:包衣和离子交换。目前,在常规的水性流延膜中,两者均可使用,但是空间可能阻止将每种途径优化。申请人不知晓在挤出薄片中存在对掩味和控释的教导。像任何工艺一样,挤出工艺参数(温度和剪切力)形成它们自身的困难。申请人在本申请中教导了使用与热熔挤出工艺相容且有益的掩味和控释。然而,挤出导致某些很独特的问题。因此,在挤出中,离子交换和环糊精是能够耐受高剪切的两种仅有的方法。这是因为在离子交换和环糊精中,大部分活性剂在某种程度上在工艺中被锁定。在挤出中,涂布尺寸不像在流延膜中那样是限制性因素。同样,在挤出中,离子交换和环糊精是可以使用的两种附加技术。
目前离子交换的其它好处还有活性剂的分子释放(由于与交换树脂的分子反应)、纳米尺度的活性剂的释放以及还有受控释放(取决于与交换树脂的结合强度)。
本发明还可以在所有主要的治疗类别中用于药物(包括植物药)掩味,只要它们需要掩味。另外,在所有主要的治疗类别中,分子或纳米尺度的活性剂是期望的,以用于更有效的摄入。此外,本发明为给定的化合物提供控释。最后,主要由于能够使用较低剂量,本发明还可以将副作用最小化。
优选用于本发明的薄片的离子交换树脂是水溶性的,并且由含有共价结合的官能团的在药物学上为惰性的有机或无机基质组成,所述官能团为离子的或能够在合适的pH值条件下离子化。有机基质可以是合成的(例如丙烯酸、甲基丙烯酸、磺化苯乙烯、磺化二乙烯基苯的聚合物或共聚物)或部分合成的(例如改性纤维素和葡聚糖)。无机基质也可以是例如通过加入离子基团而改性的硅胶。共价结合的离子基团可以是强酸性的(例如磺酸)、弱酸性的(例如羧酸)、强碱性的(例如季铵)、弱碱性的(例如伯胺),或酸性基团和碱性基团的组合。通常,适合用于离子交换色谱和用于诸如水的去离子的应用的那些类型的离子交换剂适合用于这些控释药物制剂。这样的离子交换剂可以是但不限于H.F.Walton在“PrinciplesofIonExchange”(离子交换原理)中所记载的那些,该文献的全部内容通过引用纳入本文中(312-343页)。可用于本发明的离子交换树脂具有低于约6毫当量每克(meq/g)的交换容量,并且优选低于约5.5meq/g。
该树脂用选自能够使聚苯乙烯交联的双官能化合物的交联剂进行交联;它们本领域公知的。优选地,交联剂是二乙烯基或多乙烯基化合物。最优选地,交联剂是二乙烯基苯。该树脂交联到约3至约20重量%的程度,优选约4至约16重量%,更优选约6至约10重量%,最优选约8重量%,基于全部树脂。通过本领域公知的方式用交联剂使树脂交联。
离子交换树脂的尺寸应当优选地落在约20至约200微米的范围内。显著低于下限的颗粒尺寸难以在工艺的所有步骤中处理。显著高于上限的颗粒尺寸,例如具有球形和最高达约1000微米的直径的市售离子交换树脂在液体剂型中有如沙粒,并且当经受干燥-水合周期时具有更大的破裂倾向。
可用于本发明的代表性的树脂包括AMBERLITEIRP-69(从Rohm&Haas获得)和DowXYS-40010.00(从Dow化学公司获得)。两者均为用8%的二乙烯基苯交联的聚苯乙烯组成的磺化聚合物,离子交换容量为约4.5至5.5meq/g干燥树脂(H+-形式)。它们的主要区别是物理形式。AMBERLITEIRP-69包含尺寸范围在47至149微米的不规则形状的颗粒,它通过AMBERLITEIRP-120的大尺寸母体球的碾磨而产生。DowXYS-40010.00产品包含尺寸范围在45至150微米的球形颗粒。另一种有用的交换树脂DowXYS-40013.00是用8%的二乙烯基苯交联并用季铵基团官能化的聚苯乙烯组成的聚合物;它的交换容量通常在3至4meq/g干燥树脂范围内。
最优选的树脂是AMBERLITEIRP-69。然而,在不太优选的实施方案中,掩味剂不需要是离子交换树脂。在这些实施方案中,掩味剂可以是例如三硅酸镁。参见Peters等人的美国专利No.4,650,663和4,581,232。也可以用聚合物例如EUDRAGITE(Rohm&Haas)和/或纤维素制品例如乙基纤维等进行掩味。
生物活性剂与离子交换树脂之比或树脂与生物活性剂之比可以从小于1:100例如0.1:100变化到100:0.1。
然而,离子交换生物活性剂/树脂的组合具有很对其它功能,主要是将生物活性剂以其分子状态释放并从而强化生物活性材料的吸收。和薄膜不同,板材剂型可以携带高得多的材料负荷,并因而首次在口腔溶解控释剂型中使得可以以任何需要的比例以及在更高剂量的药物中使用该组合。这可以通过注意美国专利No.7,067,116中的比例限制而归纳地看出。此外,板材的携带能力还使得该颊用剂型可以携带渗透/吸收增强剂(例如环糊精或perscutol等)并且因而有助于难于溶解的生物活性剂的使用。
除了通过药物-离子交换树脂复合物实现持续释放或控释,还可以通过改变含生物活性剂的基体本身的溶解而实现持续释放。从实施例中看出,教导了具有崩解时间的单层产品。该时间可以通过包括不溶性层的多层产品以及向组合物中加入不溶性材料而延长。由于它们出色的工艺简单性,单层薄片仍然是本发明的优选实施方案。
也可以使用用于掩味的普通包衣以及用于掩味和控释的常规封装技术。
上述非水性组合物可以通过下文更详细说明的挤出或热熔成形形成包含薄片或板材的药物产品形式,所述薄片包含基体,所述基体包含至少一种热塑性聚合物和分布于该基体中的生物活性成分,该基体可溶于使用者口腔粘膜中并获得生物活性成分向使用者的持续释放。
该药物产品可以为具有有助于放置在使用者粘膜上的形状(折叠或非折叠状态)的板材形式,例如矩形或圆形,所述粘膜例如为颊粘膜、上颚粘膜、舌下粘膜、齿龈粘膜、鼻粘膜、直肠粘膜、阴道粘膜等。此外,该板材可以对半弯曲以形成V形结构,这将有助于它停留在粘膜上并且可能是某些人喜欢的。此外,可以将该材料咀嚼一次或两次,然后“停靠”在粘膜上。
通过用含烟碱的薄片来递送药物烟碱,证明了通过薄片与颊粘膜的持续接触来进行颊递送的有效性。通过将烟草以25%的装载量放置在薄片中(总烟草量为75毫克,具有大的表面积,花费大约四十五分钟时间溶解于颊中),获得了比两种常规无烟烟草产品所递送的大5倍以上的烟碱吸收,并且峰值烟碱血浆浓度比2毫克烟碱policrilex咀嚼口香糖大接近50%,这种口香糖含有与通常认为75毫克烟草中所含的相同量或者甚至略多的烟碱。这种在吸收上的显著差异可以归结为薄片剂型相对于参照产品的含药口香糖递送的优越性。
当制备薄片剂型时,可以避免对增塑剂的需求。在柔韧性上依赖于增塑剂的薄片会具有物理稳定性问题,因为增塑剂在某些情况下会倾向于随着时间挥发,从而降低产品的柔韧性。防止增塑剂损失可能需要采取预防措施,例如昂贵的阻隔包装和缩短的保存期以保证在产品寿命期间保持物理稳定性。
还希望避免薄片组合物的过度粘着。由于这样的组合物通常在制造后并且在最终包装之前进行卷绕,过度的粘着将需要使用背衬将卷中的产品层分开。除了背衬自身的成本以外,在包装过程中将薄片卷从背衬上分离将是个问题。因此,不粘的组合物和产品是期望的。
本发明不限于口服,也可以用于局部、阴道、直肠和体内。例如,可以挤出含壳聚糖的薄片。高装载的该材料可以用于伤口,通过导致红血球形成凝块而止血。由于该挤出薄片的总体装载能力,该材料也可以含有苯坐卡因或利多卡因。这是该挤出薄片的另一种局部用途。
该药物产品薄片优选地具有至少2磅的抗拉强度,优选4磅(根据以下实施例所述的拉伸/撕裂试验测量),以便进行有效的包装操作。
该药物产品薄片优选地具有在±10%范围内,更优选±5%范围内的含量均匀性。也就是说,薄片的厚度和生物活性剂含量优选地在其整个表面积内相对该薄片的平均厚度以最多±10%,更优选±5%并且最优选2%的比例变化。该薄片可以用许多不同的方法包装,其中一些对于本领域的技术人员是明显的。
本领域技术人员将会理解,螺杆设计对于薄片的含量均匀性是重要的,以保证发生合适的混合并且组成部分不分离。
加工温度与使用的聚合物的类型、挤出机中使用的压力、通过挤出机的传送时间以及最终混合物的粘度有关。在给出的实施例中,温度范围从140F至350F,并且暴露时间通常<3分钟,优选<2分钟并且最优选<90秒。
该生物活性产品的一种包装实施方案是在单个的类似袋的容器中,其可以根据需要具有或不具有防止儿童的功能。作为一种防止袋中的各剂量单位粘着或胶粘的方法,如果需要,可以将可食用材料的颗粒撒布或喷撒在该薄片上。这样的喷撒可以在成卷备料生产过程中或在最后切割和包装过程中完成。可以使用任何可食用的非干扰性的非吸湿性粉末材料。还可以使用该薄片上的隆起的表面并起防粘着功能。
该包装可以见于独立的小袋(sachet),类似于目前由NovartisConsumerHealth以的商标销售的带状产品。或者使用CardinalHealth的的独立的小箔袋。这样的小袋的很多实例目前存在于市场上,用于多种薄膜药物产品,包括Pfizer的,FleetLabs带,GSK的BreatheRightAntiSnore,以及Gas-X(r)带。因而,一次用包装可以包含生物活性产品的薄片以及封装该薄片的包装,所述生物活性产品的薄片包含挤出的非水性组合物,该组合物包含至少一种热塑性聚合物和除烟草以外的生物活性剂,该薄片具有将生物活性剂的单次剂量给与使用的尺寸。
降低薄片的粘着或胶粘的另一方法是生产没有平滑表面区域的薄片。表面区域越平滑,薄片和容器之间的接触表面积越大。相反,较粗糙的表面区域会趋向于减小其间的接触表面积。通常,这样的接触表面积减小会降低粘着或胶粘的趋势。较粗糙的表面区域可以用各种方法获得。例如可以使用足够大小的不溶颗粒以在最终产品中保留粒状质地。这样的不溶颗粒可以是非活性成分或活性成分,包括成分颗粒。薄片的表面也可以用有纹理的辊进行物理破坏—基本上将粗糙性压印到薄片的表面。
用可食用油墨的喷墨印刷可以用来在产品上印刷标签、商标名称或其他图案。
该产品可以通过将上述非水性组合物热熔成型或者特别地热熔挤出而生产。申请人知道的目前制作这种产品的最有效的方法是使用热熔挤出技术,以便该产品在经济上可行并且具有优良的流变性能。该产品可以用现有技术的单螺杆或多螺杆挤出机挤出,该挤出机优选地带有适当的冷却罩、管和泵以及通气口。某些组合物可能需要在通气口上抽真空。例如,当使用其中可能有多余水分的混合物时,通过挤出机通气口抽真空可能会有用。如果那样,应当调整操作温度以补偿由各种调味剂包造成的沸点的降低和升高。
或者,可以将该产品在例如下部的热平板上的箔层之间熔化,并且用上部的热表面压成所需的形状和厚度。可以用冷却液冷却该箔来冷却该产品,然后将该产品从箔层上剥离。其他热熔系统像加热枪也可以用来熔化该组合物。
然而,制作该药物产品的一种优选的方法是通过挤出机挤出上述非水性组合物以形成非水性组合物的挤出板材或薄片。优选地,组合物的挤出在没有气体注入该组合物的情况下完成。
该挤出薄片然后被切成许多更小的板材,该更小的板材具有适当的大小和形状,即产生舒适的口感并且抵靠颊、舌、舌下或齿龈粘膜的大小和形状。这样的切割成片可以用大量现有的切割方法完成,包括F&G旋转式刀片组和包装机、闸刀式切割机、冲切机、DoyenMedipharm的独立小袋生产装置等。
在很多情况下,可以将切割后丢弃的该挤压薄片的任何部分循环到挤出机的进口。例如,该产品可以在包装中经受一定的产品损失,例如成卷备料的边缘可被修剪或切掉以确保所有产品具有统一外观。此外,可在包装步骤中产生废料。为重新使用这些损失的产品,可以将该损失的产品切碎并添加到放在挤出机中的组合物中。
这种重新使用的方法使得可以使用非矩形形状。这样的形状可以从薄片上冲切,但在湿法流延薄膜工业中因为造成的产品损失(理论上等于矩形的面积减去冲切量的面积并且实际上更大)而一般不受欢迎。
重要的是要指出,在这一系统中,正常消耗的碎片可以再次使用,因为它们具有与其放入用来再挤出的混合物相同的组成,所以不妨碍最终产品的含量均匀性。然而,并不认为这是必须的,因为非水性挤出的产出百分比非常高,这是因为在混合步骤中几乎不存在损失,并且开始挤出合格产品时涉及的损失也非常少。
挤出的薄片可以卷绕在辊上以形成一卷挤出薄片,而不是马上切割该挤出薄片。该挤出产品是非粘性的并且可以在没有背衬且不存在相互粘着的卷层的情况下进行卷制。该卷可以用垂直于该辊的轴的普通纵断器在一些地方切开以形成多个宽度为例如1英寸的卷或线轴。然后将这些切开的线轴切成片。也可以将该挤出薄片通过一个切割刀片网络切割,以便将在线轴上已经切割-从而在挤出之后且卷起之前切割该产品。
标识符,不带限制地包括商标名称和图案,可以用目前在薄膜药物递送工业中使用的常规的可食用喷墨技术印在每片上。
对于较厚的薄片,可能需要在薄片的外部添加口香糖糖胶树胶(chewinggumchickle)。这提供了最初的令人愉快的味道并使得更容易放在口中。
较厚的薄片,例如大于10密耳,优选大于25密耳,即使没有添加糖胶树胶也可以由使用者咀嚼。也可以将其咀嚼然后留在嘴唇或颊褶皱中。
挤出之后可以使该薄片立即通过至少一个辊的一部分。该至少一个辊可以是光滑或可以是有纹理的,来给挤出薄片的一面或两面提供有纹理的表面。在一面或两面上有纹理的表面能帮助或阻碍粘膜粘附。例如,该至少一个辊可以为经刻制的以向该挤出薄片的至少一面的表面上提供图案。
在又一种替代方案中,挤出后该薄片可以通过双加热辊以确保对应于辊间距的绝对一致的厚度。如果两个辊都加热会获得更好的传热,但不是绝对必要。如果加热使该薄片变粘,可以提供用有机硅处理的或做成不粘的背衬基板,它可以通过该薄片的一面或两面以便防止粘在辊上,然后马上卷在卷带盘上,或者该辊可以做成具有不粘的(如聚四氟乙烯)表面。该背衬基板恰好使粘性的聚合物不粘在辊上。此外,为了提高工艺速度,可以包括将降低薄片的后加热/拉平步骤的温度的冷却辊。某些热塑性聚合物需要更多的增塑剂以便增塑并且不粘,例如支链淀粉可需要20-30%的甘油,而其他聚合物像HPCLF不能加多达3或4%的甘油而不发粘。这是天然聚合物的Tg的问题。HPCLF具有比支链淀粉低得多的Tg,不需要那么多分子间结合的中断,而增塑剂趋向于这样的中断。LF聚合物是粘的,因为该塑化聚合物的Tg低于室温。如果Tg是例如45℃,那么它在室温下触摸不会发粘。但是,如果温度升高到45℃,同样的聚合物将会发粘。这就是为什么为了得到低挤出温度聚合物人们应该寻找低Tg的聚合物(像HPC)或者在低温下结晶和熔化的聚合物(像PEO)。
在某些情况下,可能需要使薄片一端(横跨其宽度)比另一端更厚,即大体上为楔形薄片。挤出时,通过一边比另一边宽的模具很容易实现这一点。
挤出机可以为单螺杆挤出机。在本发明的一个实施方案中,该非水性组合物通过单螺杆挤出机挤出。或者,挤出机可以为带有泵的双螺杆挤出机,该泵把该非水性组合物在恒压下泵送通过其模具。该挤出机可以包含齿轮泵和衣架型模具以控制挤出机中的压力和整个薄片宽度上的薄片厚度。它也可以包括非常精密的进料器以便于将操作压力保持在窄参数范围。另外,在任一实施方案中,beta型量规可以不断地监测产品厚度,并且甚至成为向压力控制点的反馈网络的一部分。因此,可以通过用厚度计(例如beta)系统监测挤出薄片的厚度并且根据监测的厚度控制向挤出机进料的进料器和将非水性组合物泵送通过模头的泵的压力,而控制挤出薄片的厚度。
挤出机模头可以带有通过压入造成标记或线条的小的突起部。该标记或线条用来为使用者标示薄片上的折叠标记,出于上文所述的V形结构的原因。优选地,为了有效的包装操作,该薄片具有至少2磅的抗拉强度,优选4磅以下)。包装的效率是指包装速度/产量和产率。良好的抗拉强度是指该薄片原料在包装过程中在放于这样的原料上的拉伸下不会破裂。源于这样的拉伸的破裂由于停机时间而降低了产量也降低了产率,因为包装机必须重新穿进。
优选地,组合物在加工中暴露于加热的时间小于90秒以减少生物活性成分暴露于加热。
在挤出过程中,可以向挤出机提供诸如CO2液体的超临界液体注入,以制造快速溶解挤出泡沫板材。
本发明可用于制造由多个挤出薄片组成的多层产品。这样的多层复合物是可含有一个或多个具有或不具有生物活性成分的层的叠片。包括不溶性层在内的附加层可用于采用可变的溶解速度。另一实施方案包括使用带有pH值缓冲系统的附加层来动态控制pH值以优化生物活性剂的吸收。层也可以用来增加总组合物的生物活性剂含量。可以在生产工艺中将附加层直接挤出在前面挤出的层之上或与前面挤出的层联合挤出(共挤出)。
酶介导材料可以用于组合物中,例如CMC酶,以帮助板材或薄片在口腔的潮湿环境下破裂。另一个例子是将淀粉酶添加到组合物中(也在唾液中自然存在)以帮助所含的淀粉的溶解。
可能需要在该产品的某些实施方案中通过使用某些局部有效的试剂来增强麻刺感的感觉。例如薄荷醇可以提供一种与生物活性成分的功效有关的相似的局部感受。有其他试剂能够造成这样的结果,例如薄荷、留兰香、冬青和许多不胜枚举但为本领域的技术人员所熟知的其他试剂。
此外,为了帮助吸收,可能还需要在薄片中形成泡腾。
进入挤出机的干燥混合物的流动性是重要的。有团聚或趋向于团聚的混合物可造成不均匀、不一致的挤出组合物。因此,在某些情况下需要使用诸如二氧化硅衍生物(例如硅酸钙)的助流剂来提高流动性和产生最终产品的均匀性和一致性。
流动性也可以通过适当的混合技术产生。例如,可能需要使用高剪切混合机来防止源于成分中的调味剂或残留水分的“鱼眼”或团聚的形成。当把任何带水分的产物(通常残留在前面的配料工艺中)添加到产品混合物时,高剪切混合是必不可少的。鱼眼或团聚一旦形成,它们极其难以消除;因此必须从一开始就采用高剪切混合。一个实例是使用有高残留水分的植物性生物活性成分,当在没有高剪切的情况下时,形成了导致劣质的不均匀薄片的团聚。如果在具有高剪切混合的情况下(例如高速Cuisinart刀片式混合)添加相同原料,不会发生这种情况并且该薄片很好。
根据本发明的一个方面,该生物活性产品可以通过如图1和2所示的非限制性实例的方法生产。
如图1所示,所有固体原料用天平2称量并在搅拌机中与切碎的循环料(choppedrecycle)预混合。也称量调味剂和增塑剂并可以在混合搅拌机4中混合。可以将混合搅拌机4中的混合物添加到带有切碎机6的搅拌机中,也可以将切碎的循环料添加入其中,在此完成混合。然后可以将该混合物储存在制成料容器8中。
与水性组合物相区别的是,本发明的非水性组合物更容易混合。非水性组合物意味着较低的混合体积且不存在脱气问题。可以使用常规搅拌机。混合物向挤出机的送料必须在受控的速率下(例如,使用ktronic进料器)进行以确保挤出机中和槽模上恒定的压力。
图2是显示一种可以用于本发明的生物活性产品的生产方法的挤出工艺/挤出机10的一个实例的示意图。将典型的带加热区11、冷却区13、模头15和驱动器19的单螺杆挤出机根据该实施方案改进以更好地加工本发明的组合物。挤出机螺杆轴12的前部的冷却可以通过水冷孔14完成。由附加的套筒和送料部分冷却区17对套筒16和通过送料料斗20送料的送料部分18周围区域的冷却,避免产品熔化和塞住料斗20。螺杆设计非常均衡以使螺杆12充满而没有空洞,以保持压力恒定。提供排气口22以去除蒸气/气体以使薄片保持无气泡且平滑。
图3是显示一种可以用于本发明的生物活性产品的生产方法的小型挤出工艺的一个实例的示意图。在图3中,把完成的混合料24,包括固体和液体,从失重给料器26送料到挤出机10的料斗20。来自模头15的挤出薄片27围绕冷辊28传送并经过辊30的某些部分。再通过转矩卷绕机32将其卷绕到辊29上。
图4是显示一种可以用于本发明的药物产品的生产方法的中型挤出工艺的一个实例的示意图。图4显示了一种类似于图3那样的工艺,但是可以将固体混合物24'和液体形式的调味剂/增塑剂混合物25由配量泵34单独送料。这一实施方案具有减少交叉污染和减少清理时间的优点。
图5是显示一种可以用于本发明的药物产品的生产方法的大型挤出工艺的一个实例的示意图。图5显示了一种类似于图4那样的工艺,但是可以将聚合物24a、小部分固体混合物24b和药物生物活性剂24c分别用失重给料器26a、26b和26c单独送料。这一实施方案具有减少交叉污染、减少清理时间、减少批次数量和减小搅拌器尺寸的优点。
图6是显示一种可以用于本发明的药物产品的生产方法的挤出工艺的一个实例的示意图,其带有可选的压辊36和加热辊38以保证整个薄板的厚度均匀性。
本发明的另一方面是一种通过提供包含挤出的非水性组合物的薄片,该组合物包含至少一种热塑性聚合物和一种或多种生物活性剂,并将该薄片放在使用者的颊腔中、腭上或舌下或肛门中或阴道中或用于使用者局部,把产品的生物活性剂从烟草产品递送给使用者的方法。本发明使生物活性剂能够以可生物利用的形式递送给使用者。在将薄片放在如颊腔中之前,该薄片可以在大约其长度的中点折叠以形成V型折叠薄片。
使用本发明的生物活性薄片时,通过使用者折叠该薄片以形成本文所称的“V结构”可以实现将薄片粘在颊腔中并增加崩解或溶解时间。可以把该生物活性薄片出售或切割成舒适性和用途所要求的尺寸。然后这种切割药物薄片由消费者或制造商在该薄片的大约中点处折叠,做成0.5x乘y的薄片。术语“V结构”指的是产生的形状。该药物薄片目前更厚并显示出弹簧般的特性来向外推。然后将该薄片放在颊腔中并且该弹簧般的特性使该药物薄片无论怎么放都更容易粘在颊腔中。
生物活性剂在挤出机内的停留时间可以通过使用适当的干混合物的精确进料装置,连同适当的螺杆设计以便有时可以避免泵的使用来降低。
此外,可以在维持熔化基材(holdmeltbase)已经形成之后再把生物活性剂注入挤出机。还已发现,对于大约1英寸以上的大尺寸螺杆,需要具有从螺杆芯进入并排出的冷却管线。
以下是本发明的非限制性的实施例。
实施例B、C和D使用的工艺设备为:
天平:OhausModelCD-11
搅拌机:Cuisinart杯式处理机
进料器:RandcastleVolumetricConveyer型
挤出机:RandcastleTaskmaster1000,具有3个通气口,L/D为36/1,具有3个加长的具有专利的螺杆
板材出口:Randcastle6英寸柔性唇模头,具有2英寸的冷却辊和转矩卷绕机
实施例A
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量10千克的干燥混合物。
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为230°F且后续区和槽模为300°F的单螺杆挤出机(L/D比36)。向挤出机以每小时7千克材料的速度送料。调味剂的液体基材从挤出机排出。槽模设置为30密耳。该槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出13密耳的厚度,然后卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。测量厚度并且确定在薄板的横向和辊的各处是一致的。
该薄片柔韧且结实。切成尺寸为1英寸乘1英寸的碎片。该碎片可以弯曲180度而不破裂。将这些碎片折叠并放在上齿龈上,显示出12-25分钟的溶解时间。当放在有更多唾液的下齿龈上时,该折叠样本显示出8-15分钟的溶解时间。长期的溶解导致了很长一段时间独特的薄荷气息。这远远超出了常规流延薄膜和流延薄膜口气清新剂的持续影响。观察到不含有烟草的该实施例的组合物作为长效口气清新剂将非常有用。
实施例B
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量3千克的干燥混合物。
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为160°F且后续区和槽模升至240°F的单螺杆挤出机(L/D比36)。向挤出机以每小时7千克材料的速度送料。调味剂的液体基材从挤出机排出。槽模设置为30密耳。该槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出15密耳的厚度,然后卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。测量厚度并且确定在薄板的横向和辊的各处是一致的。
该薄片柔韧且结实。切成碎片,并且该碎片可以重复弯曲180度而不破裂。将这些碎片由4个健康的志愿者取样试验,每个志愿者均反映口味很好-从而证实通过基础工艺后树脂结合的完整性得以保持。
在最终的薄片中观察到药物/树脂颗粒,其外观没有被工艺改变。将这些碎片不加以分离地放置在容器中,并且观察到碎片之间彼此保持分离(即没有粘着);也没有在成卷备料中观察到粘连。
实施例C
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量4千克的干燥混合物。
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为160°F且后续区和槽模升至最高240°F的单螺杆挤出机(L/D比36)。向挤出机以每小时7千克材料的速度送料。调味剂的液体基材从挤出机排出。槽模设置为30密耳。该槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出16密耳的厚度,然后卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。测量厚度并且确定在薄板的横向和辊的各处是一致的。
该薄片柔韧且结实。切成碎片,并且该碎片可以重复弯曲180度而不破裂。
将这些碎片由4个健康的志愿者取样试验,每个志愿者均反映口味很好-从而证实通过基础工艺后树脂结合的完整性得以保持。在最终的薄片中观察到药物/树脂颗粒,其外观没有被工艺改变。溶解时间为大约20多分钟,具有良好的颊粘附。将这些碎片不加以分离地放置在容器中,并且观察到碎片之间彼此保持分离(即没有粘着);也没有在成卷备料中观察到粘连。
实施例D
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量4千克的干燥混合物。
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为160°F且后续区和槽模升至最高240°F的单螺杆挤出机(L/D比36)。向挤出机以每小时7千克材料的速度送料。调味剂的液体基材从挤出机排出。槽模设置为30密耳。该槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出16密耳的厚度,然后卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。测量厚度并且确定在薄板的横向和辊的各处是一致的。
该薄片柔韧且结实。切成碎片,并且该碎片可以重复弯曲180度而不破裂。
将这些碎片由4个健康的志愿者取样试验,每个志愿者均反映口味很好-从而证实通过基础工艺后树脂结合的完整性得以保持。在最终的薄片中观察到药物/树脂颗粒,其外观没有被工艺改变。溶解时间为大约20多分钟,具有良好的颊粘附。将这些碎片不加以分离地放置在容器中,并且观察到碎片之间彼此保持分离(即没有粘着);也没有在成卷备料中观察到粘连。
实施例E
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量8千克的干燥混合物。
根据实施例B中所述的工艺将该产品挤出。这得到壳聚糖薄片的很好的卷材,将其切割成各种尺寸的碎片。该产品具有全身用途和伤口护理用途(显然,将不对其使用调味剂)。产品为16密耳厚。
实施例F
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量5千克的干燥混合物。
成分 | % | 供应商 |
HPC ELF | 52 | Aqualon(Hercules) |
木糖醇NF | 5.25 | Roquette Maltisorb P200 |
三氯蔗糖 | 2 | Tate&Lyle |
苯佐卡因USP | 5 | Changzhou Sunlight |
玉米淀粉 | 31 | Argo |
Red#40 | 0.75 | Colorcon |
樱桃 | 2 | Ungerer |
TiO2 | 2 | DNP International |
总计 | 100 |
根据实施例B中所述的工艺将该产品挤出,并且发现薄板具有15密耳的均匀厚度。使用冲切机从薄板上切下二百二十毫克的碎片。四个健康的志愿者测试了该产品,在舌上测试以向喉咙释放活性物并且在颊腔中测试。察觉到很强烈的麻木作用并且产品在颊腔中持续二十至三十分钟。
该产品表现出相当高水平的粘性,这是由于苯佐卡因充当增塑剂的倾向。观察到应当使用背衬层或喷粉以避免成卷备料中的产品层彼此粘合。
实施例G
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量5千克的干燥混合物。
成分 | % | 供应商 |
PEO 1105 | 5.5 | Dow(Colorcon) |
PEO N80 | 30.94 | Dow(Colorcon) |
PEO N10 | 13.75 | Dow(Colorcon) |
HPC LF | 4.81 | Aqualon |
麦芽糖醇 | 12.75 | Roquette |
三氯蔗糖 | 2 | Tate&Lyle |
烟草 | 25 | Bruton |
维生素E TPGS | 2 | Eastman Chemical |
薄荷调味剂 | 2 | Ungerer |
柠檬酸NF CL-131 | 1 | Spectrum |
TiO2 | 0.25 | DNP International |
总计 | 100 |
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为230°F且后续区和槽模为300°F的单螺杆挤出机(L/D比36)。挤出机以每小时7千克材料的速度送料。调味剂的液体基材从挤出机排出。槽模设置为30密耳。槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出12密耳的厚度,并卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。
测量厚度并且确定在薄板的横向和辊的各处是一致的。
该薄片柔韧且结实。切成尺寸为1英寸乘1英寸的碎片。该碎片可以弯曲180度而不破裂。这一配方表现出粘膜粘附性。
实施例H
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量10千克的干燥混合物。
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为230°F且后续区和槽模为300°F的单螺杆挤出机(L/D比36)。挤出机以每小时7千克材料的速度送料。调味剂的液体基材从挤出机排出。槽模设置为30密耳。槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出13密耳的厚度,然后卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。测量厚度并且确定在薄板的横向和辊的各处是一致的。
该薄片柔韧且结实。切成尺寸为1英寸乘1英寸的碎片。该碎片可以弯曲180度而不破裂。将这些碎片折叠并放在上齿龈上,显示出12-25分钟的溶解时间。当放在有更多唾液的下齿龈上时,该折叠样本显示出8-15分钟的溶解时间。
实施例I
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器混合成总量11磅的干燥混合物。
该组合物按照实施例A阐述的工艺挤出,并获得同样一致的产品薄板。如预期的,甘油的减少降低了得到的薄片的粘着性。
实施例J
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量6磅的干燥混合物。
成分 | % | 供应商 |
HPC LF | 61 | Aqualon(Hercules) |
木糖醇NF | 6 | Roquette |
苦味遮蔽剂 | 2 | Ungerer |
三氯蔗糖 | 2 | Tate&Lyle |
鼻烟 | 25 | Bruton |
薄荷调味剂 | 2 | Ungerer |
TiO2 | 2 | DNP International |
总计 | 100 |
该组合物按照实施例A阐述的工艺挤出,并获得同样一致的产品薄板。其他配方中含有的增塑剂即丙二醇的去除没有不利地影响该薄片的柔韧性和强度。把样本从辊上切割下来,并在60天的观察期内保持其柔韧性和强度。增塑剂的缺失对于极端气候条件下的稳定性(和粘着性的缺乏)是可取的。
实施例K
以下成分分多批次在Hamilton8杯HamiltonBeach/Cuisinart式食品处理器中混合成总量6磅的干燥混合物。
成分 | % | 供应商 |
HPC LF | 57 | Aqualon(Hercules) |
木糖醇NF | 5 | Roquette |
三氯蔗糖 | 2 | Tate&Lyle |
淀粉 | 6.25 | Argo |
烟草 | 25 | Bruton |
樱桃 | 2 | Ungerer |
TiO2 | 2 | DNP |
Red#40 | 0.75 | Lognis |
总计 | 100 |
把该干燥混合物送入每分钟转速设置为180并且初始区的套筒温度设置为260°F且后续区和槽模为260°F的单螺杆挤出机(L/D比36)。向挤出机以每小时7千克材料的速度送料。一些调味剂的液体基材挥发物从挤出机排出。槽模设置为30密耳。槽模具有10英寸的宽度。薄片用牵引辊挤出并且显示出13密耳的厚度,然后卷在不使用任何背衬材料的辊上。材料在挤出机中的停留时间为大约90秒。测量厚度并且确定在薄板的横向以及辊的各处是一致的。
该薄片柔韧且结实,尽管组合物中没有任何常规增塑剂。检查该辊并且发觉淀粉添加到该组合物中用来进一步降低粘着。据观察,硅酸盐也可以起到这种作用。据观察,淀粉和硅酸盐的添加对于避免极端气候条件下的粘着是可取的。
实施例L
把来自实施例K的薄片切割并堆叠在塑料冰球式容器中。将Bruton鼻烟洒入该容器。发现添加的松散烟草使该容器打开时气味芳香。此外,该容器暴露于极端的温度和湿度,没有观察到薄片碎片的粘着。这归因于松散烟草在碎片之间保持分离的作用。
实施例M
从实施例A的产品上切割每片重350毫克的碎片,对折,在四个健康志愿者中在颊腔中测试崩解时间。颊腔中的崩解花费六十五至八十分钟。
实施例N
进行测试以确定产品的pH值是否稳定。把实施例A的薄片溶解-10克薄片溶解在20克的水瓶中。用Oakton酸碱计,确定pH值为6.8。两个月后以同样的方式测试同样的材料,结果是6.71。
实施例O
根据实施例A的工艺将六磅的以下组合物混合并挤出。进行测试以确定碳酸氢钠的加入对组合物pH值的影响。确定pH值为7.34。
成分 | % | 供应商 |
HPC LF | 53 | Aqualon(Hercules) |
丙二醇FCC,NF | 3 | Spectrum |
木糖醇NF | 5.25 | Roquette |
苦味遮蔽剂 | 2 | Ungerer |
三氯蔗糖 | 2 | Tate&Lyle |
鼻烟 | 25 | Bruton |
樱桃 | 4 | Tobacco Technology |
Red#40 | 0.75 | Colorcon |
碳酸氢钠 | 1 | Armin Hammer |
TiO2 | 2 | DNP |
柠檬酸 | 1 | |
甘油 | 1 | |
总计 | 100 |
实施例P
拉伸/断裂试验:
将来自实施例A的样本的上端夹在连接于Baker0-25磅弹簧秤底部吊钩上的强力长尾夹上,将下端夹在另一强力长尾夹上。把夹在测试样本的底部的强力长尾夹在秤设置为10磅的情况下慢拉直到该样本产品失效(断裂)。Listerine口气清新贴(冰凉薄荷)(刚购买的)在0.5磅失效,由MonosolRx,LLC生产的Cough,ColdandAllergy带(Cough,ColdandAllergystrip)在0.25磅失效,而根据本发明的烟草/NICOTINE薄片在7.5镑失效。
这些拉伸结果是如此重要的主要原因之一是抗拉强度的缺失(如两个比较产品样品所示的)在分切和包装方面非常成问题。如果辊突然折断,生产线会停下。适当的产品,如本发明的那种,应该有足够的撕裂强度以承受住分切和包装。
实施例Q
本发明的烟草口腔薄片中的烟碱生物利用度vs.NulifeChewettes中的烟碱生物利用度:
该实施例使用含有75毫克烟草的实施例A的薄片。
来自无烟烟草的烟碱吸收被普遍认为是烟草满足感的一个关键组成部分。来自无烟烟草的烟碱摄入已被广泛研究。大多数公共健康专家认为,瑞典鼻烟型无烟烟草提供了目前市场上的无烟烟草产品的最好的烟碱吸收。“瑞典鼻烟的相对高的烟碱递送与香烟相似,并远高于大多数现有的烟碱替代疗法,包括烟碱口香糖、糖锭、吸入器和鼻用喷雾。”(见“IsLow-nicotineMarlborosnusreallysnus,"JonathanFoulds和HelenaFurberg,HarmReductionJournal20085:9)。
领先的鼻烟制造商SwedishMatch已经将ErikLunell和MarienneLunell进行的烟碱吸收研究吸收为其Gothiatek标准的一部分。Lunell的研究的题目是“SteadystatenicotineplasmalevelsfollowinguseoffourdifferenttypesofSwedishSnuscomparedwitha2-mgchewinggum:crossoverstudy.”(Nicotine&TobaccoResearch第7卷,第3期(2005年6月)397-403)。
在Gothiatek中引用了Lunell的研究,患者服用-每小时一次共12小时-四种不同强度的瑞典鼻烟之一,并以不同的时间间隔服用2毫克烟碱口香糖。由此产生的烟碱血浆浓度曲线如图7所示。
Lunell的研究表明,来自2毫克口香糖的烟碱吸收几乎反映了来自“CatchDryMini”的烟碱吸收。CatchDryMini是含有300毫克烟草的鼻烟袋(参见Lunell)。烟碱血浆水平比含有800毫克烟草的CatchLicorice的2毫克口香糖几乎翻倍。
为了测试本发明,对六位患者进行单剂量研究(区别于患者以附加剂量每小时服用的Lunell的研究),把来自含有75毫克烟草的烟草薄片的烟碱吸收与2毫克口香糖进行比较。烟碱血浆浓度的时间曲线如图8所示。
更特别地,进行一个开放标签、随机、双治疗、两期、两序列、单剂量、交叉对比生物利用度的研究,把本发明的烟草产品薄片的烟碱与印度CeejayHealthcarePrivateLtd.(与美国纽约PositiveHealthcareLLC技术合作)的NulifeChewettes(含有相当于2毫克烟碱的烟碱PolacrilexUSP)相比较,给六个健康成年男性受试者在饱食条件下的每次施用之间至少有7天洗脱期。
研究的产品:
测试:单个口服剂量的本发明的颊用烟草薄片(以下简称为“FT-TBF”)75毫克。
参照:单个口服剂量的由印度CeejayHealthcarePrivateLtd.(与美国纽约PositiveHealthcareLLC技术合作)生产的NulifeChewettes(含有相当于2毫克烟碱的烟碱PolacrilexUSP)。
这项研究是按照ICH-良好临床实践指南、印度良好临床实践指南(2005),ICMR-对人类参与者的生物医学研究的伦理准则(2006)和赫尔辛基宣言(WMAGeneralAssembly,东京2004年)中阐述的原则实施的。
该研究的目标是(1)研究两种产品在健康成年男性受试者在饱食条件下的相对烟碱生物利用度,和(2)监测临床状况、不良事件,评估FT-TBF和NulifeChewettes的相对安全性和耐受性。健康成人男性志愿者从一组志愿者中挑选,并在涵盖包括人口统计学、医学、个人及家庭史以及常规检查的研究中筛选。此外,进行诸如X射线胸片、心电图、血液、生化、血清学及尿液分析的实验室化验作为筛选程序的一部分。对选定的健康志愿者进行评估预检查。所有选定的受试者都进行酒精呼气分析和药物滥用试验。如医疗/用药史、身体检查、实验室化验、心电图和X射线所确定的并且满足该研究的入选及排除标准的所有受试者是健康的。
用药前2小时提供给所有受试者一份标准食物。整个研究期间受试者被禁止吸烟/酒精/碳酸饮料/葡萄柚或含有葡萄柚的产品/含有黄嘌呤的产品。受试者用药前后15分钟不准吃或喝。第一期08年04月05日和第二期08年04月12日在上午九点半给受试者服用单剂量的75毫克的FT-TBF或2毫克的NulifeChewettes。在一个研究期中接受了测试产品的受试者按照随机进度接受另一期的参照产品。两期之间有7天的洗脱期。在每期中,在用药后00.00小时(用药前)、00.08、00.16、00.25、00.50、00.75、01.00、01.25、01.50、02.00、03.00、04.00、06.00和08.00小时采集总计14例血液样本(各1×5毫升)。每位受试者在该研究中被提取的血液总量为大约166毫升。采集后,血液样本以3000转/分钟在4℃下离心10分钟以分离血浆。将所有血浆样本等分成两份(2组)并在-20℃储存。第一份1毫升的血浆样本在第一等份中采集而剩余量的血浆样品在第二等份中采集。对所有受试者监测任何不良事件。
分析物烟碱、可替宁和内标美托洛尔是从0.250毫升等份的人EDTA血浆中通过固相萃取法用剑桥的PhenomenexStrata-X33Jm,30mg/1mlSPE滤筒(cartridge)提取的。用PhenomenexLunaHILIC200A,100×2毫米,5J柱把样品注入液相色谱结合质谱仪(LC-MS/MS)。流动相由10毫摩尔的甲酸铵缓冲液(pH3.5):乙腈(10:90)的混合物组成。通过峰面积比值法定量。进行加权(1/x2)线性回归分析以确定分析物的浓度。
每期服用单个口服剂量的本发明的颊用烟草薄片(FT-TBF)或Nulifechewettes。治疗期通过每种药物服用之间的7天洗脱期分隔。
将所有受试者分配给两种治疗。在FT-TBF的服用之后,全部受试者保留该薄片直到其完全溶解。该薄片用了19-34分钟完全溶解。当该研究的临床阶段结束时,生命体征的测量和研究后实验室化验证实,受试者的健康状况没有重大变化。两种配方都有很好的耐受性并且没有观察到制剂之间的安全药历的差异。
样本分析用质谱仪(LC-MS/MS)完成。整个研究中受试者具有正常生命体征并且没有过敏反应报告。
数据分析时观察到,该测试产品(FT-TBF)显示出比参照产品(R)印度CeejayHealthcarePrivateLtd.的NulifeChewettes(含有相当于2毫克烟碱的烟碱PolacrilexUSP)更好的生物利用度药历。用于测试和参照的烟碱的PK参数Cmax、AUCt和AUCinf分别为5.66、19.54、27.30和3.89、15.30、22.87。用于测试和参照的可替宁的PK参数Cmax、AUCt和AUCinf分别为19.34、112.41、886.01和15.37、87.01、233.17。烟碱及可替宁的测试和参照的Vz(分布容量)分别为14260188.25、488454.45和4319888.30、127879.28,甚至清除率(CI)也描绘出更好的烟碱及可替宁的测试和参照药历,例如分别为3378838.03、110488.18和153492.40、9106.64。
上述中:
Cmax=在指定时间跨度期间最高测定血浆浓度。
AUCt=血浆浓度对时间的曲线以下的面积,从时间0到最后可测量的浓度,以线性梯形法计算。
AUCinf=血浆浓度对时间的曲线以下的面积,时间从0到无穷大。AUC0-∞定义为AUCO-t加上最后可测量的血浆浓度与消除速率常数之比的总和。
AUCExtrap=血浆浓度对时间以下的外推面积
Vz基于末端相的分布容积
CI=全部体清除率,并且定义为CL=剂量/AUC
MRTlast=当药物浓度分布曲线没有外推到无穷大,而是基于直到并包括最后测定的浓度时的平均停留时间:
MRTlast=AUMClast/AUClast
MRTINF=当药物浓度分布曲线外推到无穷大时的平均停留时间
AUMClast=最后一次观察计算的力矩曲线以下的面积。
TBF=烟草颊膜(薄片)
CRF=病例报告表
AE=不良事件
ANOVA=方差分析
对于本发明的样本(曲线40)和参照样本(曲线41),所有受试者的血液中的烟碱的浓度的平均值对时间绘制在图8中。
本发明的75毫克烟草薄片具有5.66的平均Cmax(最大血浆浓度),相比2毫克口香糖的3.89的平均Cmax-超过参照口香糖30%。75毫克烟草薄片具有27.30的平均AUCinf(血浆浓度对时间从零到无穷大的曲线以下的面积),相比2毫克口香糖的22.87的平均AUCinf-超过参照口香糖16%。
这项研究表明本发明的薄片中含有的烟草的烟碱生物利用度显著提高。75毫克薄片递送的烟碱大大超过2毫克烟碱口香糖,而Lunell的研究表明,300毫克鼻烟袋仅仅模拟了2毫克烟碱口香糖的烟碱递送。
实施例R
将每片1.2克的十片Nicorette浸泡在水中以浸泡掉糖胶树胶(chickle)涂层;浸泡掉糖胶树胶涂层之后,目前每片各1克,因此全部十片共计10克。将这10克加到30克的实施例A的起始组合物中,彻底混合并加热以在两片冷箔片之间形成薄片。作为对照实例,将10克的实施例A的起始组合物做成薄片。然后都切成500毫克的碎片。将对照实施例A吸吮5分钟则重量降为155毫克。7分钟时,存在痕量的对照品。然后完成500毫克Nicorette(25%或125毫克为口香糖基材)的吸吮试验,则5分钟时重277毫克,7分钟时261毫克,10分钟时237毫克。因此,结论是Nicorette中使用的不溶的聚合物polacrilex会延长溶解时间,因为它不溶于水。
用500毫克的对照实例重复该试验,获得如下结果:
用500毫克的这一带有不溶的聚合物(polacrilex)和(125毫克口香糖基材)的实施例P重复该试验:
结论是:不溶的聚合物会延长溶解时间。也会传递微粒的不受欢迎的味道。(Polacrilex是一种以Hydrogen形式提供的高纯度交联聚丙烯酸共聚物。这一聚合物具有以下技术特性:
实施例S
将五磅的实施例A的初始组合物用与实施例A相同的方法混合。用相同的工艺条件挤出薄片,不同之处在于模头被完全打开并且牵引辊放缓。这具有将薄片的厚度增加到25密耳的效果。据观察,通过从180转/分钟增加螺杆的每分钟转数,该组合物还可以做得更厚。切割成一英寸见方的碎片,并大约花45分钟溶解。发现该卷材制成后以及暴露于环境条件60天后是柔韧的。
实施例T
通过实施例A的组合物和工艺制备成卷备料并将其用常规方法切割成小碎片。将3磅的实施例A的组合物混合,包括30%的所述切割的材料。然后将该新的材料根据实施例A的工艺参数挤出。挤出的成卷备料很好并且与根据实施例A制造的成卷备料区分不出来。因此,观察到本发明的方法支持废料的再利用。
实施例U
将一磅的实施例A的初始组合物用与实施例A相同的方法混合。将该混合料压在两片铝箔之间。将该箔夹心材料夹在一块325华氏度的热板和压在夹层上的热熨斗之间。高温和压力使该组合物熔成薄片。由此产生的薄片厚度不均,平均厚度为30密耳并且是柔韧的。
实施例V
将实施例A的挤出组合物的样本送往一家认证的第三方实验室以便化验其烟碱浓度。结果如下:
这些结果的回顾显示了碎片的极好的含量均匀性,如烟碱浓度的标准偏差所表现出的。
以下是本发明的实施方案:
1.一种非水性的、可挤出的组合物,其包含至少一种超过总组合物20wt%的量的热塑性聚合物和除烟草以外的生物活性剂,该组合物不包含聚卡波非。
2.根据实施方案1的非水性的、可挤出的组合物,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,或它们的盐。
3.根据实施方案1的非水性的、可挤出的组合物,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐,以及增塑剂。
4.根据实施方案1的非水性的、可挤出的组合物,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐、增塑剂以及聚环氧乙烷。
5.根据实施方案1的非水性的、可挤出的组合物,其中该至少一种热塑性聚合物包含羟丙基纤维素(HPC)。
6.根据实施方案5的非水性的、可挤出的组合物,其中该HPC包括HPCLF、HPCELF或HPCEF。
7.根据实施方案1的非水性的、可挤出的组合物,其中该至少一种聚合物包含从由纤维素醚、聚环氧乙烷、聚甲基丙烯酸酯、泊洛沙姆、可挤出的碳水化合物、聚乙二醇、PVP、聚乙烯醇、丙烯酸酯、乙基纤维素、醋酸丁酸纤维素、聚(乙烯-共聚-醋酸乙烯酯)共聚物、聚醋酸乙烯酯、聚(甲基乙烯基醚/马来酸酐)共聚物、支链淀粉、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、无定形多糖和聚卡波非组成的组中选出的至少一种聚合物。
8.根据实施方案1的非水性的、可挤出的组合物,其中该至少一种热塑性聚合物包含聚环氧乙烷(PEO)。
9.根据实施方案1的非水性的、可挤出的组合物,其中该生物活性剂是干燥粉末。
10.根据实施方案1的非水性的、可挤出的组合物,其中该生物活性剂是非水性液体。
11.根据实施方案10的非水性的、可挤出的组合物,其中该生物活性剂是二甲硅油。
12.根据实施方案1的非水性的、可挤出的组合物,其进一步包含粘膜吸收增强剂。
13.根据实施方案12的非水性的、可挤出的组合物,其中该粘膜吸收增强剂为聚乙二醇。
14.根据实施方案1的非水性的、可挤出的组合物,其进一步包含用于控制该组合物的pH值的缓冲剂。
15.根据实施方案14的非水性的、可挤出的组合物,其中该缓冲剂以当该组合物在使用者口中时向该组合物提供3至9的pH值的量存在。
16.根据实施方案14的非水性的、可挤出的组合物,其中该缓冲剂以当该组合物在使用者口中时向该组合物提供6至8的pH值的量存在。
17.根据实施方案1的非水性的、可挤出的组合物,其中该组合物包含小于10wt%的水。
18.根据实施方案1的非水性的、可挤出的组合物,其中该生物活性剂可溶于水。
19.根据实施方案1的非水性的、可挤出的组合物,其中该生物活性剂不溶于水。
20.根据实施方案1的非水性的、可挤出的组合物,其进一步包含调味剂。
21.根据实施方案1的非水性的、可挤出的组合物,其进一步包含增塑剂。
22.根据实施方案21的非水性的、可挤出的组合物,其中该增塑剂为聚丙二醇、聚乙二醇、甘油、丙三醇及水溶性可食用多元醇中的至少一种。
23.根据实施方案22的非水性的、可挤出的组合物,其中该增塑剂以最高达基于该热塑性聚合物重量的30%的量存在。
24.根据实施方案21的非水性的、可挤出的组合物,其中该至少一种聚合物包含HPC,并且该增塑剂包含聚环氧乙烷。
25.根据实施方案1的非水性的、可挤出的组合物,其中该至少一种热塑性聚合物包含水溶性聚合物。
26.根据实施方案1的非水性的、可挤出的组合物,其中该至少一种热塑性聚合物以全部组合物的至少30wt%的量包含。
27.根据实施方案1的非水性的、可挤出的组合物,其中该至少一种热塑性聚合物以全部组合物的最高达50wt%的量包含。
28.根据实施方案1的非水性的、可挤出的组合物,其中该生物活性剂包含离子交换树脂。
29.根据实施方案1的非水性的、可挤出的组合物,其中该生物活性剂包括壳聚糖。
30.一种挤出的生物活性产品,其包含通过非水性组合物的挤出或热熔成型制成的薄片,所述非水性组合物包含至少一种热塑性聚合物和除烟草以外的生物活性剂,该组合物不包含聚卡波非,该薄片包含含有至少一种热塑性聚合物的基体和分布于该基体中的生物活性剂,该基体可溶于使用者粘膜中并导致生物活性剂控释给该使用者。
31.根据实施方案30的挤出的生物活性产品,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,或它们的盐。
32.根据实施方案30的挤出的生物活性产品,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐,以及增塑剂。
33.根据实施方案30的挤出的生物活性产品,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐、增塑剂以及聚环氧乙烷。
34.根据实施方案30的挤出的生物活性产品,其中该薄片具有矩形形状。
35.根据实施方案34的挤出的生物活性产品,其中该薄片具有10至50密耳的厚度。
36.根据实施方案30的挤出的生物活性产品,其中该至少一种聚合物包含聚环氧乙烷(PEO)。
37.根据实施方案30的挤出的生物活性产品,其中该至少一种聚合物包含羟丙基纤维素(HPC)。
38.根据实施方案37的挤出的生物活性产品,其中该HPC包括HPCLF、HPCELF或HPCEF。
39.根据实施方案30的挤出的生物活性产品,其中该生物活性剂为粉末形式。
40.根据实施方案30的挤出的生物活性产品,其中该生物活性剂为非水性液体形式。
41.根据实施方案30的挤出的生物活性产品,其进一步包含粘膜吸收增强剂。
42.根据实施方案30的挤出的生物活性产品,其进一步包含用于控制该组合物的pH值的缓冲剂。
43.根据实施方案42的挤出的生物活性产品,其中该缓冲剂以当该组合物在使用者口中时提供具有2.5至9的pH值的产品的量存在。
44.根据实施方案30的挤出的生物活性产品,其中该生物活性剂包含离子交换树脂。
45.根据实施方案44的挤出的生物活性产品,其中该生物活性产品为具有大于10密耳的厚度的薄片的形式。
46.根据实施方案30的挤出的生物活性产品,其中该生物活性产品为具有大于10密耳的厚度的薄片的形式。
47.根据实施方案30的挤出的生物活性产品,其中该生物活性剂包括壳聚糖。
48.根据实施方案30的挤出的生物活性产品,其中该挤出组合物包含小于4wt%的水。
49.根据实施方案30的挤出的生物活性产品,其进一步包含调味剂。
50.根据实施方案30的挤出的生物活性产品,其进一步包含增塑剂。
51.根据实施方案50的挤出的生物活性产品,其中增塑剂为聚丙二醇、聚乙二醇、甘油和丙三醇中的至少一种。
52.根据实施方案51的挤出的生物活性产品,其中该增塑剂以最高达基于该热塑性聚合物重量的30%的量存在。
53.根据实施方案50的挤出的生物活性产品,其中该增塑剂以最高达基于该热塑性聚合物重量的30%的量存在。
54.根据实施方案53的挤出的生物活性产品,其中该薄片具有5至50分钟的平均溶解时间并具有大约10-50密耳的厚度以溶解在口腔中。
55.根据实施方案30的挤出的生物活性产品,其中该薄片具有至少4磅的抗拉强度。
56.根据实施方案30的挤出的生物活性产品,其中该薄片具有±10%范围内的均匀性。
57.根据实施方案30的挤出的生物活性产品,其中该至少一种热塑性聚合物以全部组合物的至少20wt%的量包含。
58.根据实施方案30的挤出的生物活性产品,其中该至少一种热塑性聚合物包含水溶性聚合物。
59.根据实施方案30的挤出的生物活性产品,其中该组合物含有小于80wt%的生物活性剂。
60.一种挤出的生物活性产品,其包含非水性组合物,所述非水性组合物包含至少一种热塑性聚合物和除烟草以外的生物活性剂,该组合物不包含聚卡波非,为可以放置在粘膜组织上的形式并具有5至50分钟的平均溶解时间,该平均溶解时间针对薄片形式的组合物而测定,该薄片具有适应于舒适性和生物活性剂加载的表面积以及大约10-50密耳的厚度。
61.根据实施方案60的挤出的生物活性产品,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,或它们的盐。
62.根据实施方案60的挤出的生物活性产品,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐,以及增塑剂。
63.根据实施方案60的挤出的生物活性产品,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐、增塑剂以及聚环氧乙烷。
64.根据实施方案60的挤出的生物活性产品,其中该生物活性剂包含离子交换树脂。
65.根据实施方案64的挤出的生物活性产品,其中该生物活性产品为具有大于10密耳的厚度的薄片的形式。
66.根据实施方案60的挤出的生物活性产品,其中该生物活性产品为具有大于10密耳的厚度的薄片的形式。
67.根据实施方案60的挤出的生物活性产品,其中该生物活性剂包括壳聚糖。
68.根据实施方案60的挤出的生物活性产品,其进一步包含调味剂。
69.根据实施方案60的挤出的生物活性产品,其中该生物活性产品为薄片形式。
70.根据实施方案60的挤出的生物活性产品,其中该组合物包含少于50wt%的生物活性剂。
71.一种挤出薄片形式的挤出的生物活性产品,其包含至少一种热塑性聚合物和生物活性材料,所述生物活性材料包含除烟草以外的生物活性剂和离子交换树脂。
72.根据实施方案71的挤出的生物活性产品,其中该薄片具有大于10密耳的厚度。
73.一种挤出的含烟碱的生物活性产品,其包含热塑性聚合物基体和烟碱并且在单剂量服用时具有大于4纳克/毫升的最大测定烟碱血浆浓度。
74.一种制造剂量单位的方法,其包括通过挤出机挤出包含大于全部组合物的20wt%的量的至少一种热塑性聚合物和除烟草以外的生物活性剂的非水性组合物以形成该非水性组合物的挤出薄片,其中该组合物不包含聚卡波非。
75.根据实施方案74的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,或它们的盐。
76.根据实施方案74的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐,以及增塑剂。
77.根据实施方案74的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐、增塑剂以及聚环氧乙烷。
78.根据实施方案74的方法,其中该生物活性剂包含离子交换树脂。
79.根据实施方案78的方法,其中该挤出薄片具有大于10密耳的厚度。
80.根据实施方案78的方法,其中生物活性剂与离子交换树脂之比为0.1:100至100:0.1。
81.根据实施方案74的方法,其中该挤出薄片具有大于10密耳的厚度。
82.根据实施方案74的方法,其中该生物活性剂包括壳聚糖。
83.根据实施方案74的方法,其中该组合物的挤出是在没有将气体注入该组合物的情况下进行的。
84.根据实施方案74的方法,其中该至少一种聚合物包含聚环氧乙烷(PEO)。
85.根据实施方案74的方法,其中该至少一种聚合物包含羟丙基纤维素(HPC)。
86.根据实施方案74的方法,其中该挤出薄片具有10至50密耳的厚度。
87.根据实施方案74的方法,其中将该组合物以足够低的温度和足够短的时间挤出以便不使生物活性剂降解。
88.根据实施方案74的方法,其中将该组合物在低于200°F的温度下挤出。
89.根据实施方案74的方法,其中将该组合物在350°F或更低的温度下并且用2分钟或更少的时间挤出。
90.根据实施方案74的方法,其中将该组合物在400°F或更低的温度下并且用2分钟或更少的时间挤出。
91.根据实施方案74的方法,其中该非水性组合物进一步包含调味剂。
92.根据实施方案91的方法,其中该非水性组合物的调味剂为液体形式并且使该挤出机排气。
93.根据实施方案74的方法,其中使该挤出机排气。
94.根据实施方案74的方法,该非水性组合物进一步包含增塑剂。
95.根据实施方案94的方法,其中增塑剂为聚丙二醇、聚乙二醇、甘油、丙三醇及水溶性可食用多元醇中的至少一种。
96.根据实施方案95的方法,其中该增塑剂以最高达基于该热塑性聚合物重量的30%的量存在。
97.根据实施方案94的方法,其中该增塑剂以最高达基于该热塑性聚合物重量的30%的量存在。
98.根据实施方案74的方法,其进一步包括切割挤出薄片以形成多个更小的薄片。
99.根据实施方案98的方法,其中各个该更小的薄片具有矩形细带形状或卵形形状。
100.根据实施方案99的方法,其中该薄片具有矩形细带形状,该矩形细带具有1/16英寸至4英寸长的长度,1/16英寸至4英寸的宽度和5至50密耳的厚度。
101.根据实施方案98的方法,其进一步包括将挤出薄片的任何丢弃部分循环到该挤出机的入口。
102.根据实施方案74的方法,其进一步包括将该挤出薄片卷绕在辊上以形成一卷该挤压薄片。
103.根据实施方案74的方法,其进一步包括将该挤出薄片围绕至少一个辊的一部分传送。
104.根据实施方案103的方法,其中该至少一个辊是平滑的或有纹理的。
105.根据实施方案74的方法,其进一步包括使挤出薄片在两个辊之间通过以便为该挤出薄片提供对应于两个辊之间的距离的厚度。
106.根据实施方案74的方法,其进一步包括通过用厚度计监测挤出薄片的厚度并且根据监测的厚度控制向挤出机进料的进料器和将非水性组合物泵送通过模头的泵的压力,而控制挤出薄片的厚度。
107.根据实施方案103的方法,其中该至少一个辊是经刻制的以在挤出薄片的至少一面的表面上提供图案。
108.根据实施方案74的方法,其中该挤出机为单螺杆挤出机。
109.根据实施方案108的方法,其中该非水性组合物通过该单螺杆挤出机挤出。
110.根据实施方案74的方法,其中该挤出机是双螺杆挤出机,其带有泵以把该非水性组合物在恒压下泵送过其中的模头。
111.根据实施方案74的方法,其中该挤出机包括模头和控制该模头上的压力的泵。
112.根据实施方案74的方法,其中该组合物在加工中暴露于加热的时间小于90秒。
113.一种用于把烟碱从生物活性产品递送给使用者的方法,包括:
提供包含挤出的非水性组合物的生物活性产品的薄片,该组合物包含至少一种热塑性聚合物和烟碱;和
将该薄片放在使用者的颊腔中、腭上或舌下。
114.根据实施方案113的方法,其进一步包括在将薄片放在颊腔中之前,在其长度的大约中点折叠该薄片以形成V型折叠薄片。
115.根据实施方案113的方法,其中该非水性组合物包含口气清新材料并且该方法导致使用者的长时间的清新口气。
116.根据实施方案113的方法,其中该组合物不包含聚卡波非。
117.根据实施方案113的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,或它们的盐。
118.根据实施方案113的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐,以及增塑剂。
119.根据实施方案113的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐、增塑剂以及聚环氧乙烷。
120.一种用于给与凝血剂的方法,包括:
提供包含挤出的非水性组合物的生物活性产品的薄片,该组合物包含至少一种热塑性聚合物和凝血剂;和
将该薄片放在受伤的使用者的体表或体内。
121.根据实施方案120的方法,其中该凝血剂是壳聚糖。
122.根据实施方案120的方法,其中该组合物不包含聚卡波非。
123.根据实施方案120的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,或它们的盐。
124.根据实施方案120的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐,以及增塑剂。
125.根据实施方案120的方法,其中该组合物不包含聚卡波非、卡波姆、丙烯酸类聚合物、聚丙烯酸、这些聚合物的共聚物、甲基乙烯基醚和马来酸或酸酐的共聚物的水溶性盐,和它们的盐、增塑剂以及聚环氧乙烷。
126.一种单次使用包装,其包含生物活性产品的薄片以及封装该薄片的包装,所述生物活性产品包含挤出的非水性组合物,该组合物包含至少一种热塑性聚合物和除烟草以外的生物活性剂,该薄片为向使用者给与生物活性剂的单次剂量的尺寸。
Claims (19)
1.一种挤出的生物活性产品,其包含通过非水性组合物的挤出或热熔成型制成的薄片,所述非水性组合物包含至少一种热塑性聚合物、除烟草以外的生物活性剂和离子交换树脂,该组合物不包含聚卡波非或聚氧化乙烯(PEO),该薄片包含含有至少一种热塑性聚合物的基体和分布于该基体中的生物活性剂,该基体可溶于使用者粘膜中并导致生物活性剂控释给该使用者,其中该生物活性产品为具有大于10密耳的厚度的薄片的形式,其中该至少一种热塑性聚合物以全部组合物的超过20wt%且少于50wt%的量包含。
2.根据权利要求1的挤出的生物活性产品,其中该薄片具有矩形形状。
3.根据权利要求1的挤出的生物活性产品,其中该至少一种聚合物包含羟丙基纤维素(HPC)。
4.根据权利要求1的挤出的生物活性产品,其中该生物活性剂为非水性液体形式。
5.根据权利要求1的挤出的生物活性产品,其进一步包含粘膜吸收增强剂。
6.根据权利要求1的挤出的生物活性产品,其进一步包含用于控制该组合物的pH值的缓冲剂。
7.根据权利要求6的挤出的生物活性产品,其中该缓冲剂以当该组合物在使用者口中时提供具有2.5至9的pH值的产品的量存在。
8.根据权利要求1的挤出的生物活性产品,其中该生物活性剂与该离子交换树脂结合。
9.根据权利要求1的挤出的生物活性产品,其中该离子交换树脂与该生物活性剂之比超过3比1(wt/wt)。
10.根据权利要求1的挤出的生物活性产品,其中该生物活性剂包括凝血剂。
11.根据权利要求1的挤出的生物活性产品,其中该生物活性剂包括壳聚糖。
12.根据权利要求1的挤出的生物活性产品,其中该挤出组合物包含小于6wt%的水。
13.根据权利要求1的挤出的生物活性产品,其进一步包含调味剂。
14.根据权利要求1的挤出的生物活性产品,其进一步包含增塑剂。
15.根据权利要求14的挤出的生物活性产品,其中该薄片具有5至50分钟的平均溶解时间并具有10-50密耳的厚度以溶解在口腔中。
16.根据权利要求1的挤出的生物活性产品,其中该薄片具有至少4磅的抗拉强度。
17.根据权利要求1的挤出的生物活性产品,其中该薄片具有±10%范围内的厚度均匀性。
18.根据权利要求1的挤出的生物活性产品,其中该至少一种热塑性聚合物包含水溶性聚合物。
19.根据权利要求1的挤出的生物活性产品,其中该生物活性剂包括烟碱。
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