CN1572326A - 包括生物利用度增强子的治疗用组合物 - Google Patents
包括生物利用度增强子的治疗用组合物 Download PDFInfo
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- CN1572326A CN1572326A CNA2004100475967A CN200410047596A CN1572326A CN 1572326 A CN1572326 A CN 1572326A CN A2004100475967 A CNA2004100475967 A CN A2004100475967A CN 200410047596 A CN200410047596 A CN 200410047596A CN 1572326 A CN1572326 A CN 1572326A
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- resin
- exchange resin
- acid
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- enhancer
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Abstract
本发明涉及一种包括生物增强子和负载在其上的非必要的治疗用活性成分或其前体的树脂。生物增强子是可电离或不可电离的，并且树脂可以是阳离子交换树脂或阴离子交换树脂。
Description
发明背景
本发明涉及治疗用组合物，该组合物包括生物利用度增强子，和更特别地包括负载在离子交换树脂上的生物增强子和生物增强子/治疗剂。
药物制剂由两类成分组成。第一类成分是能引起患者体内所需的治疗响应的活性药物成分(“药物”)。第二类成分已知为赋形剂，包括该赋形剂以保证剂型的稳定性、准确度和精度，改进制造性能，提供所需的治疗性能，和作为活性成分受控释放的手段。这些生物增强子以许多方式起作用，包括增加活性成分的溶解度，或增加活性成分的渗透性。如在美国临时专利申请No.WO2002064543A2中所描述的，本领域的缺点在于O-去甲基(desmethyl)-文拉法辛的富马酸盐具有不合适的物理化学和渗透性特性。
人们已经进行了许多尝试以取得活性成分的受控，延长，或改进的释放。自身不是生物增强子的赋形剂不需要改进或受控的释放，实际上是其自身用于产生改进或受控的释放。对于生物增强子不是这种情况。生物增强子的受控或改进释放的益处可包括通过输送它到最优位置或在最优速率下输送而获得的生物增强子改进的效能。这些益处也可包括对生物增强子在不利条件中的保护，该不利条件可在生物增强子达到其最优活性位置之前将其破坏。此类型不利条件的例子是胃中的强酸性条件，该强酸性条件可降解酸敏感性化合物。
已经用于制药领域以取得药物受控和改进释放的一种方法是将药物转化成与离子交换树脂的络合物以形成树脂酸盐。树脂酸盐是在离子交换树脂和可电离的活性成分之间形成的盐。阳离子交换树脂与碱性活性成分形成树脂酸盐。阴离子交换树脂与酸性活性成分形成树脂酸盐。在树脂酸盐中，活性成分和树脂以其离子化的形式存在。当树脂酸盐暴露于流体，比如生理性流体中时，活性成分可通过离子交换的机制从树脂酸盐中释放出来。活性成分从树脂酸盐中的释放速率依赖于几个因素。这些因素包括，但不限于，离子交换树脂的交联程度、树脂酸盐的颗粒大小、树脂官能团的pK值、活性成分在释放流体中的溶解度、释放流体的离子强度和pH值、活性成分的pK值、活性成分的分子量和温度。采用可渗透性膜涂敷树脂也可改变释放速率。依赖于膜溶解的条件，采用不透性膜涂敷树脂可改变释放发生的条件。
本领域中的问题涉及生物增强子在包括胃液的各种有害介质中的降解，和/或生物增强子的受控输送。本领域还没有关于使用生物增强子的树脂酸盐解决生物增强子降解，或解决具有不合适的物理化学和渗透性特性的治疗剂问题的单独或结合的教导或建议。
发明概述
本发明涉及可用于控制生物增强子输送的生物增强子的树脂酸盐。此外，可以将治疗活性成分和适当的生物增强子加入到相同的树脂酸盐中。在本发明的一个变化方案中，提供了一种包括治疗活性成分和其上负载生物增强子的树脂。
在本发明的另一个变化方案中，提供了一种包括生物增强子的树脂。该生物增强子是可电离或不可电离的。在仍然其它的变化方案中，树脂是阳离子树脂或阴离子树脂。在仍然进一步的变化方案中，阴离子树脂是苯乙烯类强碱性阴离子交换树脂。在各种实施方案中，苯乙烯类强碱性阴离子交换树脂进一步包括季胺官能度或叔胺官能度。
在仍然其它方面，树脂是具有非必要的磺酸类官能度、膦酸官能度、或其结合的苯乙烯类强酸性阳离子交换树脂。在仍然进一步的变化方案中，树脂是具有羧酸类官能度、酚酸官能度、或其结合的阳离子交换树脂。
在此处的说明书中提供本发明的这些和其它变化方案。
发明详述
除具有本领域已知的意义以外，在此使用的以下术语具有此处的以下含义：
术语“生物增强子”表示一种包括在药物剂型中的物质，该物质用于增加活性成分对活体内目标的生物利用度。
在此使用的术语“释放速率分布”表示负载在树脂上的活性成分出现在释放介质的溶液中的速率。这可表达为作为时间函数的溶液中活性成分的瞬时浓度，或表达为作为时间函数的出现在释放介质的溶液中的可利用的总活性成分百分比。
在此使用的术语“释放介质”表示活性成分释放到其中的液体介质。释放介质的例子可以是水，模拟肠液，模拟胃液，模拟唾液，或这些流体、水、和各种缓冲液的真正生理变型。
在此使用的术语“离子交换树脂”表示可用作离子交换剂的任何不溶性聚合物。
在此使用的术语“释放”表示活性成分从树脂酸盐向释放介质中的转移。当应用于树脂或树脂酸盐时，在此使用的术语“吸收”表示释放的反过程，即活性成分从介质向离子交换树脂或树脂酸盐中的转移。
在此使用的术语“保水能力”用于描述离子交换树脂在聚合物相中和任何孔中可保留的最大含水量。(ASTM D2187：粒状离子交换树脂物理和化学性能的标准测试方法。测试方法B：保水能力)
术语“树脂酸盐”表示在活性成分，生物增强子，或活性成分和生物增强子，和离子交换树脂之间形成的络合物。它也已知为负载的树脂。术语“树脂酸盐”也可涉及活性成分/离子交换树脂络合物、活性成分/生物增强子树脂络合物、或生物增强子树脂络合物。
此外，离子交换树脂的特征为其交换离子的能力。这表达为“离子交换能力”。对于阳离子交换树脂，使用的术语是“阳离子交换能力”，对于阴离子交换树脂，使用的术语是“阴离子交换能力”。离子交换能力测量为可交换的离子当量数和可以根据聚合物质量(在此缩写为“重量能力”)或其体积(通常缩写为“体积能力”)表达。对于重量能力通常使用的单位是“毫当量交换能力/克干燥聚合物”。这通常缩写为“meq/g”。
离子交换树脂可制造成不同的形式。这些形式可包括，例如，大小为0.00001-2mm的球形和非球形微粒。通常通过研磨球形微粒制造非球形微粒。以此方式制备的产物的微粒大小典型地为0.0001-0.2mm。球形微粒通常在本领域已知为“整体珠粒”。非球形微粒通常在本领域已知为“粉末”。
可以通过本领域任何已知的方法制备树脂/治疗活性成分络合物。本发明的组合物可包括以纯形式或作为树脂酸盐的活性成分。在其中活性成分和生物增强子都是酸性、或都是碱性、或都为不可电离的情况下，可以将活性成分和生物增强子负载到相同的树脂上。例如，如果药物含有羧酸基团，它可以负载到阴离子交换树脂上。如果生物增强子含有磺酸或羧酸，它可以负载到相同的阴离子交换树脂上。获得的树脂酸盐包含活性成分和生物增强子两者。
本发明的组合物可包括以纯形式或作为树脂酸盐的活性成分。在其中活性成分和生物增强子都是酸性、或都是碱性、或都为不可电离的情况下，可以将活性成分和生物增强子负载到相同的树脂上。例如，如果药物含有羧酸基团，它可以负载到阴离子交换树脂上。如果生物增强子含有磺酸或羧酸，它可以负载到相同的阴离子交换树脂上。获得的树脂酸盐包含活性成分和生物增强子两者。
用于实施本发明的离子交换树脂包括，但不限于，阴离子交换树脂和阳离子交换树脂。优选，当应用于药物时，树脂适用于人体和动物摄入。以下是用于本发明变化方案的离子交换树脂的例子：阴离子交换树脂包括，但不限于，重量能力为0.1-15meq/g的具有季胺官能度的苯乙烯类强碱性阴离子交换树脂、重量能力为0.1-8.5meq/g的具有伯胺、仲胺、或叔胺官能度的苯乙烯类弱碱性阴离子交换树脂、重量能力为0.1-12meq/g的具有季胺官能度的丙烯酸类或甲基丙烯酸类强碱性阴离子交换树脂、和重量能力为0.1-12meq/g的具有伯胺、仲胺、或叔胺官能度的丙烯酸类或甲基丙烯酸类弱碱性阴离子交换树脂、和重量能力为0.1-24meq/g的具有伯胺、仲胺、或叔胺官能度的烯丙基类和乙烯基类弱碱性阴离子交换树脂。
在本发明的另一个变化方案中，阴离子交换树脂包括，但不限于，重量能力为0.1-6meq/g的具有季胺官能度的苯乙烯类强碱性阴离子交换树脂、重量能力为0.1-8.5meq/g的具有叔胺官能度的苯乙烯类弱碱性阴离子交换树脂、重量能力为0.1-8meq/g的具有季胺官能度的丙烯酸类或甲基丙烯酸类强碱性阴离子交换树脂、重量能力为0.1-12meq/g的具有叔胺官能度的丙烯酸类或甲基丙烯酸类弱碱性阴离子交换树脂、和重量能力为0.1-24meq/g的具有伯胺、仲胺、或叔胺官能度的烯丙基类和乙烯基类弱碱性阴离子交换树脂。
在本发明的仍然另一个变化方案中，阴离子交换树脂包括，但不限于，重量能力为0.1-6meq/g的具有季胺官能度的苯乙烯类强碱性阴离子交换树脂和重量能力为0.1-12meq/g的具有叔胺官能度的丙烯酸类阴离子交换树脂。重量能力为4.0-4.5meq/g的具有季胺官能度的苯乙烯类强碱性阴离子交换树脂也称为胆苯烯胺(cholestyramine)树脂。
在本发明的仍然其它变化方案中，阳离子交换树脂包括，但不限于，重量能力为0.1-8meq/g的具有磺酸或膦酸官能度的苯乙烯类强酸性阳离子交换树脂、重量能力为0.1-8.5meq/g的具有羧酸或酚酸官能度的苯乙烯类弱酸性阳离子交换树脂、和重量能力为0.1-14meq/g的具有羧酸或酚酸官能度的丙烯酸类或甲基丙烯酸类弱酸性阳离子交换树脂。
在本发明的仍然进一步其它变化方案中，阳离子交换树脂包括，但不限于，重量能力为0.1-8meq/g的具有磺酸官能度的苯乙烯类强酸性阳离子交换树脂、重量能力为0.1-8.5meq/g的具有酚酸官能度的苯乙烯类弱酸性阳离子交换树脂、和重量能力为0.1-14meq/g的具有羧酸或酚酸官能度的丙烯酸类或甲基丙烯酸类弱酸性阳离子交换树脂。
在本发明的仍然其它变化方案中，阳离子交换树脂包括，但不限于，重量能力为0.1-8meq/g的具有磺酸官能度的苯乙烯类强酸性阳离子交换树脂、和重量能力为0.1-14meq/g的具有羧酸官能度的丙烯酸类或甲基丙烯酸类弱酸性阳离子交换树脂。
在一个变化方案中，用于本发明的离子交换树脂的含水量在0％和树脂的保水能力之间。用于本发明的离子交换树脂是粉末或整体珠粒的形式。在本发明的仍然进一步变化方案中，用于实施本发明的强酸性和弱酸性阳离子交换树脂为酸形式或盐形式或部分盐形式。在本发明的变化方案中，用于本发明的强碱性阴离子交换树脂为盐形式。本发明的变化方案中，用于本发明的弱碱性阴离子交换树脂为游离碱形式或盐形式或部分盐形式。用于本发明的树脂粒度由所需的释放速率分布限定并可以由本领域技术人员根据经验确定。在本发明的一个变化方案中，典型的粒度范围是0.00001-2mm。用于本发明的其它尺寸范围是0.001-1mm，和0.001-1.0mm。
可以非必要地涂敷本发明的组合物。用于本发明的可渗透性涂料包括EudragitRL100、和EudragitRS100(Rohm-Pharma Darmstadt，德国)。用于本发明的非渗透性涂料包括AquacoatCPD(FMCCorporation，Philadelphia，PA，USA)、EudragitE100、EudragitL100、EudragitS100(Rohm-Pharma Darmstadt，德国)、KollicoatMA 30DP(BASF Aktiengesellschaft，Ludwigshafen，德国)。
用于实施本发明的活性成分包括，但不限于，生理活性成分和维生素。其它活性成分包括：抗微生物剂如：环丙沙星、头孢美唑、perfloxacin、氧氟沙星、诺氟沙星、青霉素V、氨苄西林、阿莫西林、红霉素、氯唑西林、罗红霉素、阿奇霉素、头孢氨苄、头孢羟氨苄、cerfuoxime、cerfuoximeaxetil、头孢克肟、复方磺胺甲基异噁唑、阿昔洛韦、头孢克洛、氯法齐明、氟康唑、灰黄霉素、酮康唑；抗原虫剂如：甲硝唑、替硝唑、奎宁、氯喹、伯氨喹、磺胺多辛、乙胺嘧啶；驱肠虫药如：甲苯达唑、吡喹酮、噻嘧啶、非班太尔；心血管药如：氨氯地平、地尔硫、阿替洛尔、赖诺普利、洛伐他汀、吉非贝齐、硝苯地平、依那普利、心得安(propanolol)；对中枢神经系统起作用的药物：左旋多巴、丁螺环酮、右丙氧芬、喷他佐辛、吗啡衍生物、地西泮、劳拉西泮、阿普唑仑、氟哌啶醇、氯丙嗪、舒必利、硫利达嗪、文拉法辛、O-去甲氧基(desmethoxy)文拉法辛；非甾体抗炎药如：双氯芬酸、酮咯酸、吡罗昔康、布洛芬、吲哚美辛、萘普生；用于呼吸系统病症治疗的药物如：沙丁胺醇(solbutamol)、特布他林、茶碱、溴己新；抗组胺药如：阿司咪唑、特非那定、氯雷他定；促运动药物(prokinetic)如：甲氧氯普胺、多潘立酮、西沙必利；皮质类固醇如：泼尼松龙、地塞米松、倍他米松；类固醇激素如：康力龙(stanazolol)、口服避孕药；维生素如A、C、E、和K；抗溃疡药如：奥美拉唑、雷尼替丁、femotidine；中央肌松弛药如：卡立普多、氯美扎酮；抗癌药如烷基化试剂：merchlorthiamine、环磷酰胺、异环磷酰胺、苯丁酸氮芥、六甲蜜胺、塞替派、白消安、卡莫司汀、洛莫司汀、司莫司汀、链脲菌素、氮烯咪胺(decarbazine)；抗癌药如抗代谢药：氨甲喋呤(methatrexate)、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯嘌呤、硫鸟嘌呤、喷司他丁；天然产物的抗癌药物如：长春新碱、长春碱、依托泊苷、dectinmycin、柔红霉素、多柔比星、表柔比星、伊达比星、博来霉素、methramicin、丝裂霉素、L-门冬酰胺酶；抗癌药物如：顺铂、卡铂、米托蒽醌、羟基脲、丙卡巴肼、米托坦、氨鲁米特；激素和激素拮抗剂如：泼尼松龙、羟孕酮、甲羟孕酮、甲地孕酮、己烯雌酚、炔雌醇、他莫昔芬、睾酮、氟甲睾酮、氟他胺、leuprolide。可以理解上述药物的前体和衍生物也可用于本发明。
组合物的活性成分的组分可以足以产生有益效果的任何含量存在。
组合物的生物增强子组分可以足以产生有益效果的任何含量存在。生物利用度增强子的例子包括：一元羧酸及其盐、多元羧酸及其盐、磺酸及其盐、胺及其盐、皂草苷、甘油单酯、甘油二酯和甘油三酯。在其它变化方案中，生物增强子的例子包括，但不限于，抗坏血酸、柠檬酸、苹果酸、富马酸、琥珀酸、己酸、辛酸、甘氨胆酸、胆酸、2-正辛基十二烷酸、月桂基硫酸氢盐、硫辛酸、棕榈酰肉碱、氨基酸、胡椒碱、四氢胡椒碱、4-吖啶甲酰胺、也称为Elacridar的N-[4-[2-(3，4-二氢-6，7-二甲氧基-2(1H)-异喹啉基)乙基]苯基]-9，10-二氢-5-甲氧基-9-氧代-(9CI)、氨丁三醇、琥珀酸二辛酯磺酸钠、脱氧胆酸盐、甘氨胆酸盐、十二烷基麦芽苷、油酸、亚油酸、亚麻酸、N-乙酰化氨基酸、月桂基肉碱、己酸的甘油单酯、甘油二酯和甘油三酯、辛酸的甘油单酯、甘油二酯和甘油三酯、酰基胆碱、和烷酰基胆碱。
最终的剂型可以是本领域已知的许多变体的任何一种。这些变体可包括，但不限于，乳膏、片剂、粉末、丸剂、糖浆、硬胶囊和软胶囊。
本发明不限于仅使用一种负载的树脂。多种相同类型或不同类型的负载的树脂也可以按照需要用于产生所需的治疗结果。
本发明不限于仅使用一种活性成分或生物增强子。多种活性成分或生物增强子可用于在单一树脂或多种树脂上产生所需的有益效果。
树脂的混合物也可用于本发明。作为例子，将其上含有治疗活性化合物的第一树脂与其上含有生物增强子的第二树脂混合。按经验确定第一和第二树脂的剂量。然后将第一树脂与第二树脂混合并以剂型提供给患者。
在仍然进一步的变化方案中，本发明提供一种施用药物的方法，使得药物具有增加的生物利用度。在一个变化方案中，该方法包括一起施用药物与含有生物利用度增强子的树脂。在另一个变化方案中，该方法包括施用其上含有生物利用度增强子和非必要的治疗剂的树脂。
在一个变化方案中，本发明负载一种新颖的O-去甲基-文拉法辛的盐，O-去甲基-文拉法辛琥珀酸盐、或其前体、或其衍生物(以下称为“ODV琥珀酸盐”)到一种或多种本发明的树脂上。在一个变化方案中，将琥珀酸盐负载在第一树脂的一个部位，并将O-去甲基-文拉法辛负载到相同树脂的第二个部位。在另一个变化方案中，将琥珀酸盐负载到第一树脂的一个部位(珠粒或类型)，并将O-去甲基-文拉法辛负载到第二树脂的一个部位(珠粒或类型)。琥珀酸盐用作治疗用化合物的生物利用度增强子。这样的化合物描述于题目为“O-去甲基-文拉法辛的新颖琥珀酸盐”的美国临时专利申请No.WO2002064543 A2。
本发明使用的盐形式具有特别适用于药物的性能，该性能包括改进的溶解度，渗透性，和生物利用度。例如，ODV/琥珀酸盐树脂络合物发挥作用使得活性成分在胃肠道中得到良好的吸收。此外，与不同于ODV琥珀酸盐的文拉法辛、O-去甲基-文拉法辛、和O-去甲基10文拉法辛的盐的口服药相比，认为ODV琥珀酸树脂络配合物的口服药有可能导致恶心、呕吐、腹泻、腹痛、头痛、血管-迷走神经不适、和/或牙关紧闭的更少发生。另外，与文拉法辛、O-去甲基-文拉法辛、和O-去甲基文拉法辛盐的口服药(不是ODV琥珀酸盐持续释放的口服制剂)相比，ODV琥珀酸盐持续释放的口服制剂导致恶心、呕吐、腹泻、腹痛、头痛、血管-迷走神经不适、和/或牙关紧闭的更少发生。
本发明也提供包括ODV/琥珀酸盐树脂络合物和药物上可接受载体或赋形剂的药物组合物。优选，该药物组合物包括有效治疗动物，如人类中所需适应症含量的ODV琥珀酸盐。
在本发明的进一步实施方案中，提供治疗患以下疾病的患者的方法：抑郁症(包括，但不限于，重度抑郁症、双相性精神障碍和精神抑郁症)、焦虑症、惊恐性障碍、泛化性焦虑症、创伤后应激障碍、月经前焦虑、纤维肌痛、旷野恐怖症、注意力缺陷障碍(具有或不具有25功能亢进)、强制性障碍(包括拨毛发癖)、社交焦虑障碍、孤独症、精神分裂症、肥胖症、神经性厌食症、神经性贪食症、杜尔雷特综合症、血管舒缩冲洗、可卡因和酒精成瘾、性功能障碍(包括，但不限于，早泄)、边缘型人格障碍、慢性疲劳综合症、尿失禁、疼痛(包括，30但不限于，偏头痛、慢性背痛、假肢痛、中枢疼痛、神经性疼痛如糖尿病性神经病变和带状疱疹神经病)、夏-德综合症、雷诺氏综合症、帕金森氏病和癫痫症，该方法包括向患者提供有效量的ODV琥珀酸盐。也可使用本发明的ODV琥珀酸盐以防止抑郁症的复发或再发，使-2诱导认知增强，以治疗认知损伤，和用于吸烟或其它烟草使用停止的治疗。另外，可以使用在此所述的ODV/琥珀酸盐树脂络合物或混合物以治疗抑郁和非抑郁女性的下丘脑性闭经。这些方法包括向需要的患者施用有效量的在此所述的化合物或在此所述组合物中的基本纯的ODV多晶型物，或其混合物。
本发明在一个变化方案中使用一种O-去甲基-文拉法辛的新颖盐、O-去甲基-文拉法辛琥珀酸盐或其组分，如琥珀酸盐和其余的治疗剂(以下称为“ODV琥珀酸盐”)。由于它的高溶解度，渗透性和生物利用度，ODV琥珀酸盐为制剂提供了最优的性能。O-去甲基-文拉法辛的琥珀酸盐以对映体存在并且本发明非必要地使用其外消旋混合物及其立体异构纯的形式。在此使用的术语“ODV琥珀酸盐”表示外消旋混合物和立体异构纯形式的ODV琥珀酸盐，其前体和其衍生物。
术语“立体异构纯”表示由较旋光对映体更大比例的所需异构体组成的化合物。立体异构纯化合物一般由至少约90％的所需异构体组成，基于ODV琥珀酸盐100％的总重量。
琥珀酸是二元羧酸和本发明因此包括以下两种盐：其中O-去甲基-文拉法辛与酸的比例(按摩尔)是1∶1(即单琥珀酸盐)的盐和其中O-去甲基-文拉法辛与酸的比例(按摩尔)是2∶1(即二琥珀酸盐)的盐，以及混合盐，例如碱金属或铵阳离子。本发明也使用ODV琥珀酸盐和O-去甲基-文拉法辛游离碱的混合物。ODV琥珀酸盐的结晶多晶型物(即形式I、II、III、和IV)和无定形形式是单琥珀酸盐，或其组分，即O-去甲基-文拉法辛与酸的摩尔比是1∶1，被用于本发明的一个变化方案中。
本发明的盐可以是结晶并可以多于一种多晶型物的形式存在。每种多晶型物形成本发明的另一个方面。盐的水合物以及无水形式也可用于本发明。在一个变化方案中，使用O-去甲基文拉法辛琥珀酸盐的一水合物。ODV琥珀酸盐在水中的溶解度一般大于30mg/mL。在另一个变化方案中，在25℃下ODV琥珀酸盐在水中的溶解度至少是25、30、32、35、40、或45mg/mL。可以使化学计量的酸与O-去甲基文拉法辛游离碱接触形成琥珀酸盐。或者，可以过量使用酸，通常不大于1.5当量。
不同形式的O-去甲基文拉法辛可用于本发明。
实施例1-活性成分树脂酸盐
在此实施例中，使用的树脂是在干燥基础上重量能力为4.5meq/g的氢离子形式的强酸性阳离子交换树脂。树脂的含水量是6％w/w。树脂为粉末形式。活性成分是舒必利。混合9.2g树脂与350ml的25％的乙醇水溶液。向其中加入3.3g舒必利。将混合物搅拌12小时，然后过滤。将滤出物(filtrate)用水洗涤，然后在60℃下真空中干燥到恒重。每克树脂酸盐包含大约0.27g舒必利。
实施例2-生物增强子树脂酸盐
在此实施例中，使用的树脂是在干燥基础上重量能力为4.25meq/g的氯离子形式的水合强碱性阴离子交换树脂。树脂的含水量是70％w/w。树脂为粉末形式。生物增强子是癸酸。混合33.3g树脂与400ml水。向其中加入5.4g癸酸钠。将混合物在50℃下搅拌12小时，然后过滤。将滤出物用水洗涤，然后在60℃下真空中干燥到恒重。每克树脂酸盐包含大约0.17g癸酸钠。
实施例3-去甲基文拉法辛/琥珀酸盐树脂酸盐
此实施例示范包含活性成分和生物增强子的树脂酸盐的制备。使用的树脂是在干燥基础上重量能力为4.6meq/g的氢氧根形式的强碱性阴离子交换树脂。树脂的含水量是6％w/w。树脂为粉末形式。混合5.0g树脂与500ml的25％乙醇。加入1.16g的O-去甲基文拉法辛并搅拌混合物6小时。然后加入0.53g琥珀酸并进一步搅拌混合物12小时。然后过滤混合物并将滤出物采用25％乙醇洗涤，然后用水洗涤。然后将洗涤的滤出物悬浮在150ml水中并非常缓慢地加入1％盐酸直到上层清液的pH～10。将混合物过滤并用水洗涤。将洗涤的滤出物在60℃下真空中干燥。一克获得的树脂酸盐包含大约0.25g的O-去甲基文拉法辛琥珀酸盐。
Claims (11)
1.一种包括生物增强子和负载在其上的非必要的治疗用活性成分或其前体的树脂。
2.权利要求1的树脂，其中该生物增强子是可电离的。
3.权利要求1的树脂，其中该生物增强子是不可电离的。
4.权利要求1的树脂，其中该树脂是阴离子交换树脂。
5.权利要求4的树脂，其中该阴离子交换树脂是苯乙烯类强碱性阴离子交换树脂。
6.权利要求5的树脂，其中该苯乙烯类强碱性阴离子交换树脂进一步包括季胺官能度。
7.权利要求5的树脂，其中该树脂是具有叔胺官能度的丙烯酸类阴离子交换树脂。
8.权利要求1的树脂，其中该树脂是阳离子交换树脂。
9.权利要求8的树脂，其中该阳离子交换树脂是苯乙烯类强酸性阳离子交换树脂。
10.权利要求9的树脂，其中该苯乙烯类强酸性阳离子交换树脂进一步包括磺酸类官能度、膦酸官能度、或其结合。
11.权利要求9的树脂，其中该苯乙烯类阳离子交换树脂包括羧酸类官能度、酚酸官能度、或其结合。
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| CN105246493A (zh) * | 2013-03-19 | 2016-01-13 | 生物生命有限责任公司 | 止血装置和方法 |
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| US20080058428A1 (en) * | 2006-09-01 | 2008-03-06 | Lyn Hughes | Method and composition for eliminating odors in ion exchange resins |
| TWI561303B (en) * | 2014-04-09 | 2016-12-11 | Rohm & Haas | Catalyst resin |
| JP6253102B2 (ja) * | 2014-05-30 | 2017-12-27 | 株式会社吉野工業所 | 泡吐出器 |
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| US5980882A (en) * | 1997-04-16 | 1999-11-09 | Medeva Pharmaceuticals Manufacturing | Drug-resin complexes stabilized by chelating agents |
| NZ539791A (en) * | 2001-02-12 | 2006-11-30 | Wyeth Corp | Novel succinate salt of o-desmethyl-venlafaxine |
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2004
- 2004-02-05 JP JP2004029032A patent/JP2004359665A/ja not_active Withdrawn
- 2004-05-18 EP EP20040252933 patent/EP1481690A1/en not_active Withdrawn
- 2004-05-26 CN CNA2004100475967A patent/CN1572326A/zh active Pending
- 2004-05-27 US US10/854,906 patent/US20040241135A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1985842B (zh) * | 2006-12-13 | 2011-06-15 | 深圳致君制药有限公司 | 阿奇霉素树脂口服混悬液及其制备方法 |
| CN105246493A (zh) * | 2013-03-19 | 2016-01-13 | 生物生命有限责任公司 | 止血装置和方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1481690A1 (en) | 2004-12-01 |
| JP2004359665A (ja) | 2004-12-24 |
| US20040241135A1 (en) | 2004-12-02 |
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