CN114767663A - 一种口溶膜剂及其制备方法 - Google Patents
一种口溶膜剂及其制备方法 Download PDFInfo
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- CN114767663A CN114767663A CN202210407979.9A CN202210407979A CN114767663A CN 114767663 A CN114767663 A CN 114767663A CN 202210407979 A CN202210407979 A CN 202210407979A CN 114767663 A CN114767663 A CN 114767663A
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- film
- brexpiprazole
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- sodium
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Classifications
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Abstract
本发明涉及一种依匹哌唑口溶膜剂及其制备方法,该膜剂包括a)依匹哌唑0.5%‑20%;b)高分子成膜材料20%‑90%;c)增稠剂1%~40%;d)增塑剂4%~20%;e)矫味剂1%‑10%。本发明制备的膜剂外观良好、厚度均匀、韧性较好、无刺激性口味,药物含量均匀,用于重度抑郁症和精神分裂症的治疗。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种依匹哌唑口溶膜剂及其制备方法。
背景技术
依匹哌唑是一种新型非典型抗精神病药,由日本大冢制药和丹麦灵北制药联合开发,用于重度抑郁症的辅助治疗和精神分裂症的治疗。依匹哌唑的作用机制尚未完全清楚,但可以通过对5-HT1A和多巴胺D2受体的部分激动作用和对5-HT2A受体的拮抗作用起效。目前依匹哌唑上市产品仅有片剂,已在美国、欧盟和日本等地上市,商品名为“REXULTI”,上市规格有0.25mg、0.5mg、1mg、2mg、3mg、4mg,依匹哌唑片尚未在我国上市。
对患者来说,片剂易出现吞咽困难、拒绝服药及口腔藏药等服药问题。而口溶膜是一种新的药物传递系统,将依匹哌唑片改为依匹哌唑口溶膜,在临床上存在一定的优势:①无需咀嚼,也无需用水送服,在口腔内即可快速溶化分散,提高了患者的服药便利性和依从性;对于具有重度抑郁症和精神分裂症患者,可有效提高患者服药依从性,避免患者藏药行为,从而改善治疗效果。②本品的体积小、质量轻、方便服用和携带。因此根据患者人群的特点及药物的特性,将依匹哌唑制备成口溶膜剂是一种有效提高患者顺应性、发挥药物更好疗效的办法。口溶膜在制备过程中需将原料均匀分散在胶液中,然而,依匹哌唑在纯化水中几乎不溶,且呈疏水性,即使通过搅拌均质等方式将依匹哌唑在纯化水中分散均匀,静置后又会聚集成团,从而导致成品含量和含量均匀度不合格,严重影响药品质量。因此,解决原料分散不均匀问题,避免原料聚集成团,是本品开发过程中亟需解决的技术难题。
发明内容
针对以上技术难题,本发明提供了一种依匹哌唑口溶膜及其制备方法:在纯化水中加入适量的增稠剂,改变纯化水的表面张力和黏度,再加入平均粒径不超过30μm的依匹哌唑原料,通过搅拌和均质处理,原料可以分散均匀,且静置放置可以保持稳定,原料未聚集成团,之后再加入其余辅料,通过均质、脱气、涂布、裁切和包装,最终制成依匹哌唑口溶膜,该口溶膜外观良好、厚度均匀、韧性较好、无刺激性口味,药物含量均匀,便于携带和服用。本发明人还发现,加入增稠剂后依匹哌唑口溶膜的化学稳定性优于其他专利中的实施例(CN105395528A)。
为实现本发明的目的,本发明的依匹哌唑口溶膜包括以下占膜重量百分比的各组分:
依匹哌唑0.5%-20%
高分子成膜材料20%-90%
增稠剂1%-40%
增塑剂4%~20%
矫味剂1%-10%
作为优选,所述依匹哌唑的平均粒径(d90)不超过30μm,更优选平均粒径(d90)不超过20μm。
作为优选,所述依匹哌唑占膜剂重量的5%~15%。
作为优选,所述高分子成膜材料包括普鲁兰多糖、明胶、琼脂、壳聚糖、聚乙烯醇、预胶化淀粉、羟丙甲纤维素和羟丙纤维素中的一种或多种。
作为优选,所述增稠剂选自黄原胶、角豆胶、卡拉胶、阿拉伯胶、西黄蓍胶、瓜尔胶、聚丙烯酸钠、海藻酸钠、羧甲基纤维素钠、酪蛋白酸钠、海藻糖、聚氧乙烯、聚乙烯吡咯烷酮、泊洛沙姆、卡波姆、麦芽糊精、甲基纤维素、羟乙纤维素、藻酸丙二醇酯中的一种或多种。
作为优选,所述增塑剂选自柠檬酸三乙酯、甘油和聚乙二醇中的一种或多种。
作为优选,所述矫味剂为安赛蜜、三氯蔗糖、甜菊糖苷、糖精钠、阿斯巴甜、甜蜜素、葡萄糖、果糖、蔗糖、麦芽糖、淀粉糖和乳糖中的一种或多种。
本发明具有的优点与积极效果是:
(1)所述膜剂在37±1℃的纯化水中60s内完全崩散,释放依匹哌唑;
(2)所述膜剂表面光滑,厚度均匀,韧性较好;
(3)所述膜剂厚度为50~100μm,大小为20×14mm~20×30mm,易于服用,便于携带;
(4)所述膜剂含量均匀,符合临床使用要求;
(5)所述膜剂添加增稠剂后,具有意想不到的有益的化学稳定性。
与现有的依匹哌唑片相比,本发明通过将依匹哌唑制成口溶膜剂,剂量精确,无需用水送服,用药方便,提高了患者服药的顺应性。
具体实施方式
以下实例用于进一步说明和理解本发明的实质,但本发明的保护范围不限于下列实例。
以下各实施例的物料来源如表1所示。
表1:物料信息
注:本文各实施例和对比例中,若无特别说明,依匹哌唑的平均粒径(d90)均不超过30μm。
实施例1~3:
以羟丙甲基纤维素和羟丙纤维素为成膜剂;以聚乙烯吡咯烷酮为增稠剂;甘油为增塑剂;三氯蔗糖为矫味剂;原料药依匹哌唑的粒径分别为10μm、20μm、30μm,制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表2:实施例1-3依匹哌唑口溶膜处方
实施例1的制备工艺:①将增稠剂聚乙烯吡咯烷酮加入纯化水中,加热并搅拌,使其完全溶解;②再加入依匹哌唑原料,搅拌并均质,使原料分散均匀;③再加入其余辅料,搅拌并均质,制成胶液;将胶液置真空干燥箱中,在真空环境下脱气;④将胶液加入薄膜制作机中,进行涂布和干燥;⑤将干燥后的药膜按合适的大小进行裁切和包装。实施例2~3的制备工艺:与实施例1一致。
实施例4~6:
实施例4~6的处方见表3,制备工艺同实施例1。实施例4~6以羟丙甲基纤维素和羟丙纤维素为成膜剂;以聚乙烯吡咯烷酮为增稠剂;甘油为增塑剂;三氯蔗糖为矫味剂;原料药依匹哌唑的用量分别为0.5%、10%、20%,制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表3:实施例4-6依匹哌唑口溶膜处方
成份 | 实施例4 | 实施例5 | 实施例6 |
依匹哌唑 | 0.13g(0.5%) | 2.89g(10%) | 6.5g(20%) |
羟丙甲纤维素 | 15g(57.41%) | 15g(51.92%) | 15g(46.15%) |
羟丙纤维素 | 1.5g(5.74%) | 1.5g(5.19%) | 1.5g(4.62%) |
聚乙烯吡咯烷酮 | 6.5g(24.88%) | 6.5g(22.5%) | 6.5g(20%) |
甘油 | 2g(7.65%) | 2g(6.92%) | 2g(6.15%) |
三氯蔗糖 | 1g(3.83%) | 1g(3.46%) | 1g(3.08%) |
纯化水 | 130g | 130g | 130g |
实施例7~12:
实施例7~12的处方见表4,制备工艺同实施例1。实施例7~12采用不同的高分子成膜材料;以聚乙烯吡咯烷酮为增稠剂;甘油为增塑剂;三氯蔗糖为矫味剂;制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表4:实施例7-12依匹哌唑口溶膜处方
实施例13~15:
实施例13~15的处方见表5,制备工艺同实施例1。实施例13~15采用聚乙烯醇为成膜材料,用量在20%~90%之间;以聚乙烯吡咯烷酮或黄原胶为增稠剂;甘油为增塑剂;三氯蔗糖为矫味剂;制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表5:实施例13-15依匹哌唑口溶膜处方
成份 | 实施例13 | 实施例14 | 实施例15 |
依匹哌唑 | 2g(7.14%) | 2g(7.14%) | 0.25g(0.89%) |
聚乙烯醇 | 5.6g(20%) | 15.4g(55%) | 25.2g(90%) |
聚乙烯吡咯烷酮 | 17.4g(62.14%) | 6.5g(23.21%) | / |
黄原胶 | / | / | 0.55(1.96%) |
甘油 | 2g(7.14%) | 2g(7.14%) | 1.5g(5.36%) |
三氯蔗糖 | 1g(3.57%) | 2.1g(7.5%) | 0.5g(1.79%) |
纯化水 | 130g | 130g | 130g |
实施例16~33:
实施例16~33的处方见表6和表7,制备工艺同实施例1。实施例16~33采用羟丙甲纤维素和羟丙纤维素为成膜材料;以甘油为增塑剂;三氯蔗糖为矫味剂;采用不同的增稠剂,制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表6-1:实施例16-20依匹哌唑口溶膜处方
成份 | 实施例16 | 实施例17 | 实施例18 | 实施例19 | 实施例20 |
依匹哌唑 | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) |
羟丙甲纤维素 | 21g(75%) | 21g(75%) | 19g(67.86%) | 19.5g(69.64%) | 21g(75%) |
羟丙纤维素 | 1.5g(5.36%) | 1.5g(5.36%) | 1.5g(5.36%) | 1.5g(5.36%) | 1.5g(5.36%) |
黄原胶 | 0.5g(1.79%) | / | / | / | / |
角豆胶 | / | 0.5g(1.79%) | / | / | / |
卡拉胶 | / | / | 2.5g(8.93%) | / | / |
阿拉伯胶 | / | / | / | 2g(7.14%) | / |
聚丙烯酸钠 | / | / | / | / | 0.5g(1.79%) |
海藻酸钠 | / | / | / | / | / |
聚氧乙烯 | / | / | / | / | / |
泊洛沙姆 | / | / | / | / | / |
卡波姆 | / | / | / | / | / |
甘油 | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) |
三氯蔗糖 | 1g(3.57%) | 1g(3.57%) | 1g(3.57%) | 1g(3.57%) | 1g(3.57%) |
纯化水 | 130g | 130g | 130g | 130g | 130g |
表6-2:实施例21-24依匹哌唑口溶膜处方
表7-1:实施例25-29依匹哌唑口溶膜处方
表7-2:实施例30-33依匹哌唑口溶膜处方
成份 | 实施例30 | 实施例31 | 实施例32 | 实施例33 |
依匹哌唑 | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) |
羟丙甲纤维素 | 18.8g(67.14%) | 19g(67.86%) | 19g(67.86%) | 21g(75%) |
羟丙纤维素 | 1.5g(5.36%) | 1.5g(5.36%) | 1.5g(5.36%) | 1.5g(5.36%) |
瓜尔胶 | / | / | / | / |
西黄蓍胶 | / | / | / | / |
羧甲基纤维素钠 | / | / | / | / |
酪蛋白酸钠 | / | / | / | / |
海藻糖 | / | / | / | / |
麦芽糊精 | 4.2g(15%) | / | / | / |
甲基纤维素 | / | 2.5g(8.93%) | / | / |
羟乙纤维素 | / | / | 2g(7.14%) | / |
藻酸丙二醇酯 | / | / | / | 1g(3.57%) |
甘油 | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) | 2g(7.14%) |
三氯蔗糖 | 1g(3.57%) | 1g(3.57%) | 1g(3.57%) | 1g(3.57%) |
纯化水 | 130g | 130g | 130g | 130g |
实施例34~36:
实施例34~36的处方见表8,制备工艺同实施例1。实施例34~36采用羟丙甲纤维素和羟丙纤维素为成膜材料;以黄原胶或聚乙烯吡咯烷酮为增稠剂,用量在1%~40%范围内;以甘油为增塑剂;三氯蔗糖为矫味剂;制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表8:实施例34-36依匹哌唑口溶膜处方
实施例37~41:
实施例37~41的处方见表9,制备工艺同实施例1。实施例37~41采用羟丙甲纤维素和羟丙纤维素为成膜材料;以聚乙烯吡咯烷酮为增稠剂;三氯蔗糖为矫味剂;采用不同的增塑剂,且用量在4%~20%之间,制备的药膜表面光滑,韧性较好,含量均匀,口感合适。
表9:实施例37-41依匹哌唑口溶膜处方
对比例1:
对比例1~6的处方见表10,制备工艺同实施例1。对比例1以平均粒径(d90)为35μm为的依匹哌唑原料制备样品,制备的药膜表面粗糙,有肉眼可见的原料颗粒。
对比例2依匹哌唑的用量为25%,制备的药膜表面粗糙,有未分散开的原料。
对比例3增稠剂用量为0.5%,制备的药膜表面粗糙,有未分散开的原料。
对比例4增稠剂用量为50%,制备的药膜表面粗糙,有未分散开的原料。
对比例5增塑剂用量为2%,制备的药膜韧性较差,较脆。
对比例6增塑剂用量为25%,制备的药膜韧性较软。
表10:对比例1-6依匹哌唑口溶膜处方
注:对比例1的依匹哌唑原料平均粒径(d90)为35μm,对比例2~5均不超过30μm。
对比例7:
对比例7参照专利CN105395528A中的实施例4制备样品。
检测上述各实施例和对比例药膜的外观、崩解时限、含量、含量均匀度、口感和拉伸强度,结果如下:
表11:实施例1-10依匹哌唑口溶膜检测结果
表12:实施例11-20依匹哌唑口溶膜检测结果
表13:实施例21-30依匹哌唑口溶膜检测结果
表14:实施例31-41依匹哌唑口溶膜检测结果
表15:对比例1-6依匹哌唑口溶膜检测结果
检测上述实施例1、实施例7、实施例13和对比例7在加速试验条件下(40℃,75%RH)的化学稳定性,结果如下:
表16:实施例1、实施例7、实施例13和对比例7加速试验结果
各实施例和对比例的检测方法详述如下:
崩解时限:取药膜一片,用回形针夹住,投入崩解仪内,参照《中华人民共和国药典(2020年版)》四部通则0921崩解时限检查法进行检查;
拉伸强度:将药膜按2cm×3cm的大小进行裁切,置万能拉力测试仪内(厂家:东莞市力显仪器科技有限公司,型号:1007C),测试药膜的拉伸强度。
含量:参照表17中的检测方法进行检测,依匹哌唑含量应为标示量的90.0%~110.0%;
表17:依匹哌唑口溶膜含量检测方法
含量均匀度:参照《中华人民共和国药典(2020年版)》四部通则0941含量均匀度检查法检进行检查,应符合规定。
有关物质:参照表18中的检测方法进行检测;
表18:依匹哌唑口溶膜有关物质检测方法
由以上结果可知,对比例1以平均粒径(d90)为35μm的依匹哌唑原料制备样品,药膜表面有原料颗粒,药膜含量偏低,且含量均匀度不符合要求;对比例2依匹哌唑的用量为25%,药膜表面有未分散开的原料,影响药膜含量和含量均匀度;对比例3增稠剂用量为0.5%,对比例4增稠剂用量为50%,制备的药膜表面粗糙,有未分散开的原料,可见增稠剂用量太低或太高,均不利于原料的分散;对比例5增塑剂用量为2%,药膜韧性较差,较脆;对比例6增塑剂用量为25%,制备的药膜韧性较软,不利于后续的包装工序,且不便服用。对比例7在加速条件下,杂质C、杂质D和总杂的涨幅显著大于实施例1、实施例7和实施例13,可见增稠剂的加入,有助于本品的稳定。
而实施例1~41的药膜外观良好,可快速崩解,口感可接受,含量和含量均匀度均符合相关标准。因此,本发明易被患者接受,可有效提高患者顺应性,发挥药物更好疗效,在临床使用中,具有积极效益。
Claims (10)
1.一种依匹哌唑口溶膜剂,其特征在于包含下列占膜剂重量百分比的各组分:
依匹哌唑0.5%-20%;
高分子成膜材料20%-90%;
增稠剂1%-40%;
增塑剂4%~20%;
矫味剂1%-10%。
2.根据权利要求1所述的依匹哌唑口溶膜剂,其特征在于,依匹哌唑占膜剂重量优选为5%~15%。
3.根据权利要求1所述的依匹哌唑口溶膜剂,其特征在于,依匹哌唑的平均粒径(d90)不超过30μm。
4.根据权利要求3所述的依匹哌唑口溶膜剂,其特征在于,依匹哌唑的平均粒径(d90)优选不超过20μm。
5.根据权利要求1所述的依匹哌唑口溶膜剂,其特征在于,所述高分子成膜材料选自普鲁兰多糖、明胶、琼脂、壳聚糖、聚乙烯醇、预胶化淀粉、羟丙甲纤维素和羟丙纤维素中的一种或多种。
6.根据权利要求1所述的依匹哌唑口溶膜剂,其特征在于,所述增稠剂选自黄原胶、角豆胶、卡拉胶、阿拉伯胶、西黄蓍胶、瓜尔胶、聚丙烯酸钠、海藻酸钠、羧甲基纤维素钠、酪蛋白酸钠、海藻糖、聚氧乙烯、聚乙烯吡咯烷酮、泊洛沙姆、卡波姆、麦芽糊精、甲基纤维素、羟乙纤维素、藻酸丙二醇酯中的一种或多种。
7.根据权利要求1所述的依匹哌唑口溶膜剂,其特征在于,所述增塑剂选自柠檬酸三乙酯、甘油或聚乙二醇。
8.根据权利要求1所述的依匹哌唑口溶膜剂,其特征在于,所述矫味剂为安赛蜜、三氯蔗糖、甜菊糖苷、糖精钠、阿斯巴甜、甜蜜素、葡萄糖、果糖、蔗糖、麦芽糖、淀粉糖和乳糖中的一种或多种。
9.一种如权利要求1至8中任一权利要求所述的依匹哌唑口溶膜剂的制备方法,其特征在于,包括如下步骤:a)将增稠剂加入纯化水中,使增稠剂完全溶解;b)将依匹哌唑原料加入上述溶液中,使其分散均匀;c)将其他物料加入上述溶液中,搅拌并均质,制成胶液;d)将胶液置真空环境下进行脱气;e)将脱气后的胶液涂至薄膜上,干燥;f)将干燥后的药膜置于薄膜包装机中,裁切后进行包装。
10.权利要求1至8中任一权利要求所述膜剂在制备治疗重度抑郁症和精神分裂症药品中的应用。
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WO2023240971A1 (zh) * | 2022-06-16 | 2023-12-21 | 江苏慧聚药业股份有限公司 | 药物组合物及依匹哌唑口溶膜 |
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