CN114053232A - 一种乌布吉泮冻干口崩片及制备方法 - Google Patents
一种乌布吉泮冻干口崩片及制备方法 Download PDFInfo
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- CN114053232A CN114053232A CN202111390882.3A CN202111390882A CN114053232A CN 114053232 A CN114053232 A CN 114053232A CN 202111390882 A CN202111390882 A CN 202111390882A CN 114053232 A CN114053232 A CN 114053232A
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- Prior art keywords
- freeze
- liquid medicine
- orally disintegrating
- sodium
- disintegrating tablet
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- 238000004108 freeze drying Methods 0.000 claims description 49
- 238000003756 stirring Methods 0.000 claims description 46
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 20
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明提供了一种乌布吉泮冻干口崩片及其制备方法,属于药物制剂领域,该乌布吉泮冻干口崩片由乌布吉泮或其盐与其他基质组成,采用混悬乳液冻干直接赋型的方式制备,本发明的冻干口崩片制备方法分为散装药液配制、注模、快速预冻处理、低温冰晶重排、冷冻干燥、产品包装。本发明的乌布吉泮冻干口崩片便于运输、携带和保存,服用简便、无需用水送服、吸收快、起效快。
Description
技术领域
本发明涉及一种乌布吉泮冻干口崩片及其制备方法,制剂规格50mg和100mg。属于医药技术领域。
背景技术
偏头痛是慢性神经血管性疾病,目前全球发病率第三,疾病导致的经济负担在全部脑部疾病中居第二位,是导致残疾的最主要原因。全球偏头痛发病人群占总人口13%以上。偏头痛是临床最常见的原发性头痛类型,临床以发作性中重度、搏动样头痛为主要表现,头痛多为偏侧,一般持续4~72小时,可伴有恶心、呕吐,光、声刺激或日常活动均可加重头痛。
偏头痛多起病于儿童和青春期,中青年期达发病高峰,女性多见,男女患者比例约为1∶2~3,人群中患病率为5%~10%,常有遗传背景。
偏头痛频繁发作将影响患者的生活工作,最直接的就是影响睡眠,因为睡眠不足,白天就没精神,工作也大受影响。而且有部分患者常常是一工作就发作,十分耽误事。同时,人久患头痛疾病,性格发生变化,往往性情变得暴躁。又因为久治不愈,生活受到重大影响,心理脆弱,丧失信心,时间长了对人的心脑血管将产生不利影响,临床上头痛发作后脑血栓,高血压,脑出血,是偏头痛引起的常见严重疾病。
乌布吉泮一种口服降钙素基因相关肽(cGRP)拮抗剂,cGRP是已知的最强的扩血管物质,具有下降血压、外周阻力降低、肾动脉舒张、肾血流量明显增加的作用。cGRP对冠状动脉亦有强大的舒张作用,对粥样硬化的冠状动脉亦有效,其舒张作用比硝酸甘油、硝普钠约强240倍,这一舒张作用不依赖于血管内皮的存在,也不受A、B和5-羟色胺受体阻断剂的影响,cGRP结合于特异性的cGRP受体。cGRP还能使冠脉灌流压降低,冠脉血流量明显增加,心律加快,心肌收缩力增强,cGRP具有明显的正性肌力和正性变时作用,这种作用较去甲肾上腺素强,但可被B受体阻滞剂取消,其机制可能与升高心肌细胞内cAMP水平有关。cGRP的抗心律失常作用比钙通道拮抗剂约强220倍,其作用机制可能是调节心肌细胞的内流。cGRP对所有的血管均有明显的舒张作用,其作用较乙酰胆碱等物质强。
cGRP广泛分布于中枢、外周和其他系统中。在中枢神经系统cGRP主要分布于杏仁核、尾核、脊髓脊角和三叉神经束,垂体、下丘脑、延髓和海马也有一定分布,脊髓中含量最高,大脑皮层其含量则极低。但其受体密度高,均有较多的特异性结合点。心血管系统广泛分布丰富的cGRP神经纤维,cGRP几乎存在于所有的血管神经纤维内,其分布与血管紧密联系,在血管中cGRP的含量明显高于心脏。cGRP的神经纤维在血管外膜或平滑肌交织成网包绕整个血管。在心脏cGRP神经纤维一般沿心肌纤维或冠状动脉平行走向,也可交织成网形神经丛。心内cGRP分布是不均匀:心房高于心室、右心房高于左心房,近心外膜高于近心内膜。因此,cGRP是调节心血管活动的重要肽能神经纤维。研究证实,cGRP与受体结合后,激活腺苷酸环化酶,使细胞内cAMP升高,发挥其生物学效应。
乌布吉泮作为cGRP拮抗剂是急性偏头痛治疗的最新的作用机制,用于偏头痛的急性发作的治疗。
根据WHO公布的资料(2015年)表明,全世界近60%病患人群具有不同程度吞咽障碍,包括吞咽障碍、胃肠道应激反应强烈、意识不清、无自主意识、精神异常不配合等特殊人群,其中用药过程中,全世界约有1/3的死亡病例的原因来自用药的不合理性,而非疾病本身,因此提高给药依从性、提高给药剂量准确度是提高药物治疗效果、减少不合理用药的关键节点。
冻干口崩片使一种由水溶性骨架材料经冷冻干燥制成的空间网状的布满缝隙的速溶制剂,特点在于冻干片剂以单剂量规格为给药单位,无需水送服,直接放入口腔后,冻干片剂接触口腔唾液即迅速溶解,分散于唾液中,口服吸收快,药物活性成分可通过口腔粘膜进入人体循环,生物利用度高,避免肝脏受过效应,获得同等治疗效果时,降低了给药剂量,降低毒副作用,提高了用药安全性。
采用冻干直接赋型制备的乌布吉泮口腔速溶制剂体积小,携带方便,服用不需水送服,不受环境限制,任何时间、任何地点偏头痛急性发作时仅需将药物制剂放入口腔,口腔内极少量唾液即可使制剂在2S内完全溶化,避免因偏头痛恶心、呕吐症状导致的无法服药;对于症状稍轻的病患,亦能够杜绝常规制剂水送服药物过程中的恶心、呕吐感加重以及吞咽动作导致的眩晕、疼痛。
发明内容
本发明中所说的乌布吉泮冻干口崩片是指在制备过程中采用乌布吉泮或乌布吉泮盐为制剂原料的冻干口腔速溶片剂,乌布吉泮盐可以是乌布吉泮无机酸盐或有机酸盐,本发明采用乌布吉泮。
本发明中所说的乌布吉泮冻干口崩片中乌布吉泮,采用混悬液冻干赋型法,控制其粒径小于70μm,便于其更好的在药液体系中分散,其粒度分布最好为0.2~20μm。
本发明的目的是提供一种给药量精准且便于服用的乌布吉泮冻干口崩片,采用真空冷冻干燥技术制成,服用过程不需要任何辅助形式送服,方便偏头痛急性发作患者使用。
乌布吉泮几乎不溶于水,因此采用混悬液直接冻干赋型的方式,为获得良好的分散和冻干效果,散装药液中包含有助悬剂和分散剂。
本发明提供了一种乌布吉泮冻干口崩片,该口崩片由基质和有效剂量的乌布吉泮或乌布吉泮盐制成,其特征在于:骨架支撑材料占制剂总固形物重量的1%~60%,冻干保护剂占制剂总固形物重量的0~5%;有效成分乌布吉泮占制剂总固形物重量的5~80%。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:骨架支撑材料由单一辅料或由多种辅料组成,骨架支撑材料包括粘合剂和骨架剂。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:单一辅料组成的骨架支撑材料,其特征在于:具有较高的粘性和良好的空间支撑性能和成膜性能。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:骨架支撑材料可作为冻干保护剂、助悬剂。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:骨架材料为水溶性材料。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:骨架剂包括但不限于高聚物、高聚糖、糖醇类、糖类或氨基酸类。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:骨架剂选自甘露醇、木糖醇、山梨糖醇、麦芽糖醇、乳糖醇、赤藓糖醇、糊精、右旋糖苷、普鲁兰多糖、乳糖、海藻糖、聚乙烯醇、甘氨酸中的一种或几种。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:粘合剂包括但不限于蛋白、植物胶、氨基酸、多肽、高聚糖、高聚物类。
本发明提供了一种乌布泮冻干口崩片,其特征在于:粘合剂选自水溶性多肽、明胶、水解明胶、阿拉伯胶、琼脂、右旋糖苷、普鲁兰多糖、聚乙烯醇中的一种或几种。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于冻干保护剂选自海藻糖、乳糖、甘露醇、普鲁兰多糖、水溶性多肽、甘氨酸中的一种或几种。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于该冻干口崩片中还可以含有助悬剂和分散剂、矫味剂、pH调节剂、抗氧剂、防腐剂、着色剂等。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:助悬剂和分散剂包括但不限于阿拉伯胶、瓜耳豆胶、吐温80、司盘80、羧甲基纤维素钠等。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:矫味剂包括甜味剂和/或不同口味的香精,其中甜味剂选自:阿斯巴甜、安赛蜜、三氯蔗糖、甜菊苷中的一种或几种;香精包括但不限于:柠檬酸钠、草莓味香精、香橙味香精、柳橙味香精、西瓜味香精、牛奶味香精、巧克力味香精、香草味香精、薄荷味香精。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:pH调节剂包括但不限于无机盐、有机盐、弱酸、弱碱、缓冲对;无机盐包括但不限于氯化钠、碳酸氢钠、碳酸氢钾、磷酸氢二钠、磷酸二氢钠等,有机盐包括但不限于:枸橼酸钠、琥珀酸钠等;弱酸包括:枸橼酸、琥珀酸、马来酸等;弱碱包括但不限于:氢氧化钙等;缓冲对包括但不限于:磷酸氢二钠—磷酸二氢钠,枸橼酸—枸橼酸钠等。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:抗氧剂包括但不限于亚硫酸钠、依地酸二钠、焦亚硫酸钠、硫代硫酸钠等。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:防腐剂可以采用水溶性材料,亦可以采用脂溶性材料,包括但不限于苯甲醇、尼泊金甲酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金丙酯钠等。
本发明提供了一种乌布吉泮冻干口崩片,其特征在于:可食用着色剂可选择水溶性材料,亦可以选择脂溶性材料,包括但不限于天然色素、合成色素等。
本发明提供了一种乌布吉泮冻干口崩片,其特征还在于溶剂包括纯化水、乙醇、叔丁醇中的一种或几种,其中有机溶剂占溶剂总量的0~20%。
本发明提供了一种乌布吉泮冻干口崩片,其特征还在于:散装药液的pH≤9.0,其最佳pH范围为7.5~8.5。
本发明还提供了一种瑞美吉泮冻干口崩片的制备方法,步骤如下:
散装药液配制:将骨架材料溶于8~80℃纯化水中,搅拌至完全溶解,加入其他辅料继续搅拌至完全溶解,将药液温度降低至室温;乌布吉泮加入至上述药液并以纯化水定容至处方量,搅拌至药液均一稳定,完成散装药液配制;
灌装:将散装药液灌装至已成型的冷冲压成型复合硬片或PVC/PVDC泡罩中;
预冻:泡罩中药液至于-40℃~-110℃环境下使药液迅速冷冻成固态,或在-10℃~-110℃环境下连续梯度降温使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-10℃~-30℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表1 冻干曲线
包装:在相对湿度5~25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
对于预冻工序,药液在冷冻过程中可能因冻结速率差异导致局部药液中固形物浓度发生改变,为了降低或杜绝该现象,在制备过程中选择液氮速冻或以低温硅油作为传热介质将预冻腔体内温度降低至-50℃以下,腔体内采用低送风方式进行冷量传导,使药液迅速冻结为固体;亦可设定速冻腔体内多温度梯度降温方式:不同温度梯段腔体段温度以20℃为梯度,起始腔体内温度-10℃直至最后一个腔体内温度-110℃,使药液保持过冷形成更多的晶核。上述两种预冻方式均有利于药液中固形物的分散,防止预冻过程中相分离现象的发生。
具体实施方式
以下实施例是为了更好的说明本发明,不用以限定本发明的保护范围。
实施例1:
本实施例提供了50mg规格乌布吉泮冻干口崩片及其制备方法:
表2 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将聚乙烯醇投入240ml煮沸的纯化水中,搅拌至药液均匀;将水解明胶投入上述药液中搅拌至药液呈无色澄清透明状;将右旋糖苷投上述水溶液中搅拌至药液呈无色澄清透明状;加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精继续搅拌至完全溶解,将药液温度降低至室温;加入乌布吉泮至上述药液并以纯化水定容至300ml,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取0.3ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表3 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例2:
本实施例提供了50mg规格乌布吉泮冻干口崩片及其制备方法:
表4 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入240ml煮沸的纯化水中,搅拌至药液均匀;将水解明胶和阿拉伯胶投上述水溶液中搅拌至药液呈无色澄清透明状;加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精继续搅拌至完全溶解,将药液温度降低至室温;加入吐温80,搅拌至药液呈无色澄清透明状态,将乌布吉泮加入上述药液并以纯化水定容至300ml,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取0.3ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表5 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例3:
本实施例提供了50mg规格乌布吉泮冻干口崩片及其制备方法:
表6 处方组成
冻干口崩片制备步骤如下:
散装药液配制:将明胶置于180ml纯化水中至明胶溶胀完全,加热至60℃并搅拌,至明胶完全溶解,加入水解明胶和阿拉伯胶搅拌至药液呈淡黄色澄清透明状态;继续加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精搅拌至完全溶解,将药液温度降低至室温;加入吐温80,搅拌至药液呈无色澄清透明状态,乌布吉泮加入上述药液并以纯化水定容至300ml,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取0.3ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表7 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例4:
本实施例提供了100mg规格乌布吉泮冻干口崩片及其制备方法:
表8 处方组成
冻干口崩片制备步骤如下:
将聚乙烯醇投入320ml煮沸的纯化水中,搅拌至药液均匀;将水解明胶投入上述药液中搅拌至药液呈无色澄清透明状;将右旋糖苷投上述水溶液中搅拌至药液呈无色澄清透明状;加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精继续搅拌至完全溶解,将药液温度降低至室温;加入乌布吉泮至上述药液并以纯化水定容至400ml,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取0.4ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表9 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例5:
本实施例提供了100mg规格乌布吉泮冻干口崩片及其制备方法:
表10 处方组成
成分 | 含量(g) | 作用 |
乌布吉泮 | 100.00 | 药物活性成份 |
普鲁兰多糖 | 8.00 | 粘合剂 |
水解明胶 | 8.00 | 粘合剂 |
甘露醇 | 14.00 | 骨架剂 |
阿拉伯胶 | 0.12 | 助悬剂 |
吐温80 | 0.04 | 分散剂 |
枸橼酸钠 | 1.80 | pH调节剂 |
三氯蔗糖 | 1.60 | 矫味剂 |
薄荷味香精 | 0.40 | 矫味剂 |
纯化水 | 至400ml | 溶剂 |
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入320ml煮沸的纯化水中,搅拌至药液均匀;将水解明胶和阿拉伯胶投上述水溶液中搅拌至药液呈无色澄清透明状;加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精继续搅拌至完全溶解,将药液温度降低至室温;加入吐温80,搅拌至药液呈无色澄清透明状态,将乌布吉泮加入上述药液并以纯化水定容至400ml,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取0.4ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表11 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例6:
本实施例提供了100mg规格乌布吉泮冻干口崩片及其制备方法:
表12 处方组成
成分 | 含量(g) | 作用 |
乌布吉泮 | 100.00 | 药物活性成份 |
明胶 | 3.20 | 粘合剂 |
水解明胶 | 12.00 | 粘合剂 |
阿拉伯胶 | 0.12 | 助悬剂 |
吐温80 | 0.04 | 分散剂 |
甘露醇 | 14.00 | 骨架剂 |
枸橼酸钠 | 1.80 | pH调节剂 |
三氯蔗糖 | 1.60 | 矫味剂 |
薄荷味香精 | 0.40 | 矫味剂 |
纯化水 | 至400ml | 溶剂 |
冻干口崩片制备步骤如下:
散装药液配制:将明胶置于240ml纯化水中至明胶溶胀完全,加热至60℃并搅拌,至明胶完全溶解,加入水解明胶和阿拉伯胶搅拌至药液呈淡黄色澄清透明状态;继续加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精搅拌至完全溶解,将药液温度降低至室温;加入吐温80,搅拌至药液呈无色澄清透明状态,乌布吉泮加入上述药液并以纯化水定容至400ml,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取0.4ml/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表13 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例7:
本实施例提供了50mg规格乌布吉泮冻干口崩片及其制备方法:
表14 处方组成
成分 | 含量(kg) | 作用 |
乌布吉泮 | 50.00 | 药物活性成份 |
普鲁兰多糖 | 6.00 | 粘合剂 |
水解明胶 | 6.00 | 粘合剂 |
甘露醇 | 9.00 | 骨架剂 |
阿拉伯胶 | 0.09 | 助悬剂 |
吐温80 | 0.03 | 分散剂 |
枸橼酸钠 | 1.50 | pH调节剂 |
三氯蔗糖 | 1.50 | 矫味剂 |
薄荷味香精 | 0.36 | 矫味剂 |
纯化水 | 至312kg | 溶剂 |
冻干口崩片制备步骤如下:
散装药液配制:将普鲁兰多糖投入240kg煮沸的纯化水中,搅拌至药液均匀;将水解明胶和阿拉伯胶投上述水溶液中搅拌至药液呈无色澄清透明状;加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精继续搅拌至完全溶解,将药液温度降低至室温;加入吐温80,搅拌至药液呈无色澄清透明状态,将乌布吉泮加入上述药液并以纯化水定容至312kg,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取312mg/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表15 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
实施例8:
本实施例提供了100mg规格乌布吉泮冻干口崩片及其制备方法:
表16 处方组成
成分 | 含量(kg) | 作用 |
乌布吉泮 | 100.00 | 药物活性成份 |
明胶 | 3.20 | 粘合剂 |
水解明胶 | 12.00 | 粘合剂 |
阿拉伯胶 | 0.12 | 助悬剂 |
吐温80 | 0.04 | 分散剂 |
甘露醇 | 14.00 | 骨架剂 |
枸橼酸钠 | 1.80 | pH调节剂 |
三氯蔗糖 | 1.60 | 矫味剂 |
薄荷味香精 | 0.40 | 矫味剂 |
纯化水 | 至412kg | 溶剂 |
冻干口崩片制备步骤如下:
散装药液配制:将明胶置于240kg纯化水中至明胶溶胀完全,加热至60℃并搅拌,至明胶完全溶解,加入水解明胶和阿拉伯胶搅拌至药液呈淡黄色澄清透明状态;继续加入甘露醇、枸橼酸钠、三氯蔗糖、薄荷味香精搅拌至完全溶解,将药液温度降低至室温;加入吐温80,搅拌至药液呈无色澄清透明状态,乌布吉泮加入上述药液并以纯化水定容至412kg,以高速剪切乳化机以7000rpm转速搅拌至药液均一,完成散装药液配制;
灌装:吸取412mg/片散装药液灌装至已成型的冷冲压成型复合硬片泡罩中;
预冻:泡罩中药液至于-80℃±10℃环境下使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-20℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表17 冻干曲线
包装:在相对湿度≤25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
口感测试:
自愿受试者60名,年龄25岁~45岁间,分别取具体实施例1~具体实施例8制备的乌布吉泮冻干口崩片5片进行口感测试,每片次测试前以120ml纯化水漱口3次,测试结果如表18所示:
表18 口感测试结果
实施例序号 | 口崩片外观 | 气味 | 口感 | 溶化时间 |
实施例1 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例2 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例3 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例4 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例5 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例6 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例7 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
实施例8 | 白色圆形冻干片 | 薄荷香气 | 薄荷味道微凉 | 2S以内 |
含量及均匀度测定结果:
对实施例7~8进行含量均匀度测试,结果如下:
表19 含量及均匀度测试结果
Claims (10)
1.一种乌布吉泮冻干口崩片(Ubrogepant Lyophilized orally disintegratingtablets),该口崩片由基质与有效剂量的乌布吉泮制成,其特征在于:该制剂的基质包括:骨架支撑材料占制剂总固形物重量的1%~60%,冻干保护剂占制剂总固形物重量的0~5%;有效成分乌布吉泮占制剂总固形物重量的5~80%。
2.如权利要求1所述的冻干口崩片,其特征在于:骨架支撑材料由单一辅料或由多种辅料组成;由多种辅料组成的骨架支撑材料,其特征在于:骨架支撑材料由粘合剂和骨架剂组成;由单一辅料组成的骨架支撑材料,其特征在于:具有较高的粘性和良好的空间支撑性能和成膜性能。
3.如权利要求1~2任一所述的骨架支撑材料,其特征还在于:可作为冻干保护剂、助悬剂。
4.如权利要求1~3所述的骨架材料,其特征在于:骨架材料为水溶性材料。
5.如权利要求1~4所述的骨架支撑材料,其特征在于骨架剂包括但不限于高聚物、高聚糖、糖醇类、糖类或氨基酸类,选自甘露醇、木糖醇、山梨糖醇、麦芽糖醇、乳糖醇、赤藓糖醇、糊精、右旋糖苷、普鲁兰多糖、乳糖、海藻糖、聚乙烯醇、甘氨酸中的一种或几种。
6.如权利要求1~4所述的骨架支撑材料,其特征在于粘合剂包括但不限于蛋白、植物胶、氨基酸、多肽、高聚糖、高聚物类,选自水溶性多肽、明胶、水解明胶、阿拉伯胶、琼脂、右旋糖苷、普鲁兰多糖、聚乙烯醇中的一种或几种。
7.如权利要求1所述的冻干口崩片剂,其特征在于冻干保护剂选自海藻糖、乳糖、甘露醇、普鲁兰多糖、水溶性多肽、甘氨酸中的一种或几种。
8.如权利要求1~7所述的冻干口崩片剂,其特征在于该冻干口崩片中还可以含有助悬剂和分散剂、矫味剂、pH调节剂、抗氧剂、防腐剂、着色剂等;助悬剂和分散剂包括但不限于阿拉伯胶、瓜耳豆胶、吐温80、司盘80、羧甲基纤维素钠等;矫味剂包括甜味剂和/或不同口味的香精,其中甜味剂选自:阿斯巴甜、安赛蜜、三氯蔗糖、甜菊苷中的一种或几种;香精包括但不限于:柠檬酸钠、草莓味香精、香橙味香精、柳橙味香精、西瓜味香精、牛奶味香精、巧克力味香精、香草味香精、薄荷味香精;pH调节剂包括但不限于无机盐、有机盐、弱酸、弱碱、缓冲对;无机盐包括但不限于氯化钠、碳酸氢钠、碳酸氢钾、磷酸氢二钠、磷酸二氢钠等,有机盐包括但不限于:枸橼酸钠、琥珀酸钠等;弱酸包括:枸橼酸、琥珀酸、马来酸等;弱碱包括但不限于:氢氧化钙等;缓冲对包括但不限于:磷酸氢二钠—磷酸二氢钠,枸橼酸—枸橼酸钠等;抗氧剂包括但不限于亚硫酸钠、依地酸二钠、焦亚硫酸钠、硫代硫酸钠等;防腐剂可以采用水溶性材料,亦可以采用脂溶性材料,包括但不限于苯甲醇、尼泊金甲酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金丙酯钠等;可食用着色剂可选择水溶性材料,亦可以选择脂溶性材料,包括但不限于天然色素、合成色素等。
9.如权利要求1~8所述的冻干口崩片,其特征还在于溶剂包括纯化水、乙醇、叔丁醇中的一种或几种,其中有机溶剂占溶剂总量的0~20%。
10.一种权利要求1~9任一项所述的冻干口崩片的制备方法,步骤如下:
散装药液配制:将骨架材料溶于8~80℃纯化水中,搅拌至完全溶解,加入其他辅料继续搅拌至完全溶解,将药液温度降低至室温;乌布吉泮加入至上述药液并以纯化水定容至处方量,搅拌至药液均一稳定,完成散装药液配制;
灌装:将散装药液灌装至已成型的冷冲压成型复合硬片或PVC/PVDC泡罩中;
预冻:泡罩中药液至于-40℃~-110℃环境下使药液迅速冷冻成固态,或在-10℃~-110℃环境下连续梯度降温使药液迅速冷冻成固态;
冻干:冻干机设定搁板预冷模式,设定温度-10℃~-30℃,将装有已固化药液的泡罩放入冻干机中,开始进行冻干,冻干曲线如下表所示:
表1 冻干曲线
包装:在相对湿度5~25%环境下覆铝纸复合膜,喷墨打印生产日期和批号。
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