CN114630656A - 黏膜黏附剂组合物及其使用方法 - Google Patents
黏膜黏附剂组合物及其使用方法 Download PDFInfo
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- CN114630656A CN114630656A CN202080075478.4A CN202080075478A CN114630656A CN 114630656 A CN114630656 A CN 114630656A CN 202080075478 A CN202080075478 A CN 202080075478A CN 114630656 A CN114630656 A CN 114630656A
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- vinyl ether
- agents
- maleic acid
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Abstract
一种包括义齿黏附剂组合物的黏膜黏附剂组合物,包含:以组合物的总重量计(i)10重量%至约75重量%的马来酸或酸酐共聚物;(ii)10重量%至约50重量%的纤维素醚;(iii)0.1重量%至10重量%的可溶胀但不溶于水的交联的聚乙烯吡咯烷酮;和(iv)30重量%至70重量%的口服可接受的载体。还公开了其使用方法及其制备方法。
Description
技术领域
本申请涉及一种黏膜黏附剂组合物,更具体地,涉及一种包括义齿黏附剂组合物的黏膜黏附剂组合物,该义齿黏附剂组合物包含(i)马来酸共聚物、或马来酸酐共聚物、或马来酸共聚物或马来酸酐共聚物的盐;(ii)纤维素醚;(iii)可溶胀但不溶于水的交联的聚乙烯吡咯烷酮聚合物;和(iv)作为载体的疏水性油或亲水性非油组分。
背景技术
黏膜黏附剂组合物,包括义齿黏附剂制剂,通常以膏剂、粉末或挤出的干片/干膜的形式获得,用于为部分或全部义齿的使用者提供将人工义齿牢固地保持在口腔中,或通过局部应用将治疗活性物质递送至口腔内的期望区域。通常,包括义齿黏附剂膏剂的黏膜黏附剂组合物由悬浮在口腔可接受的载体基质中的水溶性或水可溶胀的黏附剂聚合物组成,该载体基质通常由不同比例的长链烃或长链脂肪酸如矿物油、植物油、凡士林等构成。在使用过程中,黏膜黏附剂组合物(特别是义齿黏附剂膏)中的黏附剂组分在与唾液接触时发生活化,使得施加在牙床和义齿之间的义齿黏附剂制剂的水合、溶胀、并随后形成黏附和有内聚力的保持。义齿黏附剂制剂提供的黏附保持的持续时间和强度是义齿黏附剂的主要定量性能参数。用于定义义齿黏附剂制剂的整体性能特征的其他半定量或定量参数可能包括膜厚度和由牙床和义齿之间的义齿黏附剂提供的缓冲效果,通过提供优异的间隙密封来防止食物颗粒进入牙床和义齿之间的间隙空间,并且防止由于在使用过程中渗出导致的牙床和义齿之间的义齿黏附剂材料的损失。由于包括义齿黏附剂膏剂的普通黏膜黏附剂组合物本质上是固体活性成分在包含多种类型油的半固体或液体基质中的悬浮剂或散剂,由于载体基质的脱水收缩和分离导致制剂的保质期稳定性损失,并且固体活性成分也可能对黏附性能产生不利影响。
因此,理想的黏膜黏附剂组合物(特别是义齿黏附剂膏剂)应在持续的一段时间内具有合适的保质期稳定性,在使用期间提供足够高的即时干黏性和延长的黏附保持,在牙床和义齿之间提供足够的缓冲以确保使用舒适,能够密封义齿和牙床之间的间隙以防止食物颗粒进入间隙,减少因牙床和义齿之间部分水合的义齿黏附剂渗出而导致的口腔不适感,以及使用后易于清洁。
美国专利3440065A描述了羧甲基纤维素的钠盐(CMC钠)用作义齿黏附剂制剂中的活性黏附剂成分。
美国专利4514528A描述了低级烷基乙烯基醚-马来酸酐共聚物(更具体为甲基乙烯基醚-马来酸酐共聚物)的部分钠/钙混合盐用作为义齿黏附剂制剂中的黏附剂活性物质。
美国专利4569955A描述了义齿黏附剂制剂中CMC钠和低级烷基乙烯基醚-马来酸酐(特别是甲基乙烯基醚-马来酸酐)的共聚物的Ca/Na盐的结合物。从那时起,低级烷基乙烯基醚(最常见的是甲基乙烯基醚)和马来酸酐的一类合成共聚物、这些聚合物的金属盐、或这些聚合物的金属交联形式、或这些聚合物与不同类型的水溶性纤维素材料(最常见,但不限于CMC钠)的混合物被用于油基义齿黏附剂制剂。
DE3228335A1公开了聚乙烯吡咯烷酮(PVP)用作义齿黏附剂制剂的黏附剂活性物质。
EP2620136B1和US9408780B2描述了在义齿黏附剂制剂中以以下目的使用PVP:提高油基义齿黏附剂制剂的初始干黏性,作为无油义齿黏附剂制剂的黏附剂活性物质,作为制剂和稳定助剂以及作为油基义齿黏附剂制剂的水合促进剂。
尽管在使用期间与唾液接触的黏附剂活性物质的水合对于活化并建立黏膜黏附剂组合物(特别是义齿黏附剂)的黏附特性至关重要,但是黏附剂活性物质的水合速率和程度对于黏膜黏附剂组合物(特别是义齿黏附剂制剂)的整体性能至关重要。黏附剂活性物质如低级烷基乙烯基醚-马来酸酐(特别是甲基乙烯基醚-马来酸酐)的共聚物的Ca/Na盐、水溶性纤维素如CMC和内酰胺聚合物如PVP水合物在使用过程中溶解在唾液中。溶解的黏附剂活性物质从牙床和义齿之间以“渗出”形式的损失会不利地影响黏附剂的保持、缓冲、食物密封,并导致不舒适的口感。
本申请描述了黏膜黏附剂组合物,特别是义齿黏附剂组合物的总体性能特性的定性和定量改进,其通过将疏水改性的聚合的黏附剂活性物质纳入包括义齿黏附剂制剂的油基和无油黏膜黏附剂组合物而实现。疏水改性的范围从聚合的主链上的短链疏水物到长链疏水物的轻取代,到聚合的主链与疏水性交联剂的轻链或重链内和/或链间交联,使得普通水溶性聚合的黏附剂活性物质具有微水溶性、水分散性或完全不溶于水。同时,由于它们的类比化学结构和侧基与普通聚合的黏附剂活性物质相似,除了通过在包括义齿黏附剂水凝胶的水合黏膜黏附剂组合物中建立不溶于水但水可溶胀的互穿网络作为内聚力建设者发挥作用之外,这些疏水改性的聚合物保留了其固有的黏附功能。与基准制剂相比,在包括义齿黏附剂制剂的标准油基和无油黏膜黏附剂组合物中纳入疏水改性的黏附剂聚合物作为添加剂或作为一种或多种黏附剂活性物质的完全替代物在黏附保持的强度和持续时间、膜厚度和缓冲效果、渗出控制、保质期存储稳定性和易清洁性方面表现出改进的义齿黏附性能。
发明内容
本申请的主要方面是提供一种改良的黏膜黏附剂组合物,包含:(i)约10重量%至约75重量%的马来酸共聚物或马来酸酐共聚物、或马来酸共聚物或马来酸酐共聚物的盐;(ii)约10重量%至约50重量%的至少一种纤维素醚;(iii)约0.1重量%至约10重量%的可溶胀但不溶于水的交联的聚乙烯吡咯烷酮聚合物;和(iv)约30重量%至约70重量%的口服可接受的载体。
本申请的一个方面提供了一种黏膜黏附剂口腔组合物,包含:(i)约10重量%至约75重量%的马来酸共聚物或马来酸酐共聚物、或马来酸共聚物或马来酸酐共聚物的盐;(ii)约10重量%至约50重量%的至少一种纤维素醚;(iii)约0.1重量%至约10重量%的可溶胀但不溶于水的交联的聚乙烯吡咯烷酮聚合物;和(iv)约30重量%至约70重量%的口服可接受的载体;和(v)约0.01重量%至约20重量%的活性成分,其选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂及其混合物,并且进一步其中所述组合物是凝胶或液体的形式。
本申请的另一方面提供了一种义齿组合物,包含:(i)约10重量%至约75重量%的马来酸共聚物或马来酸酐共聚物、或马来酸共聚物或马来酸酐共聚物的盐;(ii)约10重量%至约50重量%的至少一种纤维素醚;(iii)约0.1重量%至约10重量%的可溶胀但不溶于水的交联的聚乙烯吡咯烷酮聚合物;(iv)约30重量%至约70重量%的口服可接受的载体;和(v)约0.01重量%至约20重量%的活性成分,其选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂和其混合物,并且进一步其中所述组合物为凝胶或液体形式。
本申请的一个方面提供了一种包括义齿黏附剂组合物的黏膜黏附剂组合物,其中所述马来酸共聚物或马来酸酐共聚物包含马来酸或马来酸酐和C1-C4烷基乙烯基醚,其具有约500,000至3,000,000的预定重均分子量,适用于通过以下制备义齿黏附剂:在溶剂或无溶剂工艺中,在约50℃至150℃,在存在自由基引发剂下,使约50摩尔%的马来酸酐、约50摩尔%的C1-C4烷基乙烯基醚共聚,以产生基本上没有残留马来酸酐的均一细粉末。
本申请的另一方面提供了一种包括义齿黏附剂组合物的黏膜黏附剂组合物,其中甲基乙烯基醚-马来酸(MVE-MA)共聚物或甲基乙烯基醚-马来酸酐(MVE-MA)共聚物的数均分子量为约50,000至约500,000,其中聚合物中约50重量%至约100重量%的羧基单元转化为金属盐的混合物,其中金属可以选自钙、钠、锶、锌、镁、铁、硼、铝、钾、钒、铬、锰、镍、铜、钇、钛及其混合物。
本申请的又一方面公开了一种包括义齿黏附剂组合物的黏膜黏附剂组合物,其中烷基乙烯基醚-马来酸共聚物的盐或烷基乙烯基醚-马来酸酐共聚物的盐当在25℃在甲乙酮(MEK)溶液中以1重量/体积%溶液进行测量时具有2.5至5.0的比粘度。
在另一方面,本申请公开了一种包括义齿黏附剂组合物的黏膜黏附剂组合物,所述义齿黏附剂组合物包含:(i)约15重量%至约70重量%的马来酸共聚物,其选自甲基乙烯基醚-马来酸(MVE-MA)共聚物或甲基乙烯基醚-马来酸酐(MVE-MA)共聚物或其盐;约10重量%至约50重量%的羧甲基纤维素(CMC);约0.1重量%至约10重量%的不溶于水的交联的聚乙烯吡咯烷酮聚合物;和约10重量%至约60重量%的口服可接受的载体。
本申请的另一方面公开了一种将具有生物接触表面的义齿黏附至牙床或口腔顶部的方法,所述方法包括用黏膜黏附剂组合物,特别是义齿黏附剂组合物处理义齿的生物接触表面,所述义齿黏附剂组合物包含:(i)约15重量%至约70重量%的马来酸共聚物,其选自甲基乙烯基醚-马来酸(MVE-MA)共聚物或甲基乙烯基醚-马来酸酐(MVE-MA)共聚物或其盐;(ii)约10重量%至约50重量%的羧甲基纤维素;(iii)约0.1重量%至约10重量%的水不溶性交联的聚乙烯吡咯烷酮聚合物;(iv)约10重量%至约60重量%的口服可接受的载体;和(v)约0.01重量%至约20重量%的活性成分,其选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂及其混合物,并且进一步其中所述组合物为凝胶或液体。
附图说明
本申请的其他实施方案可以通过附图来理解。
图1-4表示油基义齿黏附剂样品对比实施例E1、E12-16的平均黏附谱的重叠。
图5示出每种代表性义齿黏附剂制剂的总黏附力。
图6表示无油义齿黏附剂样品OF1和OF2的平均黏附谱的重叠。
图7示出每种代表性无油义齿黏附剂制剂的总黏附力。
图8示出所选油基义齿黏附剂制剂在45℃下12周后的稳定性。
具体实施方式
在详细解释所公开和/或要求保护的发明构思的至少一个方面之前,应当理解,所公开和/或要求保护的发明构思在其应用中不限于以下描述中阐述或在附图中示出的组件或步骤或方法的构造和布置细节。所公开的和/或要求保护的发明构思能够具有其他方面或者能够以多种方式实践或执行。此外,应当理解,这里使用的措辞和术语是为了描述的目的而不应被视为限制性的。
如根据本公开所使用的,除非另有说明,否则以下术语应理解为具有以下含义。
除非本文另有定义,否则与所公开和/或要求保护的发明构思结合使用的技术术语应具有本领域普通技术人员通常理解的含义。此外,除非上下文另有要求,否则单数术语应包括复数,复数术语应包括单数。
单数形式的“一种”、“一个”(“a”,“an”)和“所述”(“the”)包括复数形式,除非上下文明确指明通过引用的上下文另外指定或明确暗示相反。术语“包括”和“包含”包括限制性更强的声明,例如“基本上由……组成”和“由……组成”。
出于以下详细描述的目的,除了在任何操作实例中或在另外指明的情况下,表示例如在说明书和权利要求书中使用的成分的量的数值应理解为在所有情况下通过术语“约”进行修饰。说明书和所附权利要求书中阐述的数值参数是近似值,其可以根据在实施本发明中获得的期望特性而变化。
除非另有说明,本文所用的所有百分比、份数、比例和比率均以总组合物的重量计。与所列成分相关的所有此类重量均基于活性水平,因此,除非另有说明,否则不包括可能包含在市售材料中的溶剂或副产品。
本文引用的所有出版物、文章、论文、专利、专利公开文本和其他参考文献均出于所有目的以与本文公开内容一致的范围整体并入本文。
术语“至少一个”的使用将被理解为包括一个以及多于一个的任何数量,包括但不限于1、2、3、4、5、10、15、20、30、40、50、100等。术语“至少一个”可以扩展到100或1000或更多,这取决于它后接的术语。此外,100/1000的数量不应被视为限制,因为更低或更高的限度也可能产生令人满意的结果。
如本文所用,词语“包含(comprising)”(以及任何形式的包含(comprising),例如“包含(comprise)”和“包含(comprises)”)、“具有(having)”(以及任何形式的具有(having),例如“具有(have)”和“具有(has)”),“包括(including)”(以及任何形式的包括(including),例如“包括(includes)”和“包括(include)”)或“含有(containing)”(以及任何形式的含有(containing),例如“含有(contains)”和“含有(contain)”)是包容性的或开放式的,并且不排除额外的、未列举的元素或方法步骤。
术语“各自独立地选自”是指当一个基团在结构中出现多于一次时,该基团可以在其每次出现时被独立地选择。
术语“聚合物”是指包含通过共价化学键连接的重复结构单元(单体)的化合物。聚合物可以进一步衍生、交联、接枝或封端。聚合物的非限制性实例包括共聚物、三元共聚物、四元共聚物、四元聚合物和同系物。术语“共聚物”是指基本上由两种或更多种不同类型的单体组成的聚合物聚合获得的所述共聚物。
术语“黏膜黏附剂”是指粘合或黏附至皮肤或黏液或黏膜细胞或牙齿表面的黏附剂。
如本文所用,“义齿”是指部分的或完全的上义齿或下义齿,或以上的全部。理想地,组合物应该起到隔离、缓冲和牢固定位义齿的有效手段的作用。所述组合物应在多种气候条件如温度和湿度下在存储期间保持其粉末和膏剂形式的特性和性质;能够迅速且容易地应用于义齿表面;不会对用户造成刺激或不舒服;安全无毒;没有令人不快的气味或颜色;没有难吃的味道;提供防腐和杀菌特性以防止或抑制口腔中常见的生物体的生长;并起到除臭剂或防止滞留在义齿下方或附近的食物分泌物的腐败或恶臭分解的试剂的作用。
如本文所用,“烷基乙烯基醚共聚物”是指预定重均分子量为约500,000至3,000,000,其适用于通过以下制备义齿黏附剂:在溶剂或无溶剂工艺中,在约50℃至150℃,在自由基引发剂存在下,使约50摩尔%的马来酸酐、约50摩尔%的C1-C4烷基乙烯基醚共聚以产生基本上没有残留马来酸酐的均一细粉末。
烷基乙烯基醚马来酸酐共聚物是通过将烷基乙烯基醚单体例如甲基乙烯基醚、乙基乙烯基醚、二乙烯基醚、丙基乙烯基醚和异丁基乙烯基醚与马来酸酐共聚以生成相应的烷基乙烯基醚-马来酸酐共聚物而获得的,其容易水解成酸共聚物。酸酐和酸形式也可从商业供应商处获得。例如,Ashland LLC以“GANTREZ”商标提供聚合的游离酸形式和相应的酸酐形式,分别为“GANTREZ S系列”和“GANTREZ AN系列”。
如本文所用,“纤维素醚”是指通过使用醚化剂将纤维素的羟基醚化而获得的纤维素衍生物。有用的纤维素醚可以选自甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、疏水改性的羟烷基纤维素、羧甲基纤维素钠及其混合物。
本申请的包括义齿黏附剂组合物的黏膜黏附剂组合物包含烷基乙烯基醚-马来酸/马来酸酐共聚物的金属盐,其中,所述金属选自钙、钠、锶、锌、镁、铁、硼、铝、钾、钒、铬、锰、镍、铜、钇、钛及其混合物。
甲基乙烯基醚-马来酸/马来酸酐共聚物的盐形式可以通过甲基乙烯基醚-马来酸/马来酸酐共聚物或三元共聚物与金属(例如钙、钠、锶、锌、镁、铁、硼、铝、钾、钒、铬、锰、镍、铜、钇、钛及其混合物)的至少一种无机盐的相互作用来制备。在一个实施方案中,氢氧化钠或氢氧化钙用于本申请的目的。
如本文所用,“交联的”是指组合物包含分子内和/或分子间交联,无论是通过共价键合还是非共价键合产生。“非共价”键合包括氢键合和静电(离子)键合。
根据本申请的一个实施方案,使用可从Ashland LLC获得商标名为FlexiThixTM的强溶胀的、中度交联的PVP(聚乙烯吡咯烷酮)聚合物,该聚合物通过在有机溶剂中在预定量的多功能交联剂和自由基引发剂的存在下,乙烯基吡咯烷酮的沉淀聚合而直接以细粉末获得。交联的PVP在4%水性溶液中具有至少约500cps至约50,000cps的布氏粘度。本申请中交联的PVP的优选粘度范围可以为约500cps至约50,000cps、或约800cps至约20,000cps、或约1000cps至约10,000cps。布氏粘度可以在2.5、5、10、12、20、30或50RPM且在25℃下测量。
可用于实施本申请的交联的PVP聚合物可以根据授给ISP Investments Inc.的美国专利第5,073,614号和美国专利第5,130,388号制备。这些参考文献的教导被有利地用于本申请的目的。此外,这些参考文献通过引用的方式整体并入本文。
根据本申请的增稠添加剂组合物的一个要素是增稠剂,其包含如美国专利第5,312,619号和第5,139,770号中共同拥有的所述的强溶胀的、轻度至中度交联的聚乙烯吡咯烷酮,其内容通过引用整体并入本文。除非另有说明,术语“强溶胀的、轻度至中度交联的PVP”具体是指基本上由轻度至中度交联的聚(N-乙烯基-2-吡咯烷酮)组成的聚合物,该聚合物具有至少一种以下非限制特性:(1)由其凝胶体积定义的水溶胀参数为约15mL/g至约300mL/g,更特别为约15mL/g至约250mL/g,在其他情况下为约15mL/g至约150mL/g,或(2)在25℃,在包含水的液体载体中以5%交联的PVP进行测量的布氏为粘度至少2,000cP,更特别优选为至少约5,000cP,在某些情况下为至少约10,000cP。这些参数范围的参考在美国专利第5,073,614号(通过引用并入本文)和Shih,J.S.等人(1995年)中提供。交联的PVP的合成方法在许多参考文献(包括美国专利第5,073,614号、第5,654,385号和第6,177,068号)中公开,其内容通过引用并入本文。本领域的聚合物技术人员应理解,多种合成方法都是可能的,条件是所产生的聚合物达到上述定义的参数中的至少一个。
预期使用本领域技术人员已知的任何其他可能的聚合方法,其可以提供这种强溶胀的、中度交联的细白色粉末的PVP。这样的聚合方法可以包括但不限于沉淀聚合、反相乳液聚合、凝胶聚合、分散聚合、溶液聚合、乳液聚合、本体聚合、悬浮聚合、液体分散聚合(LDP)和离子聚合。
用于制备本申请的聚合物的其他优选的聚合技术公开于(1)George Odian的Wiley,“Principles of Polymerization”,第4版,2004年,和(2)转让给ISP InvestmentsInc.的WO2012061147A1,其公开内容通过引用并入本文。此外,可用于本申请的实践的聚合物的聚合可以任选地根据所采用的聚合技术的类型需要合适的催化剂或引发剂、稳定剂、盐、pH调节剂、助分散剂、增稠剂、溶剂、酸性剂、碱性剂和/或光引发剂。本领域技术人员可以容易地从本领域已知的相关文献或从George Odian的Wiley的“Principles ofPolymerization”,第4版,2004,获得这样的信息,其通过引用整体并入本文。
在一个实施方案中,所述聚合物是聚-N-乙烯基-聚-2-吡咯烷酮。聚-N-乙烯基-聚-2-吡咯烷酮也通常称为聚乙烯吡咯烷酮或“PVP”。PVP是指包含乙烯基吡咯烷酮(也称为N-乙烯基吡咯烷酮、N-乙烯基-2-吡咯烷酮和N-乙烯基-2-吡咯烷酮)为单体单元的聚合物。合适的乙烯基吡咯烷酮聚合物包括聚(-乙烯基-吡咯烷酮)(PVP)和S-630、K-90、K-120。
交联的聚乙烯吡咯烷酮主要以相对粗品的形式用作片剂崩解剂(120微米范围的Kollidon CL,130微米范围Polyplasdone XL的),其中平均颗粒尺寸大于100微米。
在另一实施方案中,本申请涉及可溶胀的交联的PVP聚合物,其可以在有机溶剂(优选脂肪烃,例如C3-C10饱和的、支链或非支链、环状或无环脂肪烃,最优选环己烷或庚烷,或其混合物)中,在预定量的交联剂和游离自由基聚合引发剂的存在下,通过乙烯基吡咯烷酮的沉淀聚合而直接制备为细白色粉末的形式。
在本申请的多个实施方案中,即使在润湿和溶胀时仍呈多孔粒状或珠状形式的乙烯基吡咯烷酮的交联聚合物(包括乙烯基吡咯烷酮和其他单体材料的共聚物)是在电解质的水溶液中通过所述单体材料与受控量的交联剂聚合产生的。形成不溶性聚合物,并通过机械搅拌使过量的单体保持悬浮。
在本发明的多个实施方案中,交联的乙烯基吡咯烷酮聚合物即使在被液体溶胀时也保持颗粒形式,并且包含多孔粒状或珠状形式的乙烯基吡咯烷酮聚合物和一个或多个可共聚的单体。为了制备形状保持、多孔、粒状或珠状形式的乙烯基吡咯烷酮聚合物,在自由基聚合过程中通过机械方式使单体材料和至少临界量的交联剂在电解质的水性溶液中保持悬浮。
在一个实施方案中,本申请使用强溶胀的、中度交联的PVP聚合物,其通过在有机溶剂中,在预定量的多官能交联剂和自由基引发剂的存在下,沉淀聚合乙烯基吡咯烷酮而直接以细粉末获得。
在另一实施方案中,本申请采用强溶胀的、中度交联的PVP聚合物基细粉末,其特征在于约15ml/g至150ml/g的聚合物的水凝胶体积和在5%水溶液中至少为1000cps至10,000cps的布氏粘度。
根据本申请的多个实施方案,一定分子量范围的甲基乙烯基醚和马来酸酐的共聚物可商购自商标名(Ashland)。具体地,AN是一种优选的共聚物。其他可用的共聚物包括以S提供的游离酸形式的AN、以MS提供的S的钠和钙混合盐,以及以ES提供的S的半酯衍生物。
根据本申请的一个实施方案,使用了交联的甲基乙烯基醚/马来酸酐共聚物Stabileze QM。优选1,9-癸二烯交联的共聚物,例如可商购自Ashland LLC的StabilezeQM-PVM/MA共聚物。以单乙烯基烷基醚计,交联剂的量通常为约1摩尔%至约5摩尔%。合适的交联剂的实例包括脂肪族二醇的二乙烯基醚,例如1,2-乙二醇、1,3-丙二醇、1,4-丁二醇、1,5-戊二醇、1,6-己二醇、1,7-庚二醇、1,8-辛二醇、1,9-壬二醇、1,10-癸二醇、1,11-十一烷二醇和1,12-十二烷二醇的二乙烯基醚,以及二甘醇、三甘醇、四甘醇、五甘醇、六甘醇、七甘醇、八甘醇、九甘醇、十甘醇以及分子量最高达约5900的聚亚烷基二醇的二乙烯基醚。其他合适的交联剂包括1,7-辛二烯;1,9-癸二烯;二乙烯基苯;N,N'-双-亚甲基丙烯酰胺;丙烯酸酯如聚乙二醇二丙烯酸酯、三羟甲基丙烷三丙烯酸酯、丙二醇二丙烯酸酯;用丙烯酸三烯丙胺、四烯丙基乙二胺、邻苯二甲酸二烯丙酯等酯化一次或两次的多元醇。
本申请包含口腔可接受的载体或载剂,其优选包含疏水性(油)或亲水性(非油)组分。
本申请的疏水性油或亲水性非油组分可以选自:液态凡士林、凡士林、矿物油、甘油、天然和合成油、脂肪、硅酮和硅酮衍生物、聚乙酸乙烯酯、聚乙二醇、丙二醇、聚丙二醇、聚(环氧乙烷-环氧丙烷)共聚物、二甘醇、三甘醇、山梨糖醇、水、口腔可接受的表面活性剂及其混合物;天然和合成蜡如蜂蜡、羊毛脂和虫胶等动物蜡;烃;烃衍生物;植物油蜡如巴西棕榈蜡、坎德拉和杨梅蜡;植物油如辛酸/癸酸甘油三酯;植物油如玉米油、葵花籽油、大豆油、蓖麻油、棕榈油、椰子油、橄榄油和菜籽油或其混合物;和动物油如鱼油和油酸,及其混合物。
在另一实施方案中,本申请公开了制备黏膜黏附剂口腔组合物和使用此类制剂来缓释活性成分,所述活性成分选自但不限于抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂和甜味剂。
本申请的抗细菌化合物可以选自:卤代二苯醚(例如三氯生)、草药提取物和精油(例如迷迭香提取物、茶提取物、木兰提取物、百里酚、薄荷醇、桉油精、香叶醇、香芹酚、柠檬醛、日桧醇、儿茶酚、水杨酸甲酯、没食子表儿茶素酸酯、表儿茶素、没食子酸、miswak提取物、沙棘提取物)、双胍类抗细菌剂(例如,洗必泰、阿来昔定或奥替尼定)、季铵化合物(例如氯化十六烷基吡啶(CPC)、苯扎氯铵、氯化十四烷基吡啶(TPC)、氯化N-十四烷基-4-乙基吡啶(TDEPC))、酚类抗细菌剂、海克西定、奥替尼啶、血根碱、聚维酮碘、地莫匹诺、5-正辛酰-3'-三氟甲基苯基水杨酰胺(salifluor)、金属离子(例如锌盐如氯化锌、乳酸锌、硫酸锌;亚锡盐;铜盐;铁盐)、血根碱、蜂胶、氟化亚锡、氟化钠、氟化钾、单氟磷酸钠、氟硅酸钠、氟硅酸铵、氟化胺和氟化铵。本申请的抗炎化合物可以选自但不限于:曲安奈德(商品名:Kenalog)、氟轻松(商品名:Vanos)、地塞米松(商品名:decadron)、疱疹、氨来诺(aphthasol)、酮咯酸、氟比洛芬、布洛芬、萘普生、消炎痛、阿司匹林、酮洛芬、吡罗昔康和甲氯芬那酸。
本申请的缓解疼痛的化合物可以选自但不限于:苯佐卡因、利多卡因、普鲁卡因、丙胺卡因、甲哌卡因、阿司匹林、布洛芬、双氯芬酸和水杨酸甲酯。
本申请的抗氧化剂化合物可以选自但不限于:维生素E、抗坏血酸、尿酸、类胡萝卜素、维生素A、类黄酮、多酚、草药抗氧化剂、褪黑素、氨基吲哚、硫辛酸、咖啡酸、β-胡萝卜素、鞣花酸、表儿茶素、没食子表儿茶素酸酯、阿魏酸、染料木黄酮、曲酸、α-硫辛酸、番茄红素、白藜芦醇、间苯二酚、迷迭香酸、水飞蓟宾、茶黄素、生育酚、生育三烯酚、trolox和泛醌-10。
本申请的酶可以选自但不限于:蛋白酶:木瓜蛋白酶、菠萝蛋白酶、糜蛋白酶、无花果蛋白酶和碱性蛋白酶;糖酶:葡糖淀粉酶、α-淀粉酶、β-淀粉酶、葡聚糖酶和变形酶;脂肪酶:植物脂肪酶、胃脂肪酶和胰脂肪酶;以及葡糖淀粉酶、黑曲霉(Aspergillus niger)来源的糖化葡糖淀粉酶。
本申请的调味剂可以选自但不限于:精油和各种调味醛、酯、醇。精油的实例包括留兰香、薄荷、冬青、黄樟、丁香、鼠尾草、桉树、马郁兰、肉桂、香芹酮、茴香脑、柠檬、酸橙、葡萄柚和橙子的油、野生牛至油、茶树叶油、冬青油、椰子油、没药油和葡萄柚皮油。
本申请的凉味剂可以选自但不限于:薄荷醇、乳酸薄荷酯、单琥珀酸薄荷酯、碳酸薄荷醇乙二醇酯、碳酸薄荷醇丙二醇酯、薄荷酮甘油缩酮、3-(l-薄荷氧基)丙烷-1,2-二醇、(-)-异胡薄荷、WS-3[N-乙基-对薄荷烷-3-甲酰胺]、WS-23(2-异丙基-N,2,3-三甲基丁酰胺)、WS-5[3-(对薄荷烷-3-甲酰胺基)乙酸乙酯]。
本申请的凉味剂可以选自但不限于:乙酰磺胺酸钾、阿斯巴甜、纽甜、糖精、三氯蔗糖、甜叶菊、Advantame、环磺酸盐、山梨糖醇、木糖醇和赤藓糖醇。
在一些实施方案中,以包括本申请的义齿黏附剂组合物的黏膜黏附剂组合物的总重量计,烷基乙烯基醚-马来酸/马来酸酐或其盐的共聚物为约10重量%至约20重量%、或约20重量%至约30重量%、或约30重量%至约40重量%、或约40重量%至约50重量%、或约50重量%至约60重量%、或约60重量%至约75重量%的范围的合适量。
在一些实施方案中,以包括本申请的义齿黏附剂组合物的黏膜黏附剂组合物的总重量计,纤维素醚以约10重量%至约20重量%、或约20重量%至约30重量%、或约30重量%至约40重量%、或约40重量%至约50重量%的范围的合适量。
在一些实施方案中,以包括义齿黏附剂组合物的黏膜黏附剂组合物的总重量计,交联的PVP以约0.1重量%至约1重量%、或约0.1重量%至约5重量%、或约5重量%至约10重量%的范围的合适量。
在本申请的一些实施方案中,以包括义齿黏附剂组合物的黏膜黏附剂组合物的总重量计,交联的甲基乙烯基醚/马来酸酐(例如,StabilizeTM QM)、或交联的甲基乙烯基醚/马来酸或其盐为约0.1重量%至约1重量%、或约1重量%至约5重量%、或约5重量%至约10重量%的范围的合适量。
在一些实施方案中,以包括义齿黏附剂组合物的黏膜黏附剂组合物的总重量计,基于疏水性油或亲水性非油组分的载体为约10重量%至约20重量%、或约20重量%至约30重量%、或约30重量%至约40重量%、或约40重量%至约50重量%、或约50重量%至约60重量%或约60重量%至约75重量%的范围的合适量。
在一些实施方案中,以包括义齿黏附剂组合物的黏膜黏附剂组合物的总重量计,抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂和甜味剂为约0.01重量%至约0.1重量%、或约0.1重量%至约1重量%、或约1重量%至约10重量%或约10重量%至约20重量%的范围的合适量。
在一些实施方案中,存在于本申请的组合物中的烷基乙烯基醚-马来酸/酸酐共聚物的重均分子量为约500,000至3,000,000,其适用于通过以下制备义齿黏附剂:在溶剂或无溶剂工艺中,在约50℃至150℃,在自由基引发剂的存在下,使约50摩尔%的马来酸酐、约50摩尔%的C1-C4烷基乙烯基醚共聚以产生基本上没有残留马来酸共聚物或马来酸酐共聚物的均一细粉末。马来酸酐和C1-C4烷基乙烯基醚的共聚物优选地具有约50,000cps至约150,000cps的布氏粘度。
在一些实施方案中,存在于本申请的组合物中的甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物(PVM/MA共聚物)的数均分子量为约50,000至约500,000道尔顿,其中聚合物中约50重量%至约100重量%的羧基单元转化为金属盐的混合物,进一步,其中,金属选自钙、钠、锶、锌、镁、铁、硼、铝、钾、钒、铬、锰、镍、铜、钇、钛及其混合物。
在一些实施方案中,烷基乙烯基醚-马来酸的共聚物的盐或烷基乙烯基醚-马来酸酐的共聚物的盐在25℃下,在甲乙酮(MEK)溶液中,以1重量/体积%溶液进行测量时具有2.5至5.0的比粘度。
如本文所公开,在一些实施方案中,甲基乙烯基醚的重均分子量(Mw)范围为约700,000至约3,000,000。在一些实施方案中,甲基乙烯基醚共聚物的重均分子量(Mw)范围为500,000至3,000,000。
如本文所公开,在一些实施方案中,甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物或其盐(PVM/MA共聚物)的数均分子量的范围为50,000至约500,000。
如本文所公开,在一些实施方案中,羧甲基纤维素钠的分子量为约500,000至约1,200,000道尔顿。在一些实施方案中,羧甲基纤维素钠的分子量范围为600,000至约800,000道尔顿。
根据本申请的另一实施方案,预期使用至少一种赋形剂。用于本申请目的的合适赋形剂选自防腐剂、调味试剂、着色剂、甜味剂、增塑剂、黏结剂、增稠剂、载剂、着色剂、载体、调味剂、香料、感觉剂(sensate)和其混合物。
在一个实施方案中,黏膜黏附剂组合物是洁牙剂、义齿清洁剂、口香糖、锭剂、口腔喷雾剂、摩丝、泡沫、牙科用具(牙线或牙带)、牙科溶液、义齿清洁剂、牙膏、牙粉、外用口腔凝胶、漱口水、口腔喷雾剂、义齿产品、可溶解膜、条带、口服片剂、气雾剂、薄片、口香糖或口气清新剂的形式的口腔凝胶、口腔软膏、口腔洗剂、口腔颊部组合物、舌下组合物、腭部组合物和义齿黏附剂组合物。
在一个实施方案中,预期使用适用于包括义齿黏附剂的黏膜黏附剂组合物的材料,特别是在相关浓度下用于卫生组合物例如液体、粉末、膏剂、凝胶、热塑性固体、水凝胶或其组合是安全且可口的。
提供以下实施例的目的是为了说明但并非限制聚合物的制备和使用。在这些实施例中,使用了以下缩写:
PVP :聚乙烯吡咯烷酮
MVE :甲基乙烯基醚
MA :马来酸酐/马来酸
CMC :羧甲基纤维素
wt% :重量百分数
Flexithix :轻度至中度交联的聚乙烯吡咯烷酮
Polyplasdone XL-10 :自交联的聚乙烯吡咯烷酮
Stabilieze QM :与1,9-癸二烯交联的聚(甲基乙烯基醚/马来酸酐)
PVP K-90 :平均分子量为1,300,000道尔顿的聚乙烯吡咯烷酮粉末
Gantrez MS-955 :聚(甲基乙烯基醚/马来酸酐)的钠/钙混合盐
Aqualon CMC 7H3SXF :羧甲基纤维素钠
Germaben II :含有丙二醇、对羟基苯甲酸丙酯、对羟基苯甲酸甲酯和重氮烷基脲的液体
PVP K-15 :平均分子量为8,000道尔顿的聚乙烯吡咯烷酮粉末
此外,通过以下实施例详细说明本申请的某些方面。在此给出的实施例用于说明本申请并且不旨在对其进行限制。
实施例
可用于本发明的性能增强剂材料是可溶胀的或部分溶于水/唾液的亲水性聚合物。这些聚合物可以通过它们的化学结构对水溶液的显著亲和力来表征,它们在水性溶液中会溶胀而不是溶解。这些聚合物的吸收范围从低到中,通常在其结构内保留1重量%-30重量%的水。可以保留其重量的30重量%以上的水的超强吸收的聚合物不能用于这种应用,因为它们倾向于通过吸收促进渗出的过量唾液来破坏义齿黏附剂膏剂的稳定性。
表1:性能增强剂和黏附剂聚合物
对比实施例1:标准油基义齿黏附剂制剂(E1)
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的标准油基义齿黏附剂制剂。加热夹套设置为保持194℉(90℃)的恒定温度。按照表1添加制作义齿黏附剂膏剂所需的成分。将凡士林(40g)和白矿物油(40g)装入KitchenAid混合器的加热碗中,低速混合10分钟,直到凡士林完全融化并产生均质透明液体。将羧甲基纤维素钠(54g)加入KitchenAid中并与油剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(66g)加入KitchenAid中,并以中速再混合30分钟以产生均匀稠度的糊状物。加入合适的色素并混合直至均匀分散。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例2:实验的油基义齿黏附剂制剂(E12)5% PVP K-90
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的实验的油基义齿黏附剂制剂。加热夹套设置为保持194℉(90℃)的恒定温度。按照表1添加制作义齿黏附剂膏剂所需的成分。将凡士林(40g)和白矿物油(40g)装入KitchenAid混合器的加热碗中,低速混合10分钟,直到凡士林完全融化并产生均质透明液体。将未交联的PVP(PVP-K-90)(10g)加入KitchenAid中,并与油剧烈混合15分钟直至均匀分散。将羧甲基纤维素钠(50g)加入KitchenAid中,并与油剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(60g)加入KitchenAid中,并以中速再混合30分钟以产生均匀稠度的糊状物。加入合适的色素并混合直至均匀分散。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例3:实验的油基义齿黏附剂制剂(E13) 3%Stabileze QM
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的实验的油基义齿黏附剂制剂。加热夹套设置为保持194℉(90℃)的恒定温度。按照表1添加制作义齿黏附剂膏剂所需的成分。将凡士林(40g)和白矿物油(40g)装入KitchenAid混合器的加热碗中,低速混合10分钟,直到凡士林完全融化并产生均质透明液体。将交联的聚(MVE/MA)(6g)加入KitchenAid中,并与油剧烈混合15分钟直至均匀分散。将羧甲基纤维素钠(50g)加入KitchenAid中,并与油剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(64g)加入KitchenAid中,并以中速再混合30分钟以产生均匀稠度的糊状物。加入合适的色素并混合直至均匀分散。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例4:实验的油基义齿黏附剂制剂(E14)3% Polyplasdone XL-10
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的实验的油基义齿黏附剂制剂。加热夹套设置为保持194℉(90℃)的恒定温度。按照表1添加制作义齿黏附剂膏剂所需的成分。将凡士林(40g)和白矿物油(40g)装入KitchenAid混合器的加热碗中,低速混合10分钟,直到凡士林完全融化并产生均质透明液体。将交联的PVPPolyplasdone XL-10(6g)加入KitchenAid中并与油剧烈混合15分钟直至均匀分散。将羧甲基纤维素钠(50g)加入KitchenAid中,并与油剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(64g)加入KitchenAid中,并以中速再混合30分钟以产生均匀稠度的糊状物。加入合适的色素并混合直至均匀分散。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例5:实验的油基义齿黏附制剂(E15)3%Flexithix
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的实验的油基义齿黏附剂制剂。加热夹套设置为保持194℉(90℃)的恒定温度。按照表1添加制作义齿黏附剂膏剂所需的成分。将凡士林(40g)和白矿物油(40g)装入KitchenAid混合器的加热碗中,低速混合10分钟,直到凡士林完全融化并产生均质透明液体。将交联的PVP,Flexithix(6g)加入KitchenAid中,并与油剧烈混合15分钟直至均匀分散。将羧甲基纤维素钠(50g)加入KitchenAid中,并与油剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(64g)加入KitchenAid中,并以中速再混合30分钟以产生均匀稠度的糊状物。加入合适的色素并混合直至均匀分散。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例6:实验的油基义齿黏附剂制剂(E16)2.5%Polyplasdone XL-10+2.5%
Flexithix
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的实验的油基义齿黏附剂制剂。加热夹套设置为保持194℉(90℃)的恒定温度。按照表1添加制作义齿黏附剂膏剂所需的成分。将凡士林(40g)和白矿物油(40g)装入KitchenAid混合器的加热碗中,低速混合10分钟,直到凡士林完全融化并产生均质透明液体。将交联的PVP,Polyplasdone XL-10(5g)和Flexithix(5g)加入KitchenAid中,并与油剧烈混合15分钟直至均匀分散。将羧甲基纤维素钠(50g)加入KitchenAid中,并与油剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(60g)加入KitchenAid中并以中速再混合30分钟以产生均匀稠度的糊状物。加入合适的色素并混合直至均匀分散。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例7:实验的无油义齿黏附剂制剂(OF1)1%PVP K-15
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的标准无油义齿黏附剂制剂。加热夹套设置为保持115℉(~46℃)的恒定温度。按照表2添加制作义齿黏附剂膏剂所需的成分。将丙二醇(38.5g)和PEG-400(38.5g)加入KitchenAid混合器的加热碗中,低速混合20分钟,直至获得均质透明液体。将PVP K-15(2g)添加到KitchenAid混合器中并高速混合45分钟直至获得澄清溶液。然后将羧甲基纤维素钠(54g)加入KitchenAid中,并剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的Ca/Na混合盐(66g)加入KitchenAid中并以中速再混合30分钟以产生均匀稠度的糊状物。之后加入GermabenII防腐剂(1g)并再混合15分钟。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
实施例8:实验的无油义齿黏附剂制剂(OF2)1%Flexithix
在配备有数控恒温加热夹套的KitchenAid行星式混合器中制备200g批次的标准无油义齿黏附剂制剂。加热夹套设置为保持115℉(~46℃)的恒定温度。按照表2添加制作义齿黏附剂膏剂所需的成分。将丙二醇(39.5g)和PEG-400(39.5g)加入KitchenAid混合器的加热碗中,低速混合20分钟,直至获得均质透明液体。将交联的PVP,Flexithix(2g)添加到KitchenAid混合器中,并高速混合45分钟直至获得澄清的薄凝胶。然后将羧甲基纤维素钠(54g)加入KitchenAid中,并剧烈混合30分钟直至均匀分散。然后将聚(MVE/MA)的混合Ca/Na盐(66g)加入KitchenAid中,并以中速再混合30分钟以产生均匀稠度的糊状物。之后加入Germaben II防腐剂(1g)并再混合15分钟。关闭加热,连续中速搅拌2小时使义齿黏附剂膏剂冷却至室温。冷却至室温后,将50g义齿黏附剂样品装入适当的分配管中并热封。剩余的义齿黏附剂装入透明玻璃罐中,用于存储稳定性研究。
表2:油基义齿黏附剂组合物
实施例9:义齿黏附剂的测试方法
黏附力和相对的义齿黏附剂的膜厚度在来自Stable Microsystems TextureTechnologies Corp.的TA.XT Plus质构分析仪仪器上记录,该仪器配备有50Kg测力传感器并与运行Exponent软件版本6.1.11.0的PC连接。质构分析仪配备有定制的义齿形有机玻璃探针-夹具组件。使用蠕动泵实现了有机玻璃探针-夹具组件的壁之间的人工唾液灌注。使用佳能EOS 5d Mark IV数码单反相机记录在质构分析仪仪器上进行黏附性能评估的义齿黏附剂膏剂的实时延时图像。
将含有义齿黏附剂膏剂的样品管排出截留的空气,并在盖上盖子的情况下,挤压几次以使管内的内容物均质化。始终丢弃从管中出来的前100mg材料。
在分析天平上,将三个几乎相同的义齿黏附剂膏剂的条称重到底部有机玻璃夹具的义齿形空腔中。对于每次测试,应用于底部夹具的义齿黏附剂膏剂的总质量为2.0(+0.1)g。将底部夹具安装到质构分析仪仪器上,将顶部探针向下移动到底部夹具的空腔中,以在4.5Kg的精确压缩力下均匀涂抹义齿黏附剂膏剂并填充空腔的下半部分。开始灌注人工唾液。在整个实验过程中,义齿黏附剂膏剂保持接触并浸没在以1毫升/分钟的流速持续更新的薄人工唾液层中。一旦义齿黏附剂膏剂层被人工唾液完全覆盖,7小时的测试程序就开始了。在实验期间连续测量咀嚼时的黏附力(以牛顿为单位)以及顶部和底部探针之间的义齿黏附剂的膜厚度(以mm为单位)。对制备的义齿黏附剂制剂的每个样品进行四次连续的试验。对于黏附性能和厚度变化,比较每个样品4次试验的平均曲线。每个样品的总黏附力计算为每个样品连续4次试验的平均曲线下的面积。
表3:无油义齿黏附剂组合物
实施例10:黏附结果
图1-4表示样品油基义齿黏附剂E1、E12-16的平均黏附谱的重叠。每个义齿黏附剂样品的黏附谱轨迹是四次连续试验的平均值。每个重叠曲线被划分为缓慢咀嚼运动或休息阶段(RP)和快速咀嚼运动或动态咀嚼(DM)的交替阶段。黏附力以牛顿(N)记录和报告。图5示出了每种代表性义齿黏附剂制剂的总黏附力。总黏附力(以N为单位)测量为每种代表性义齿黏附制剂的平均黏附曲线轨迹下的总面积。
图6表示样品无油义齿黏附剂OF1和OF2的平均黏附谱的重叠。每个义齿黏附剂样品的黏附力谱轨迹是四次连续试验的平均值。每个重叠的曲线被划分为缓慢咀嚼运动或休息阶段(RP)和快速咀嚼运动或动态咀嚼(DM)的交替阶段。黏附力以牛顿(N)记录和报告。图7示出了每种代表性无油义齿黏附剂制剂的总黏附力。总黏附力(以N为单位)测量为每种代表性义齿黏附剂制剂的平均黏附曲线轨迹下的总面积。
实施例11:义齿黏附剂制剂的稳定性
图8示出所选的油基义齿黏附剂制剂在45℃存储12周后的稳定性。将制剂中的疏水性载体在45℃存储12周后的的脱水收缩程度视为油分离,计算为由于脱水收缩而作为油分离出来的制剂的高度%,并被认为是制剂稳定性的量度。油分离%越低,样品在45℃存储12周后稳定性则越好。
实施例12:黏膜黏附剂制剂
口腔可接受的黏膜黏附制剂的实例描述于表4和5中。
表4:油基黏膜黏附剂组合物
表5:无油黏膜黏附剂组合物
虽然已就具体方面描述了所公开和/或要求保护的发明构思的组合物和方法,但对于本领域普通技术人员来说显而易见的是可以对本文描述的组合物和/或方法以及方法的步骤或步骤顺序进行改变,而不背离所公开和/或要求保护的发明构思的构思、精神和范围。所有这种类似的替代品和修改。
Claims (22)
1.一种黏膜黏附剂组合物,包含:
i.约10重量%至约75重量%的马来酸共聚物或马来酸酐共聚物或其盐;
ii.约10重量%至约50重量%的至少一种纤维素醚;
iii.约0.1重量%至约10重量%的可溶胀但不溶于水的交联的聚乙烯吡咯烷酮聚合物;和
iv.约30重量%至约70重量%的口服可接受的载体。
2.根据权利要求1所述的黏膜黏附剂组合物,其中,所述马来酸共聚物或马来酸酐共聚物包含马来酸或马来酸酐或其盐的重复单元。
3.根据权利要求1所述的黏膜黏附剂组合物,其中,所述马来酸共聚物或马来酸酐共聚物包含马来酸或马来酸酐和C1-C4烷基乙烯基醚,具有约500,000至3,000,000的预定重均分子量,通过以下制备:在溶剂或无溶剂工艺中,在约50℃至150℃,在自由基引发剂的存在下,使约50摩尔%的马来酸或马来酸酐、约50摩尔%的C1-4烷基乙烯基醚共聚,以产生基本上没有残留马来酸酐的均一细粉末。
4.根据权利要求3所述的黏膜黏附剂组合物,其中,甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物的数均分子量为约50,000至约500,000,其中所述聚合物中约50重量%至约100重量%的羧基单元转化为金属盐的混合物,所述金属选自钙、钠、锶、锌、镁、铁、硼、铝、钾、钒、铬、锰、镍、铜、钇、钛及其混合物。
5.根据权利要求4所述的黏膜黏附剂组合物,其中,所述甲基乙烯基醚-马来酸共聚物或所述甲基乙烯基醚-马来酸酐共聚物的盐在25℃在甲乙酮(MEK)溶液中以1重量/体积%溶液进行测量时具有约2.5至5.0的比粘度。
6.根据权利要求5所述的黏膜黏附剂组合物,其中,所述甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物或其盐构成所述组合物的约18重量%至约66重量%。
7.根据权利要求6所述的黏膜黏附剂组合物,其中,所述甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-酸酐共聚物的重均分子量为约700,000至约3,000,000。
8.根据权利要求1所述的黏膜黏附剂组合物,其中,所述纤维素醚选自甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠及其混合物。
9.根据权利要求8所述的黏膜黏附剂组合物,其中,所述纤维素醚是羧甲基纤维素钠(NaCMC)。
10.根据权利要求9所述的黏膜黏附剂组合物,其中,所述羧甲基纤维素的数均分子量范围为500,000至1,200,000道尔顿。
11.根据权利要求10所述的黏膜黏附剂组合物,其中,所述羧甲基纤维素钠的数均分子量范围为约600,000至约800,000道尔顿。
12.根据权利要求11所述的黏膜黏附剂组合物,其中,所述羧甲基纤维素钠构成所述黏膜黏附剂组合物的约15重量%至约50重量%。
13.根据权利要求1所述的黏膜黏附剂组合物,其中,所述交联的聚乙烯吡咯烷酮呈细的、自由流动的白色粉末的形式。
14.根据权利要求1所述的黏膜黏附剂组合物,还包含约0.001重量%至约5重量%的赋形剂,所述赋形剂选自防腐剂、着色剂、甜味剂、色素、增塑剂、黏结剂、增稠剂、载剂、缓冲剂、保湿剂、表面活性剂、去污剂、发泡剂、胶凝剂、稳定剂、研磨剂、抗氧化载体、脱敏剂、香料、感觉剂及其混合物。
15.根据权利要求1所述的黏膜黏附剂组合物,还包含约0.01重量%至约20重量%的活性成分,所述活性成分选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂及其混合物。
16.根据权利要求1所述的黏膜黏附剂组合物,其中,所述口腔可接受的载体包含疏水性油或亲水性非油组分,选自凡士林、矿物油、橄榄油、植物油、硅或甘油、聚乙二醇、丙二醇、聚(环氧乙烷-环氧丙烷)共聚物、二甘醇、三甘醇、山梨糖醇、水、口腔可接受的表面活性剂及其混合物。
17.根据权利要求1所述的黏膜黏附剂组合物,其中,所述组合物是粉末、膏剂、糊剂、液体、凝胶、气雾剂和/或薄片形式的口腔凝胶、口腔软膏、口腔洗剂、口腔颊部组合物、舌下组合物、腭部组合物和义齿黏附剂组合物。
18.一种黏膜黏附剂口腔组合物,包含:
i.约15重量%至约70重量%的马来酸共聚物,所述马来酸共聚物选自甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物或其盐;
ii.约10重量%至约50重量%的至少一种羧甲基纤维素;
iii.约0.1重量%至约10重量%的可溶胀的、不溶于水的交联的聚乙烯吡咯烷酮;
iv.约10重量%至约60重量%的口服可接受的载体;和
v.约0.01重量%至约20重量%的活性成分,所述活性成分选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂及其混合物,并且进一步其中所述组合物是凝胶或液体。
19.一种义齿黏附剂组合物,包含:
i.约15重量%至约70重量%的马来酸共聚物,所述马来酸共聚物选自甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物或其盐;
ii.约10重量%至约50重量%的至少一种羧甲基纤维素;
iii.约0.1重量%至约10重量%的可溶胀的、不溶于水的交联的聚乙烯吡咯烷酮;
iv.约10重量%至约60重量%的口服可接受的载体;和
v.约0.01重量%至约20重量%的活性成分,所述活性成分选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂及其混合物,并且进一步其中所述组合物是凝胶或液体。
20.根据权利要求19所述的义齿黏附剂组合物,其中,所述组合物以有效的义齿保持量涂布在义齿的内表面上。
21.根据权利要求19所述的义齿黏附剂组合物,其中,所述组合物用于改善义齿黏附性能,包括黏附保持的强度和持续时间、膜厚度、缓冲效果、渗出控制、保质期存储稳定性、易清洁性、延长的保持时间和增黏性能。
22.一种将具有生物接触表面的义齿黏附至牙床或口腔顶部的方法,所述方法包括用义齿黏附剂组合物处理所述义齿的所述生物接触表面,所述义齿黏附剂组合物包含:
i.约15重量%至约70重量%的马来酸共聚物,所述马来酸共聚物选自甲基乙烯基醚-马来酸共聚物或甲基乙烯基醚-马来酸酐共聚物或其盐;
ii.约10重量%至约50重量%的至少一种羧甲基纤维素;
iii.约0.1重量%至约10重量%的可溶胀的、不溶于水的交联的聚乙烯吡咯烷酮;
iv.约10重量%至约60重量%的口服可接受的载体;和
v.约0.01重量%至约20重量%的活性成分,所述活性成分选自抗细菌剂、抗炎剂、镇痛剂、抗氧化剂、酶、调味剂、凉味剂、甜味剂及其混合物。
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US20130209376A1 (en) * | 2010-04-14 | 2013-08-15 | Ips Investments Inc. | Oral care compositions |
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GB1117515A (en) * | 1966-07-08 | 1968-06-19 | Ici Ltd | Maleic anhydride/alkyl vinyl ether copolymer |
JPH06511001A (ja) * | 1991-09-19 | 1994-12-08 | スミスクライン・ビーチャム・コーポレイション | 接着生成物 |
DE4404011A1 (de) * | 1994-02-09 | 1995-08-10 | Jenapharm Gmbh | Neue, adhäsiv wirkende Zubereitungen für mit Flüssigkeit benetzte Oberflächen, Verfahren und Vorrichtung zur Erfassung der Adhäsionszeit diesbezüglicher Zubereitungen |
JP2000197645A (ja) * | 1998-12-29 | 2000-07-18 | Sunstar Inc | 粉末エアゾ―ル式義歯安定剤 |
CA2628101C (en) * | 2005-11-09 | 2013-01-08 | The Procter & Gamble Company | Denture adhesive articles |
JP2010501609A (ja) * | 2006-08-30 | 2010-01-21 | ヤゴテック アーゲー | コア層と1又は複数のバリヤー層を含む徐放性経口投与用配合剤 |
JP2012520317A (ja) * | 2009-03-11 | 2012-09-06 | アイエスピー インヴェストメンツ インコーポレイテッド | 増粘添加組成物 |
US8906349B2 (en) * | 2009-08-12 | 2014-12-09 | Colgate-Palmolive Company | Oral care composition |
CA2908523A1 (en) * | 2013-04-10 | 2014-10-16 | The Procter & Gamble Company | Oral care compositions containing polyorganosilsesquioxane particles |
JP2016516778A (ja) * | 2013-04-10 | 2016-06-09 | ザ プロクター アンド ギャンブル カンパニー | ポリオルガノシルセスキオキサン粒子を含有する口腔ケア組成物 |
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US4514528A (en) * | 1983-02-16 | 1985-04-30 | Richardson-Vicks Inc. | Hydrophilic denture adhesive |
US5872161A (en) * | 1997-03-27 | 1999-02-16 | The Procter & Gamble Company | Denture adhesive compositions |
US20130209376A1 (en) * | 2010-04-14 | 2013-08-15 | Ips Investments Inc. | Oral care compositions |
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