CN1092955C - 口服或直肠给药的多层固体药物剂型的生产方法 - Google Patents

口服或直肠给药的多层固体药物剂型的生产方法 Download PDF

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CN1092955C
CN1092955C CN96197791A CN96197791A CN1092955C CN 1092955 C CN1092955 C CN 1092955C CN 96197791 A CN96197791 A CN 96197791A CN 96197791 A CN96197791 A CN 96197791A CN 1092955 C CN1092955 C CN 1092955C
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J·伯莱顿巴赫
A·P·哈托
J·霍夫曼
J·罗森伯格
M·希索
H·D·采特勒
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Abstract

本发明涉及一种口服或直肠给药的多层固体药物剂型的生产方法，该方法包括共挤出至少两种在各种情况下均包含热塑性、生理可接受的聚合物粘合剂的组合物，所述粘合剂在生理环境中可溶解或溶胀，并且至少一种组合物含有药物活性成分，然后成形共挤出的多层物料，形成所需药物剂型。

Description

口服或直肠给药的多层固体药物剂型的生产方法
本发明涉及一种口服或直肠给药的多层固体药物剂型的生产方法，还涉及采用本发明的方法获得的该药物剂型。
例如为使彼此不相容的活性成分结合或在控释药物剂型的情况下释放起始和维持剂量，包括数层，例如层压或多层片剂的药物剂型的使用日益增加，所述片剂可被包衣。这类剂型可通过常规方法生产。因此，层压片可通过干燥包衣法生产，多层片可通过压制两层或多层颗粒的方法生产。为此要求使用特殊机器和并以操作模式装配普通旋转机，其中需要带至少两套填充和冲压装置。因此这些常规方法费事并且成本高。
一种被认为较常规的多步、分批制片法简单的片剂生产方法公知已有一段时间了。该方法包括将活性成分加到聚合物粘合剂中，以适当方式将含活性成分的聚合物熔融物从挤压机中挤出并成形，参见例如EP-A 240904和240906。
共挤出法在塑料加工技术中是公知的，该技术使得从不止一台挤压机中挤出的熔融物流结合塑模，如此获得所需层状结构的各种热塑性塑料。共挤出法在药物工业中的应用主要限于包装膜的生产。此外，聚合物胶囊和以鱼药形式包衣活性成分及植入剂的生产是公知的：WO-A 89/12442描述了一种鱼药药物剂型。通常，药物通过饲料给鱼施用，即将药物与饲料混合。这种方式存在的问题是含药物的饲料由于其味道而不被鱼接受。结果大部分含药物的饲料仍长时间存在于水中而未被食用或沉落。这导致药物向水中的不利释放，自然导致了水污染。
为解决该问题，WO 89/12442建议了一种通过共挤出法获得的剂型，该剂型包括环绕内室的外层包衣。为使鱼接受该剂型，该外层由含适宜动物或植物料的淀粉衍生物组成。此外，该外层是水和包含于内室中的活性成分均不可渗透的。内室的粘稠悬浮液中含有活性成分，该悬浮液仅部分填充了内室。这样提供了空间，给予了该剂型飘浮在水面上而不会下沉所需的浮力。
美国专利5283187描述了包含一种细胞悬浮液作为活性成分的植入剂，该悬浮液包封在一种半透性聚合物膜中。该植入剂通过将该细胞悬浮液与聚合物在适宜的、与水混溶的有机溶剂中的溶液共挤出来生产。所选择的聚合物须在挤出时凝聚并形成通道网，从而使膜具有半渗透性。
EP-A 303306描述一种圆柱形植入剂，它具有熔体流动指数为10g/10min并且乙酸乙烯基酯含量至少为20％(重量)的乙烯/乙酸乙烯基酯共聚物核。该核环绕有厚度为50-250μm的膜，该膜也由乙烯/乙酸乙烯基酯共聚物组成。但是该聚合物的熔体流动指数低于10g/10min并且乙酸乙烯基酯的含量低于20％(重量)。该膜用于控制核中含有的活性成分避孕药的释放，采用这种方式，在至少两年时间里，每日所释放的避孕药剂量为15-30μg。该植入剂通过将两层聚合物共挤出生产。
上述植入剂经非胃肠，如皮下给药。所设计的植入剂外层应不溶于体液，因此可采用简单方法将植入剂从机体取出。
可口服或直肠给药，并允许对所需活性成分的释放特性进行特定调整的药剂符合的要求完全不同于植入剂。该类药剂旨在使活性成分以所需方式在所需部位相对快速地(与植入剂相比)释放并易于溶于体液。
本发明的目的是提供可口服或直肠给药的固体药物剂型，和生产该剂型的方法，该方法使得该剂型可采用简单和温和方法生产并确保所需的释放特性。
我们发现该目的可通过一种多层固体药物剂型实现，该剂型可通过将两种可药用热塑性聚合物的组合物共挤出获得，其中至少一种组合物中含有药物活性成分。
因此本发明涉及口服或直肠给药的多层固体药物剂型的生产方法，该方法包括共挤出至少两种在各种情况下均包含热塑性、生理可接受的聚合物粘合剂的组合物，所述粘合剂在生理环境中可溶解或溶胀，并且至少一种组合物含有药物活性成分，然后成形共挤出的多层物料形成所需药物剂型，本发明还涉及由该方法获得的药物剂型。
附图1显示使用塑模辊的共挤出和片剂成形的代表性截面图。
附图2显示使用冲床的片剂成形的代表性截面图。
口服或直肠给药的固体药物剂型尤其包括片剂、包衣片剂、锭剂和糖衣片以及栓剂。
优选将本发明生产的药物剂型设计为外层(一层或多层)不是膜，而是溶于和/或溶胀于体液的外层，如果合适，可用保护层或粘附层表示。
依据本发明生产的药物剂型优选包括两层或三层。它们可以是开放或封闭形式的，尤其可呈开放或封闭的多层片剂。
至少一层中含有至少一种药物活性成分。也可在另一层含有另一种活性成分。这对于加工两种彼此不相容的活性成分或者控制活性成分的释放特性是有益的。例如，可通过将活性成分包含于一外层中提供起始剂量，通过将活性成分包含于内层中提供维持剂量。
层的厚度可根据所需的释放特性进行选择。活性成分的延迟释放随层的厚度增加而增强，即作用持续越久。
本发明的药物剂型尤其适用于所谓克隆靶。为此，可通过选择合适材料以时间、pH或酶依赖方式控制活性成分的释放。时间依赖性控制可例如通过层厚度和/或快速或缓慢溶解材料的选择实现。相对快速的溶解可使用，例如聚乙烯吡咯烷酮实现，而相对缓慢的溶解可使用乙基纤维素、聚丙烯酸酯或聚甲基丙烯酸酯(Eudragit RL，RS)实现。
pH依赖性控制可通过使用溶于胃液的材料(如聚乙烯吡咯烷酮)和/或对胃液有抗性但溶于肠液的材料(如纤维素邻苯二甲酸酯、聚丙烯酸酯或甲基丙烯酸酯(Eudragit D或S))实现。
酶依赖性控制可通过例如使用仅暴露于肠内的酶时才释出活性成分的材料如半乳甘露聚糖实现。
药物剂型的生产以至少两种在各种情况下均包含至少一种热塑性的可药用聚合物粘合剂的单独组合物(混合物)为原料，如果合适，还含有一种或多种药物活性成分和一种或多种常用辅剂，所述组合物由于至少一种成分的熔融或软化成为糊状或粘稠状(热塑性的)，因而可挤出。组合物的玻璃化温度低于组合物中所有各组分的分解温度。粘合剂应优选可溶于或溶胀于生理环境的。适宜的粘合剂实例是聚乙烯吡咯烷酮(PVP)、N-乙烯基吡咯烷酮(NVP)和乙烯基酯(尤其是乙酸乙烯基酯)的共聚物、乙酸乙烯基酯和巴豆酸的共聚物、特别是氢化的聚乙酸乙烯基酯、聚乙烯醇、聚(丙烯酸羟烷基酯)、聚(甲基丙烯酸羟烷基酯)、聚丙烯酸酯和聚甲基丙烯酸酯(Eudragit类)、甲基丙烯酸甲酯和丙烯酸的共聚物、纤维素酯、纤维素醚(尤其是甲基纤维素和乙基纤维素)、羟烷基纤维素(尤其是羟丙基纤维素)、羟烷基烷基纤维素(尤其是羟丙基乙基纤维素)、纤维素邻苯二甲酸酯(尤其是纤维素乙酸邻苯二甲酸酯)和羟丙基甲基纤维素、淀粉、淀粉衍生物(如麦芽糖糊精)、糖醇(如甘露糖醇或palatinose)、和甘露聚糖(尤其半乳甘露聚糖)。聚合物的K值(根据H.Fikentscher，纤维素化学13(1932)，58-64和71-74)应在10-100、优选12-70、尤其是12-35范围内，PVP的K值优选为12-35，尤其是12-17。
适合于活性成分的优选粘合剂是聚乙烯吡咯烷酮、N-乙烯基吡咯烷酮和乙烯基酯的共聚物以及丙烯酸羟烷基酯。
用于不含活性成分的层的优选粘合剂是不溶于含水介质或pH小于5的粘合剂，尤其是羟烷基纤维素、烷基纤维素、羟烷基烷基纤维素、聚丙烯酸酯、纤维素邻苯二甲酸酯、聚交酯和半乳甘露聚糖。
所有成分的整个混合物中的聚合物粘合剂必须在50-180℃，优选60-130℃软化或熔融，以使组合物可被挤出。因此，混合物的玻璃化温度必须低于180℃，优选低于130℃。如果需要，可通过常用可药用增塑剂降低，所述增塑剂是例如长链醇、乙二醇、丙二醇、甘油、三羟甲基丙烷、三甘醇、糖醇(如丁烷二醇)、戊醇(如季戊四醇)或己醇、聚乙二醇、聚丙二醇、聚乙/丙二醇、聚硅氧烷、芳族羧酸酯(如邻苯二甲酸二烷基酯、偏苯三酸酯、苯甲酸酯和对苯二酸酯)或脂族二羧酸酯(如己二酸二烷基酯、癸二酸酯、壬二酸酯、柠檬酸酯和酒石酸酯)、脂肪酸酯(如甘油一、二或三乙酸酯)或二乙基磺酰琥珀酸钠。增塑剂的浓度通常为用于特定层的组合物总量的0.5-15％，优选为0.5-5％。混合物优选不含增塑剂。
总量可高达聚合物重量100％的常用药物辅助物质的实例是：
填充剂或增量剂，例如硅酸盐或硅藻土、氧化镁、氧化铝、二氧化钛、硬脂酸或其盐，如其镁盐或钙盐、甲基纤维素、羧甲基纤维素钠、滑石、蔗糖、乳糖、谷物或玉米淀粉、土豆粉、聚乙烯醇，其浓度尤其为用于特定层的组合物总重的0.02-50％，优选0.20-20％；
润滑剂，如硬脂酸铝或钙、滑石和聚硅氧烷，其浓度为用于特定层的组合物总重的0.1-5％，优选0.1-3％；
染料，例如偶氮染料、有机或无机颜料或含无机颜料的天然染料，其浓度为用于特定层的组合物总重的0.001-10％，优选0.5-3％；
助流剂，例如动物或植物脂肪，尤其是氢化形式的和那些在室温是固体的脂肪。这些脂肪的熔点优选为50℃或更高。优选C12、C14、C16和C18脂肪酸的甘油三酯。也可使用蜡，如巴西棕榈蜡。这些脂肪和蜡可单独掺入或与单和/或二酸甘油酯或磷脂，尤其是卵磷脂一起掺入。所述单和二酸甘油酯优选由上述类型的脂肪酸衍生。脂肪、蜡、单和二酸甘油酯和/或卵磷脂的总量为用于特定层的组合物总重的0.1-30％，优选为0.1-5％；
稳定剂，例如抗氧剂、光稳定剂、氢过氧化物破坏剂、自由基清除剂、抗微生物稳定剂。
还可加入润湿剂、防腐剂、崩解剂、吸收剂和脱模剂以及发泡剂(参见，例如H.Sucker等，制药技术，Thieme-Verlay，Stuttgart 1978)。
用于本发明目的的辅助物质还指用于生产药物活性成分的固体溶液的物质。这类辅助物质的实例是季戊四醇和四乙酸季戊四醇酯、聚合物如聚氧化乙烯和聚氧化丙烯及它们的嵌段共聚物(Poloxamers)、磷脂如卵磷脂、乙烯基吡咯烷酮的均聚物和共聚物、表面活性剂如聚氧乙烯40硬脂酸酯和柠檬酸以及琥珀酸、胆酸、甾醇及例如J.L. Ford，Pharm.Acta Helv.61，69-88(1986)中所述其它物质。
对辅助物质适用性的唯一先决条件是足够的温度稳定性。
用于本发明目的的药物活性成分是指所有具有药理作用和较低副作用的物质，只要它们在加工条件下不分解即可。每单位药剂的活性成分的量和浓度可依据其功效和释放速率在较大范围内变动。唯一的条件它们足以产生所需的作用。因此，活性成分的浓度可在0.1-95％，优选20-80％，尤其是30-70％(重量)。也可将活性成分结合使用，例如异丁苯丙酸/咖啡因。用于本发明目的的活性成分也可以是维生素和矿物质，以及谷物处理剂和杀虫剂。维生素包括A族维生素和B族维生素，B族维生素是指除B1、B2、B6和B12以及烟酸和烟酰胺外，还包括具有维生素B性质的化合物，例如腺嘌呤、胆碱、泛酸、生物素、腺苷一磷酸、叶酸、乳清酸、潘盖米酸、肉碱、对氨基苯甲酸、肌醇和硫辛酸；和维生素C，以及D族、E族、F族、H族、I族和J族、K族和P族维生素。用于本发明目的的活性成分还包括有治疗作用的肽。
本发明的方法适用于，例如加工下述活性成分：醋丁洛尔、乙酰半胱氨酸、乙酰水杨酸、阿昔洛韦、阿普唑仑、阿法骨化醇、尿囊素、别嘌呤、氨溴索、阿米卡星、阿米洛利、甘氨酸、胺碘酮、氧阿米替林、氨氯地平、阿莫西林、氨苄西林、抗坏血酸、阿司帕坦、阿司咪唑、阿替洛尔、倍氟米松、苄丝肼、苯扎氯胺、苯佐卡因、苯甲酸、倍他米松、苯扎贝特、生物素、吡哌立登、比索洛尔、溴西泮、溴己新、溴隐亭、布地萘德、丁苯羟酸、丁洛地尔、丁螺环酮、咖啡因、樟脑、卡托普利、卡马西平、卡比多巴、卡铂、头孢克洛、头孢氨苄、cefatroxil、头孢唑啉、头孢克肟、头孢噻肟、头孢他啶、头孢曲松、头孢夫辛、司来吉兰、氯霉素、氯己定、氯苯那敏、氯噻酮、胆碱、环孢子菌素、西司他丁、西米替丁、环丙沙星、西沙必利、顺铂、甲红霉素、克拉维酸、氯米帕明、氯硝西泮、可乐定、克霉唑、可待因、考来烯胺、色甘酸、氰钴胺、环丙孕酮、去氧孕烯、地塞米松、右泛醇、右美沙芬、右丙氧芬、安定、双氯芬酸、地高辛、双氢可待因、双氢麦角胺、双氢麦角碱、地尔硫卓、苯海拉明、双嘧达莫、安乃近、丙吡胺、多潘立酮、多巴胺、脱氧土霉素、依那普利、麻黄碱、肾上腺素、维生素D2、麦角胺、红霉素、雌二醇、乙炔雌二醇、依托泊甙、桉树球(Eucalyptus globulus)、法莫替丁、非洛地平、非诺贝特、非诺特罗、芬太尼、黄素单核苷酸、氟康唑、氟桂利嗪、氟尿嘧啶、氟西汀、氟比洛芬、呋塞米、甲洛帕米、吉非贝齐、庆大霉素、银杏、格列本脲、格列吡嗪、氯氮平、光甘草、灰黄霉素、愈创甘油醚、氟哌啶醇、肝素、透明质酸、氢氯噻嗪、氢可酮、氢化可的松、氢吗啡酮、异丙托氢氧铵、布洛芬、亚胺培南、吲哚美辛、磺海醇、碘帕醇、硝酸异山梨酸酯、单硝酸异山梨酸酯、异维A酸、酮替芬、酮康唑、酮洛芬、酮洛酸、拉贝洛尔、乳果糖、卵磷脂、左卡尼汀、左旋多巴、左谷酰胺、左炔诺孕醇、左甲状腺素、利多卡因、脂肪酶、米帕明、赖诺普利、洛哌丁胺、劳垃西泮、洛伐他汀、甲羟孕酮、薄荷醇、甲氨蝶呤、甲基多巴、甲泼尼龙、甲氧氯普胺、美托洛尔、咪康唑、咪达唑仑、米诺环素、米诺地尔、米索前列醇、吗啡、多种维生素混合物或结合物及矿物盐、N-甲基麻黄碱、萘呋胺、萘普生、新霉素、尼卡地平、尼麦角林、烟酰胺、烟碱、烟酸、硝苯地平、尼莫地平、硝西泮、尼群地平、尼扎替丁、炔诺酮、诺氟沙星、炔诺孕酮、去甲替林、制霉菌素、氧氟沙星、奥美垃唑、昂丹司琼、胰酶、泛醇、本多生酸、对乙酰氨基酚、青霉素G、青霉素V、苯巴比妥、己酮可可碱、苯氧甲基青霉素、苯福林、苯丙醇胺、苯妥因、吡罗昔康、多粘菌素B、聚维酮碘、普伐他汀、普拉西泮、哌唑嗪、泼尼松龙、泼尼松、溴隐亭、普罗帕酮、普萘洛尔、丙羟茶碱、伪麻黄碱、吡多辛、奎尼丁、雷米普利、雷尼替丁、利血平、维生素A、核黄素、利福平、芦丁、糖精、沙丁胺醇、salcatonin、水杨酸、辛伐他汀、生长激素、索他洛尔、螺内酯、硫糖铝、舒巴坦、磺胺甲恶唑、柳氮磺胺吡啶、舒必利、他莫昔芬、替加氟、替普瑞酮、特拉唑嗪、特布他林、特非那定、四环素、茶碱、硫胺、噻氯匹啶、噻吗洛尔、氨甲环素、维A酸、曲安萘德、氨苯蝶啶、甲氧苄啶、曲克芦丁、尿嘧啶、丙戊酸、万古霉素、维拉帕米、维生素E、亚叶酸、齐多夫定。
优选的活性成分是布洛芬(为外消旋体、对映体或浓缩(enriched)对映体)、酮洛芬、氟比洛芬、乙酰水杨酸、维拉帕米、对乙酰氨基酚、硝苯地平或卡托普利。
本发明可特别地形成固体溶液。术语“固体溶液”是本领域普通专业人员所熟知的术语，例如出现于上述引用的文献中。在药物活性成分的聚合物固体溶液中，活性成分以分子分散形式存在于聚合物中。
共挤出前，分别制备药物剂型各层的组合物。为此，在分别的带有下游齿轮泵的挤压机或熔融容器中加工原料成分(不使用溶剂)。这样可使成分单独或以干燥混合物形式连续加料(如通过差示重量加料器)。然后在挤压机或熔融容器中混合和/或软化或熔化组合物。如果希望掺入尤其是温度敏感的活性成分，则可在组合物软化或熔融后方便地加入，活性成分可通过在挤压机或捏合机或混合反应器中纵向或横向混合而掺入，从而使组合物均匀化。挤压机，尤其是带有混合装置的双蜗杆挤压机或单蜗杆挤压机对于制备组合物尤其方便，这是由于可在特定物料的最佳条件下进行加工。例如对于每层可选择不同的加工温度。
各个挤压机或其它仪器中的熔融或塑性组合物通过联合共挤压机口型并挤出。共挤压机口型的形状取决于所需药物剂型。例如合适的是带有平口型缝的口型(称为长方口型)和带有环形缝的口型。口型设计还取决于使用的聚合物粘合剂和所需的药物剂型。
在共挤压机口型的下游使所需剂型成形。可根据共挤压机口型和成形类型生产大量成形剂型。例如开放的多层(尤其是两层或三层)片剂可由经冲切或切割形成的长方形口型的挤出物生产。另外，开放多层片剂可经环形缝口型在挤出后立即切割或削刨挤出物，或者优选在挤出物部分冷却后切割或削刨挤出物进行分割。
封闭药物剂型，即其中含活性成分的层完全被一不含活性成分的层包围的药物剂型尤其可使用环形缝口型通过在一合适的例如附图1和2中所示的冲压装置中处理挤出物获得，这在下面的实施例中将进一步加以说明。有益地是在外层冷却后，多层片剂的内层在进入冲压装置时仍是塑性可变的。因此可采用这种方式生产尤其是片剂，优选椭圆形片剂、包衣片、锭剂和糖衣片。
多层药物剂型可在下游步骤中制成圆形和/或采用常规方法进行包衣。该圆形化优选用辊、带和压力进行，包衣可在包衣锅或流化床中进行。
因此可用本发明的方法以及其简单和温和的方式生产口服和直肠给药的固体药物剂型。此外，该方法提供了通过选择药物剂型和其结构以及选择聚合物粘合剂在很宽范围内调整所需释放特性的可行性。
下述实施例将说明本发明而非限定本发明。
实施例1
连续计量10kg/h羟丙基纤维素(Klucel F)并使其通过双蜗杆挤压机(ZSK25型)熔融。同时，在另一双蜗杆挤压机(XSK30型)中制备含30％布洛芬为活性成分的30kg/h聚乙烯吡咯烷酮(PVP)。通过同心共挤压机环形缝口型挤出挤出物，在下列条件下生产由含活性成分的PVP核和Klucel覆盖层组成的挤出物：ZSK 30挤压机：                ZSK 25挤压机：第1部分：43℃                 第1部分：70℃第2部分：57℃                 第2部分：120℃第3部分：120℃           第3部分：110℃第4部分：100             第4部分：100第5部分：100             第5部分：100℃机头：   100             机头：   110口型：   100℃           口型：   100℃
然后用如附图1和2所示的冲压装置将挤出物分割为封闭的椭圆形片剂。在附图1中，共挤压机口型由1确定。从该口型(附图中未显示各层)出来的挤出物2进入带有两个反转塑模辊3的压延机中。塑模辊带有经条6隔离的凹陷5。所选择的塑模辊3之间的距离应使它们彼此可沿一条6上的线接触或者两者之间仅有很小的距离。凹陷5形状的选择可在较宽的范围内选择，这样可生产多种药物剂型。
从共挤压机口型1出来的挤出物2进到凹陷5和由条6分割为独立的药物剂型。使用附图1所示的装置，可获得仍通过溢料8连接的椭圆形片剂4。
另外，可使用附图2所示的装置进行冲压。由共挤压机口型出来的挤出产物2进入带有双冲条7的装置，所述双冲条位置相对并包括挤出物2。该冲条7可垂直于挤出物2移动(如附图2箭头所示)并且具有相当于在附图1中压延辊3上的凹陷的相对凹陷。为分割药物剂型，将冲条7朝挤出物2移动直至它们彼此接触或相距很近的距离。这样分割了药物剂型，但单个药物剂型仍通过溢料8连接的。另外，封闭椭圆形片剂也可使用附图2所示的装置获得。所得椭圆形片剂可用常规方法除去溢料，例如在转盘中除去。
所得椭圆形片剂的Klucel外层覆盖膜可减缓分散在PVP核中的活性成分的释放。
实施例2
采用实施例1的方法并使用其中所述的原料和含5％咖啡因的羟丙基纤维素获得核中含布洛芬和外层膜中含咖啡因的片剂。实施例3
连续计量10kg/h重量比为8∶1的羟丙基纤维素和乙基纤维素的混合物并在双蜗杆挤压机(ZSK25型)中熔融。同时，在第2台双蜗杆挤压机(ZSK30)中制备含40％(重量)对乙酰氨基酚为活性成分的15kg/h聚乙烯吡咯烷酮。在第3台挤压机中通过齿轮泵运输含40％(重量)对乙酰氨基酚为活性成分的15kg/h羟丙基纤维素熔融物。
将这些熔融物挤压过同心环形共挤压机口型以生产有缓释速率的羟丙基纤维素核、高速释放的聚乙烯吡咯烷酮包围层和羟丙基纤维素/乙基纤维素覆盖膜组成的挤出物(挤出条件如实施例1所示)。
通过如附图1或附图2所示的冲压装置将挤出物分割为单个封闭片剂。
采用所得的多层片剂，活性成分释放的动力学得到了最佳控制，提高了患者的耐受性。
实施例4
在双蜗杆挤压机(ZSK30型)中制备含30％(重量)尼非地平为活性成分的15kg/h聚乙烯基吡咯烷酮。同时，在另一台挤压机中通过齿轮泵运输含40％(重量)尼非地平为活性成分的15kg/h羟丙基纤维素熔融物。
将这两种挤出物挤压过长方形口型(3个长方形)，得到三明治结构的组合物，包括具有缓释速率并且双侧被高释放速率的聚乙烯吡咯烷酮层包围的羟丙基纤维素层(挤出条件如实施例1所示)。
通过冲压装置将挤出物分割为开放多层片剂。
在随后的步骤中，将所得的开放多层片剂用丙烯酸共聚物在包衣锅中包衣。
采用该三明治结构的多层片剂，活性成分释放的动力学得到了最佳控制，提高了患者的耐受性。
实施例5
采用实施例1所示方法，使用其中所示原料生产挤出物，然后采用合适的冷切割机将挤出物分割为开放多层片剂。Klucel外层覆盖膜可减缓分散在PVP核中的活性成分的释放。
实施例6
使用实施例3所述的原料并采用实施例3描述的方法生产挤出物，该挤出物由缓慢释放速率的羟丙基纤维素核、高释放速率的聚乙烯吡咯烷酮包围层和羟丙基纤维素/乙基纤维素外层组成。可采用冷切割机将挤出物分割为单个开放多层片剂。
采用如此组合的多层片剂，活性成分释放的动力学得到了最佳控制，提高了患者的耐受性。
实施例7
连续计量10kg/h聚交酯并在双蜗杆挤压机(ZSK25型)中熔融。同时，在另一台双蜗杆挤压机(ZSK30型)中制备含40％(重量)布洛芬为活性成分的30kg/h聚乙烯吡咯烷酮。将这两种挤出物挤压通过环形共挤压机口型，得到由含活性成分的PVP核和聚交酯覆盖膜组成的挤出物(挤出条件如实施例1所示)。
可采用冷切割机将挤出物分割为单个开放多层片剂。
聚交酯覆盖膜是水解稳定的，可经酶促或水解分解，由此活性成分从核基质中释放。
实施例8
在双蜗杆挤压机(ZSK25型)中熔融含40％(重量)甘露醇和30％(重量)维拉帕米的10kg/h乙烯吡咯烷酮/乙酸乙烯基酯(6∶4)共聚物(30％(重量))。同时，在另一台挤压机(ZSK30)中制备含30％(重量)维拉帕米为活性成分的30kg/h羟丙基纤维素。两种挤出物在如实施例1所示条件下挤压通过环形共挤压机口型。通过实施例1所示方法和附图2所示装置使片剂成形。该片剂由含活性成分的羟丙基纤维素核和乙烯基吡咯烷酮/乙酸乙烯基酯共聚物/甘露醇覆盖膜组成。
实施例9
采用实施例2所示方法生产具有含维生素A和E的羟丙基纤维素核(低取代度的羟丙基纤维素，LH31型)以及含维生素C的羟丙基纤维素覆盖膜(Klucel F)的片剂。

Claims (10)

1.一种口服或直肠给药的多层固体药物剂型的生产方法，该方法包括共挤出至少两种在各种情况下均包含热塑性、生理可接受的聚合物粘合剂的组合物，所述粘合剂在生理环境中可溶解或溶胀，并且至少一种组合物含有药物活性成分，然后成形共挤出的多层物料，形成所需药物剂型。
2.根据权利要求1的方法，其中用于层的不含活性成分的聚合物粘合剂选自羟烷基纤维素、烷基纤维素、羟烷基烷基纤维素、纤维素邻苯二甲酸酯、聚丙烯酸酯、半乳甘露聚糖和聚交酯。
3.根据权利要求1或2的方法，其中用于层的含活性成分的聚合物选自聚乙烯吡咯烷酮、N-乙烯基吡咯烷酮和乙烯基酯的共聚物以及丙酸羟烷基酯。
4.根据任一项前述权利要求的方法，其中所用的活性成分选自布洛芬、酮洛芬、氟比洛芬、乙酰水杨酸、维拉帕米、对乙酰氨基酚、尼非地平、咖啡因、卡托普利和维生素或两种或多种这些活性成分的混合物。
5.根据任一项前述权利要求的方法，其中为生产封闭药物剂型，使用同心环形共挤压机口型进行共挤出并在塑模压延机中或采用热或冷切割方法成形。
6.根据权利要求1-4任一项的方法，其中为生产开放药物剂型，尤其是开放多层药物片剂，使用长方形口型进行共挤出并通过冲压成形。
7.根据权利要求5或6的方法，其中使用羟丙基纤维素作为外层的聚合物粘合剂，并将聚乙烯吡咯烷酮用于内层和核。
8.根据权利要求5-7任一项的方法，其中仅使用布洛芬或使用布洛芬/咖啡因或维生素A、C、E为活性成分，其中布洛芬或维生素A和E位于核中，而咖啡因或维生素C位于外层。
9.根据任一项前述权利要求的方法，其中在随后的步骤中，使多层药物剂型成圆形或进行包衣。
10.一种口服或直肠给药的多层药物剂型，可采用权利要求1-9任一项的方法获得。
CN96197791A 1995-10-23 1996-10-23 口服或直肠给药的多层固体药物剂型的生产方法 Expired - Fee Related CN1092955C (zh)

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Families Citing this family (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1252185B (it) * 1991-12-11 1995-06-05 Therapicon Srl Preparazioni farmaceutiche a liberazione programmata
DE19629753A1 (de) * 1996-07-23 1998-01-29 Basf Ag Verfahren zur Herstellung von festen Arzneiformen
IT1297886B1 (it) * 1997-02-28 1999-12-20 Carmine Antropoli Nifedipina per uso topico
DE19710213A1 (de) * 1997-03-12 1998-09-17 Basf Ag Verfahren zur Herstellung von festen Kombinationsarzneiformen
DE59812488D1 (de) * 1997-07-09 2005-02-17 Swiss Caps Rechte & Lizenzen Verfahren und vorrichtung zum herstellen einer mehrschichtigen, physiologisch verträglichen darreichungsform
FR2766088B1 (fr) * 1997-07-17 2001-01-05 Dow Corning Sa Dispositifs a liberation controlee d'un agent pharmaceutique, leur fabrication par co-extrusion et article intermediaire
ES2216351T3 (es) * 1997-12-08 2004-10-16 Altana Pharma Ag Nueva forma de supositorio que comprende un compuesto activo labil o acidos.
DE19814730A1 (de) * 1998-04-02 1999-10-07 Basf Ag Verwendung von N-Vinyllacram oder N-Vinylamin haltigen Copolymeren als Matrix zur Herstellung von festen pharmazeutischen und kosmetischen Darreichungsformen
DE19840256A1 (de) * 1998-09-03 2000-03-09 Basf Ag Verfahren zur Herstellung von beschichteten festen Dosierungsformen
DE19841244A1 (de) * 1998-09-09 2000-03-16 Knoll Ag Verfahren und Vorrichtung zum Herstellen von Tabletten
US6797283B1 (en) * 1998-12-23 2004-09-28 Alza Corporation Gastric retention dosage form having multiple layers
US6733789B1 (en) 1999-01-21 2004-05-11 Biovail Laboratories, Inc. Multiparticulate bisoprolol formulation
US6217895B1 (en) 1999-03-22 2001-04-17 Control Delivery Systems Method for treating and/or preventing retinal diseases with sustained release corticosteroids
US6248760B1 (en) * 1999-04-14 2001-06-19 Paul C Wilhelmsen Tablet giving rapid release of nicotine for transmucosal administration
ATE374682T1 (de) * 1999-06-25 2007-10-15 Sumika Color Company Ltd Verfahren und vorrichtung zum herstellen von mehrschichtgranulaten
US6555139B2 (en) 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
DE19943501A1 (de) * 1999-09-10 2001-03-15 Basf Ag Unterwassergranulation wirkstoffhaltiger Schmelzen
US6437006B1 (en) * 1999-09-27 2002-08-20 American Cyanamid Company Pharmaceutical carrier formulation
US6372259B1 (en) * 1999-11-10 2002-04-16 University Of Iowa Research Foundation Palatable, sustained release drug granules
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
ATE329579T1 (de) * 1999-11-12 2006-07-15 Abbott Lab Feste dispersion mit ritonavir, fenofibrat oder griseofulvin
MY125516A (en) * 1999-11-16 2006-08-30 Smithkline Beecham Plc Novel composition based on thiazolidinedione and metformin and use
US20040185099A1 (en) * 2000-01-20 2004-09-23 Biovail Laboratories, Inc. Multiparticulate bisoprolol formulation
US6375972B1 (en) 2000-04-26 2002-04-23 Control Delivery Systems, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof
US7838032B2 (en) * 2000-04-28 2010-11-23 Reckitt Benckiser Inc. Sustained release of guaifenesin
US7985420B2 (en) * 2000-04-28 2011-07-26 Reckitt Benckiser Inc. Sustained release of guaifenesin combination drugs
US6955821B2 (en) 2000-04-28 2005-10-18 Adams Laboratories, Inc. Sustained release formulations of guaifenesin and additional drug ingredients
US8012504B2 (en) * 2000-04-28 2011-09-06 Reckitt Benckiser Inc. Sustained release of guaifenesin combination drugs
FI111057B (fi) * 2000-05-29 2003-05-30 Conenor Oy Ekstruusiomenetelmä ja ekstruusiolaite
DE10026698A1 (de) * 2000-05-30 2001-12-06 Basf Ag Selbstemulgierende Wirkstoffformulierung und Verwendung dieser Formulierung
FR2809618A1 (fr) * 2000-05-31 2001-12-07 Didier Henri Michel Louis Cugy Procede relatif a l'optimisation de la delivrance de substances pharmacologiques
AU2001289653A1 (en) * 2000-07-14 2002-01-30 Universiteit Gent Composite solid shaped articles for the controlled delivery of biologically active ingredients
GB2367030B (en) * 2000-09-20 2002-12-31 Reckitt Benckiser Nv Method and apparatus for manufacturing multi-layer press molded bodies
EP1365745A2 (en) 2001-02-15 2003-12-03 King Pharmaceuticals, Inc. Stabilized pharmaceutical and thyroid hormone compositions and method of preparation
US6555581B1 (en) 2001-02-15 2003-04-29 Jones Pharma, Inc. Levothyroxine compositions and methods
JP4993652B2 (ja) * 2004-03-31 2012-08-08 リンテック株式会社 経口投与剤
WO2002087622A1 (fr) * 2001-04-24 2002-11-07 Lintec Corporation Preparations orales et supports pour preparations orales
US8268333B2 (en) * 2001-04-24 2012-09-18 Lintec Corporation Orally administered agent and an orally administered agent/supporting substrate complex
US20030070584A1 (en) 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing cellulose ethers
US20030072731A1 (en) * 2001-05-15 2003-04-17 Cynthia Gulian Dip coating compositions containing starch or dextrin
US6767619B2 (en) * 2001-05-17 2004-07-27 Charles R. Owens Preform for manufacturing a material having a plurality of voids and method of making the same
US20030190349A1 (en) * 2001-08-10 2003-10-09 Franz G. Andrew Methods of stabilizing pharmaceutical compositions
US20030198671A1 (en) * 2001-08-10 2003-10-23 Franz G. Andrew Levothyroxine compositions having unique plasma AUC properties
US7122143B2 (en) 2001-09-28 2006-10-17 Mcneil-Ppc, Inc. Methods for manufacturing dosage forms
US20040146559A1 (en) * 2002-09-28 2004-07-29 Sowden Harry S. Dosage forms having an inner core and outer shell with different shapes
BR0212950A (pt) 2001-09-28 2004-10-26 Mcneil Ppc Inc Formas de dosagens compósitas tendo uma porção inserida
US7838026B2 (en) 2001-09-28 2010-11-23 Mcneil-Ppc, Inc. Burst-release polymer composition and dosage forms comprising the same
US7323192B2 (en) * 2001-09-28 2008-01-29 Mcneil-Ppc, Inc. Immediate release tablet
US8309118B2 (en) 2001-09-28 2012-11-13 Mcneil-Ppc, Inc. Film forming compositions containing sucralose
US6837696B2 (en) 2001-09-28 2005-01-04 Mcneil-Ppc, Inc. Apparatus for manufacturing dosage forms
US20030171436A1 (en) * 2001-10-29 2003-09-11 Franz G. Andrew Levothyroxine compositions having unique triiodothyronine Tmax properties
US7491407B2 (en) * 2001-10-31 2009-02-17 North Carolina State University Fiber-based nano drug delivery systems (NDDS)
US20030091633A1 (en) * 2001-11-15 2003-05-15 John Kelly Methods and compositions for use of (S)-bisoprolol
US20030118652A1 (en) * 2001-11-15 2003-06-26 John Kelly Methods and compositions for use of (S)-bisoprolol
DE10209982A1 (de) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Oral zu applizierende Darreichungsform für schwerlösliche basische Wirkstoffe
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US6958161B2 (en) 2002-04-12 2005-10-25 F H Faulding & Co Limited Modified release coated drug preparation
US20030203027A1 (en) * 2002-04-26 2003-10-30 Ethicon, Inc. Coating technique for deposition of drug substance on a substrate
US8871241B2 (en) * 2002-05-07 2014-10-28 Psivida Us, Inc. Injectable sustained release delivery devices
JP2005532313A (ja) * 2002-05-07 2005-10-27 コントロール・デリバリー・システムズ・インコーポレイテッド 薬物送達装置の形成方法
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
US20060083796A1 (en) * 2002-09-09 2006-04-20 Sylvie Pridmore-Merten Orally administrable composition for improving hair and coat quality
US7807197B2 (en) 2002-09-28 2010-10-05 Mcneil-Ppc, Inc. Composite dosage forms having an inlaid portion
GB0222612D0 (en) * 2002-09-30 2002-11-06 Univ Gent Controlled delivery system for bioactive substances
JP2006518380A (ja) * 2003-01-31 2006-08-10 スミスクライン・ビーチャム・コーポレイション 固体分散体組成物
EP1615625A4 (en) 2003-04-21 2010-12-15 Euro Celtique Sa INVIOLABLE DOSAGE FORM CONTAINING CO-EXTRUDED PARTICLES OF REPELLENT AGENT AND METHOD OF MANUFACTURING THE SAME
ITMI20031096A1 (it) * 2003-05-30 2004-11-30 Eurand Spa Microcapsule per coacervazione contenenti farmaco incorporato nel polimero di rivestimento
US20050025825A1 (en) * 2003-07-31 2005-02-03 Xanodyne Pharmacal, Inc. Tranexamic acid formulations with reduced adverse effects
DE102004032051A1 (de) 2004-07-01 2006-01-19 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten, festen Darreichungsform
DE10361596A1 (de) 2003-12-24 2005-09-29 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform
DE102005005446A1 (de) 2005-02-04 2006-08-10 Grünenthal GmbH Bruchfeste Darreichungsformen mit retardierter Freisetzung
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE10336400A1 (de) 2003-08-06 2005-03-24 Grünenthal GmbH Gegen Missbrauch gesicherte Darreichungsform
US8377952B2 (en) 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
NO319624B1 (no) 2003-09-15 2005-09-05 Trouw Internat Bv Fiskefôr for laksefisk i ferskvann og anvendelse av slikt fôr.
BRPI0415242B8 (pt) 2003-10-10 2021-05-25 Ethypharm Sa microgrânulos de liberação gradual contendo extrato de gingko biloba e o processo para fabricar estes
EP1680079A4 (en) * 2003-10-24 2008-01-02 Adhesives Res Inc QUICKLY FILING FILMS FOR THE DISTRIBUTION OF PHARMACEUTICAL OR COSMETIC AGENTS
US8883204B2 (en) * 2003-12-09 2014-11-11 Purdue Pharma L.P. Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same
WO2005055981A2 (en) * 2003-12-09 2005-06-23 Euro-Celtique S.A. Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same
US7947739B2 (en) 2004-03-04 2011-05-24 Ferring B.V. Tranexamic acid formulations
US20050244495A1 (en) 2004-03-04 2005-11-03 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US20090215898A1 (en) * 2004-03-04 2009-08-27 Xanodyne Pharmaceuticals, Inc. Tranexamic acid formulations
US8022106B2 (en) 2004-03-04 2011-09-20 Ferring B.V. Tranexamic acid formulations
DK1729730T3 (da) * 2004-03-30 2009-03-23 Euro Celtique Sa Manipulationssikker doseringsform, der omfatter et adsorberende stof og et kontramiddel
DE102004032049A1 (de) 2004-07-01 2006-01-19 Grünenthal GmbH Gegen Missbrauch gesicherte, orale Darreichungsform
US20060147518A1 (en) * 2004-12-30 2006-07-06 Pierre Fabre Medicament Stable solid dispersion of a derivative of vinca alkaloid and process for manufacturing it
DE102005005449A1 (de) 2005-02-04 2006-08-10 Grünenthal GmbH Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform
US8673352B2 (en) 2005-04-15 2014-03-18 Mcneil-Ppc, Inc. Modified release dosage form
KR100697093B1 (ko) * 2005-05-09 2007-03-20 주식회사 대웅제약 비타민 ｃ 및 감기 치료제를 함유하는 이중정 제형 및 그의제조방법
US20060280788A1 (en) * 2005-05-09 2006-12-14 Casey Stephen M Delivery and formulations of mast cell stabilizers
GT200600371A (es) * 2005-08-17 2007-03-21 Formas de dosis sólidas de valsartan y amlodipina y método para hacer las mismas
JP4092587B2 (ja) * 2005-10-17 2008-05-28 株式会社栗本鐵工所 二軸混練機を用いた乾式コーティング
US20100172989A1 (en) 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
CA2647801C (en) * 2006-03-24 2015-04-14 Auxilium Pharmaceuticals, Inc. Process for the preparation of a hot-melt extruded laminate
US7659344B2 (en) * 2006-06-08 2010-02-09 E. I. Du Pont De Nemours And Company Shaped articles containing poly(vinylpyrrolidone)-iodine complex
WO2008102235A1 (en) * 2007-02-20 2008-08-28 Aurobindo Pharma Limited Controlled release formulations of alfuzosin
DE102007011485A1 (de) 2007-03-07 2008-09-11 Grünenthal GmbH Darreichungsform mit erschwertem Missbrauch
RS51313B (sr) * 2007-11-09 2010-12-31 Acino Pharma Ag.51311 Retard tablete sa hidromorfonom
NZ586792A (en) 2008-01-25 2012-09-28 Gruenenthal Chemie Tamper resistant controlled release pharmaceutical tablets form having convex and concave surfaces
BRPI0912014A2 (pt) 2008-05-09 2019-03-06 Grünenthal GmbH processo para a preparação de uma formulação em pó intermediária e uma forma de dosagem sólida final sob uso de uma etapa de congelamento por atomização
US20100280117A1 (en) * 2009-04-30 2010-11-04 Xanodyne Pharmaceuticals, Inc. Menorrhagia Instrument and Method for the Treatment of Menstrual Bleeding Disorders
ES2718688T3 (es) 2009-07-22 2019-07-03 Gruenenthal Gmbh Forma de dosificación resistente a la manipulación para opioides sensibles a la oxidación
CA2765971C (en) 2009-07-22 2017-08-22 Gruenenthal Gmbh Hot-melt extruded controlled release dosage form
PE20131102A1 (es) 2010-09-02 2013-10-12 Gruenenthal Chemie Forma de dosificacion resistente a manipulacion que comprende una sal inorganica
NZ608865A (en) 2010-09-02 2015-03-27 Gruenenthal Chemie Tamper resistant dosage form comprising an anionic polymer
MX336980B (es) * 2010-12-21 2016-02-09 Senosiain S A De C V Lab Combinacion y composicion para el tratamiento de obesidad.
SI2736497T1 (sl) 2011-07-29 2017-12-29 Gruenenthal Gmbh Tableta, odporna proti zlorabi, ki zagotavlja takojšnje sproščanje zdravila
EP2736495B1 (en) 2011-07-29 2017-08-23 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
EP2750666B1 (en) * 2011-08-30 2017-10-04 Universiteit Gent Multi-layered release formulation
JP6117249B2 (ja) 2012-02-28 2017-04-19 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 薬理学的に活性な化合物および陰イオン性ポリマーを含むタンパーレジスタント剤形
JP6282261B2 (ja) 2012-04-18 2018-02-21 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 不正使用防止および過量放出防止医薬剤形
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
MX371432B (es) 2013-05-29 2020-01-30 Gruenenthal Gmbh Forma de dosificacion resistente al uso indebido que contiene una o mas particulas.
AR096439A1 (es) 2013-05-29 2015-12-30 Gruenenthal Gmbh Forma de dosificación resistente al uso indebido que contiene una o más partículas
JP6449871B2 (ja) 2013-07-12 2019-01-09 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング エチレン−酢酸ビニルポリマーを含有する改変防止剤形
WO2015078891A1 (en) 2013-11-26 2015-06-04 Farmaceutici Formenti S.P.A. Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10836089B2 (en) * 2014-02-20 2020-11-17 Guill Tool & Engineering Co., Inc. Multicomponent approach to standard and microlayer coextrusion
EP3142646A1 (en) 2014-05-12 2017-03-22 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
JP2017516789A (ja) 2014-05-26 2017-06-22 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング エタノール過量放出に対して防護されている多粒子
DE202014008800U1 (de) * 2014-11-05 2014-11-17 Automatik Plastics Machinery Gmbh Quetschwalzengranulator mit Quetschwalzenpaar und Verwendung desselben
WO2016130094A1 (en) * 2015-02-10 2016-08-18 PHARMACTlVE ILAÇ SANAYI VE TlCARET A.Ş. A pharmaceutical composition containing ibuprofen, pseudoephedrine and vitamin c
BR112017021475A2 (pt) 2015-04-24 2018-07-10 Gruenenthal Gmbh forma de dosagem resistente à adulteração (tamper) com liberação imediata e resistência contra extração de solvente
JP2018526414A (ja) 2015-09-10 2018-09-13 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング 乱用抑止性の即放性製剤を用いた経口過剰摂取に対する保護
EP3364955B1 (en) 2015-10-09 2022-04-20 RB Health (US) LLC Pharmaceutical formulation
WO2017100367A1 (en) 2015-12-08 2017-06-15 Lyndra, Inc. Geometric configurations for gastric residence systems
CN105967695A (zh) * 2016-05-04 2016-09-28 蚌埠隆华压铸机有限公司 一种陶瓷注射成型粘结剂及其制备方法
AU2017268840B2 (en) * 2016-05-27 2022-02-10 Lyndra Therapeutics, Inc. Materials architecture for gastric residence systems
US11576866B2 (en) 2016-09-30 2023-02-14 Lyndra Therapeutics, Inc. Gastric residence systems for sustained delivery of adamantane-class drugs
EP3634382A4 (en) 2017-06-09 2021-07-07 Lyndra Therapeutics, Inc. STOMACHING SYSTEMS WITH RELEASE RATE MODULATING FILMS
CN111031996B (zh) * 2017-07-10 2022-04-15 盖尔凯普科技有限公司 双释放剂型胶囊及其制备方法、装置和系统
TWI837082B (zh) * 2017-11-22 2024-04-01 美商萊恩卓治療公司 用於胃滯留系統之材料架構
FR3085841B1 (fr) * 2018-09-14 2020-12-04 Oreal Procede de preparation de capsules et systeme associe
JP2022150038A (ja) 2021-03-25 2022-10-07 富士フイルムビジネスイノベーション株式会社 樹脂粒子

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010425A1 (en) * 1990-01-08 1991-07-25 Brown University Research Foundation Cell capsule extrusion systems

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1144911B (it) * 1981-03-19 1986-10-29 Pharmatec Spa Composizione farmaceutica a rilascio controllato contenente ibuprofen
DE3612211A1 (de) * 1986-04-11 1987-10-15 Basf Ag Kontinuierliches verfahren zum tablettieren
DE3612212A1 (de) * 1986-04-11 1987-10-15 Basf Ag Verfahren zur herstellung von festen pharmazeutischen formen
DE19975054I2 (de) * 1987-08-08 2000-04-13 Akzo Nobel Nv Kontrazeptives Implantat
US5283187A (en) * 1987-11-17 1994-02-01 Brown University Research Foundation Cell culture-containing tubular capsule produced by co-extrusion
NO882653D0 (no) * 1988-06-15 1988-06-15 Apothekernes Lab Doseringsform.
IT1264696B1 (it) * 1993-07-09 1996-10-04 Applied Pharma Res Forme farmaceutiche destinate alla somministrazione orale in grado di rilasciare sostanze attive a velocita' controllata e differenziata

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010425A1 (en) * 1990-01-08 1991-07-25 Brown University Research Foundation Cell capsule extrusion systems

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AU7491296A (en) 1997-05-15
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