CN116421581A - 一种帕洛诺司琼透皮贴片及其制备方法 - Google Patents
一种帕洛诺司琼透皮贴片及其制备方法 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及一种帕洛诺司琼透皮贴片及其制备方法。该发明透皮贴片由背衬层、载药压敏胶层及防粘层构成;载药压敏胶层包括帕洛诺司琼游离碱、压敏胶、抗氧剂、经皮吸收促进剂。其中帕洛诺司琼游离碱用量占总重的5%~20%,优选5%~15%,抗氧剂占总重的0.01%~0.1%,经皮吸收促进剂占总重的5%~10%,压敏胶占74.9%~89.99%。本发明提供的帕洛诺司琼经皮透皮贴片选用不同基团的混合压敏胶提高其粘附性及稳定性,可实现帕洛诺司琼游离碱7日内的缓慢释放。
Description
技术领域
本发明属于医药技术领域,具体涉及一种帕洛诺司琼透皮贴片及其制备方法。
背景技术
化疗引起的恶心和呕吐(CINV)是癌症治疗中一个不能忽视的不良反应。70%到80%的患者在癌症治疗过程中会经历呕吐,且10%~44%的患者会经历习惯性呕吐。CINV会对于患者的生活质量(QOL)有明显的负面影响,可能导致患者不依从治疗或使剂量降低。由于化疗和特殊的患者体质,CINV的风险会增高。CINV会导致虚弱、体重降低、电解质紊乱、脱水和厌食症且与很多其他的并发症有关,包括骨折、食管撕裂、体质和精神状态逐渐衰弱还有伤口裂开。患者会脱水、虚弱或营养不良,那些最近经历过手术或放射治疗的患者会经历更严重的CINV并发症。
尽管引入了更有效的止吐药(五羟色胺5-HT3和神经激肽-1受体拮抗剂),恶心和呕吐仍然是化疗中很重要的并发症。帕洛诺司琼是一个有效的高选择性血清素5-HT3受体抑制剂,被用于防治化疗引起的恶心和呕吐。它在中枢神经系统和胃肠道都具有止吐活动性。相比第一代的5-HT3受体拮抗剂(多拉司琼,格拉司琼,或昂丹司琼),它对5-HT3受体拮抗剂具有更高的亲和力,并且有更高的效能,更长的半衰期(约40小时,比多拉司琼,格拉司琼,或昂丹司琼约长4~5倍,且血浆蛋白结合率适中(62%)),以及更好的安全性。
作为常用的治疗CINV的药物,帕洛诺司琼已经在临床使用,已上市的剂型有注射型和胶囊型。口服胶囊剂会产生胃肠道副作用且具有肝脏首过效应;注射剂则不利于患者顺应性,且注射部位也会出现疼痛、淤青等现象,容易导致局部组织坏死。因此,采用一种新型的给药途径以减小药物胃肠道副作用、提高患者顺应性十分必要。
经皮给药系统能够长期稳定的持续给药,维持平稳的血药浓度,从而减少首过效应,减少毒副作用,提高患者顺应性。目前国内外对于帕洛诺司琼的经皮给药的研究较少,且国内外市场中还未出现帕洛诺司琼的经皮给药剂型。然而经皮给药的贴剂在储存过程中出现结晶沉淀是一个很严重的稳定性问题,若不从根本上解决,难以保证贴剂在储存期间再次出现结晶因而降低疗效。
专利WO2009139411在贴剂中加入脂肪醇类抑制帕洛诺司琼结晶,提高其稳定性,但该专利贴剂的制备过程中加入了氢氧化钠,其加入会影响体系的稳定性;专利CN104069505B采用将帕洛诺司琼包合在环糊精中,解决活性物质易结晶问题,且实现了药物7日内的缓慢释放,但其制备过程中需先将活性物质包合,制备工序较为复杂。因此,有待于开发一种处方工艺简单、无药物结晶沉淀、稳定性好、刺激性小且同时兼具缓释效果的帕洛诺司琼透皮贴片。
发明内容
本发明的目的在于提供制剂粘附性好、稳定性高及药物成分缓慢释放的帕洛诺司琼透皮贴片及其制备方法。该发明贴片由背衬层、载药压敏胶层和防粘层组成,其特征在于,所述载药压敏胶层包括帕洛诺司琼游离碱、抗氧剂、含羧基与羟基官能团的聚丙烯酸酯类压敏胶和经皮吸收促进剂,其重量组成百分含量为:帕洛诺司琼游离碱用量占载药压敏胶层总重的5%~20%,优选5%~15%,抗氧剂占载药压敏胶层总重的0.01%~0.1%,经皮吸收促进剂占载药压敏胶层总重的5%~10%,压敏胶占载药压敏胶层总重的74.9%~89.99%。
帕洛诺司琼的游离碱通过如下方法制备:将盐酸帕洛诺司琼溶解于纯化水中,然后滴加氢氧化钠的水溶液至不再有白色浑浊产生,使用过量乙酸乙酯分次进行萃取,合并萃取液,加入适当的无水硫酸钠进行脱水,然后旋转蒸发干燥既得。
为了提高药物粘附性,载药压敏胶层中加入压敏胶74.9%~89.99%,优选不同基团混合,包括87-2287、87-2074、87-2156,其中87-2074为含羧基基团的聚丙烯酸酯类压敏胶,87-2156及87-2287为含羟基基团的聚丙烯酸酯类压敏胶。
进一步的,含羧基官能团的压敏胶与羟基官能团的压敏胶组成的混合压敏胶的配比为1:1。
进一步地,载药压敏胶层中加入的抗氧剂为维生素E,用量占载药压敏胶层总重的0.01%~0.1%。
背衬层所选用的材料为弹性无纺布。
防粘层所选用的材料为一层或多层膜复合聚酯(PET)薄膜。
所述载药压敏胶层厚度为100~130μm。
有益效果
本发明选用不同基团的混合压敏胶能提高其粘附性及稳定性,制备得到的经皮吸收贴剂,稳定性好,对皮肤刺激性小,粘附性强,贴剂作用于皮肤后,帕洛诺司琼能长时间、持续定量地释放;在制备工艺上,无需使用环糊精包合,处方工艺简单。
具体实施方式:
下面通过实施例的方式对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
在以下实施例中,所涉及物料的用量均是以无水物计。
实施例1
将0.5g盐酸帕洛诺司琼溶解于20ml蒸馏水中,滴加氢氧化钠的水溶液至不再有白色浑浊产生。用200ml乙酸乙酯分5次萃取,合并萃取液,加入适量的无水硫酸钠进行脱水,然后旋转蒸发干燥即得帕洛诺司琼游离碱。
实施例2
将0.5g帕洛诺司琼碱溶解在4.50g(87-2156)与4.50g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(5%w/w载药量,5%促进剂)。
实施例3
将0.5g帕洛诺司琼碱溶解在4.50g(87-2287)与4.50g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(5%w/w载药量,5%促进剂)。
实施例4
将1g帕洛诺司琼碱溶解在4.25g(87-2156)与4.25g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(10%w/w载药量,5%促进剂)。
实施例5
将1.5g帕洛诺司琼碱溶解在4.00g(87-2156)与4.00g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(15%w/w载药量,5%促进剂)。
实施例6
将2.0g帕洛诺司琼碱溶解在3.75g(87-2156)与3.75g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(20%w/w载药量,5%促进剂)。
实施例7
将1.5g帕洛诺司琼碱溶解在3.75g(87-2156)与3.75g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯1.0g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(15%w/w载药量,10%促进剂)。
对比例1
将0.5g帕洛诺司琼碱溶解在9g(87-2156)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(5%w/w载药量,5%促进剂)。
对比例2
将0.5g帕洛诺司琼碱溶解在9g(87-2074)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(5%w/w载药量,5%促进剂)。
对比例3
将0.5g帕洛诺司琼碱溶解在9g(87-2287)混合压敏胶中,加入0.01g维生素E,加入肉豆酸蔻异丙酯0.5g,加入10ml乙酸乙酯混匀,室温静置1h脱气,转移涂布在防粘层上,烘干过程溶剂,复合上背衬层,形成厚度为120μm的帕洛诺司琼透皮贴片(5%w/w载药量,5%促进剂)。
试验结果1粘附性研究
为了考察不同处方制剂的的粘附性能,特对实施例1-7与对比例1-3的粘附性进行评价,具体数据如下:
实施例编号 | 初粘力 | 持粘力 | 剥离试验 | 黏着力 |
实施例2 | 28号小球 | 约41分钟 | 1.956kn/m | 3257mN |
实施例3 | 23号小球 | 约27分钟 | 1.612kn/m | 2251mN |
实施例4 | 27号小球 | 约36分钟 | 1.823kn/m | 3031mN |
实施例5 | 26号小球 | 约35分钟 | 1.756kn/m | 2981mN |
实施例6 | 24号小球 | 约28分钟 | 1.598kn/m | 2300mN |
实施例7 | 23号小球 | 约30分钟 | 1.687kn/m | 2651mN |
对比例编号 | 初粘力 | 持粘力 | 剥离试验 | 黏着力 |
对比例1 | 21号小球 | 约26分钟 | 1.525kn/m | 2234mN |
对比例2 | 24号小球 | 约26分钟 | 1.643kn/m | 2358mN |
对比例3 | 18号小球 | 约23分钟 | 1.317kn/m | 2011mN |
通过以上数据表明,压敏胶混合使用粘附力优于单个使用,不同载药量对粘附力影响不大。
试验结果2累积透过量研究
为了考察不同载药量的释放情况,采用扩散池法,应用有机膜对相关实施例及对比例制备的透皮贴片进行释放情况研究,具体数据如下:
通过以上数据表明,使用混合压敏胶制得的透皮贴片制剂整体释放情况呈现较好的线性趋势,优选87-2074型和87-2156型混合压敏胶;其中,15%载药量制剂的释放情况较好。
试验结果3稳定性研究
为了考察理化稳定性,在加速条件下(温度40±2℃、相对湿度75%±5%)下6个月内对相关实施例及对比例的结晶性、含量及有关物质进行测定,具体数据如下:
检测项 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 |
是否结晶(6月) | 否 | 否 | 否 | 否 | 否 | 否 |
含量(0天,%) | 98.8 | 98.4 | 98.9 | 98.1 | 98.5 | 97.9 |
含量(3月,%) | 98.1 | 98.7 | 98.1 | 97.6 | 98.1 | 98.1 |
含量(6月,%) | 98.7 | 98.3 | 98.6 | 98.2 | 98.8 | 97.6 |
总杂(0天,%) | 0.01 | 0.03 | 0.02 | 0.02 | 0.02 | 0.03 |
总杂(3月,%) | 0.04 | 0.06 | 0.04 | 0.02 | 0.03 | 0.08 |
总杂(6月,%) | 0.06 | 0.09 | 0.05 | 0.03 | 0.04 | 0.07 |
通过以上数据显示,混合压敏胶使用优于单一压敏胶,使用混合压敏胶制得的透皮贴片稳定性良好,可以耐受较长的货架期。
本发明的上述实施例仅仅是为清楚地说明本发明所作的举例,而并非是对本发明的实施方式的限定,对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动,这里无法对所有的实施方式予以穷举,凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。
Claims (10)
1.一种帕洛诺司琼透皮贴片,所述透皮贴片由背衬层、载药压敏胶层和防粘层组成,其特征在于,所述的载药压敏胶层包括帕洛诺司琼游离碱、抗氧剂、含羧基官能团的聚丙烯酸酯类压敏胶和含羟基官能团的聚丙烯酸酯类压敏胶组成的混合压敏胶和经皮吸收促进剂,其重量组成百分含量为:帕洛诺司琼游离碱用量占载药压敏胶层总重的5%~20%,压敏胶占载药压敏胶层总重的74.9%~89.99%,经皮吸收促进剂占载药压敏胶层总重的5%~10%。
2.根据权利要求1所述的一种帕洛诺司琼透皮贴片,其特征在于,所述帕洛诺司琼游离碱用量占载药压敏胶层总重的5%~15%。
3.根据权利要求1所述的一种帕洛诺司琼透皮贴片,其特征在于,所述的含羧基官能团的聚丙烯酸酯类压敏胶为:87-2074;所述的含羟基官能团的聚丙烯酸酯类压敏胶为:87-2156、87-2287。
4.根据权利要求1所述的一种帕洛诺司琼透皮贴片,其特征在于,所述的含羧基官能团的压敏胶与羟基官能团的压敏胶组成的混合压敏胶的质量比为1:1。
5.根据权利要求1所述的一种帕洛诺司琼透皮贴片,其特征在于,所述的经皮吸收促进剂为肉豆酸蔻异丙酯;所述的肉豆酸蔻异丙酯的用量占载药压敏胶层总重的5%~10%。
6.根据权利要求1所述的一种帕洛诺司琼透皮贴片,其特征在于,所述的抗氧剂为维生素E,所述的维生素E的用量占载药压敏胶层总重的0.01%~0.1%。
7.根据权利要求1-6所述的任一项的一种帕洛诺司琼透皮贴片,其特征在于,所述的载药压敏胶层厚度为100μm~130μm。
8.根据权利要求1-6所述的任一项的一种帕洛诺司琼透皮贴片,其特征在于,所述的帕洛诺司琼的游离碱通过如下方法制备:用氢氧化钠的水溶液来滴定盐酸帕洛诺司琼的水溶液,至不再有白色浑浊产生,再用单一有机溶剂对其进行萃取,脱水后蒸发有机溶剂干燥即得。
9.根据权利要求8所述的一种帕洛诺司琼透皮贴片,其特征在于,所述的有机溶剂为乙酸乙酯。
10.一种帕洛诺司琼透皮贴片的制备方法,其特征在于,将帕洛诺司琼的游离碱溶解在羟基基团和羧基基团的混合压敏胶中,分别加入维生素E、肉豆酸蔻异丙酯,再加入乙酸乙酯混合均匀,室温静置1h脱气,转移涂布与防粘层,再烘干过程溶剂,复合背衬层,即得帕洛诺司琼透皮贴片。
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