CN105873582A - 消旋卡多曲液体组合物 - Google Patents
消旋卡多曲液体组合物 Download PDFInfo
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- CN105873582A CN105873582A CN201480070556.6A CN201480070556A CN105873582A CN 105873582 A CN105873582 A CN 105873582A CN 201480070556 A CN201480070556 A CN 201480070556A CN 105873582 A CN105873582 A CN 105873582A
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- racecadotril
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Abstract
本发明公开了一种包含消旋卡多曲和环糊精的液体组合物。
Description
技术领域
本发明涉及液体组合物。更具体地，本发明涉及包含消旋卡多曲的液体组合物以及制备所述组合物的方法。
背景技术
腹泻是一种肠道疾病，其特征在于水样大便的频率增加。腹泻可能由多种原因引起，包括细菌或病毒引起的腹泻。由过敏症引起的食物不耐症或食用食物诸如脂肪或辛辣食物可能导致腹泻。食物中毒也可能导致腹泻。在一些情况下，腹泻可能是其他病症和疾病的症状。
腹泻是肠道或其他身体功能疾病的症状。可服用多种处方和非处方产品来减轻病痛。然而，这些产品中的许多产品在减轻病痛的同时具有副作用。
消旋卡多曲也用于治疗腹泻。其减少了(i)水和电解质过多分泌到肠腔中，(ii)急性腹泻的发生率和持续时间以及(iii)腹泻相关的症状。
目前，消旋卡多曲具有固态口服剂型。
发明内容
本发明涉及一种包含消旋卡多曲和环糊精的液体组合物。
在一个实施方案中，本发明的组合物包含约0.01重量％至约24.0重量％的消旋卡多曲以及约1重量％至约95重量％的环糊精，其中各个重量％基于100mL的组合物计。
本发明还包括一种用于对出现腹泻的受检者进行治疗的方法，包括受检者口服包含消旋卡多曲和环糊精的组合物的步骤。
具体实施方式
如本文所用，“稳定”是指基本上不具有消旋卡多曲的化学降解或实质颜色变化的液体组合物。在一个实施方案中，在40℃下储存三个月时，基于消旋卡多曲的总重量％计，消旋卡多曲的总化学降解产物应少于0.2重量％，例如少于0.1重量％。在另一个实施方案中，在40℃下储存六个月时，基于消旋卡多曲的总重量％计，消旋卡多曲的总化学降解产物应少于0.2重量％，例如少于0.1重量％。
通过计算HPLC色谱图中的降解产物峰面积相对于消旋卡多曲峰的峰面积的峰面积％来确定降解产物的百分比。在一个实施方案中，在40℃下保存3个月时，基于消旋卡多曲的总％计，消旋卡多曲的总化学降解产物应少于消旋卡多曲的0.5％，例如少于0.2％。
本发明为一种包含消旋卡多曲和环糊精的液体组合物。
消旋卡多曲在减轻腹泻症状方面的药效已在多个研究中得到证实。使用消旋卡多曲与其他治疗方法相比的优势之一在于在对比试验中消旋卡多曲被证明具有更少的不良事件，诸如治疗后便秘。
在本发明中，消旋卡多曲被包含在稳定的液体组合物中。
消旋卡多曲是一种具有低水溶性的化合物，使得其难以配制成液体组合物。然而，口服液体组合物是为儿童群体施用药物的最优选的剂型。
在一个实施方案中，使用消旋卡多曲的RS外消旋构型。在另一个实施方案中，使用消旋卡多曲的R构型。
消旋卡多曲被包含在液体组合物中，在每100mL的液体组合物中的量为约0.01克至约0.5克。优选地，每100mL的液体组合物中的消旋卡多曲为约0.05克至约0.4克，并且更优选地为约0.1克至约0.3克。在一个实施方案中，每100mL的液体组合物中的消旋卡多曲为约0.25克。
在一个实施方案中，在室温(25℃)下使用布氏粘度计测得的液体组合物的粘度为约1厘泊至约500厘泊。
液体组合物的pH为约1至约6。优选地，pH为约3至约5。更优选地，pH为约4.5。
在一个实施方案中，可包含缓冲体系以将pH保持在某一数值或所需范围内。缓冲剂可为柠檬酸盐、醋酸盐、磷酸盐或它们的混合物。优选地，使用醋酸盐缓冲剂。
在一个实施方案中，将消旋卡多曲溶于液体组合物中。
环糊精是用于包括药品、食品、消费品和化学品等多种产品中的化合物。环糊精经由酶促反应由淀粉合成。
合适的环糊精包括例如α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精、羟丙基-γ-环糊精或它们的混合物。
在一个实施方案中，环糊精为羟丙基-β-环糊精。羟丙基-β-环糊精的一个来源是购自美国国际特品公司(ISP)的CAVASOL W7。
在另一个实施方案中，环糊精是β-环糊精的磺丁基醚衍生物，其以商品名CAPTISOL购自Captisol。
环糊精被包含在组合物中，在每100mL的液体组合物中的量为约1克至约70克。优选地，每100mL的液体组合物中的环糊精为约5克至约60克，并且更优选地为约5克至约50克。
在一个实施方案中，每100mL的液体组合物中的环糊精为约40克至约60克。
在另一个实施方案中，每100mL的液体组合物中的环糊精为约15克至约30克。
液体组合物还含有水。水是在已添加所有其他组分之后填充空隙的溶剂。所包含的水的量有所变化，因为添加水以便使组合物达到至多所需的体积量。
任选地，本发明的液体组合物中可包含多种成分。
例如，液体组合物中可包含丙二醇。丙二醇有许多用途，诸如食品和药品中的保湿剂，以及作为食品着色剂和调味料的溶剂。它是无色、几乎无味、透明的粘性液体，具有淡淡的甜味，可吸湿，并且可与水、丙酮和氯仿混溶。
任何适合用于食品或药品中的着色剂均可用于本发明的组合物。典型的着色剂包括例如偶氮染料、喹酞酮染料、三苯甲烷染料、呫吨类染料、靛青类染料、氧化铁、氢氧化铁、二氧化钛、天然染料以及它们的混合物。更具体地，合适的着色剂包括但不限于专利蓝V、酸亮绿BS、红2G、偶氮玉红、胭脂红4R、苋菜红、D&C红33、D&C红22、D&C红26、D&C红28、D&C黄10、FD&C黄5、FD&C黄6、FD&C红3、FD&C红40、FD&C蓝1、FD&C蓝2、FD&C绿3、亮黑BN、炭黑、氧化铁黑、氧化铁红、氧化铁黄、二氧化钛、核黄素、胡萝卜素、花青素、姜黄、胭脂虫提取物、叶绿素、角黄素、焦糖、甜菜苷以及它们的混合物。
相似地，液体组合物中可包含风味剂。添加到组合物中的风味剂的量将取决于所需的口味特征。
该组合物可包含其他成分或组分，例如：芳香剂；甜味剂，诸如山梨糖醇、高果糖玉米糖浆、糖、以及高强度甜味剂(诸如三氯蔗糖、天冬甜素和糖精)等；粘度调节剂诸如黄原胶；防腐剂诸如苯甲酸钠NF、缓冲剂(诸如柠檬酸和/或氯化钠)；表面活性剂，诸如聚山梨醇酯80和/或月桂基硫酸钠或它们的混合物。
在一个实施方案中，本发明的液体组合物包含约0.1重量％至约0.3重量％的消旋卡多曲以及约40重量％至约65重量％的环糊精，其中各个重量％基于100mL的组合物计。
在另一个实施方案中，本发明的液体组合物包含约0.1重量％至约0.3重量％的消旋卡多曲以及约10重量％至约40重量％的环糊精，其中各个重量％基于100mL的组合物计。
本发明组合物中的消旋卡多曲的溶解度为约1.5mg/mL至4.0mg/mL。
本发明的液体组合物可通过本领域的技术人员已知的任何方法制备，只要能得到所需组合物即可。
合适的方法包括例如在混合罐中合并每种成分，其中该成分可连续地或以任何方式添加，只要达到预期结果即可。此外，混合操作应当足以将每种成分掺入组合物中。
在一个实施方案中，本发明的液体包含第二活性成分。第二活性成分可以是例如以混悬状态存在，或者可溶于液体组合物中。在一个实施方案中，第二活性成分为消化健康活性成分，可以是例如轻泻剂、抗酸剂、质子泵抑制剂、防气剂、止吐药、H2阻滞剂、第二止泻剂等。在一个实施方案中，第二活性成分被微胶囊化。
合适的防气剂包括但不限于二甲基硅油。
合适的其他止泻剂包括但不限于
本发明的液体组合物可通过任何合适的递送***递送。例如，在一个实施方案中，液体组合物通过口服递送。在另一个实施方案中，组合物为液体口服剂型。在又一个实施方案中，使用软壳固体剂型来递送液体组合物。在又一个实施方案中，使用硬壳固体剂型来递送液体组合物。在又一个实施方案中，使用片剂剂型来递送液体组合物。
本发明还包括一种用于对出现腹泻的受检者进行治疗的方法，包括受检者口服包含消旋卡多曲和环糊精的组合物的步骤。
以下提供的实例进一步说明了本发明的组合物和方法。应当理解，本发明并不局限于所描述的实施方案。
实施例1
消旋卡多曲口服液制剂
消旋卡多曲口服液的组合物在表1中示出。使用表1中的材料，采用以下混合步骤：
步骤1：通过利用实验室混合器在合适的容器中混合纯化水和羟丙基-β-环糊精来形成溶液。
步骤2：将消旋卡多曲加入步骤1的溶液中，在实验室摇动器中混合至少12小时并且形成澄清溶液。
步骤3：混合柠檬酸、山梨糖醇溶液、高果糖玉米糖浆和氯化钠以形成溶液，并使用实验室混合器混合直至溶解。
步骤4：通过在合适的容器中将风味剂混合到聚乙二醇400中来制备单独的混合物。然后，将该混合物与步骤3的溶液混合，并利用纯化水稀释以定容。
表1：消旋卡多曲口服液体组合物(2.5mg/g)
| 成分 | 重量％ |
| 消旋卡多曲 | 0.25 |
| 羟丙基β-环糊精1 | 7.00 |
| 柠檬酸 | 0.21 |
| 山梨糖醇(70重量％) | 17.50 |
| 高果糖玉米糖浆(42重量％) | 49.75 |
| 氯化钠 | 0.25 |
| 聚乙二醇400 | 0.50 |
| 风味剂 | 0.10 |
| 纯化水 | 24.44 |
| 总计 | 100.0* |
1：以CAVASOL W7从ISP商购获得
实施例2：浓缩的消旋卡多曲含水组合物
在醋酸盐的含水缓冲剂中制备三种消旋卡多曲制剂，并在柠檬酸盐含水缓冲剂中制备三种消旋卡多曲制剂。利用β-环糊精的磺丁基醚衍生物中的消旋卡多曲混合物来制备三种制剂，如表2所示。
表2：基于β-环糊精的含水组合物的消旋卡多曲磺丁基醚衍生物
使用表2中的材料，采用以下混合步骤来形成溶液。
步骤1：在合适的玻璃瓶中，称量、混合并在pH为4.5的醋酸盐缓冲剂中分别配制成60％、70％和78％的制剂(制剂1、3和5)。同样，称量并在pH为4.5的柠檬酸盐缓冲剂中分别配制成60％、69％和80％的制剂(制剂2、4和6)。
步骤2：利用冰醋酸(17.4M)或柠檬酸(3M)来将每个瓶子的pH调整至pH4.5。
步骤3：将消旋卡多曲缓慢加入步骤2的每个瓶子中，利用涡旋混合器混合5分钟，然后将每个瓶子置于实验室摇动器中，混合24小时直至形成溶液。
含水溶液中的消旋卡多曲的稳定性
为了便于比较，在室温和40℃下测试消旋卡多曲的稳定性。
表3：水中的消旋卡多曲的稳定性
这些结果表明，在室温和40℃的条件下，消旋卡多曲在12小时后不稳定。此外，在1周时，消旋卡多曲以少于1％的量存在。
缓冲剂中的消旋卡多曲的稳定性
为了便于比较，将消旋卡多曲溶于pH为4.5的醋酸盐缓冲剂和pH为4.5的柠檬酸盐缓冲剂中后，分析其稳定性(表4)。
表4：缓冲剂中的消旋卡多曲的稳定性
这些数据表明，在40℃下的四周之内，尽管消旋卡多曲的稳定性有所降低，但其在缓冲剂中比在水中更稳定。这些数据还表明，消旋卡多曲在缓冲剂中比在水中更可溶。
β-羟丙基-环糊精(β-HPCD)中的消旋卡多曲的稳定性
评估β-羟丙基-环糊精中的消旋卡多曲制剂(表5)。
表5：β-羟丙基-环糊精(β-HPCD)中的消旋卡多曲的稳定性
这些数据表明，β-HPCD中消旋卡多曲的稳定性类似于其仅在缓冲剂中的稳定性，但是使用β-HPCD实现了更高的溶解度。
β-环糊精
1
的磺丁基醚衍生物溶液中的消旋卡多曲的稳定性
分析上面实例2中使用β-环糊精的磺丁基醚衍生物溶液制备的样品的稳定性。数据被示于表6中。
表6：基于β-环糊精的磺丁基醚衍生物的水溶液中的消旋卡多曲的稳
定性数据(40℃下长达37.6周)
制剂1、制剂3、制剂5
制剂2、制剂4、制剂6
*由于两峰之间的不可分离的积分所造成的测量误差
制剂
1—pH为4.5的醋酸盐缓冲剂中，60重量％的
2—pH为4.5的柠檬酸盐缓冲剂中，60重量％的
3—pH为4.5的醋酸盐缓冲剂中，70重量％的
4—pH为4.5的柠檬酸盐缓冲剂中，69重量％的
5—pH为4.5的醋酸盐缓冲剂中，78重量％的
6—pH为4.5的柠檬酸盐缓冲剂中，80重量％的
测试方法
样品制备：
1.移取1mL消旋卡多曲溶液至100mL容量瓶(V.F.)中。
2.然后利用与溶液制备中相同的缓冲剂来稀释以定容。
3.如有必要，将样品溶液进一步稀释至约0.1mg/mL。
样品分析
在与下文建议相似的条件下，将标准品(0.1mg/mL消旋卡多曲乙腈溶液)和样品注入到合适的HPLC***上。可修改参数以优化色谱法。
通过使用注入的外标来确定对消旋卡多曲的测定。通过相对于消旋卡多曲色谱峰的峰面积％来确定降解产物含量。
色谱分离条件(欧洲药典消旋卡多曲方法)：
梯度表：
流动相A：磷酸盐缓冲剂，pH2.5(缓冲剂制备：将1g磷酸二氢钾溶解于水中，利用磷酸来将pH调节至2.5，利用水稀释至1000ml)
流动相B：100％乙腈
40℃下β-羟丙基-环糊精(β-HPCD)中的消旋卡多曲的稳定性
虽然上文已结合本发明的具体实施方案描述了本发明，但明显的是，在不脱离本文所公开的发明构思的条件下，可作出多种变化、修改和变型。因此，本文旨在涵盖属于所附权利要求书的实质和广义范围内的所有此类变化、修改和变型。本文引用的所有专利申请、专利以及其它出版物均全文以引用方式并入。
Claims (20)
1.一种液体组合物，所述液体组合物包含消旋卡多曲和羟丙基-β-环糊精。
2.根据权利要求1所述的液体组合物，其中所述消旋卡多曲为RS外消旋构型或R构型。
3.根据权利要求1所述的液体组合物，其中所述消旋卡多曲以每100mL的所述液体组合物约0.10克至约0.30克的量存在。
4.根据权利要求1所述的液体组合物，其中所述羟丙基-β-环糊精以每100mL的所述液体组合物约5克至约50克的量存在。
5.根据权利要求1所述的液体组合物，还包含选自由以下各项组成的组的成分：缓冲剂、防腐剂、甜味剂、粘度调节剂、着色剂、芳香剂、风味剂以及它们的混合物。
6.根据权利要求6所述的液体组合物，其中所述缓冲剂是柠檬酸盐、醋酸盐、磷酸盐或它们的混合物。
7.根据权利要求6所述的液体组合物，其中所述甜味剂是山梨糖醇、高果糖玉米糖浆、三氯蔗糖、天冬甜素、糖精、蔗糖或它们的混合物。
8.根据权利要求6所述的液体组合物，其中所述防腐剂为苯甲酸钠、苯甲酸钾、对羟基苯甲酸丙酯、对羟基苯甲酸甲酯、对羟基苯甲酸丁酯或它们的混合物。
9.一种剂型，其中所述剂型包括经由软壳固体剂型、硬壳固体剂型或片剂剂型递送的根据权利要求1所述的液体组合物。
10.根据权利要求1所述的液体组合物，还包含第二活性成分，所述第二活性成分为消化健康活性成分。
11.根据权利要求1所述的液体组合物，其中所述组合物通过口服递送。
12.根据权利要求1所述的液体组合物，其中所述组合物在25℃下具有约3至约5的pH值。
13.一种剂型，其中所述剂型包括经由软壳固体剂型、硬壳固体剂型或片剂剂型递送的根据权利要求15所述的液体组合物。
14.根据权利要求15所述的液体组合物，还包含第二活性成分，所述第二活性成分为消化健康活性成分。
15.一种液体组合物，包含：
约0.1重量％至约0.3重量％的消旋卡多曲；
约6重量％至约8重量％的羟丙基-β-环糊精；
约16重量％至约19重量％的山梨糖醇；
约45重量％至约55重量％的高果糖玉米糖浆；
约0.1重量％至约0.4重量％的氯化钠；
约0.1重量％至约0.8重量％的聚乙二醇；
约15重量％至约30重量％的水；和
约0重量％至约0.5重量％的风味剂，
其中各个重量％基于100mL的所述组合物计。
16.一种用于对出现腹泻的受检者进行治疗的方法，包括所述受检者口服包含消旋卡多曲和羟丙基-β-环糊精的液体组合物的步骤。
17.根据权利要求12所述的液体组合物，其中所述消化健康活性成分是二甲基硅油。
18.根据权利要求17所述的液体组合物，其中所述消化健康活性成分是二甲基硅油。
19.根据权利要求12所述的液体组合物，其中所述消化健康活性成分是洛派丁胺。
20.根据权利要求17所述的液体组合物，其中所述消化健康活性成分是洛派丁胺。
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