CN115671078A - 一种依匹斯汀口溶膜组合物、其制备方法及应用 - Google Patents
一种依匹斯汀口溶膜组合物、其制备方法及应用 Download PDFInfo
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- CN115671078A CN115671078A CN202210645688.3A CN202210645688A CN115671078A CN 115671078 A CN115671078 A CN 115671078A CN 202210645688 A CN202210645688 A CN 202210645688A CN 115671078 A CN115671078 A CN 115671078A
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- epinastine
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Abstract
本发明提供了一种依匹斯汀口溶膜组合物、其制备方法及应用。本发明公开了一种依匹斯汀口溶膜组合物,其包含活性药物、成膜材料、增塑剂、吸收促进剂和甜味剂,所述的活性药物为如式I所示的3‑氨基‑9,13‑二氢‑1H‑二苯并[c,f]咪唑并[1,5‑a]氮杂卓和/或其药学上可接受的盐。本发明提供的依匹斯汀口溶膜组合物,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。解决了患者服药顺应性差的问题,特别适宜有吞咽困难的患者。
Description
本申请要求享有2021年7月28日向中国国家知识产权局提交的申请号为CN202110853845.5,名称为“一种依匹斯汀口溶膜组合物、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
本发明涉及一种依匹斯汀口溶膜组合物、其制备方法及应用。
背景技术
过敏性鼻炎是一种变态反应性炎症,又称常年变态反应性鼻炎、血管舒缩性鼻炎。临床表现主要是阵发性鼻痒、鼻干、喷嚏、急性发作时流出大量水样鼻涕,缓解时少而稠,并发感染者成粘脓性,间歇,或持续性,单侧或双侧鼻塞,嗅觉减退或消失,头痛耳鸣,流泪,声嘶慢性咳嗽。全身症状有头痛、食欲不振、易疲倦、记忆力减退及失眠等。近年来,过敏性反应等变态型疾病的发病率不断增加,抗组胺药的市场需求也呈现逐年上升的趋势。抗组胺类药物的发展经历了第一代与第二代,以及第二代产品的改良过程。其在临床得到了广泛应用,临床用药也日渐成熟。
盐酸依匹斯汀药物由日本BoehringerIngelheim和Sankyo公司研发,于1994年以Alesion(爱理胜)为商品名在日本上市,是一种可以口服的第二代抗组胺药。具有选择性抑制外周H1受体的作用,无中枢镇静作用和抗胆碱作用。2000年6月,国家食品药品监督管理局(SFDA)批准德国勃林格殷格翰公司(Nippon BoehringerIngelheim)的盐酸依匹斯汀进入中国药品市场。
盐酸依匹斯汀为白色至黄色结晶粉末,易溶于水、甲醇、95乙醇或醋酸,不易溶于乙腈,几乎不溶于乙醚。熔点为270℃。溶于水后味道极苦。
专利JP5291324B2公开了一种依匹斯汀口崩片制剂及其制备方法,将含有依匹斯汀采用普通压片技术制备成口崩片,使其崩解迅速,快速溶出。但该技术制备得到的样品在患者服用时依旧有较强的砂砾感、且不同的辅料崩解速度会有较大的差异。同时在压片过程较难维持片剂硬度和崩解时限的平衡。
因此,寻找性质稳定、起效快、生物利用度高、服用方便、患者顺应性好的依匹斯汀制剂是目前急需解决的技术问题。
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依匹斯汀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依匹斯汀口溶膜组合物、其制备方法及应用,本发明提供的依匹斯汀口溶膜,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。解决了患者服药顺应性差的问题,特别适宜有吞咽困难的患者。
本发明提供了一种依匹斯汀口溶膜组合物,其包含活性药物、成膜材料、增塑剂、吸收促进剂和甜味剂,所述的活性药物为如式I所示的3-氨基-9,13-二氢-1H-二苯并[c,f]咪唑并[1,5-a]氮杂卓和/或其药学上可接受的盐;
所述的活性药物的质量百分含量优选1.00%~30.00%,进一步优选10.00%~20.00%,例如14.30%、16.70%或19.00%,所述的质量百分含量是指活性药物的质量占依匹斯汀口溶膜组合物总质量的百分比。
所述的成膜材料为药物的载体,优选黄原胶、瓜尔胶、果胶、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、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、普鲁兰多糖、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种。所述的成膜材料的质量百分含量优选30.00%~70.00%,进一步优选45.00%~65.00%,例如53.30%、60.00%、59.00%或59.20%,所述的质量百分含量是指成膜材料的质量占依匹斯汀口溶膜组合物总质量的百分比。
所述的增塑剂用于降低膜的玻璃转化温度,增加塑性和韧性,提高拉伸率,优选聚乙二醇、甘油、丙二醇、硅油、聚丙二醇和己二醇中的一种或多种。所述的增塑剂的质量百分含量优选5.00%~30.00%,进一步优选10.00%~25.00%,例如14.3%、20.8%、20.9%或16.0%,所述的质量百分含量是指增塑剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
所述吸收促进剂起促进药物吸收作用,优选苯扎氯铵、西吡氯铵、环糊精、依地酸、聚山梨酯(例如聚山梨酯80)、薄荷醇和十二烷基硫酸钠中的一种或多种。所述的吸收促进剂的质量百分含量优选0.10%~15.00%,进一步优选1.00%~11.00%,例如8.3%、10.7%、8.0%或10.5%,所述的质量百分含量是指吸收促进剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
所述甜味剂在膜剂中起矫味作用,优选阿司帕坦、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。所述的甜味剂的质量百分含量优选0.05%~1.50%,进一步优选0.50%~1.00%,例如0.70%、0.80%或1.00%,所述的质量百分含量是指甜味剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
本发明所述的依匹斯汀口溶膜组合物,可以进一步包括崩解剂,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,优选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、微晶纤维素和预胶化淀粉中的一种或多种。所述的崩解剂的百分含量优选0~20.00%,进一步优选5.00%~15.00%,例如9.50%,所述的质量百分含量是指崩解剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
本发明中,所述的唾液刺激剂是指刺激唾液产生的物质,优选柠檬酸、酒石酸、苹果酸和甘露醇一种或多种。所述的唾液刺激剂百分含量优选0~10.00%,例如1.00%,所述的质量百分含量是指唾液刺激剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
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。所述的填充剂百分含量优选0~10.00%,所述的质量百分含量是指填充剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
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。所述的着色剂百分含量优选0~10.00%,所述的质量百分含量是指着色剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
本发明所述的依匹斯汀口溶膜组合物,可以为以下任一配方:
配方一:16.70%依匹斯汀、45.00%羟丙甲纤维素、8.30%聚乙烯醇、8.30%聚山梨酯80、20.80%甘油和0.80%三氯蔗糖;
配方二:14.30%依匹斯汀、13.60%羟丙甲纤维素、46.40%聚乙烯醇、10.70%环糊精、14.30%甘油和0.70%三氯蔗糖;
配方三:14.30%依匹斯汀、60.00%明胶、10.70%聚山梨酯80、14.30%甘油和0.70%三氯蔗糖;
配方四:16.70%依匹斯汀、53.30%黄原胶、8.30%环糊精、20.90%甘油和0.80%三氯蔗糖;
配方五:16.00%依匹斯汀、31.20%羟丙甲纤维素、28.00%明胶、8.00%聚山梨酯80、16.00%甘油和0.80%三氯蔗糖;
配方六:19.00%依匹斯汀、40.00%羟丙甲纤维素、19.00%聚乙烯醇、10.50%聚山梨酯80、9.50%交联聚维酮、1.00%三氯蔗糖和1.00%柠檬酸。
本发明还提供了所述的依匹斯汀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、成膜材料外的各组分溶于水中,形成溶液;
2)向步骤1)得到的溶液中加入成膜材料,60℃~70℃加热搅拌,溶化后得空白胶液;
3)将活性药物置于步骤2)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;
4)将脱泡后的步骤3)得到的含药胶液用刮刀均匀涂布于聚酯带上,加热、干燥、切割,得依匹斯汀口溶膜组合物。
所述的依匹斯汀口腔速溶膜剂,其特征在于,所述的口溶膜组合物的厚度为10μm~100μm。
所述的依匹斯汀口溶膜组合物,在37±1℃的模拟唾液中30s内能够完全溶解,并释放依匹斯汀。
本发明还提供了所述的依匹斯汀口溶薄膜组合物在制备治疗释放组胺或5-羟色胺引起的疾病的药物中的应用。所述的释放组胺或5-羟色胺引起的疾病,包括但不限于:支气管哮喘、过敏性支气管炎、过敏性鼻炎和过敏性结膜炎。
本发明还提供了一种治疗释放组胺或5-羟色胺引起的疾病的方法,其为需要的患者施用治疗有效量的所述的依匹斯汀口溶膜组合物。
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。
本发明的积极进步效果在于:本发明的依匹斯汀口溶膜组合物,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
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1-6:处方如下所示
*在工艺过程中去除
制备方法:
1)将除活性药物、成膜材料外的各组分溶于水中,形成溶液;
2)向步骤1)得到的溶液中加入成膜材料,60℃~70℃加热搅拌,溶化后得空白胶液;
3)将活性药物置于步骤2)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;
4)将脱泡后的步骤3)得到的含药胶液用刮刀均匀涂布于聚酯带上,加热、干燥、切割,得依匹斯汀口溶膜组合物。
按照实施例1至实施例6的处方,采用本发明提供的制备方法制备依匹斯汀口腔速溶膜制剂并测定其崩解时限,具体测定方法如下:
任取药膜6片,每次取1片,轻轻置于37±1℃人工唾液中,静置状态下,观察本品完全溶解的时间。
实施例 | 崩解时限(s) | 口溶膜厚度(μm) |
1 | 15 | 50~80 |
2 | 23 | 55~95 |
3 | 12 | 50~75 |
4 | 24 | 40~70 |
5 | 20 | 70~95 |
6 | 10 | 60~85 |
小结:根据上述实验数据可见本发明提供的依匹斯汀口溶膜,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。
Claims (10)
2.如权利要求1所述的依匹斯汀口溶膜组合物,其特征在于:所述的成膜材料为黄原胶、瓜尔胶、果胶、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、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、普鲁兰多糖、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种;
和/或,
所述的增塑剂为聚乙二醇、甘油、丙二醇、硅油、聚丙二醇和己二醇中的一种或多种;
和/或,
所述吸收促进剂为苯扎氯铵、西吡氯铵、环糊精、依地酸、聚山梨酯、薄荷醇和十二烷基硫酸钠中的一种或多种;
和/或,
所述甜味剂为阿司帕坦、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。
3.如权利要求1所述的依匹斯汀口溶膜组合物,其特征在于:
所述的活性药物的质量百分含量为1.00%~30.00%,所述的质量百分含量是指活性药物的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的成膜材料的质量百分含量为30.00%~70.00%,所述的质量百分含量是指成膜材料的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的增塑剂的质量百分含量为5.00%~30.00%,所述的质量百分含量是指增塑剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的吸收促进剂的质量百分含量为0.10%~15.00%,所述的质量百分含量是指吸收促进剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的甜味剂的质量百分含量为0.05%~1.50%,所述的质量百分含量是指甜味剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
4.如权利要求3所述的依匹斯汀口溶膜组合物,其特征在于:
所述的活性药物的质量百分含量为10.00%~20.00%,所述的质量百分含量是指活性药物的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的成膜材料的质量百分含量为45.00%~65.00%,所述的质量百分含量是指成膜材料的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的增塑剂的质量百分含量为10.00%~25.00%,所述的质量百分含量是指增塑剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的吸收促进剂的质量百分含量为1.00%~11.00%,所述的质量百分含量是指吸收促进剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的甜味剂的质量百分含量为0.50%~1.50%,所述的质量百分含量是指甜味剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
5.如权利要求1所述的依匹斯汀口溶膜组合物,其特征在于:
所述的依匹斯汀口溶膜组合物,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。
6.如权利要求5所述的依匹斯汀口溶膜组合物,其特征在于:所述的崩解剂为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、微晶纤维素和预胶化淀粉中的一种或多种;
和/或,
所述的唾液刺激剂为柠檬酸、酒石酸、苹果酸和甘露醇一种或多种;
和/或,
所述的填充剂为甘露醇、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,
所述的着色剂为二氧化钛、色素和色淀中一种或多种;
优选地,
所述的崩解剂的百分含量为0~20.00%,所述的质量百分含量是指崩解剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的唾液刺激剂百分含量为0~10.00%,所述的质量百分含量是指唾液刺激剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的填充剂百分含量为0~10.00%,所述的质量百分含量是指填充剂的质量占依匹斯汀口溶膜组合物总质量的百分比;
和/或,
所述的着色剂百分含量为0~10.00%,所述的质量百分含量是指着色剂的质量占依匹斯汀口溶膜组合物总质量的百分比。
7.如权利要求1所述的依匹斯汀口溶膜组合物,其特征在于:所述的依匹斯汀口溶膜组合物,为以下任一配方:
配方一:16.70%依匹斯汀、45.00%羟丙甲纤维素、8.30%聚乙烯醇、8.30%聚山梨酯80、20.80%甘油和0.80%三氯蔗糖;
配方二:14.30%依匹斯汀、13.60%羟丙甲纤维素、46.40%聚乙烯醇、10.70%环糊精、14.30%甘油和0.70%三氯蔗糖;
配方三:14.30%依匹斯汀、60.00%明胶、10.70%聚山梨酯80、14.30%甘油和0.70%三氯蔗糖;
配方四:16.70%依匹斯汀、53.30%黄原胶、8.30%环糊精、20.90%甘油和0.80%三氯蔗糖;
配方五:16.00%依匹斯汀、31.20%羟丙甲纤维素、28.00%明胶、8.00%聚山梨酯80、16.00%甘油和0.80%三氯蔗糖;
配方六:19.00%依匹斯汀、40.00%羟丙甲纤维素、19.00%聚乙烯醇、10.50%聚山梨酯80、9.50%交联聚维酮、1.00%三氯蔗糖和1.00%柠檬酸。
8.如权利要求1~7任一项所述的依匹斯汀口溶膜组合物,其特征在于:所述口溶膜组合物的厚度为10μm~100μm;
和/或,
所述的依匹斯汀口溶膜组合物,在37±1℃的模拟唾液中30s内能够完全溶解,并释放依匹斯汀。
9.如权利要求1~7任一项所述的依匹斯汀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、成膜材料外的各组分溶于水中,形成溶液;
2)向步骤1)得到的溶液中加入成膜材料,60℃~70℃加热搅拌,溶化后得空白胶液;
3)将活性药物置于步骤2)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;
4)将脱泡后的步骤3)得到的含药胶液用刮刀均匀涂布于聚酯带上,加热、干燥、切割,得依匹斯汀口溶膜组合物。
10.如权利要求1~7任一项所述的依匹斯汀口溶膜组合物在制备治疗释放组胺或5-羟色胺引起的疾病的药物中的应用;所述的释放组胺或5-羟色胺引起的疾病,包括但不限于:支气管哮喘、过敏性支气管炎、过敏性鼻炎和过敏性结膜炎。
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