CN115335080A - 新型口或鼻用组合物 - Google Patents
新型口或鼻用组合物 Download PDFInfo
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- CN115335080A CN115335080A CN202180024747.9A CN202180024747A CN115335080A CN 115335080 A CN115335080 A CN 115335080A CN 202180024747 A CN202180024747 A CN 202180024747A CN 115335080 A CN115335080 A CN 115335080A
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Abstract
本发明公开了用于口腔或鼻腔的组合物。该组合物包含生物活性剂、包含β‑葡聚糖的基质形成剂和填充剂。所述组合物还可包含另外的赋形剂，例如抗氧化剂、防腐剂、味道或风味增强剂、pH调节剂、增塑剂和甜味剂。本发明还公开了制造该组合物的方法。
Description
技术领域
本发明涉及用于口腔或鼻腔的组合物以及制备该组合物的方法，所述组合物包含生物活性剂、包含谷类β-葡聚糖的基质形成剂和填充剂。
背景技术
将药用活性剂递送至口腔和鼻腔通常是获得快速治疗起效和避免胃肠系统的代谢活动的理想给药途径和第一旁路代谢。已经开发了许多固体剂型，例如锭剂、舌下片剂、口香糖、口腔贴片或小袋，以根据通过口腔的治疗为患者获得依从剂型。此类固体剂型通常包含活性剂、填充剂、粘合剂、润滑剂和支持粘膜粘附性、适口性、依从性和活性剂释放的其他成分。
无烟烟草和尼古丁产品的供应商和开发商已经开发了许多配置为通过口腔或鼻腔输送尼古丁的产品。烟草产品包括例如口用或鼻用的咀嚼烟草、湿无烟烟草、鼻烟和干鼻烟。非烟草产品依赖于从烟草中提取的纯尼古丁或合成尼古丁与合适的添加剂一起配制成所例示的口用或鼻用剂型。对于口腔，非烟草剂型可以例如依赖于纤维填充剂材料和充当粘合剂的基质形成剂。尼古丁(3-(1-甲基-2-吡咯烷基)吡啶)是一种挥发性化合物，在热、氧和光的影响下易降解。出于这个原因，寻找合适的非烟草剂型作为抵消其制造过程中的降解、提供合适的尼古丁储存稳定性同时允许在口腔中实现理想的尼古丁释放速率并且对用户具有依从性的产品，是一项技术挑战。由于这些原因，尼古丁剂型的开发人员正在寻找新的试剂来替代烟草，但支持延长保质期、理想的释放曲线和对消费者的高依从性。
WO 2010/011445公开了一种适合于递送如尼古丁等活性剂的口用植物纤维产品。海藻酸盐作为基质形成剂的引入为产品提供了理想的释放特性和对易受影响的活性剂的适当稳定化。
WO 2010/104464公开了封装在袋中的包含如尼古丁等活性剂的用于口腔的海藻酸盐颗粒。
WO 2015/051308和US 2015/0098996公开了烟草或尼古丁锭剂，其具有至少40％重量的主要是麦芽糖糊精的水溶性纤维和少于15％的水。然而，没有公开关于尼古丁的保质期或尼古丁在口腔中的释放特性的任何内容。
EP1622627描述了包含谷类β-葡聚糖和药剂的药用组合物，被建议用于在口腔中递送如局部麻醉剂等药剂。然而，在该文献中没有制造或实际测试过此类产品，因此无法断定谷类β-葡聚糖是否是用于向口腔或鼻腔递送易受影响的活性剂的合适赋形剂。
US2010/158988描述了基于谷类β-葡聚糖的可口腔中使用的干燥、可溶解膜或包衣，其可包含至多10重量％的填充剂。然而，这些膜没有显示出任何作为适于将尼古丁递送至口腔或鼻腔的尼古丁产品的适应性。EP1790687描述了可包含尼古丁的类似干膜，但没有教导与传统烟草产品具有类似的消费者依从性的尼古丁剂型。
WO2010091649涉及用于口腔的无烟草尼古丁产品，从而描述了pH值。然而，没有公开如何通过有目的地选择的支持性试剂来影响尼古丁的稳定性和释放。
CN10707494公开了一种口香糖，其包含树胶基质、β-葡聚糖、甜味剂和作为活性剂的纤维素卵磷脂。
CN104784197公开了一种专门用于递送活性剂表没食子儿茶素没食子酸酯的组合物，其包含β-葡聚糖。
US6499490公开了一种包含β-葡聚糖和烟叶提取物的烟草替代片材。
发明内容
本发明的一个目的是提供适合将生物活性剂递送口腔或鼻腔的组合物，该组合物允许活性剂在整个制造和储存过程中的稳定性，同时允许所述活性剂的合适释放曲线。
本发明的另一个目的是提供支持活性剂的受控释放速率和所述释放速率的合适持续时间的组合物。
本发明的另一个目的是提供下述组合物，该组合物促进在储存期间易于降解的活性剂的稳定化，从而在具有较高含水量的组合物中也获得具有长保质期的稳定产品。
本发明的另一个目的是提供对口腔或鼻腔粘膜具有高依从性的组合物，以避免因重复或长期暴露而引起的局部刺激和副作用。
本发明的又一个目的是提供适合将尼古丁递送至口腔或鼻腔的组合物，从而满足用户对可比的常规烟草产品或药物产品依从性的期望。
总的来说，本发明涉及用于口腔或鼻腔的组合物，所述组合物包含生物活性剂、包含β-葡聚糖的基质形成剂和填充剂。
在本发明的一般语境中，基质形成剂能够与填充剂一起提供内聚的均质的组合物，该组合物包含生物活性剂并有助于对易受影响的此类试剂发挥稳定化效果，同时有助于活性剂在与口腔或鼻腔接触时的可控的理想的释放曲线。稳定化效果和释放曲线在一方面可以由与填充剂(例如在基质形成剂和填充剂的纤维之间)的相互作用或协同作用引起。因此，在本发明的组合物中，活性剂和基质形成剂之间的相互作用可用于调节和控制释放速率。
本发明的基质形成剂还用于在组合物中以受控的方式结合生物活性剂。例如，当活性剂是尼古丁时，可以选择基质形成剂，使得受控量的尼古丁是游离的、未结合的尼古丁，并且受控量的尼古丁从基质形成剂中逐渐可控地释放。例如，通过增加本发明组合物中基质形成剂的量，更多的尼古丁被结合并逐渐释放。因此，可以开发组合物以向用户提供令人满意的施用到口腔或鼻腔的尼古丁初始剂量，并在预定时长内提供从组合物中逐渐释放的尼古丁。对于尼古丁产品，基质形成剂可用于满足用户依从性的不同要求。
在一方面，本发明的组合物包含少于50重量％的基质形成剂，例如少于40重量％或少于30重量％和少于20重量％，或0.1重量％至10重量％，或0.5重量％至5重量％。
在其他方面，本发明的组合物包含超过50重量％的基质形成剂，例如50重量％至90重量％，或50重量％至70重量％。
此外，在这种一般情况下，填充剂将主要有助于组合物的体积和形状，例如允许在口腔不同部分的用户依从性和/或有助于方便地制造、处理和施用组合物。在实施方式中，填充剂还可以与基质形成剂正向相互作用以稳定试剂并诱导理想的释放特性。
组合物的β-葡聚糖可从各种来源获得，包括谷类和酵母，并且包含至少30％的β(1-3)β(1-4)葡聚糖，优选包含70％至99％或几乎100％的β(1-3)β(1-4)葡聚糖。β-葡聚糖优选从谷类中获得，更优选从燕麦获得。谷类β-葡聚糖可通过例如Journal of FoodScience,2017,82(9)(G Maheshwari等人)和Chemical Engineering and Processing,2014,84,第90-97页(O Benito-Román等人)中概述的方法精制为适当的高等级。
在一个方面，本发明的组合物包含基质形成剂，该基质形成剂包含至少50重量％的β-葡聚糖。本发明的组合物可以包含基质形成剂，该基质形成剂还包含至少一种另外的食品或药品级的药学上可接受的树胶或形成凝胶的多糖，优选地选自海藻酸及其合适的盐、黄原胶、角叉菜胶、甲基纤维素、凝胶多糖、支链淀粉、瓜尔胶、阿拉伯胶和类似的多糖，优选所述另外的树胶为海藻酸盐，更优选为海藻酸钠。
本发明组合物的填充剂包含纤维材料，其可以是天然或合成来源。纤维优选来源于植物、藻类或真菌，并且它可以是天然的或用生物工艺或化学方法改性的。在优选的方面，纤维材料是植物纤维，更优选填充剂包含天然或改性纤维素纤维，最优选至少一种微晶纤维素。
在各种实施方式中，填充剂中所含有的植物纤维可以来源于茶、咖啡、烟草、可可、玉米、竹子、燕麦、大麦、黑麦、甜菜、香草、荞麦、土豆、西红柿、茄子、花椰菜、苹果、马黛茶或各种来源的纤维素纤维及类似物。植物纤维可以是天然的或用各种生物或化学方法改性的。烟草纤维可以根据各种用于白度和/或减少亚硝胺的常规技术进行加工。
适于填充剂的微晶纤维素(MCC)可以选自
等级PH-100、PH-102、PH-103、PH-105、PH-112、PH-113、PH-200、PH-300、PH-302，
等级101、102、12、20，
等级50M和90M，
等级，例如
90M等，以及它们的混合物。对于其中需要水溶性微晶纤维素的本发明组合物的实施方式，胶体微晶纤维素级是有用的，例如各种等级的
对于其中需要水溶性微晶纤维素的本发明组合物的实施方式，例如用于鼻腔的粉末组合物，合适的胶体微晶纤维素级是具有Cas No.51395-75-6的等级，例如各种品牌的
优选的这种胶体凝胶化MCC的商品名为FEIYUN XW591。
在本发明组合物的实施方式中，填充剂包含多元醇，优选包含选自甘露醇、木糖醇、山梨糖醇、麦芽糖醇和/或异麦芽糖醇、乳糖醇和赤藓糖醇中的一种或多种的多元醇。合适地，本发明组合物包含植物纤维材料和5重量％至70重量％的多元醇，优选填充剂包含甘露醇和至少一种微晶纤维素。
在涉及用于鼻腔的粉末组合物的本发明的实施方式中，填充剂可包含选自纤维素衍生物、淀粉衍生物和聚乙烯吡咯烷酮中的至少一种的粘膜粘附剂，优选地，所述粘膜粘附剂选自羟基乙酸淀粉钠和交联聚乙烯吡咯烷酮中的至少一种。在这样的实施方式中，填充剂可以包含瓜尔胶或淀粉。合适的淀粉是玉米淀粉、预糊化淀粉、羟丙基淀粉和改性或未改性淀粉。
在涉及用于鼻腔的粉末组合物的本发明的实施方式中，所述组合物包含具有例如0.01mm至2mm、或0.05mm至0.5mm、或0.02mm至0.2mm、或0.01mm至0.1mm的受控平均尺寸(直径)的粉末颗粒。对于该组合物，考虑到避免气溶胶化和当颗粒尺寸接近<10μm时有粉末意外分布到肺部的风险，以及避免依从性不足和分布有尺寸超过约数毫米的大颗粒，优化粉末粒径。
生物活性剂可以是通常不被视为药物的治疗性或非治疗性物质，例如自然疗法制剂、兴奋剂或营养保健品。可以通过本发明组合物单独或组合施用的治疗性生物活性物质的实例包括：尿失禁剂；抗组胺药、镇痛药、抗炎药、止吐药、抗癫痫药、血管扩张药、镇咳药和祛痰药、抗痉挛药、激素、利尿药、降血压药、支气管扩张药、抗炎类固醇、抗生素、镇静剂、中枢神经系统活性物质、大麻素，例如Δ9-四氢大麻酚(THC)或大麻二酚(CBD)、减充血剂、泻药和抗酸剂。通常，该组合物可用作药物递送剂型用于患有如昏迷、严重偏头痛、急性中风或胃肠道阻塞等导致无法接受常规吞咽用片剂的并发症的患者。合适的非治疗剂的实例是咖啡因、醇粉末、乙醇、维生素B12、维生素C、维生素E、
辅酶Q10、硒、谷胱甘肽、α-硫辛酸、叶酸、人参、花粉提取物、抗氧化剂、矿物质、扑热息痛、乙酰水杨酸、俄罗斯根和玫瑰根等。
在本发明的实施方式中，组合物具有至少6.5的pH，优选8至9的pH，并且生物活性剂是尼古丁或大麻素，例如THC。
在实施方式中，生物活性剂是尼古丁。术语尼古丁包括合成尼古丁和来自如烟草属等烟草植物或其他植物来源的尼古丁提取物，并且包括任何固体或液体形式的尼古丁或尼古丁衍生物，例如无定形、结晶、多晶形等物理形式，或如异构体和对映异构体等化学形式，以及它们的任何药学上可接受的盐、络合物或溶剂化物。本文中的术语尼古丁还包括尼古丁碱和/或其盐，例如尼古丁盐酸盐、尼古丁二盐酸盐、尼古丁单酒石酸盐、尼古丁酒石酸氢盐、尼古丁硫酸盐、尼古丁氯化锌(一水合物)和尼古丁水杨酸盐。
以游离碱计算，尼古丁通常存在的浓度为约0.1重量％至约5重量％，例如约0.1重量％至约4重量％、约0.1重量％)至约3重量％、约0.1重量％至约2重量％、约0.1重量％至约1重量％、约0.1重量％至约0.75重量％、约0.2重量％至约0.5重量％或约0.2重量％至约0.4重量％。与本发明组合物一起使用的尼古丁或其盐优选具有高纯度，例如99.5％纯度。
本发明组合物的抗氧化剂是在至少6.5、例如8至9的pH下有效的抗氧化剂，优选所述抗氧化剂是络合结合抗氧化剂，更优选所述抗氧化剂选自抗坏血酸的碱金属和/或碱土金属盐、柠檬酸钙、乳酸钙、马来酸钙、酒石酸钙、乙二胺四乙酸钙二钠、磷酸钙和柠檬酸铵中的至少一种，更优选所述抗氧化剂是选自抗坏血酸磷酸钠、抗坏血酸钾、抗坏血酸钙、抗坏血酸磷酸钙、抗坏血酸镁中的抗坏血酸盐。最优选所述抗氧化剂是抗坏血酸钙。当生物活性剂是尼古丁时，这种类型的抗氧化剂通常是优选的。然而，其他类型的活性剂可能需要补充或不同的抗氧化剂或抗氧化剂体系以获得合适的储存稳定性。
本发明的组合物还包含选自增塑剂、pH调节剂、防腐剂、味道或风味增强剂、着色剂和甜味剂中的至少一种赋形剂。
增塑剂可以是例如聚乙二醇、丙二醇、甘油和山梨糖醇。优选的增塑剂是山梨糖醇，可选地与一部分甘油一起。
pH调节剂能够在组合物中维持至少6.5的pH并且可举出碳酸盐，包括单碳酸盐、碳酸氢盐和倍半碳酸盐，以及生理上可接受的酸的其他碱金属盐，例如乙酸盐、甘氨酸盐、葡糖酸盐、硼酸盐、甘油磷酸盐，或如柠檬酸等弱有机酸、磷酸盐、如氢氧化钠和氢氧化钾等金属氢氧化物，以及它们的混合物。合适的pH调节剂的实例是碳酸氢钠和碳酸钠以及它们的混合物。优选在生产组合物时pH较高，例如pH为8至9，但pH调节剂应能够在整个储存和使用过程中保持pH>6.5。
防腐剂可以选自食品和制药工业中批准的试剂，例如山梨酸、山梨酸盐、苯甲酸、乳酸和生理上可接受的盐。优选的防腐剂是山梨酸钾。
味道或风味增强剂包括氯化铵、精油(包括包含醇、酯、醛和内酯的混合物的切碎的花、叶、果皮或浆化全果的蒸馏物、溶剂提取物或冷榨物)或香精(包括精油的稀释溶液或合成化学共混物的混合物)，以匹配来自例如佛手柑、桉树、橙子、橘子、柑橘、柠檬、胡椒薄荷、薄荷、薄荷醇、甘草、冬青、烟草、咖啡、香草、酸橙、苹果、桃及其混合物的所需风味。其他实例包括：酿造物和烈酒(例如干邑、威士忌、罗姆酒、杜松子酒、雪利酒、波特酒和葡萄酒)、桉树、甘草和薄荷醇的人造和天然香料。
着色剂可以选自含有吸收光的化学基团的染料，包括例如靛蓝胭脂红、苋菜红、赤藓红、炭黑、二氧化钛及其任何混合物等染料。
甜味剂可以是不能在口中发酵的天然甜味剂，或人造甜味剂，例如阿斯巴甜、安赛蜜、糖精、甜蜜素、甜叶菊提取物和其他类似试剂。
在本发明的一些方面，所述组合物是适于递送至鼻腔的粉末组合物并且包含：少于50％、优选0.5重量％至5重量％的所定义的基质形成剂，和少于20重量％的水、优选1重量％至15重量％的水。这种组合物的粉末颗粒的尺寸范围为0.01mm至5mm，或优选0.05mm至2mm。在这样的组合物的实施方式中，填充剂包含水溶性纤维素，优选水溶性微晶纤维素，更优选水溶性和水不溶性微晶纤维素的组合。此类组合物还可包含如上定义的活性剂、填充剂和赋形剂。在适合鼻用的一个实施方式中，组合物包含尼古丁、作为基质形成剂的β-葡聚糖、包含至少部分水溶性纤维素的填充剂、少于20重量％的水、pH调节剂、抗氧化剂以及选自防腐剂、味道/风味增强剂和甜味剂中的一种或多种的其他赋形剂。在适合鼻用的一个实施方式中，组合物是粒径小于约2mm的粉末，并且包含尼古丁、作为基质形成剂的β-葡聚糖、包含至少部分水溶性的纤维素的填充剂、少于20重量％的水、pH调节剂、抗氧化剂和选自防腐剂、味道/风味增强剂和甜味剂中的一种或多种的其他赋形剂。在适合鼻用的另一个实施方式中，组合物是粒径为0.01mm至5mm的粉末，并且包含尼古丁、作为基质形成剂的β-葡聚糖、包含至少部分水溶性的纤维素的填充剂、1重量％至15重量％的水、作为pH调节剂的碳酸氢钠、作为抗氧化剂的抗坏血酸钙和选自防腐剂、味道/风味增强剂和甜味剂中的一种或多种的其他赋形剂。
在本发明的多个方面中，组合物适于通过与粘膜接触而递送至口腔。此类组合物包含少于50％、优选0.1重量％至10重量％、更优选0.5重量％至5重量％的如上定义的基质形成剂，并且包含至少30重量％的水，优选40重量％至60重量％的水。此类组合物还可包含如上定义的活性剂、填充剂和赋形剂。在实施方式中，组合物包含至少40重量％的填充剂，所述填充剂优选包含微晶纤维素。合适地，此类组合物可以作为常规烟草产品提供，例如规定量的组合物包装在小袋中的鼻烟产品。在此类组合物的一个实施方式中，其包含尼古丁、作为基质形成剂的β-葡聚糖、包含微晶纤维素的填充剂、至少30重量％的水、pH调节剂、抗氧化剂和选自防腐剂、味道/风味增强剂和甜味剂中的一种或多种的其他赋形剂。在此类组合物的一个实施方式中，其包含尼古丁、作为基质形成剂的β-葡聚糖、包含微晶纤维素和可选的甘露醇和/或其他植物纤维的填充剂、40重量％至60重量％的水、pH调节剂、抗氧化剂和选自防腐剂、味道/风味增强剂和甜味剂中的一种或多种的其他赋形剂。在此类组合物的一个实施方式中，其包含尼古丁、包含β-葡聚糖和如上定义的一种或多种另外的药学/营养学上可接受的树胶的基质形成剂、包含微晶纤维素和可选的甘露醇和/或其他植物纤维的填充剂、40重量％至60重量％的水、pH调节剂、抗氧化剂和选自防腐剂、味道/风味增强剂和甜味剂中的一种或多种的其他赋形剂。
在本发明的多个方面中，所述组合物适于作为与唾液接触而逐渐溶解的锭剂或片剂递送至口腔。该组合物包含至少50％的如前定义的基质形成剂，其包含少于30重量％的水，优选1重量％至30重量％的水。此类组合物还可包含如上定义的活性剂、填充剂和赋形剂。在某些实施方式中，填充剂可包含微晶纤维素，并且在某些实施方式中，锭剂可具有包含活性剂的包衣，优选包含设计用于在建立逐渐释放之前为使用提供初始速效剂量的尼古丁。
在本发明的其他方面，组合物包含超过50％的基质形成剂并且配置为适合于透粘膜递送活性剂的膜。膜组合物的厚度为0.01mm至7mm，并且可选地包含增塑剂。在一个实施方式中，这些组合物包含0.05重量％至20重量％、优选5重量％至10重量％的填充剂，优选所述填充剂是微晶纤维素和增塑剂，优选所述增塑剂选自山梨糖醇和甘油中的至少一种。
填充剂和其他提到的赋形剂的成分和量可以根据最终产品的所需特性(例如为了获得口或鼻用的吸引力)而变化。
这些和其他实施方式将在以下详细描述中更充分地举例说明。
在另一个一般方面，本发明涉及用于口腔和鼻腔的组合物的制造方法。该方法包括：将填充剂、至少一种基质形成剂和抗氧化剂干混；将干燥混合物与包含pH调节剂的第一水溶液混合；添加包含防腐剂、味道或风味增强剂和甜味剂中的至少一种的第二水溶液；添加包含一种或多种生物活性剂的第三水溶液；最后将所有添加至混合物的成分与合适含量的水混合。
在该方法的一个实施方式中，将第一步骤中的填充剂与基质形成剂和抗氧化剂干混。
在该方法的一个实施方式中，将第一步骤中的填充剂与抗氧化剂干混，第三水溶液包含基质形成剂和一种或多种生物活性剂。
在一个替代方案中，该方法可以配置为通过对所得混合物的一个或多个进一步加工步骤来生产鼻用粉末组合物，例如喷雾干燥成粒径为约1mm以下的具有少于20重量％的水、例如1重量％至15重量％的水的粉末。
在另一个替代方案中，该方法可以配置为通过对所得混合物的一个或多个进一步加工步骤来生产用于口腔的组合物，所述一个或多个进一步加工步骤使用装袋、形成片剂或锭剂、挤出、冲压、流延、成型、注塑、混炼、纺丝、成膜、稀释成喷雾剂型、成形和与口香糖胶基混合中的至少一种。
具体实施方式
下面的表1进一步说明了包含合适的赋形剂的口或鼻用组合物的实例。
| 成分 | 用途 | 量(重量％) |
| 水 | 加湿 | 2％-70％ |
| 氯化钠 | 味道 | <15％ |
| 微晶纤维素 | 填充剂 | 5％-95％ |
| 碳酸氢钠/碳酸钠 | pH调节剂 | <2％ |
| β-葡聚糖>70％纯度 | 基质形成剂 | <5％ |
| 氯化铵 | 风味 | <2％ |
| 山梨酸钾 | 防腐剂 | <0.2％ |
| 木糖醇 | 甜味剂 | <5％ |
| 安赛蜜/甜叶菊 | 甜味剂 | <0.5％ |
| 薄荷醇/留兰香/柠檬/其他 | 风味 | <5％ |
| 抗坏血酸钙 | 抗氧化剂 | <5％ |
| 尼古丁 | 活性剂 | <20％ |
表1
实施例1
表2展示了使用所述的方法制造的组合物产品的具体实例。
表2
测试了表2的组合物的尼古丁稳定性，其没有香味，pH值可以为约8.5，适合包装在小袋中作为鼻烟型产品用于口腔中。在40℃和75％相对湿度下的9周(相当于在25℃、未调整相对湿度下的10个月)内比较了80g表2的组合物样品和基于烟草的市售鼻烟产品。
| 表2的组合物 | 市售产品 | |
| 含水量重量％ | 45.93 | 41.9 |
| 初始尼古丁量(mg) | 1.1 | 1.0 |
| 9周后的尼古丁量(mg) | 1.1 | 0.74 |
表3
表3表明本发明组合物的β-葡聚糖和抗氧化剂导致尼古丁稳定性显著增加。对类似于表2但没有任何抗氧化剂的组合物的之前测试表现出与市售烟草类产品相当的尼古丁稳定性。该结果表明本发明组合物的包含β-葡聚糖的基质形成剂具有与天然烟草纤维可比的保存尼古丁的能力。总之，包含β-葡聚糖的基质形成剂和螯合结合抗氧化剂的组合提供了尼古丁的有效的长期稳定性。
实施例2
表4
表4显示了包含β-葡聚糖作为基质形成剂的锭剂或水溶性片剂的实例。
锭剂或片剂是通过将表4中的所有成分干混而制成的，将所得产物转移到常规的片剂成型机中并经受高压而成型为片剂/锭剂。将片剂喷雾涂布并在涂布槽中干燥以获得所需味道的包衣，包衣包含甜味剂、芳香剂和类似试剂。包衣可以可选地包含尼古丁以提供初始剂量。
实施例3
根据本发明和表1的产品具有0.89重量％的尼古丁、约41重量％的水、1％或2％的作为基质形成剂的β-葡聚糖。该产品是用上述两种替代方法制成的。在工艺1中，在第一步骤中将β-葡聚糖与填充剂干混，在第三步骤中加入尼古丁溶液。工艺1的产品包含1重量％的β-葡聚糖。在工艺2中，在第三步骤中将1重量％或2重量％的β-葡聚糖添加到包含尼古丁的溶液中。工艺2的产品包含1重量％或2重量％的β-葡聚糖。将这些产品包装在常规的鼻烟袋中，并使用分别包含微晶纤维素作为填充剂但不包含任何β-葡聚糖作为基质形成剂的两种不含烟草的市售尼古丁产品CP1和CP2进行基准测试。研究了本发明的产品、CP1和CP2的稳定性和尼古丁释放。关于稳定性测试，将产品全部放入40℃、75％湿度的加热柜中9周(代表室温下7个月)。
| 初始尼古丁量重量％ | 7个月后的尼古丁量 | ％尼古丁损失 | |
| 工艺1的产品 | 0.89 | 0.75 | 20 |
| CP1 | 1 | 0.74 | 26 |
| CP2 | 0.61 | 0.46 | 25 |
表5
| 初始pH | 7个月后的pH值 | ％pH降低 | |
| 工艺1的产品 | 7.6 | 7.4 | 3 |
| CP1 | 8.4 | 7.9 | 6 |
| CP2 | 8.3 | 8 | 4 |
表6
| 初始含水量重量％ | 7个月后的含水量重量％ | ％变化 | |
| 工艺1的产品 | 41.2 | 43.9 | +7 |
| CP1 | 41.9 | 39.8 | -5 |
| CP2 | 45.3 | 47.9 | +6 |
表7
表5至表7的结果表明，本发明的包含使用β-葡聚糖的基质形成剂的产品在储存过程中对尼古丁和pH值二者的稳定化显著优于CP1或CP2。产品之间的含水量变化可能是由不同的填充剂造成的。
为了测试本发明的组合物的尼古丁释放能力，如上所述用工艺1和工艺2制造装有产品的小袋，并与CP1进行比较。这些产品由受访者口腔测试，在规定的时长后取出并处理剩余的尼古丁。将用过的小袋切碎装进100ml玻璃瓶并与5ml的Milli-Q水一起用超声波处理5分钟。此后，加入100ml的0.05M氢氧化钾溶液，摇晃样品，然后用超声波处理60分钟。将样品在振动台上摇晃过夜，并在第二天用超声波另外处理30分钟。此后将样品离心并稀释至所需水平，加入内标，然后通过LC/MS/MS分析样品。三次测试的平均结果如下表8所示。
表8
表8表明本发明组合物的基质形成剂的量可用于控制尼古丁的释放速率。例如，在38分钟的时长内，将β葡聚糖的量从1重量％加倍至2重量％会产生多18％的与基质形成剂结合的尼古丁。此外，制造组合物的方法可用于控制尼古丁与基质形成剂的β-葡聚糖的结合量。表8的结果表明，当作为制造工艺中的第三、即最后步骤将尼古丁与基质形成剂一起添加时，获得了更高量的结合尼古丁。
Claims (24)
1.一种用于口腔或鼻腔的组合物，其包含生物活性剂、填充剂和包含β-葡聚糖的基质形成剂。
2.根据权利要求1所述的组合物，其具有至少6.5的pH，其中，所述生物活性剂是尼古丁或大麻素。
3.根据前述权利要求中任一项所述的组合物，其中，所述β-葡聚糖包含至少30％的β(1-3)β(1-4)葡聚糖，优选70％至100％的β(1-3)β(1-4)葡聚糖，优选所述β-葡聚糖是谷类β-葡聚糖，优选从燕麦获得。
4.根据前述权利要求中任一项所述的组合物，其中，所述基质形成剂包含至少一种另外的药学上可接受的树胶，优选地选自海藻酸及其盐、黄原胶、角叉菜胶、甲基纤维素、凝胶多糖和支链淀粉，优选所述另外的树胶为海藻酸盐，更优选为海藻酸钠。
5.根据权利要求3或4所述的组合物，其中，所述基质形成剂包含至少50重量％的谷类β-葡聚糖。
6.根据前述权利要求中任一项所述的组合物，其包含在至少6.5的pH下有效、优选在8至9的pH下有效的抗氧化剂，优选所述抗氧化剂是络合结合抗氧化剂，优选地选自抗坏血酸的碱金属和/或碱土金属盐、柠檬酸钙、乳酸钙、马来酸钙、酒石酸钙、乙二胺四乙酸钙二钠、磷酸钙和柠檬酸铵中的至少一种，更优选所述抗氧化剂是抗坏血酸钙。
7.根据前述权利要求中任一项所述的组合物，其中，所述填充剂包含纤维材料，优选所述纤维材料是植物纤维，更优选所述填充剂包含天然或改性的纤维素纤维，最优选包含至少一种微晶纤维素。
8.根据前述权利要求中任一项所述的组合物，其中，所述填充剂包含多元醇，优选包含选自甘露醇、木糖醇、山梨糖醇、麦芽糖醇和/或异麦芽糖醇、乳糖醇和赤藓糖醇中的一种或多种的多元醇。
9.根据权利要求8所述的组合物，其中，填充剂包含植物纤维材料和5重量％至70重量％的多元醇，优选所述填充剂包含甘露醇和至少一种微晶纤维素。
10.根据前述权利要求中任一项所述的组合物，其包含至少一种选自防腐剂、味道或风味增强剂、pH调节剂、增塑剂和甜味剂的赋形剂。
11.根据前述权利要求中任一项所述的组合物，其包含少于50重量％、优选少于40重量％的所述基质形成剂。
12.根据前述权利要求中任一项所述的粉末组合物，其适于递送至鼻腔，包含少于20重量％、优选1重量％至15重量％的水。
13.根据权利要求12所述的组合物，其中，粉末颗粒的尺寸为0.01mm至2mm。
14.根据权利要求12或13所述的组合物，其中，所述填充剂包含水溶性纤维素，优选水溶性微晶纤维素，更优选水溶性和水不溶性微晶纤维素的组合。
15.根据权利要求1至11中任一项所述的组合物，其适于与口腔粘膜接触，包含至少30重量％的水和含有微晶纤维素的填充剂。
16.根据权利要求15所述的组合物，其包含40重量％至60重量％的水。
17.根据权利要求1至10中任一项所述的组合物，其适于作为锭剂或片剂在口腔中使用，包含1重量％至30重量％的水和填充剂，所述填充剂包含微晶纤维素、植物纤维和多元醇中的至少一种，优选所述组合物包含至少50重量％的所述基质形成剂。
18.根据权利要求1至10中任一项所述的组合物，其配置为适于透粘膜递送活性剂的厚度为0.01mm至7mm的膜，包含至少50重量％的所述基质形成剂和可选的增塑剂。
19.根据权利要求18所述的组合物，其包含0.1重量％至20重量％、优选5重量％至10重量％的填充剂，优选所述填充剂是微晶纤维素和增塑剂，优选所述增塑剂选自山梨糖醇和甘油中的至少一种。
20.一种制造权利要求1至19中任一项所述的组合物的方法，其包括：
(i)干混填充剂、至少一种基质形成剂和抗氧化剂；
(ii)将干燥混合物与包含pH调节剂的第一水溶液混合；
(iii)添加包含防腐剂、味道或风味增强剂和甜味剂中的至少一种的第二水溶液；
(iv)添加包含一种或多种生物活性剂的第三水溶液并将所有添加至混合物的成分与适量的水混合。
21.根据权利要求20所述的方法，其中，将所述填充剂与所述基质形成剂和所述抗氧化剂干混。
22.根据权利要求20所述的方法，其包括将所述填充剂和所述抗氧化剂干混，并且其中，所述第三水溶液包含所述基质形成剂和所述一种或多种生物活性剂。
23.根据权利要求20至22中任一项所述的方法，其配置为通过对所得混合物的一个或多个进一步加工步骤来生产鼻用粉末组合物，包括干燥成粒径小于2mm的含有少于15重量％水的粉末。
24.根据权利要求20至23中任一项所述的方法，其配置为通过对所得混合物的一种或多种进一步加工方法来生产用于口腔的组合物，所述一种或多种进一步加工方法使用装袋、形成片剂或锭剂、挤出、冲压、流延、成型、注塑、混炼、纺丝、成膜以及与口香糖胶基混合中的至少一种。
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| SE2050380A SE546142C2 (en) | 2020-04-03 | 2020-04-03 | New compositions for oral use |
| PCT/SE2021/050304 WO2021201765A1 (en) | 2020-04-03 | 2021-04-06 | New compositions for oral or nasal use |
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| JP (1) | JP2023520044A (zh) |
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| CN (1) | CN115335080A (zh) |
| CA (1) | CA3173771A1 (zh) |
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| WO (1) | WO2021201765A1 (zh) |
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| CN115989891A (zh) * | 2023-02-09 | 2023-04-21 | 东莞市吉纯生物技术有限公司 | 一种尼古丁盐口含制品及其制备方法 |
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| DK3773495T3 (da) | 2019-06-07 | 2023-01-16 | Philip Morris Products Sa | Sammensætning af nikotinpose |
| US20240041089A1 (en) * | 2020-12-16 | 2024-02-08 | Liw Innovation Ab | A new powder composition |
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| US3845217A (en) * | 1972-11-16 | 1974-10-29 | Helsingborg L Ab | Buffered smoking substitute compositions |
| US5362496A (en) * | 1993-08-04 | 1994-11-08 | Pharmetrix Corporation | Method and therapeutic system for smoking cessation |
| JP3212270B2 (ja) * | 1997-10-08 | 2001-09-25 | 日本たばこ産業株式会社 | 葉たばこ抽出エキスを含有する熱不可逆凝固グルカンシートの製造方法および熱不可逆凝固グルカンシートを用いたたばこ香味発生媒体の製造方法 |
| ES2294180T3 (es) * | 2001-12-11 | 2008-04-01 | Ceapro Inc. | Composiciones de beta-glucano de cereales, metodos de preparacion y usos de las mismas. |
| EP1790687A3 (en) * | 2001-12-11 | 2007-07-25 | Ceapro Inc. | Cereal beta glucan compositions, methods of preparation and uses thereof |
| US8336557B2 (en) * | 2007-11-28 | 2012-12-25 | Philip Morris Usa Inc. | Smokeless compressed tobacco product for oral consumption |
| ES2606546T3 (es) * | 2009-02-11 | 2017-03-24 | Heglund, A.S. | Compuesto destinado a la absorción bucal de nicotina con el objetivo de dejar de fumar |
| US9351936B2 (en) * | 2013-10-03 | 2016-05-31 | Altria Client Services Llc | Nicotine lozenge |
| CN104784197A (zh) * | 2015-03-30 | 2015-07-22 | 福州乾正药业有限公司 | EGCG与β-葡聚糖的组合物及其制备方法和药物应用 |
| UA118192C2 (uk) * | 2015-10-22 | 2018-12-10 | Юрій Захарович Толчеєв | Противірусна фармацевтична композиція |
| CA3020798A1 (en) * | 2016-04-12 | 2017-10-19 | Scott SCHANEVILLE | Ingestible films having substances from hemp or cannabis |
| CN107027949A (zh) * | 2017-03-29 | 2017-08-11 | 闫天罡 | 一种饱腹感口香糖及其制备方法 |
| WO2018222581A1 (en) * | 2017-05-29 | 2018-12-06 | Resinnate Therapeutics Llc | Methods and formulations for administering beta glucan |
| US20210267934A1 (en) * | 2018-07-15 | 2021-09-02 | Rapid Dose Therapeutics Corp. | Cannabinoid oral dispersible film strip |
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| CN115989891A (zh) * | 2023-02-09 | 2023-04-21 | 东莞市吉纯生物技术有限公司 | 一种尼古丁盐口含制品及其制备方法 |
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| JP2023520044A (ja) | 2023-05-15 |
| CA3173771A1 (en) | 2021-10-07 |
| US20230181558A1 (en) | 2023-06-15 |
| KR20220164725A (ko) | 2022-12-13 |
| SE546142C2 (en) | 2024-06-11 |
| EP4126056A1 (en) | 2023-02-08 |
| SE2050380A1 (en) | 2021-10-04 |
| EP4126056A4 (en) | 2024-04-24 |
| WO2021201765A1 (en) | 2021-10-07 |
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