CN114681419A - 一种丙戊酰胺缓释片的组合物及其制备方法 - Google Patents
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Abstract
本发明属药物制剂技术领域。本发明提供了一种每日服用一次的抗癫痫药丙戊酰胺的肠溶缓释制剂。该制剂为缓释骨架片芯加肠溶包衣缓释片的形式。其中片芯骨架缓释材料为纤维素衍生物，特别是纤维素醚，例如HPMC、CMC、MC、HPC，包衣隔离层含有胃溶HPMC、HPC、PEG、PVP、AEA中的一种或几种，肠溶层含有肠溶HPMC、丙烯酸树脂、PAP、CAP等中的一种或几种。本发明的制剂便于患者服用，副作用少。
Description
技术领域
本发明属于医药领域，涉及一种丙戊酰胺缓释片的组合物及其制备方法。
背景技术
丙戊酰胺系丙戊酸的前体药物，在体内代谢成丙戊酸而发挥治疗作用，故其临床用途与丙戊酸相同，也是用于癫痫病的治疗。据报道，丙戊酸的半衰期在成人中为6-17小时，在儿童中为4-14小时。这导致药物的血浆浓度有相当大的波动、尤其在长期给药时更是如此。为了维持适当稳定的血浆浓度，就需要频繁服药，这经常使得患者对处方规定的给药方案不太适应。此外，该药物血浆浓度的广泛波动可使得在保守给药方案中施用的量低于药物治疗量，或者在激进治疗中施用的量对于特定患者来说太高。为了克服该缺点，人们付出了一致努力并发现了在给药后能保持更恒定的药物血浆水平的丙戊酸制剂。这些研究的最终目标是在每天一次的给药方案中获得稳定的血浆水平。这些努力一般属于下述两类中的一类：(a)发现能更缓慢地代谢以释放到体内的活性组分形式，和(b)发现能通过定时或受控制的释放机制释放药物的制剂。但丙戊酰胺系难溶性药物，而一般难溶性药物采用单纯的缓控释技术（骨架或膜控技术）往往难以得到理想的缓控释制剂,专利US 4913906采用天然蛋白质来控制丙戊酰胺的释放速度，以制备其缓控释制剂，但由于天然蛋白质（大豆蛋白）稳定性差，以此制备的缓控释制剂稳定性不符合成药性要求，没有实际应用意义。
发明内容
本发明的目的是克服上述不足之处而研制开发缓释制剂。
本发明提供了一种每日服用一次的丙戊酰胺缓释片。本发明的片剂含有：
(1)由丙戊酰胺和下列赋形剂组成的片芯
丙戊酰胺 300mg
HPMC-K4M 70-90mg
MCC 20-30 mg
乳糖 30-40mg
PVP-K30 12-15mg
MS 7-10mg
多库酯钠 15-25mg
(2)含有胃溶HPMC和PEG及滑石组成的普通薄膜包衣层：
胃溶HPMC 25-35mg
PEG 2.0-2.5mg
滑石(100目) 5-8mg
(3)含有肠溶型丙烯酸树脂和邻苯二甲酸酯及滑石组成的肠溶包衣层：
肠溶型丙烯酸树脂 20-60mg
PEG 2.5-4mg
滑石(100目) 7-10mg
丙戊酰胺肠溶缓释片的制备方法包括下列步骤：
(1)：将丙戊酰胺、HPMC-K4M、MCC、乳糖、多库酯钠(或吐温-80、十二烷基硫酸钠)等混合，采用PVP-K30乙醇或水溶液制粒，干燥，过筛；
(2)：将步骤(1)获得的颗粒与MS混合；
(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度6-8kg 的圆形或椭圆形片剂；
(4)：或将主药与与多种赋形剂混合，直接压片。
(5)：将胃溶HPMC，PEG，滑石混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；
(6)：将肠溶丙烯酸树脂，PEG（或柠檬酸三乙酯、邻苯二甲酸酯、甘油），滑石混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
本发明涉及这种骨架片的制备，通过湿法制粒以在活性成分周围产生良好溶解的亲水性环境，完成该制粒阶段后，将混合物压片。
本发明涉及骨架片芯，主药与骨架材料及多种赋形剂用粘合剂一起制成粒状而形成包含全部活性成分的颗粒；以颗粒压制成的片芯包含颗粒，调味剂等可有可无的其他赋形剂；本发明包衣层包括普通薄膜衣层和肠溶衣层。
缓释骨架片芯，延长并控制释放，并与血药浓度相关性良好。
活性成分从凝胶中释放出来，很多聚合物都可形成这种凝胶，主要的种类是纤维素衍生物，特别是纤维素醚，例如羟丙甲纤维素，羧甲基纤维素，甲基纤维素，羟丙基纤维素。
普通薄膜衣层和肠溶衣层的工艺基本相似。
本发明通过增塑剂等改善衣层的光滑度和圆整度,增塑剂降低包衣缺陷的发生率。
薄膜衣的粗糙度随所用溶液的粘度增加而增加，与聚合物型号有关。
氧化钛及二氧化钛能够增加薄膜衣缺陷的发生率，添加剂的加入使薄膜内部应力增加，薄膜衣的弹性提高。滑石粉能降低薄膜衣缺陷的发生率。颗粒以薄片存在，平行于表面，使衣膜表面的皱缩受到限制。
肠溶包衣层含有肠溶聚合物，本发明选择聚合物是丙烯酸树脂。可将肠溶聚合物用水悬浮，在水或有机溶剂中的溶液或以粉末的形式作为包衣进行涂附。
当以含水悬浮液的形式涂附肠溶聚合物时，宜选择细颗粒级的聚合物，或在涂附前将聚合物颗粒研磨至极细，悬浮液保持均匀，避免聚合物聚集，悬浮液的温度不宜太高，临界温度可以抵达35℃。在使用丙烯酸树脂的情况下，优选增塑剂是PEG。
本发明使用表面活性剂如多库酯钠、吐温-80、十二烷基硫酸钠等来改善丙戊酰胺的亲水性，从而使丙戊酰胺能够均匀溶解扩散到溶出介质中。优选表面活性剂多库酯钠。
通常在肠溶层中加入粉末状赋形剂如滑石粉或水合二氧化硅，以增加衣层的厚度，使其坚固，减少静电荷以及降低颗粒的粘合力。可将含量为最终产物的约1％至约5％的上述固体加入肠溶聚合物混合物中，而肠溶聚合物本身的含量通常为约3％至约15％，更优选为6％至10％。
本发明提供了300mg丙戊酰胺的每日给药一次的缓释片剂，具有低服用频率，副作用少的优点。
附图说明
附图1为实施例1～5在PH6.8磷酸盐介质中的释放曲线。
具体实施方式
实施例1
300mg丙戊酰胺缓释片
骨架片芯
丙戊酰胺 300mg
HPMC-K4M 70mg
MCC 30 mg
乳糖 40mg
PVP-K30 12mg
MS 7mg
多库酯钠 15mg
普通薄膜衣层
胃溶HPMC 25mg
PEG 2.0mg
滑石(100目) 5mg
肠溶衣层
肠溶型丙烯酸树脂 20mg
邻苯二甲酸酯 2.5mg
滑石(100目) 7mg
生产方法：
(1)：将丙戊酰胺、HPMC-K4M、MCC、乳糖、多库酯钠等混合，采用PVP-K30乙醇或水溶液制粒，干燥，过筛；
(2)：将步骤(1)获得的颗粒与MS混合；
(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度6-8kg 的圆形或椭圆形片剂；
(4)：或将主药与与多种赋形剂混合，直接压片。
(5)：将胃溶HPMC，PEG，滑石混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；
(6)：将肠溶丙烯酸树脂，邻苯二甲酸酯，滑石混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
PH6.8磷酸盐介质中释放曲线见附图1。
实施例2
300mg丙戊酰胺缓释片
骨架片芯
丙戊酰胺 300mg
HPMC-K4M 90mg
MCC 20mg
乳糖 30mg
PVP-K30 15mg
MS 10mg
吐温-80 20mg
普通薄膜衣层
胃溶HPMC 35mg
PEG 2.5mg
滑石(100目) 8mg
肠溶衣层
肠溶型丙烯酸树脂 60mg
柠檬酸三乙酯 4mg
滑石(100目) 10mg
生产方法：
(1)：将丙戊酰胺、HPMC-K4M、MCC、乳糖等混合，采用PVP-K30与吐温-80的乙醇或水溶液制粒，干燥，过筛；
(2)：将步骤(1)获得的颗粒与MS混合；
(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度7-9kg 的圆形或椭圆形片剂；
(4)：或将主药与与多种赋形剂混合，直接压片。
(5)：将胃溶HPMC，PEG，滑石混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；
(6)：将肠溶丙烯酸树脂，柠檬酸三乙酯，滑石混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
PH6.8磷酸盐介质中释放曲线见附图1。
实施例3
300mg丙戊酰胺缓释片
骨架片芯
丙戊酰胺 300mg
HPMC-K4M 70mg
MCC 30 mg
乳糖 40mg
PVP-K30 12mg
MS 7mg
十二烷基硫酸钠 25mg
普通薄膜衣层
胃溶HPMC 25mg
PEG 2.0mg
滑石(100目) 5mg
肠溶衣层
肠溶型丙烯酸树脂 20mg
甘油 3.0mg
滑石(100目) 7mg
生产方法：
(1)：将丙戊酰胺、HPMC-K4M、MCC、乳糖、十二烷基硫酸钠等混合，采用PVP-K30的乙醇或水溶液制粒，干燥，过筛；
(2)：将步骤(1)获得的颗粒与MS混合；
(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度5-7kg 的圆形或椭圆形片剂；
(4)：或将主药与与多种赋形剂混合，直接压片。
(5)：将胃溶HPMC，PEG，滑石混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；
(6)：将肠溶丙烯酸树脂，甘油，滑石混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
PH6.8磷酸盐介质中释放曲线见附图1。
实施例4
300mg丙戊酰胺缓释片
骨架片芯
丙戊酰胺 300mg
HPMC-K4M 80mg
MCC 26 mg
乳糖 35mg
PVP-K30 13mg
MS 8mg
多库酯钠 25mg
普通薄膜衣层
胃溶HPMC 25mg
PEG 2.5mg
滑石(100目) 7mg
肠溶衣层
肠溶型丙烯酸树脂 40mg
PEG 4mg
滑石(100目) 9mg
生产方法：
(1)：将丙戊酰胺、HPMC-K4M、MCC、乳糖、多库酯钠等混合，采用PVP-K30乙醇或水溶液制粒，干燥，过筛；
(2)：将步骤(1)获得的颗粒与MS混合；
(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度6-8kg 的圆形或椭圆形片剂；
(4)：或将主药与与多种赋形剂混合，直接压片。
(5)：将胃溶HPMC，PEG，滑石混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；
(6)：将肠溶丙烯酸树脂，PEG，滑石混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
PH6.8磷酸盐介质中释放曲线见附图1。
实施例5
300mg丙戊酰胺缓释片
骨架片芯
丙戊酰胺 300mg
HPMC-K4M 80mg
MCC 26 mg
乳糖 35mg
PVP-K30 13mg
MS 8mg
多库酯钠 20mg
普通薄膜衣层
胃溶HPMC 25mg
PEG 2.5mg
滑石(100目) 7mg
肠溶衣层
肠溶型丙烯酸树脂 40mg
PEG 4mg
滑石(100目) 9mg
生产方法：
(1)：将丙戊酰胺、HPMC-K4M、MCC、乳糖、多库酯钠等混合，采用PVP-K30乙醇或水溶液制粒，干燥，过筛；
(2)：将步骤(1)获得的颗粒与MS混合；
(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度7-9kg 的圆形或椭圆形片剂；
(4)：或将主药与与多种赋形剂混合，直接压片。
(5)：将胃溶HPMC，PEG，滑石混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；
(6)：将肠溶丙烯酸树脂，PEG，滑石混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
PH6.8磷酸盐介质中释放曲线见附图1。
根据上述实例制备片剂，按中国药典所述片剂质量标准进行质量控制，并按稳定性实验原则进行稳定性考察，结果表明，片剂稳定性良好。
实验还表明，所述片剂在胃液中2小时内片形完好，接触到小肠的一般条件时，可缓慢释放所含丙戊酰胺。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均包含在本发明的保护范围之内。
Claims (1)
1.一种每日服用一次的抗癫痫药丙戊酰胺肠溶缓释片，其特征在于该片剂含有：(1)由丙戊酰胺和下列赋形剂组成的片芯
丙戊酰胺 300mg
HPMC-K4M 80mg
MCC 26 mg
乳糖 35mg
PVP-K30 13mg
MS 8mg
多库酯钠 20mg
(2)包衣层
普通薄膜衣层
胃溶HPMC 25mg
PEG 2.5mg
滑石(100目) 7mg
肠溶衣层
肠溶型丙烯酸树脂 40mg
PEG 4mg
滑石(100目) 9mg
一种每日服用一次的抗癫痫药丙戊酰胺肠溶缓释片的制备方法，其特征在于该方法包括下列步骤：(1)：将丙戊酰胺，HPMC-K4M，MCC，乳糖，MS，多库酯钠等混合，用PVP-K30乙醇或水溶液制粒，干燥，过筛；(2)：将步骤(1)获得的颗粒与MS混合；(3)：将步骤(2)获得的混合物在压片机上压片，从而获得硬度7-9kg的圆形或椭圆形片剂；(4)：或将主药与多种赋形剂混合，直接压片；(5)：将胃溶HPMC，PEG，滑石粉混合，以水溶解成包衣液，给(3)(4) 步骤获得的片剂包普通薄膜衣；(6)：将肠溶丙烯酸树脂，PEG，滑石粉混合，以水或乙醇溶解，成肠溶包衣液，给步骤(5)所得的片剂包肠溶衣。
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| CN1335769A (zh) * | 1998-12-18 | 2002-02-13 | 艾博特公司 | 双丙戊酸钠的控释制剂 |
| US6419953B1 (en) * | 1998-12-18 | 2002-07-16 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| CN1463697A (zh) * | 2002-06-26 | 2003-12-31 | 常州市第四制药厂 | 氟西汀缓释片 |
| CN106456539A (zh) * | 2013-12-31 | 2017-02-22 | 阿森迪亚制药有限责任公司 | 疏水性化合物的药物组合物 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1335769A (zh) * | 1998-12-18 | 2002-02-13 | 艾博特公司 | 双丙戊酸钠的控释制剂 |
| US6419953B1 (en) * | 1998-12-18 | 2002-07-16 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| CN1463697A (zh) * | 2002-06-26 | 2003-12-31 | 常州市第四制药厂 | 氟西汀缓释片 |
| CN106456539A (zh) * | 2013-12-31 | 2017-02-22 | 阿森迪亚制药有限责任公司 | 疏水性化合物的药物组合物 |
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