CN109999012A - 一种普拉克索透皮贴剂及其制备方法 - Google Patents
一种普拉克索透皮贴剂及其制备方法 Download PDFInfo
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- CN109999012A CN109999012A CN201910263671.XA CN201910263671A CN109999012A CN 109999012 A CN109999012 A CN 109999012A CN 201910263671 A CN201910263671 A CN 201910263671A CN 109999012 A CN109999012 A CN 109999012A
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- pramipexole
- transdermal patch
- drug
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- sensitive adhesive
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Abstract
本发明属于医药技术领域,公开一种普拉克索透皮贴剂及其制备方法。本发明包括背衬层、药物储库和防粘层,药物储库包括主药普拉克索、压敏胶、经皮吸收促进剂,其中主药用量占1wt%~20wt%,压敏胶用量占50wt%~90wt%,经皮吸收促进剂用量占0.5wt%~10wt%。还可以添加惰性填充剂、增黏剂和抗氧剂等,其用量分别为0.1wt%~10wt%。普拉克索透皮贴剂是一种新型的给药***,既能改善注射剂给药顺应性差的情况,又能避免口服剂型对胃肠道的刺激,缓慢释药减轻药物的毒副作用,疗效持久平稳;若要中断给药,只需揭去贴剂即可,使用方便;本透皮贴剂还具有黏附性、柔顺性好,不污染等特点。
Description
技术领域
本发明属于医药技术领域,涉及一种普拉克索透皮贴剂及其制备方法。
背景技术
帕金森病(PD)是一种常见的慢性中枢神经***变性疾病,主要临床表现为动作迟缓、静止性震颤(四肢及下颌)、运动减缓以及肌肉僵直等运动症状,同时,可表现有情绪障碍、睡眠障碍及自主功能紊乱和不宁腿等非运动症状。随着对帕金森病患者日益增多的关注,对非运动症状的治疗也逐渐引起人们的关注。该疾病给患者带来了极大的身心痛苦,降低生活质量的同时更缩短了寿命。帕金森病是阿尔兹海默病(AD)之后的第二大神经***退行性疾病,流行病学调查结果显示,60岁以上的老年人群中患病率约为1%。在欧洲,大约有120万人患有帕金森病,我国65岁以上人群帕金森患病率为1.7%。
2014年中国帕金森病治疗指南(第3版)中指出:目前大多数研究者推荐非麦角类多巴胺受体激动剂为首选,美国神经病学会、运动障碍学会也将其作为帕金森病治疗指南推荐的一线药物,国际运动障碍协会(MDS)对于非麦角类多巴胺受体激动剂的作用也给予了高度肯定。在以往的临床观察中,诸如溴隐亭、卡麦角林等麦角类多巴胺受体激动剂有损害患者心脏瓣膜导致血液返流的可能性,而非麦角类多巴胺受体激动剂却没有上述损害,尤其适用于早发型帕金森患者病程初期,这类长半衰期药物不仅能够避免对纹状体突触后膜的多巴胺受体产生“脉冲”样刺激,而且可以预防及减少运动并发症的发生。
盐酸普拉克索是一种口服的非麦角类多巴胺受体激动剂,数据表明,在美国及欧洲地区,以及世界其他国家,盐酸普拉克索被广泛用来治疗典型及特发型帕金森病,可单一用药治疗早期帕金森患者及与左旋多巴合用作为治疗晚期帕金森患者的辅助用药。盐酸普拉克索上市的剂型为速释片和缓释片,原研公司均为Boehringer Ingelheim PharmaGmbH&Co.KG,上市制剂规格:0.375mg、0.75mg、1.5mg、3.0mg、4.5mg,适应症为治疗特发性帕金森病的体征和症状,即在整个疾病过程中,包括疾病后期,当左旋多巴的疗效逐渐减弱或者出现变化和波动时(剂末现象或“开关”波动),都可以单独应用本品(无左旋多巴)或与左旋多巴联用。口服用药,一天一次服用。起始剂量为每日0.375mg,然后每5-7天增加一次剂量。如果患者可以耐受,应增加剂量以达到最大疗效。维持治疗:个体剂量应该在每天0.375mg至4.5mg之间。在剂量逐渐增加的三项重要研究中,从每日剂量为1.5mg开始可以观察到药物疗效。作进一步剂量调整应根据临床反应和耐受性进行。在临床试验中有大约5%的患者每天服用剂量低于1.5mg。当计划减少左旋多巴治疗时,每天服用剂量大于1.5mg对晚期帕金森病患者可能是有效的。在本品加量和维持治疗阶段,建议根据患者的个体反应减少左旋多巴用量。
目前,普拉克索的上市剂型为口服剂型,由于多数帕金森病患者在患病过程中常出现吞咽困难,口服剂型的给药存在很大不便,除吞咽困难外,帕金森病患者存在因情绪不稳,易怒等精神症状而拒绝服药的状况,给药的突然中断会对患者健康产生很大的不良影响,护理者们也需要在监督患者服药方面花费大量精力,从而产生很大压力与负担。因此,开发出一种提高患者依从性的透皮贴剂对于帕金森病患者及其护理者而言都具有很大意义。
经皮给药***是药剂学中一个新兴的领域,药物从透皮传递***中释放以后,药物先是分布于皮肤表面,然后再扩散通过表皮到达真皮组织,通过表皮层后,部分药物被迅速转运到微循环中。经皮给药***与传统给药方式相比具有以下的优点:可产生持久、恒定和可控的血药浓度,从而减轻不良反应;避免肝脏的首过效应,提高药物的生物利用度;减轻注射用药的痛苦;患者可自己用药,出现问题可及时停药,使用方便;减少给药次数和剂量。因此,经皮给药***具有良好的应用前景。贴剂作为一种经皮给药缓控释制剂,避免了胃肠道的刺激,提高了该药的有效性、安全性以及病人的顺应性。鉴于普拉克索的理化性质,溶解性0.14mg/ml,油水分配系数LogP0.4,熔点为116~121℃,适合将其制成透皮贴剂,使其在临床上发挥更大的作用。
目前还未见普拉克索贴剂上市,这表明现有的技术还有待提高和完善,人们期望获得一种疗效更突出、使用更安全、价格更低廉的普拉克索贴剂产品。
发明内容
本发明的目的在于提供一种普拉克索透皮贴剂及其制备方法。该透皮贴剂包括背衬层、药物储库层和防粘层,药物储库包括主药普拉克索、压敏胶、经皮吸收促进剂,其中主药用量占1wt%~20wt%,压敏胶用量占50wt%~90wt%,经皮吸收促进剂用量占0.5wt%~10wt%。还可以添加惰性填充剂、增黏剂和抗氧剂等,其用量分别为0.1wt%~10wt%。普拉克索贴剂是一种新型的给药***,既能改善注射剂给药顺应性差的情况,又能避免口服剂型对胃肠道的刺激,缓慢释药减轻药物的毒副作用,疗效持久平稳;若要中断给药,只需揭去贴剂即可,使用方便;本贴剂还具有黏附性、柔顺性好,不污染等特点。
药物储库层中,主药普拉克索为游离碱形式,用量占1wt%~20wt%。以4,5,6,7-四氢苯并[d]噻唑-2,6-二胺经酒石酸拆分得到拆分物、拆分物经中加入丙酸酐搅拌反应,反应毕,减压浓缩,浓缩残留加水、碳酸钾,用乙酸乙酯萃取,收集有机相浓缩得浓缩物,浓缩物加入四氢呋喃中,氮气保护加入硼烷溶液反应,反应后,再用适宜的单一或混合溶剂对反应物进行萃取,蒸发有机溶剂即得普拉克索游离碱。所用的单一或混合溶剂包括脂肪醇类、醚类、烷烃类、脂肪酸酯类,其中优选烷烃类或脂肪酸酯类。
药物储库层中,压敏胶所选用的基质材料为硅酮类聚合物和不含有官能团的丙烯酸类聚合物,优选硅酮类聚合物,更优选Dow Coring355及Bio-PSA Q7-2920,其用量为药物储库层的50wt%~90wt%。
药物储库层中,经皮吸收促进剂包含有薄荷醇油酸酯、薄荷醇癸酸酯、薄荷醇壬酸酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、丙二醇二壬酸酯、癸二酸二乙酯、癸二酸、二丁酯、吐温20、吐温40、吐温60、吐温80、司盘20、司盘40、司盘60、司盘80、香芹酮、长叶薄荷酮、胡椒酮、薄荷酮、橙花叔醇、香叶醇、桉叶油、土荆芥子油、衣兰油、樟脑、冰片、N-甲基-2-吡咯烷酮、2-吡咯烷酮、1,5-二甲基-2-吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、卵磷脂、豆磷脂、磷脂酰甘油、磷脂酰乙醇胺、磷脂酰胆碱、磷脂酰肌醇、磷脂酰丝氨酸、磷脂酸、鞘磷脂、丙二醇、乙醇的一种或多种,其用量为药物出库层的0.5wt%~10wt%。
背衬层选用织物或非织物,可以为铝聚乙烯复合膜、聚酯类复合膜、聚氨酯膜、聚乙烯单层膜、聚烯烃单层膜、乙烯醋酸乙烯酯膜或弹性无纺布。防粘层为表面经硅油防粘处理或含氟的聚酯膜或纸、氟聚合物涂层聚酯膜离型膜和聚酯氟聚合物涂层聚酯膜离型膜。
制备方法是将主药普拉克索、压敏胶和经皮吸收促进剂充分混合,转移涂布于防粘层上,经过30~80℃干燥,然后用包括铝聚乙烯复合膜或无纺布的裱背材料复合,冲切成一定大小、规格,即得普拉克索透皮贴剂。在本发明中,明确地提供了一种普拉克索透皮贴剂及其制备方法。经皮吸收促进剂选择了有机酸薄荷醇衍生物类。应用于本发明的体外实验皮肤模型为家兔腹部皮肤。本发明的普拉克索透皮贴剂,可通过给药面积的调整控制给药剂量,使疗效持久平稳;若要中断给药,只需揭去贴剂即可,使用方便;本透皮贴剂还具有粘附性、柔顺性好等优点。
应用于本发明的体外实验皮肤模型为家兔腹部皮肤,该皮肤模型在科学研究中已获得广泛地应用,且其角质层厚度与人体相近。试验装置为水平双室扩散池,有效扩散面积为0.95cm2,接收池体积为3.0ml,试验过程中进行持续磁力搅拌,使用外周循环水浴维持体系的温度为32℃。
附图说明
附图1为实施例4、5、6不同压敏胶制得的普拉克索透皮贴剂的透皮曲线,所用皮肤模型为离体家兔腹部皮肤(n=4);
附图2为实施例8、9、10含有不同经皮促进剂的普拉克索贴剂的透皮曲线,所用皮肤模型为离体家兔腹部皮肤(n=4)。
具体实施方式
本发明公开了一种普拉克索透皮贴剂及其制备方法,本领域技术人员可以借鉴本文内容,并对参数进行适当改进。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说都是显而易见的,它们都将被视为包括在本发明范围内。本发明的方法及应用已经通过较佳的实施例进行了描述,相关人员明显能在不脱离本发明的内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合来实现和应用本发明技术。
实施例1
以4,5,6,7-四氢苯并[d]噻唑-2,6-二胺(250g)用水溶解,经酒石酸(150g)拆分得到拆分物80g、拆分物经中加入丙酸酐(60g)搅拌反应,反应毕,减压浓缩,浓缩残留加水、碳酸钾,用乙酸乙酯萃取,收集有机相浓缩得浓缩物(100g),浓缩物加入四氢呋喃中,氮气保护加入硼烷溶液(90ml)反应,反应后,再用正庚烷萃取,蒸发有机溶剂即得普拉克索游离碱(60g),熔点为117~121℃。
实施例2
以4,5,6,7-四氢苯并[d]噻唑-2,6-二胺(25g)用水溶解,经酒石酸(15g)拆分得到拆分物8g、拆分物经中加入丙酸酐(6g)搅拌反应,反应毕,减压浓缩,浓缩残留加水、碳酸钾,用乙酸乙酯萃取,收集有机相浓缩得浓缩物(10g),浓缩物加入四氢呋喃中,氮气保护加入硼烷溶液(10ml)反应,反应后,再用乙酸乙酯萃取,蒸发有机溶剂即得普拉克索游离碱(5.8g),熔点为117~121℃。
实施例3
以4,5,6,7-四氢苯并[d]噻唑-2,6-二胺(25g)用水溶解,经酒石酸(15g)拆分得到拆分物8g、拆分物经中加入丙酸酐(6g)搅拌反应,反应毕,减压浓缩,浓缩残留加水、碳酸钾,用乙酸乙酯萃取,收集有机相浓缩得浓缩物(10g),浓缩物加入四氢呋喃中,氮气保护加入硼烷溶液(10ml)反应,反应后,再用二氯甲烷萃取,蒸发有机溶剂即得普拉克索游离碱(6.2g),熔点为117~120℃。
实施例4
将普拉克索0.1g溶于2.0g乙酸乙酯中,与5g Dwing Coring355压敏胶充分混匀,均匀涂布于防黏层上,经过20、40、80℃阶段干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例5
将普拉克索0.1g溶于2.0g乙酸乙酯中,与5g不含官能团的丙烯酸树脂压敏胶充分混匀,均匀涂布于防黏层上,经过20、40、90℃干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例6
将普拉克索0.1g溶于2.0g乙酸乙酯中,与5g Bio-PSA Q7-2920压敏胶充分混匀,均匀涂布于防粘层上,经过30、50、90℃干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例7
将普拉克索0.1g溶于2.0g二氯甲烷中,与5g Bio-PSA Q7-2920压敏胶充分混匀,均匀涂布于防粘层上,经过30、50、90℃干燥,然后用铝聚乙烯复合膜的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例8
将普拉克索0.1g溶于2.0g正庚烷中,与5g Bio-PSA Q7-2920压敏胶、薄荷醇油酸酯充分混匀,均匀涂布于防粘层上,经过30、50、80℃干燥,然后用铝聚乙烯复合膜的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例9
将普拉克索0.1g溶于2.0g正庚烷中,与5g Bio-PSA Q7-2920压敏胶、棕榈酸异丙酯充分混匀,均匀涂布于防粘层上,经过30、50、80℃干燥,然后用包括无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例10
将普拉克索0.1g溶于2.0g正庚烷中,与5g Bio-PSA Q7-2920压敏胶、橙花叔醇充分混匀,均匀涂布于防粘层上,经过30、50、80℃干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例11
将普拉克索0.1g溶于2.0g正庚烷中,与5g Bio-PSA Q7-2920压敏胶、吐温40、丙二醇充分混匀,均匀涂布于防粘层上,经过30、50、80℃干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例12
将普拉克索0.1g溶于2.0g正庚烷中,与5g Bio-PSA Q7-2920压敏胶、吐温20、卵磷脂充分混匀,均匀涂布于防粘层上,经过30、50、80℃干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
实施例13
将普拉克索0.1g溶于2.0g正庚烷中,与5g Bio-PSA Q7-2920压敏胶、癸二酸二乙酯充分混匀,均匀涂布于防粘层上,经过30、50、80℃干燥,然后用无纺布的裱背材料复合,冲切、规格,即得厚度100μm、面积50cm2的透皮贴剂。
Claims (8)
1.一种普拉克索透皮贴剂,由背衬层、药物储库层及防粘层构成,其特征在于:药物储库层包括主药普拉克索、压敏胶、经皮吸收促进剂,其中普拉克索的用量占1wt%-20wt%,压敏胶的用量占50wt%-90wt%,经皮吸收促进剂用量占0.5wt%-10wt%,所述的压敏胶所选用的基质材料为硅酮类聚合物和不含有官能团的丙烯酸树脂类聚合物。
2.根据权利要求1所述的普拉克索透皮贴剂,其特征在于:所述的普拉克索为普拉克索游离碱。
3.根据权利要求1所述的普拉克索透皮贴剂,其特征在于:所述的药物储库层还含有惰性填充剂、增塑剂、增粘剂或抗氧剂,其用量分别为0.1wt%-10wt%。
4.根据权利要求1所述的普拉克索透皮贴剂,其特征在于:所述的经皮吸收促进剂包含薄荷醇油酸酯、薄荷醇癸酸酯、薄荷醇癸酸酯、油酸、肉豆蔻酸异丙酯、棕榈酸异丙酯、丙二醇二壬酸酯、癸二酸二乙酯、癸二酸、二丁酯、吐温20、吐温40、吐温60、吐温80、司盘20、司盘40、司盘60、司盘80、薄荷醇及其有机酸酯、香芹酮、长叶薄荷酮、胡椒酮、薄荷酮、橙花叔醇、香叶醇、桉叶油、土荆芥子油、衣兰油、樟脑、冰片、N-甲基-2-吡咯烷酮、2-吡咯烷酮、1,5-二甲基-2-吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、卵磷脂、豆磷脂、磷脂酰甘油、磷脂酰乙醇胺、磷脂酰胆碱、磷脂酰肌醇、磷脂酰丝氨酸、磷脂酸、鞘磷脂的一种或多种。
5.根据权利要求1所述的普拉克索透皮贴剂,所述的压敏胶所选用的基质材料为硅酮类聚合物和不含有官能团的丙烯酸类聚合物,优选硅酮类聚合物。
6.根据权利要求1所述的普拉克索透皮贴剂,其特征在于:背衬层所选用的为含铝聚乙烯复合膜,或弹性无纺布。
7.根据权利要求1所述的普拉克索透皮贴剂,其特征在于:防粘层为表面经硅油防粘处理或含氟的聚酯膜或纸。
8.一种如权利要求1所述的普拉克索透皮贴剂的制备方法,其特征在于:将主药普拉克索、压敏胶和经皮吸收促进剂充分混合,转移涂布于防粘层上,经过20℃~80℃程序升温干燥,然后用包括含铝聚乙烯复合膜或无纺布的裱背材料复合,冲切成一定大小、规格,即制成普拉克索透皮贴剂。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112076177A (zh) * | 2020-10-28 | 2020-12-15 | 江苏集萃新型药物制剂技术研究所有限公司 | 一种口腔粘膜给药*** |
CN113171359A (zh) * | 2021-05-08 | 2021-07-27 | 沈阳药科大学 | 川丁特罗透皮贴剂及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1826113A (zh) * | 2003-07-23 | 2006-08-30 | Lts勒曼治疗***股份公司 | 含有普拉克索活性剂的透皮治疗*** |
CN103432104A (zh) * | 2013-08-09 | 2013-12-11 | 大连理工大学 | 一种含有普拉克索的透皮贴剂 |
CN104510725A (zh) * | 2015-01-22 | 2015-04-15 | 中国药科大学 | 一种普拉克索周效透皮贴剂及其制备方法 |
US20160113908A1 (en) * | 2013-05-20 | 2016-04-28 | Mylan, Inc. | Transdermal Therapeutic System for Extended Dosing of Pramipexole in Treating Neurological Disorders |
-
2019
- 2019-03-26 CN CN201910263671.XA patent/CN109999012A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1826113A (zh) * | 2003-07-23 | 2006-08-30 | Lts勒曼治疗***股份公司 | 含有普拉克索活性剂的透皮治疗*** |
US20160113908A1 (en) * | 2013-05-20 | 2016-04-28 | Mylan, Inc. | Transdermal Therapeutic System for Extended Dosing of Pramipexole in Treating Neurological Disorders |
CN103432104A (zh) * | 2013-08-09 | 2013-12-11 | 大连理工大学 | 一种含有普拉克索的透皮贴剂 |
CN104510725A (zh) * | 2015-01-22 | 2015-04-15 | 中国药科大学 | 一种普拉克索周效透皮贴剂及其制备方法 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112076177A (zh) * | 2020-10-28 | 2020-12-15 | 江苏集萃新型药物制剂技术研究所有限公司 | 一种口腔粘膜给药*** |
CN112076177B (zh) * | 2020-10-28 | 2021-08-31 | 江苏集萃新型药物制剂技术研究所有限公司 | 一种口腔粘膜给药*** |
CN113171359A (zh) * | 2021-05-08 | 2021-07-27 | 沈阳药科大学 | 川丁特罗透皮贴剂及其制备方法 |
CN113171359B (zh) * | 2021-05-08 | 2022-11-01 | 沈阳药科大学 | 川丁特罗透皮贴剂及其制备方法 |
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