CN110151708B - 含有挥发性成分的冻干口腔崩解制剂及其制备方法 - Google Patents
含有挥发性成分的冻干口腔崩解制剂及其制备方法 Download PDFInfo
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- CN110151708B CN110151708B CN201910536985.2A CN201910536985A CN110151708B CN 110151708 B CN110151708 B CN 110151708B CN 201910536985 A CN201910536985 A CN 201910536985A CN 110151708 B CN110151708 B CN 110151708B
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Abstract
本发明公开了一种冻干口腔崩解制剂,所述的冻干口腔崩解制剂中按重量比含有挥发性成分4‑20份、羟丙基β‑环糊精8‑100份、粘合剂4‑20份、骨架剂4‑20份、助悬剂0.1‑0.6份。本发明所述的冻干口腔崩解制剂解决了现有技术中挥发性成分载药量小并且无法实现定量载药、冻干口崩片成型性差的缺陷。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种含有挥发性成分的冻干口腔崩解制剂及其制备方法。
背景技术
具有挥发性的生物活性成分通常沸点低,不易溶于水,因而在制备制剂过程中往往存在添加困难、稳定性差、定量不准确等缺陷。传统方法中,通常将挥发性成分,例如挥发油,提取后再将挥发油直接喷洒在药粉上或吸附在淀粉等辅料中然后制成各种剂型。现代制剂学方法则通常利用包合法、微囊法、微乳法、纳米乳法等将挥发性成分制备成各种剂型。其中,利用环糊精及其衍生物包合法是最常用的方法,包合后能够增加难溶性挥发性成分的溶解度,减缓或抑制挥发性成分的氧化或水解,防止挥发性成分挥发,同时还能达到减少剌激、降低毒副作用,遮盖不良气味。
口腔崩解片指的是能在口腔内迅速崩解或者溶解的制剂,此类制剂在口腔中遇到唾液能迅速崩解并大部分溶解。申请人已经公开了冻干法制备崩解片的工艺,例如专利CN100366294C公开了一种涉及辅料中包含普鲁兰的口腔速溶制剂及其生产方法,包括基质和有效剂量的主药,其中基质主要由下列重量份的原料组成:骨架剂1—10重量份,普鲁兰1—10重量份,主药可以是溶于水也可以是不溶于水的药物,当主药为不溶于水或主要溶媒时,基质中还可以加入增稠助悬剂,专利CN1985799B公开了一种口腔崩解制剂的制备方法,包含:(a)采用泡罩成型设备将铝复合材料底材成型,在所述底材上形成多个铝窝,所述的铝复合材料底材包含铝箔中间层、第一外层和第二外层,所述的第一外层和第二外层的材料不相同,但其抗弯刚度相差0-30%;(b)将液体药品装入到(a)步骤所形成的铝窝内;(c)冷冻药品;(d)冷冻干燥药品;(e)将盖材附着在上述的包装材料上,以便于密封好药品。
另外,现有技术中已有将挥发性成分采用环糊精包合后制备冻干速释制剂的尝试:
专利CN103239507A中公开了一种在口腔中可快速崩溶的复方丹参膜剂,由丹参提取物、三七提取物、冰片包合物和药学上可接受的崩解剂及成膜材料组成,所述的冰片包合物由环糊精包合冰片获得,冰片与环糊精的重量比优选1:3-1:5。
专利CN102293984B公开了一种醒脑静冻干速释制剂,首先将人工麝香挥发油、郁金挥发油和冰片用少量乙醇溶解,加入到饱和的β-环糊精溶液中,制备包合物,再取栀子大孔吸附树脂纯化提取物和环糊精包合物,用蒸馏水溶解,加入甘露醇,明胶,阿斯巴甜和草莓香精适量,搅拌使溶解,加入至模具中,-40℃温度下预冻5h,在真空低温条件下-15℃温度下升华10h,压膜,包装,即得。
专利CN1785247B公开了一种口腔崩解片,取β-环糊精与冰片的投料比为7.4∶1,称取一定量的β-环糊精加入3倍量的蒸馏水,然后加入冰片乙醇溶液,在42r/min下球磨1小时,包合物低温真空干燥24小时,研碎过80目筛的粗包合物,将粗包合物用乙酸乙酯洗涤3次后晾干,即得备用疏松状白色包合物粉末,取丹参提取物、冰片包合物三七总皂甙,乳糖醇、阿拉伯胶的混合物,充分混合,压片,制得。
然而,申请人发现采用现有技术的方法,当期望获得较高的载药量时,冻干口腔崩解片的成型性将变差,挥发性成分在冻干后损失很大。而为了保持冻干口腔崩解片的主要特性,则获得大载药量以及准确定量的载药将变得困难,因此,提出一种适用于挥发性成分的口腔崩解制剂是急需解决的问题。
发明内容本发明解决了现有技术中挥发性成分载药量小、无法实现定量载药、冻干口崩片成型性差的缺陷,提供了一种载药量高、定量准确、片型好、口服吸收速度快的含有挥发性成分的冻干口腔崩解制剂。
本发明的第一方面提供了一种冻干口腔崩解制剂,所述的冻干口腔崩解制剂中按重量比含有挥发性成分4-20份、羟丙基β-环糊精8-100份、粘合剂4-20份、骨架剂4-20份、助悬剂0.1-0.6份。
本发明所述的挥发性成分通常是指沸点低于350℃的物质,优选的,所述的挥发性成分通常是指沸点低于300℃的物质,更优选的,所述的挥发性成分通常是指沸点为50-300℃的物质。本发明所述的挥发性成分可以为单一成分也可以是混合物,例如是多种挥发性成分的组合物,或者,一种或多种挥发性成分与非挥发性成分的组合物。本发明所述的挥发油成分可以是固体也可以是液体。
在本发明的一个实施方式中,所述的挥发性成分可以是天然植物提取的挥发油,例如,选自唇形科、伞形科、菊科、云香科、樟科、姜科、麻黄科、柏科、毛茛科、肉豆蔻科、马鞭草科、马兜铃科、木兰科、八角科、木犀科、莎草科、桃金娘科、天南星科、无患子科、麝香科、百合科植物提取得到的挥发油。
优选的,所述的唇形科植物为薄荷、紫苏、藿香、荆芥,小茴香、香薷等;伞形科植物为茴香、当归、芫荽、白芷、川芎、前胡、蛇床子、藁本、羌活、柴胡等;菊科植物为艾叶、茵陈蒿、苍术、白术、木香、野菊花、菊花、佩兰、木香等;云香科植物为花椒、枳壳、枳实、陈皮、青皮、佛手、香橼等;樟科植物为樟、肉桂等;姜科植物为砂仁、高良姜、草果、莪术、生姜、干姜、姜黄、郁金、豆蔻等;麻黄科植物为麻黄;柏科植物为侧柏叶;毛茛科植物为泽兰;肉豆蔻科植物为肉豆蔻;马鞭草科植物为牡荆;马兜铃科植物为细辛、青木香;木兰科植物为辛夷,厚朴;八角科植物为八角茴香;木犀科植物为连翘;莎草科植物为香附;桃金娘科植物为丁香、桉叶;天南星科植物为石菖蒲;无患子科植物为荔枝核;麝香科植物为麝香;百合科植物为大蒜。
在本发明的一个实施方式中,所述的挥发性成分可以是单体化合物,例如是单萜及倍半萜类成分及其衍生物、芳香类化合物及其衍生物,优选的,所述的挥发性成分可以为α-蒎烯、β-蒎烯、樟脑、薄荷脑、异龙脑、桂皮醛、丹皮酚、冰片、薄荷酮、大蒜素、桉油醇、柠檬烯、藁本内酯等,更优选的,所述的挥发性成分可以为薄荷脑、异龙脑或冰片。
本发明所述的冻干口腔崩解制剂中按重量比含有挥发性成分4-20份,优选为6-12份,更优选为8-10份。
本发明所述的包合材料为羟丙基β-环糊精,尽管现有技术中存在多种包合材料,例如聚山梨酯、聚维酮、β-环糊精、羟丙基β-环糊精等,由于不同材料性质的不同,在包合孔径、成型效果上存在差异,但令人惊奇的是,发明人发现采用羟丙基β-环糊精包合后的挥发性成分既能够具有较高的包合率,又能够在后续制备冻干口腔崩解制剂的过程中保持较好的成型性能。
本发明所述的冻干口腔崩解制剂中按重量比含有羟丙基β-环糊精30-90份,更优选的,所述的口腔崩解制剂中按重量比含有羟丙基β-环糊精60-80份。
本发明所述的粘合剂选自普鲁兰或明胶,更优选的,所述的粘合剂选自普鲁兰。
本发明所述的冻干口腔崩解制剂中按重量比含有粘合剂6-18份,更优选的,所述的口腔崩解制剂中按重量比含有粘合剂8-12份。
本发明所述的骨架剂选自糖类:甘露醇、山梨醇、麦芽糖醇、木糖醇、乳糖醇、赤藓糖醇、异麦芽糖醇、木棉子糖、麦芽糖、葡糖糖、半乳糖、海藻糖或糊精:无机盐:磷酸钠、氯化钠或硅酸铝;含有2个至12个碳原子的氨基酸:甘氨酸、丙氨酸、天冬氨酸、谷氨酸、羟脯胺酸、异亮氨酸、亮氨酸或苯丙氨酸中的一种或两种以上的组合,更优选的,所述的骨架剂为甘露醇。
本发明所述的冻干口腔崩解制剂中按重量比含有骨架剂6-18份,更优选的,所述的口腔崩解制剂中按重量比含有骨架剂8-12份。
本发明所述的助悬剂选自黄原胶、结冷胶、羧甲基纤维素钠、卡拉胶、瓜尔豆胶中的一种或两种以上的组合。更有选的,所述的助悬剂为黄原胶。
本发明所述的冻干口腔崩解制剂中按重量比含有助悬剂0.2-0.6份,更优选的,所述的口腔崩解制剂中按重量比含有骨架剂0.2-0.4份。
在本发明的一个实施方式中,所述的冻干口腔崩解制剂单位剂量中还可以含有矫味剂和/或防腐剂,优选的,所述的矫味剂选自阿斯巴甜、安赛蜜、三氯蔗糖、阿司帕坦、蔗糖等天然或人工合成的甜味剂中的一种或两种以上的组合,优选的,所述的防腐剂选自羟苯甲脂钠、羟苯丙脂钠中的一种或两种以上的组合。
更优选的,本发明所述的冻干口腔崩解制剂中按重量比含有矫味剂0.1-10份。
更优选的,本发明所述的冻干口腔崩解制剂中按重量比含有防腐剂0.1-2份。
本发明所述的冻干口腔崩解制剂中挥发性成分与羟丙基β-环糊精形成包合物。与现有的冻干口崩片处方不同,由于包合材料羟丙基β-环糊精的加入,使得冻干口腔崩解处方中各辅料的比例减小,因此选择合适的处方组成和比例,对口腔崩解制剂的成型以及释放效果产生关键影响。
在本发明的一个具体实施方式中,所述的冻干口腔崩解制剂单位剂量包括:
挥发性成分4-20mg;
羟丙基β-环糊精8-100mg;
普鲁兰4-20mg;
甘露醇4-20mg;
黄原胶0.1-0.6mg。
在本发明的一个具体实施方式中,所述的冻干口腔崩解制剂单位剂量包括:
挥发性成分8-10mg;
羟丙基β-环糊精60-80mg;
普鲁兰8-12mg;
甘露醇8-12mg;
黄原胶0.2-0.4mg。
在本发明的一个具体实施方式中,所述的冻干口腔崩解制剂单位剂量包括:
挥发性成分8mg;
羟丙基β-环糊精75mg;
普鲁兰12mg;
甘露醇12mg;
黄原胶0.4mg。
本发明所述的冻干口腔崩解制剂可以为冻干口腔崩解片或冻干口腔崩解颗粒或其他以冻干形式制备的剂型,更优选的,本发明所述的冻干口腔崩解制剂为冻干口腔崩解片。
本发明的第二方面提供了一种冻干口腔崩解制剂的制备方法,所述制备方法包括:
(1)取挥发性成分4-20份,添加有机溶剂,搅拌溶解,得含有挥发性成分的溶液;
(2)取羟丙基β-环糊精8-100份,加入水和含有挥发性成分的溶液,搅拌,得含挥发性成分的羟丙基β-环糊精溶液;
(3)取助悬剂0.1-0.6份,加少量水润湿,搅拌,得助悬剂溶液;
(4)取含挥发性成分的羟丙基β-环糊精溶液,加入粘合剂4-20份、骨架剂4-20份和助悬剂溶液,加水定容,搅拌,得冻干溶液,按照单位剂量放置在模具中,冻干成型。
本发明所述的步骤(1)中有机溶剂选自二氯甲烷、无水乙醇、乙酸乙酯,优选的,所述的有机溶剂选自无水乙醇。优选的,所述的有机溶剂按质量比加入量为10-20份,更优选为,所述的有机溶剂按质量比加入量为12-16份。
本发明所述的步骤(4)中所述的搅拌为匀质剪切搅拌,更优选的,所述的匀质剪切的转速为2000-8000r/min,所述的匀质剪切时间为2-15min,特别优选的,所述的匀质剪切的转速为2500-4000r/min,所述的匀质剪切时间为8-12min。
本发明所述的步骤(4)中冻干成型前包括在-40--60℃预冻5-15min,更优选,在-50℃预冻10min分钟。
本发明所述的步骤(4)中冻干成型中:冷阱温度-40℃--60℃,真空度0.05-0.25毫巴,板层温度-35℃进锅,冻干曲线为;维持-30℃--40℃,10分钟;由-30℃升至-20℃,10分钟;维持-20℃,90分钟;-20℃升至-5℃,15分钟;维持-5℃,90分钟;-5℃升至5℃,10分钟;维持5℃,60分钟。
优选的,本发明步骤(2)含挥发性成分的羟丙基β-环糊精溶液中羟丙基β-环糊精按质量百分比为20-30%,更优选得,本发明步骤(4)冻干溶液中羟丙基β-环糊精按质量百分比为30%。
在本发明的一个实施方式中,所述的冻干口腔崩解制剂的制备方法包括:
(1)称取挥发性成分,滴加无水乙醇,搅拌使挥发性成分溶解,得含有挥发性成分的溶液;
(2)称取羟丙基β-环糊精,加水,加入含有挥发性成分的溶液,搅拌均匀,制成含挥发性成分的羟丙基β-环糊精溶液,所述的含挥发性成分的羟丙基β-环糊精溶液中羟丙基β-环糊精按质量百分比为20-30%;
(3)取助悬剂,加少量水润湿,搅拌,得助悬剂溶液;
(4)取含挥发性成分的羟丙基β-环糊精溶液,加入粘合剂、骨架剂和助悬剂溶液,加水定容,转速为2000-8000r/min匀质剪切2-15min,得冻干溶液,按照单位剂量放置在模具中,在-40--60℃预冻5-15min,更优选,在-50℃预冻10min分钟,冻干成型,其中冻干曲线为:冷阱温度-40℃--60℃,真空度0.05-0.25毫巴,板层温度-35℃进锅,冻干曲线为;维持-30℃--40℃,10分钟;由-30℃升至-20℃,10分钟;维持-20℃,90分钟;-20℃升至-5℃,15分钟;维持-5℃,90分钟;-5℃升至5℃,10分钟;维持5℃,60分钟。
本发明的第三方面提供了一种冻干口腔崩解制剂在制备药物、食品或化妆品上的应用。由于冻干口腔崩解制剂的特殊制备工艺,使得在制备含有挥发性成分的冻干口腔崩解制剂时活性成分容易挥发,因此需要特殊的辅料和工艺选择,才能制备得到符合质量标准要求的制剂,而本发明所述的含有挥发性成分的冻干口腔崩解制剂配方以及工艺在保留挥发性活性成分的同时,可以定量的完成挥发性成分的包合,有效的保证冻干口腔崩解制剂的质量。
具体实施方式
下面详细描述本发明的实施例,以便为本领域普通技术人员提供如何进行和利用本发明的试验、筛选和治疗方法的充分公开和说明,需要说明的是,这些实施例仅是说明性的,而不能理解为对本发明的限制。
本发明实施例中所采用试剂均为市售获得。
本发明实施例中冻干口腔崩解制剂的检测方法均采用如下方法:
(1)片型检测:取冻干片,置于玻璃培养皿中观察。
(2)崩解时间检测:取一烧杯,加纯化水50ml,将冻干片投入其中观察现象并计时。
(3)冰片含量检测:按照中国药典2015版一部天然冰片(右旋龙脑)含量测定项下方法测定。
实施例1不同种类包合材料对冻干口腔崩解片的影响
1.1采用聚山梨酯-80作为包合剂的冻干口腔崩解片处方制备方法
a称取黄原胶0.08g,加少量水润湿,搅拌均匀,备用。
b称取冰片1.6g,加入聚山梨酯80 1.6g,搅拌均匀。加入普鲁兰2.4g、甘露醇2.4g、以及制备好的黄原胶溶液,加水定容至80g,搅拌均匀,均质机2500r/min,剪切10min,脱气,得冰片药液。
c注样,分别移取冰片药液0.4ml至铝窝中,-50℃预冻10分钟,定型。
d冻干曲线
冻干:设定冻干初始温度为-35℃,将预冻好的泡眼放入冷冻干燥箱中,冷冻干燥5小时。
具体冻干过程如下:
Ⅰ冷阱温度:-40℃~-60℃;
Ⅱ真空度:0.05~0.25毫巴;
Ⅲ板层温度:-35℃进锅;
维持-35℃,60分钟;由-35℃升至-5℃,30分钟;维持-5℃,60分钟;-5℃升至25℃,30分钟;维持25℃,120分钟;压升试验合格后,出箱;从冻干机中取出泡罩板,用铝塑袋热封包装。
1.2采用聚维酮K30作为包合剂的冻干口腔崩解片处方制备方法
a称取黄原胶0.08g,加少量水润湿,搅拌均匀,备用。
b称取聚维酮K30 2g,加水20润湿搅拌均匀,加入冰片1.6g,搅拌均匀。加入普鲁兰2.4g、甘露醇2.4g、以及制备好的黄原胶溶液,加水定容至80g,搅拌均匀,均质机2500r/min,剪切10min,脱气,得冰片药液。
c注样,分别移取冰片药液0.4ml至铝窝中,-50℃预冻10分钟,定型。
d冻干曲线
冻干:设定冻干初始温度为-35℃,将预冻好的泡眼放入冷冻干燥箱中,冷冻干燥5小时,具体冻干过程同1.1。
1.3采用β-环糊精作为包合剂的冻干口腔崩解片处方制备方法
a称取黄原胶0.08g,加少量水润湿,搅拌均匀,备用。
b称取冰片1.6g,滴加处方量无水乙醇3.0g,搅拌使冰片溶解,备用。
c取β-环糊精1.6g,加水30.4g,加入制备好的冰片溶液,搅拌均匀,制成含冰片32mg/g的3.2%β-环糊精溶液(共50g),备用。
d取含冰片32mg/g的3.2%β-环糊精溶液(共50g),加入普鲁兰2.4g、甘露醇2.4g、黄原胶溶液,加水定容至80g,均质机2500r/min,剪切10min,脱气,得冰片药液。
e注样,分别移取冰片药液0.4ml至铝窝中,-50℃预冻10分钟,定型。
f冻干曲线
冻干:设定冻干初始温度为-35℃,将预冻好的泡眼放入冷冻干燥箱中,冷冻干燥5小时。具体冻干过程同1.1。
1.4实验结果
实施例2不同种类环糊精对冻干口腔崩解片的影响
2.1采用β-环糊精作为包合剂的冻干口腔崩解片处方制备方法
采用β-环糊精作为包合剂的冻干口腔崩解片处方制备方法同1.3。
2.2采用羟丙基β-环糊精作为包合剂的冻干口腔崩解片处方制备方法
a称取黄原胶0.08g,加少量水润湿,搅拌均匀,备用。
b称取冰片1.6g,滴加处方量无水乙醇3.0g,搅拌使冰片溶解,备用。
c取羟丙基β-环糊精1.6g,加水30.4g,加入制备好的冰片溶液,搅拌均匀,制成含冰片32mg/g的3.2%羟丙基β-环糊精溶液(共50g),备用。
d取含冰片32mg/g的3.2%羟丙基β-环糊精溶液(共50g),加入普鲁兰1.6g、甘露醇1.6g、黄原胶溶液,加水定容至80g,均质机2500r/min,剪切10min,脱气,得冰片药液。
e注样,分别移取冰片药液0.4ml至铝窝中,-50℃预冻10分钟,定型。
f冻干曲线
冻干:设定冻干初始温度为-35℃,将预冻好的泡眼放入冷冻干燥箱中,冷冻干燥5小时。具体冻干过程同1.1。
2.3实验结果
实施例3羟丙基β-环糊精包合量对冻干口腔崩解片的影响
3.1采用羟丙基β-环糊精作为包合剂的冻干口腔崩解片处方制备方法
按照3.2表格中的处方,参照2.2中的方法制备得到羟丙基β-环糊精按质量百分比为3.2%、20%和30%的含冰片的包合液。
3.2实验结果
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
尽管已经示出和描述了本发明的实施例,本领域的普通技术人员可以理解:在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由权利要求及其等同物限定。
Claims (6)
1.一种冻干口腔崩解制剂的制备方法,其特征在于,所述的制备方法包括:
(1)取挥发性成分,添加有机溶剂,搅拌溶解,得含有挥发性成分的溶液;
(2)取羟丙基β-环糊精,加入水和含有挥发性成分的溶液,搅拌,得含挥发性成分的羟丙基β-环糊精溶液;
(3)取助悬剂,加少量水润湿,搅拌,得助悬剂溶液;
(4)取含挥发性成分的羟丙基β-环糊精溶液,加入粘合剂、骨架剂和助悬剂溶液,加水定容,搅拌,得冻干溶液,按照单位剂量放置在模具中,冻干成型;
所述步骤(2)含挥发性成分的羟丙基β-环糊精溶液中羟丙基β-环糊精按质量百分比为20-30%;
所述冻干口腔崩解制剂中按重量比由挥发性成分4-20份、羟丙基β-环糊精30-90份、粘合剂4-20份、骨架剂4-20份、助悬剂0.1-0.6份组成;
所述的挥发性成分为冰片。
2.权利要求1所述的制备方法,其特征在于,所述的粘合剂选自普鲁兰或明胶;所述的骨架剂选自甘露醇、山梨醇、麦芽糖醇、木糖醇、乳糖醇、赤藓糖醇、异麦芽糖醇、木棉子糖、麦芽糖、葡萄糖、半乳糖、海藻糖、糊精、磷酸钠、氯化钠、硅酸铝、甘氨酸、丙氨酸、天冬氨酸、谷氨酸、羟脯胺酸、异亮氨酸、亮氨酸、苯丙氨酸中的一种或两种以上的组合;所述的助悬剂选自黄原胶、结冷胶、羧甲基纤维素钠、卡拉胶、瓜尔豆胶中的一种或两种以上的组合。
3.权利要求1所述的制备方法,其特征在于,步骤(1)中有机溶剂选自二氯甲烷、无水乙醇、乙酸乙酯,所述的有机溶剂按质量比加入量为10-20份。
4.权利要求1所述的一种冻干口腔崩解制剂的制备方法,其特征在于,所述的步骤(4)中所述的搅拌为匀质剪切搅拌,匀质剪切的转速为2000-8000 r/min,匀质剪切时间为2-15min。
5.权利要求1所述的一种冻干口腔崩解制剂的制备方法,其特征在于,所述的步骤(4)中冻干成型前包括在-40--60℃预冻5-15min。
6.权利要求1所述的冻干口腔崩解制剂的制备方法制备的制剂在制备药物、食品或化妆品中的应用。
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