CN115192548A - 一种布瑞哌唑口溶膜组合物、其制备方法及应用 - Google Patents
一种布瑞哌唑口溶膜组合物、其制备方法及应用 Download PDFInfo
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- CN115192548A CN115192548A CN202210398190.1A CN202210398190A CN115192548A CN 115192548 A CN115192548 A CN 115192548A CN 202210398190 A CN202210398190 A CN 202210398190A CN 115192548 A CN115192548 A CN 115192548A
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- brexpiprazole
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Abstract
本发明提供了一种布瑞哌唑口溶膜组合物、其制备方法及应用。本发明公开了一种布瑞哌唑口溶膜组合物，其包含活性药物、成膜材料、增塑剂、甜味剂和有机酸中的一种或多种，所述的活性药物为如式I所示的7‑[4‑(4‑苯并[B]噻吩‑4‑基‑1‑哌嗪)丁氧基]‑2(1H)‑喹啉酮和/或其药学上可接受的盐，所述的布瑞哌唑口溶膜组合物的pH值为2.5‑4.5。本发明得到的布瑞哌唑口溶膜组合物具有良好的溶出速率，在口腔中溶解后不会有沙砾感、且外观均一、柔韧性好、同时在膜液配制过程中不会发生沉降，含量均一性符合要求。
Description
本申请要求享有2021年4月13日向中国国家知识产权局提交的申请号为CN202110395940.5，名称为“一种布瑞哌唑口溶膜组合物、其制备方法及应用”的发明专利申请的优先权。该申请的全文以引用的方式并入本文。
技术领域
本发明涉及一种布瑞哌唑口溶膜组合物、其制备方法及应用。
背景技术
布瑞哌唑片由日本大冢制药株式会社和丹麦灵北制药有限公司共同开发，并于2015年7月在FDA批准上市，剂型为片剂，规格为0.25mg、0.5mg、1mg、2mg、3mg和4mg。
布瑞哌唑片作为5-HT1A受体及多巴胺D2受体激动剂，5-HT2A受体拮抗剂，临床上用于重度抑郁症和精神分裂症的治疗。用于重度抑郁症治疗时，起始剂量为0.5mg/天或1mg/天，然后增至目标剂量2mg，每日一次，最大推荐剂量为3mg/天；用于精神分裂治疗时，起始剂量为1mg/天，推荐目标剂量为2mg至4mg，每日一次，最大推荐剂量为4mg/天。布瑞哌唑在多个单胺系统具有广泛的活性，对多巴胺D2受体的部分激动剂活性下降，且对特定5-HT受体(如5-HT1A、5-HT2A、5-HT7)的亲和力提高，具有更好的疗效和耐受性，可减少患者静坐不能、不安或失眠等不良反应。
布瑞哌唑为白色或类白色结晶粉末，在水中几乎不溶，且自身具有苦麻刺激感，可在口腔粘膜引起显著的刺激感觉。
布瑞哌唑普通片必须现在胃中崩解才能开始释放药物，起效慢，从而限制生物利用度。服用也不方便，作为精神类疾病的治疗药物，该适应症人群在配合治疗方面较差，易发生拒绝治疗、藏药、吐药等情况。
专利CN105078910A公开了一种布瑞哌唑口崩片制备方法，将含有布瑞哌唑采用冻干技术制备成冻干口崩片，使其崩解速度加快，提高溶出。但该技术相对繁琐，生产需要专门设备，产品造价高，且制备的制剂较容易碎裂，不适于运输，增加了包装、运输难度。且服用时不能沾水，提高对患者的要求，不利于精神分裂患者的顺应性。
专利CN105395528A公开了一种布瑞哌唑口腔速溶膜，但由于布瑞哌唑在水中几乎不溶，难以分散在亲水性的胶液中，在刮涂烘干过程中，药物易发生团聚现象，从而影响主药的含量均匀度。同时患者服用后也会有口感不适的现象，影响顺应性。
因此，迫切需要开发服用方便、患者顺应性好、生物利用度高、适合于工业化生产的布瑞哌唑的剂型。
发明内容
本发明所要解决的技术问题是为了克服现有技术中布瑞哌唑普通片必须现在胃中崩解才能开始释放药物、起效慢、从而限制生物利用度、服用不方便、患者顺应性差等缺陷而提供了布瑞哌唑口溶膜组合物、其制备方法及应用。本发明的布瑞哌唑口溶膜组合物，具有厚度薄、口感良好、性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点，同时工艺简单、载药量高、药物含量均匀度好，解决了精神分裂症患者服药顺应性差及藏药和吐药现象，特别适宜有吞咽困难的患者。
本发明提供一种布瑞哌唑口溶膜组合物，其特征在于包含活性药物、成膜材料、增塑剂、甜味剂和有机酸中的一种或多种，所述的活性药物为如式I所示的7-[4-(4-苯并[B]噻吩-4-基-1-哌嗪)丁氧基]-2(1H)-喹啉酮和/或其药学上可接受的盐，所述的布瑞哌唑口溶膜组合物的pH值为2.5-4.5；
本发明中，所述的布瑞哌唑口溶膜组合物的pH值可以为3.1、3.5、2.8、或4.4。所述的有机酸选自乳酸、磷酸、羟乙酸、苹果酸、酒石酸、柠檬酸、丁二酸和乙酸中的一种或多种。
本发明中，所述的活性药物的质量百分含量优选1％～30％，例如11.8％，所述的质量百分含量是指活性药物的质量占布瑞哌唑口溶膜组合物总质量的百分比。
本发明中，所述的成膜材料为药物的载体，选自明胶、虫胶、阿拉伯胶、淀粉、糊精、环糊精、糖、胆固醇、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟丙基纤维素、聚乙烯醇、聚氧乙烯、丙烯酸共聚物、聚维酮、聚乳酸和硅橡胶中的一种或多种。
本发明中，所述的成膜材料的质量百分含量优选30％～70％，例如64.1％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比。
本发明中，所述的增塑剂是用于降低膜的玻璃转化温度，增加塑性和韧性、提高拉伸率的物质，选自聚乙二醇、甘油、丙二醇、硅油、二甲硅油、聚丙二醇和己二醇中的一种或多种。
本发明中，所述的增塑剂的质量百分含量优选5％～30％，例如24.1％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比。
本发明中，所述的甜味剂是指在膜剂中起矫味作用的物质，选自阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、糖精和糖精钠中的一种或多种。
本发明中，所述的甜味剂的质量百分含量优选0.05％～0.5％，例如0.1％，所述的质量百分含量是指甜味剂的质量占布瑞哌唑口溶膜组合物总质量的百分比。
本发明所述的布瑞哌唑口溶膜组合物，优选进一步包括崩解剂，或者崩解剂与唾液刺激剂、填充剂和着色剂中的一种或多种的组合。
本发明中，所述的崩解剂是指促使药物在胃肠道中迅速崩解成小粒子的辅料，选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、淀粉、微晶纤维素、预胶化淀粉中的一种或多种。
本发明中，所述的唾液刺激剂是指刺激唾液产生的物质，选自柠檬酸、酒石酸、苹果酸和甘露醇一种或多种。
本发明中，所述的填充剂是指加入物料中可以改善物料性能，或能增容、增重，降低物料的成本的固体物质。选自甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。
本发明中，所述的着色剂是指能改善制剂的外观颜色，可用来识别制剂的浓度、区分应用方法和减少病人对服药的厌恶感的物质，选自二氧化钛、色素和色淀中一种或多种。
本发明所述的布瑞哌唑口溶膜组合物，可以为以下配方：11.8％布瑞哌唑、17.0％羟丙甲纤维素、47.1％聚乙烯醇、23.5％甘油、0.59％二甲硅油、0.1％三氯蔗糖和有机酸；所述的布瑞哌唑口溶膜组合物的pH为3.1、3.5、2.8或4.4。
本发明还提供了所述的布瑞哌唑口溶膜组合物的制备方法，其包括以下步骤：
1)将除活性药物、成膜材料和有机酸外的各组分溶于水中，形成混合物；
2)向步骤1)得到的混合物中加入有机酸，调节pH值至2.5-4.5，得到酸性溶液；
3)向步骤2)得到的酸性溶液中加入活性药物，搅拌溶解，得到溶液；
4)将增塑剂溶于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
5)将步骤3)得到的溶液置于步骤4)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
6)将步骤5)得到的含药胶液脱泡后用刮刀均匀涂布于聚酯带上，加热、干燥、切割，得布瑞哌唑口溶膜组合物。
本发明还提供了所述的布瑞哌唑口溶膜组合物在制备治疗中枢神经系统疾病的药物中的应用。所述的治疗中枢神经系统疾病可以为重度抑郁症或精神分裂症。
本发明还提供了一种治疗中枢神经系统疾病的方法，其为需要的患者施用治疗有效量的所述的布瑞哌唑口溶膜组合物。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的有益效果：
本发明得到的布瑞哌唑口溶膜组合物具有良好的溶出速率，在口腔中溶解后不会有沙砾感、且外观均一、柔韧性好、同时在膜液配制过程中不会发生沉降，含量均一性符合要求。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1-5：
处方如下所示
实施例1～4制备方法：
将除活性药物、成膜材料和有机酸外的各组分在搅拌下溶于水中，形成混合物；
向步骤1)得到的混合物中加入有机酸，调节其pH值至2.5-4.5，得到酸性溶液；
向步骤2)得到的酸性溶液中加入活性药物，搅拌溶解，得到溶液；
将增塑剂溶于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
将步骤3)得到溶液置于步骤4)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
将脱泡后的步骤5)得到的含药胶液用刮刀均匀涂布于聚酯带上，加热干燥后切割成一定尺寸，得布瑞哌唑口溶膜组合物。
实施例5制备方法：
将除布瑞哌唑和成膜材料外的各组分在搅拌下溶化或分散于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
向步骤1)得到的空白胶液中加入布瑞哌唑，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶液；
将步骤2)得到的含药胶液脱泡后用刮刀均匀涂布于聚酯带上，加热干燥后切割成一定尺寸，得布瑞哌唑口溶膜组合物。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种布瑞哌唑口溶膜组合物，其特征在于包含活性药物、成膜材料、增塑剂、甜味剂和有机酸中的一种或多种，所述的活性药物为如式I所示的7-[4-(4-苯并[B]噻吩-4-基-1-哌嗪)丁氧基]-2(1H)-喹啉酮和/或其药学上可接受的盐，所述的布瑞哌唑口溶膜组合物的pH值为2.5-4.5；
2.如权利要求1所述的布瑞哌唑口溶膜组合物，其特征在于：所述的布瑞哌唑口溶膜组合物的pH值为3.1、3.5、2.8、或4.4。
3.如权利要求1或2所述的布瑞哌唑口溶膜组合物，其特征在于：所述的有机酸选自乳酸、磷酸、羟乙酸、苹果酸、酒石酸、柠檬酸、丁二酸和乙酸中的一种或多种。
4.如权利要求1-3任一项所述的布瑞哌唑口溶膜组合物，其特征在于：所述的活性药物的质量百分含量为1％～30％，所述的质量百分含量是指活性药物的质量占布瑞哌唑口溶膜组合物总质量的百分比。
5.如权利要求1-4任一项所述的布瑞哌唑口溶膜组合物，其特征在于：
所述的成膜材料选自明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟丙基纤维素、聚乙烯醇、聚氧乙烯、丙烯酸共聚物、聚维酮、聚乳酸和硅橡胶中的一种或多种；
和/或，
所述的成膜材料的质量百分含量为30％～70％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比。
6.如权利要求1-5任一项所述的布瑞哌唑口溶膜组合物，其特征在于：所述的增塑剂选自聚乙二醇、甘油、丙二醇、硅油、二甲硅油、聚丙二醇和己二醇中的一种或多种；
和/或，
所述的增塑剂的质量百分含量为5％～30％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比；
和/或，
所述的甜味剂选自阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、糖精和糖精钠中的一种或多种；
和/或，
所述的甜味剂的质量百分含量为0.05％～0.5％，所述的质量百分含量是指甜味剂的质量占布瑞哌唑口溶膜组合物总质量的百分比。
优选地，所述的布瑞哌唑口溶膜组合物，进一步包括崩解剂，或着崩解剂与唾液刺激剂、填充剂和着色剂中的一种或多种的组合。
7.如权利要求1-6任一项所述的布瑞哌唑口溶膜组合物，其特征在于：
所述的崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、淀粉、微晶纤维素、预胶化淀粉中的一种或多种；
和/或，
所述的唾液刺激剂选自柠檬酸、酒石酸、苹果酸和甘露醇一种或多种；
和/或，
所述的填充剂选自甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种；
和/或，
所述的着色剂选自二氧化钛、色素和色淀中一种或多种。
8.如权利要求1-7任一项所述的布瑞哌唑口溶膜组合物，其特征在于：所述的布瑞哌唑口溶膜组合物，为以下配方：11.8％布瑞哌唑、17.0％羟丙甲纤维素、47.1％聚乙烯醇、23.5％甘油、0.59％二甲硅油、0.1％三氯蔗糖和有机酸；所述的布瑞哌唑口溶膜组合物的pH为3.1、3.5、2.8或4.4。
9.如权利要求1～8任一项所述的布瑞哌唑口溶膜组合物的制备方法，其特征在于包括以下步骤：
1)将除活性药物、成膜材料和有机酸外的各组分溶于水中，形成混合物；
2)向步骤1)得到的混合物中加入有机酸，调节pH值至2.5-4.5，得到酸性溶液；
3)向步骤2)得到的酸性溶液中加入活性药物，搅拌溶解，得到溶液；
4)将增塑剂溶于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
5)将步骤3)得到的溶液置于步骤4)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
6)将步骤5)得到的含药胶液脱泡后用刮刀均匀涂布于聚酯带上，加热、干燥、切割，得布瑞哌唑口溶膜组合物。
10.如权利要求1～8任一项所述的布瑞哌唑口溶膜组合物在制备治疗中枢神经系统疾病的药物中的应用；
优选地，所述的中枢神经系统疾病为重度抑郁症或精神分裂症。
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