CN102784143B - 一种含美托洛尔和非洛地平的单层渗透泵控释制剂 - Google Patents
一种含美托洛尔和非洛地平的单层渗透泵控释制剂 Download PDFInfo
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- CN102784143B CN102784143B CN201110125187.4A CN201110125187A CN102784143B CN 102784143 B CN102784143 B CN 102784143B CN 201110125187 A CN201110125187 A CN 201110125187A CN 102784143 B CN102784143 B CN 102784143B
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- metoprolol
- controlled release
- cellulose
- felodipine
- tablet core
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- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 title claims abstract description 28
- 229960003580 felodipine Drugs 0.000 title claims abstract description 28
- 230000003204 osmotic effect Effects 0.000 title claims abstract description 14
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- 238000002360 preparation method Methods 0.000 title abstract description 14
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- 239000003405 delayed action preparation Substances 0.000 claims abstract description 22
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 13
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明属于药物制剂领域,涉及一种含美托洛尔和非洛地平的单层渗透泵控释制剂。具体地,所述控释制剂由片芯和半透性薄膜包衣构成,其中,所述片芯包含如下组分:美托洛尔或其可药用盐50-100重量份,非洛地平5-10重量份,羟丙甲纤维素3-10重量份,聚维酮5-25重量份,羧甲基纤维素钠5-25重量份。本发明还涉及该制剂的制备方法和用途。本发明的控释制剂能够实现美托洛尔和非洛地平的同步恒速释放,并且与将美托洛尔包于丸芯后再与非洛地平共同制备成片剂或制备成双层渗透泵片相比,大大简化了制备工艺。
Description
技术领域
本发明属于药物制剂领域,涉及一种含美托洛尔和非洛地平的单层渗透泵控释制剂。本发明还涉及该制剂的制备方法和用途。
背景技术
高血压是最常见的心血管疾病之一,也是导致充血性心力衰竭、脑卒中、冠心病、肾功能衰竭、主动脉瘤等发病率和病死率升高的主要危险因素。
长期以来,高血压药物治疗采用的阶梯治疗和序贯治疗策略均是以单一药物治疗为基础。单一药物治疗的优点是简便、花费少,但亦有许多缺点:①单一用药一般仅可控制40%-60%甚或更少患者的血压,对重度高血压效果更差;②目前常用药物量效曲线低平,效果不好增加剂量时,疗效增加不多,而副作用可按对数级增加;③药物降压后,机体代偿机制,可产生反调节(Counter regulatory),如交感与RAS系统活化及水钠储留等,可降低甚至抵销降压效果;④患者并存疾病或危险因素常难兼顾,从而限制充足剂量的使用。
近年来,国内外高血压病的防治经验和流行病学、大规模临床试验的科研成果均表明:多种抗高血压药物联合应用可以通过不同的降压途径大大提高血压控制率,并且联用的每种药物剂量皆低于单药治疗,因而又可以大幅度减少各种不良反应的发生。联合用药作为目前临床普遍采用的策略,已成为长期有效实施降压药物治疗的主要手段之一。理论上联合用药有如下优点:(1)作用机制不同的药物降压作用可能累加、协同或互补,有效提高血压控制率,对重度高血压效果更好;(2)小剂量联合可减少单一用药时剂量加大导致的不良作用;(3)并用药物可钝化反调节,互相限制另一药物诱导的不良代偿;(4)有利于兼顾患者存在的多种危险因素与并存疾病;(5)改善患者依从性与生活质量。上述各方面最终均可促进预后改善。
国际上许多大的制药公司已开始在这方面进行了研究。上世纪90年代,瑞典As t ra制药公司据此研发的复方非洛地平一美托洛尔缓释片(Logimax,规格:FEL 5mg/MET 50mg或FEL 10mg/MET 100mg)在国外已成为高血压病的一线治疗药。专利US4942040中公开了一种这种控释制剂及其制备方法,即将难溶性二氢吡啶类药物如非洛地平分散于非离子型表面活性剂中后与包含于丸芯的美托洛尔共同分散于凝胶基质中,压制成片即可。公开号为CN1633994A的专利公开了一种含有非洛地平和美托洛尔的复方经皮控释帖片。
非洛地平(FEL)和美托洛尔(MET)分别属于二氢吡啶类钙拮抗剂和β-受体阻滞剂,其作用机制不同。钙拮抗剂可减少外周阻力,而β-受体阻滞剂主要是降低心率,进而减少心输出量,联用时两药降压有累加作用,并中和彼此触发的反调节机制:如钙拮抗剂可逆转β-受体阻滞剂引起的外周血管收缩和防止心率过缓,而后者可消除前者所致心率加快,对伴心绞痛患者更有利。β-受体阻滞剂与二氢吡啶类钙拮抗剂合用较与非二氢吡啶类钙拮抗剂合用更有利于避免对传导系统的不良作用。FEL和MET合用总有效率显著高于药物单方使用时加量,而副作用的发生率亦显著低于后者。另外,FEL剂量加倍后其费用较合用美托洛尔高许多,非一般患者所能接受,因此从降压疗效及患者的经济承受能力等多方面考虑,FEL与MET合用较药物单方使用时加大剂量治疗高血压更为有效合理。FEL和MET在临床上联用治疗高血压和稳定型心绞痛等心血管疾病的疗效已得到长期认可和广泛应用。
但是,由于没有找到合适种类和含量的粘合剂和助悬剂,以及与之联用的合适种类和含量的助溶剂和促渗透剂,难以实现美托洛尔和非洛地平在单层渗透泵制剂中的同步恒速释放,因此,迄今尚无关于美托洛尔和非洛地平的单层渗透泵制剂的报道。
发明内容
本发明人经过创造性的劳动和大量的试验,发现合适配比的羟丙甲纤维素、聚维酮和羧甲基纤维素钠能够有效地实现美托洛尔和非洛地平的同步释放,并且能够与促渗透剂一起实现这两种主药的恒速释放。特别地,当甲纤维素、聚维酮和羧甲基纤维素钠与合适的增溶剂(例如泊洛沙姆188或十二烷基硫酸钠)联用时,美托洛尔和非洛地平的同步释放达到了十分令人满意的水平。由此提供了下述发明:
本发明的一个方面涉及一种单层渗透泵控释制剂,由片芯和半透性薄膜包衣构成,其中,所述片芯包含如下组分:
不拘于理论的约束,羟丙甲纤维素、聚维酮和羧甲基纤维素钠兼起粘合剂和助悬剂的作用。
根据本发明任一项所述的控释制剂,其中,优选地,所述片芯包含如下组分:
根据本发明任一项所述的控释制剂,其中,所述羟丙甲纤维素优选为HPMC K4M,所述聚维酮优选为PVP K30,所述羧甲基纤维素钠优选为低粘度羧甲基纤维素钠。
在本发明中,术语“低粘度羧甲基纤维素钠”是指这样的羧甲基纤维素钠,当将其配制成浓度为2%的溶液时,溶液粘度为300-600mPa·s。
根据本发明任一项所述的控释制剂,其还包含如下组分:
增溶剂 10-30重量份。
优选地,为10-30重量份。
根据本发明任一项所述的控释制剂,其中,所述增溶剂选自泊洛沙姆、卵磷脂、十二烷基硫酸钠、和聚氧乙烯蓖麻油;优选为泊洛沙姆或十二烷基硫酸钠;更优选为泊洛沙姆188。
根据本发明任一项所述的控释制剂,其满足如下的(1)-(6)项中的任一项或多项:
(1)所述控释制剂还包含如下组分:
促渗透剂 50-110重量份,
其中,所述促渗透剂选自乳糖、甘露醇、果糖、蔗糖、葡萄糖、山梨醇、氯化钾、氯化钠、氯化镁、硫酸钾、硫酸钠、硫酸镁、聚环氧乙烷、聚羟基甲基丙烯酸烷基酯、聚乙烯吡咯烷酮、羧酸聚合物、聚丙烯酸、以及聚环氧乙烷聚合物中的一种或多种,其中优选的是乳糖;优选地,所述促渗透剂为50-110重量份;
(2)所述控释制剂还包含如下组分:
填充剂 10-20重量份,
其中,所述填充剂选自淀粉、预胶化淀粉、糊精、糖粉、乳糖、甘露醇、微晶纤维素、硫酸钙、碳酸钙、以及葡萄糖中的一种或多种;
(3)所述控释制剂还包含如下组分:
润滑剂 5-10重量份,
其中,所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、氢化植物油、滑石粉、微粉硅胶、石蜡中的一种或多种;
(4)所述美托洛尔或其可药用盐选自美托洛尔、酒石酸美托洛尔、琥珀酸美托洛尔、以及富马酸美托洛尔;
(5)所述半透性薄膜包衣重量为片芯重量的3%-20%,优选为5%-15%,更优选为10%;
(6)所述半透性薄膜包衣上带有一个或多个释药孔,所述释药孔是在片芯的一侧或两侧机械钻孔或激光打孔。
根据本发明任一项所述的控释制剂,其中,所述半透性薄膜包衣的包衣液中每100ml包衣液中非挥发性成分组成为(重量/mg)或体积/ml):
根据本发明任一项所述的控释制剂,其满足如下的(1)-(4)项中的任一项或多项:
(1)所述包衣材料选自醋酸纤维素、甲基纤维素、乙基纤维素、丙酸纤维素、琥珀酸酯醋酸羟甲基纤维素、聚邻苯二甲酸乙酸乙烯酯、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙甲纤维素酯、聚碳酸酯、醋酸纤维素酞酸酯、羟丙甲基纤维素酞酸酯、聚乙烯、聚乙烯醇、以及乙烯基乙酸酯中的一种或多种;
(2)所述增塑剂选自邻苯二甲酸甲酯、柠檬酸酯、邻苯二甲酸乙酯、柠檬酸三乙酯、甘油三醋酸酯、蓖麻油、乙酰化甘油酸酯、硅油、司盘、甘油、丙二醇、甘油酯、琥珀酸酯、苯甲酸酯、磷酸酯、己二酸酯、酒石酸酯、以及分子量400-10000(优选分子量4000-6000)的聚乙二醇中的一种或多种;
(3)所述致孔剂选自分子量4000-6000的聚乙二醇(例如PEG4000、PEG6000)、羟丙甲基纤维素、聚乙烯醇、尿素、司盘、甘油、丙二醇、中的一种或多种;
(4)所述着色剂选自水溶性色素、水不溶性色素、色淀中的一种或多种,例如柠檬黄、或者氢氧化铝、滑石粉或硫酸钙吸附各类色素而成的色淀。
根据本发明任一项所述的控释制剂,其组分及含量如下面的(1)-(3)组中的任一组所示:
(1)
(2)
(3)
本发明的另一方面涉及本发明中任一项所述的控释制剂的制备方法,包括下述步骤:
(1)将美托洛尔、非洛地平、羟丙甲纤维素、聚维酮、羧甲基纤维素钠、增溶剂、促渗透剂、填充剂以等量加减法混和,过筛,充分混匀,用乙醇和水混合溶液制软材,20目制粒,40℃-55℃(优选45℃)烘干,加润滑剂,18目整粒,充分混匀,压成片芯;
(2)将包衣材料、致孔剂、着色剂与增塑剂溶于丙酮-水的混合溶媒中,将片芯置于包衣锅或流化床内进行包衣;
(3)将包衣片在30-50℃条件下干燥8-24小时使包衣膜固化;和
(4)使用机械钻孔或激光打孔机在片芯的一侧或者两侧制备一个或多个直径0.05-1.0mm的小孔。
本发明的还一方面涉及本发明中任一项所述的控释制剂在制备治疗高血压、心绞痛、心律失常、肥厚型心肌病、或甲状腺机能亢进的药物中的用途。
本发明的还一方面涉及一种治疗和/或预防高血压、心绞痛、心律失常、肥厚型心肌病、或甲状腺机能亢进的方法,包括给予有效量的本发明中任一项所述的控释制剂的步骤。
本发明控释制剂的用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的疾病和该疾病的严重程度,患者的年龄、体重、一般健康状况、性别和饮食,治疗持续时间以及医疗领域公知的类似因素。
发明的有益效果
本发明的控释制剂能够实现美托洛尔和非洛地平的同步恒速释放,并且与将美托洛尔包于丸芯后再与非洛地平共同制备成片剂或制备成双层渗透泵片相比,大大简化了制备工艺。
附图说明
图1:实施例1所制备渗透泵片的体外累积释放曲线。
图2:实施例2所制备渗透泵片的体外累积释放曲线。
图3:实施例3所制备渗透泵片的体外累积释放曲线。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。其中,实施例中所用CMC-Na为安徽山河药用辅料股份有限公司生产的低粘度羧甲基纤维素钠。
实施例1:控释制剂样品1的制备
片芯处方以1000片计,
衣膜处方(对应于100ml包衣液),
制备方法如下:
称取处方量主药与辅料HPMC、CMC-Na、PVP、泊洛沙姆、乳糖及微晶纤维素(MCC)以等量递加法充分混合,然后过筛混匀,加入90%乙醇溶液适量,制成合适的软材,20目筛制粒,45℃烘干,加入处方量的硬脂酸镁,18目整粒,充分混匀,颗粒含量检验合格后压片,即得片芯。
称取处方量的聚乙二醇4000,加入处方量的水,充分振摇,使其溶解后,加入处方量的丙酮,混匀后,边搅拌边加入处方量的醋酸纤维素,使其基本溶胀后再加入邻苯二甲酸二乙酯,搅拌使其完全溶解即可。然后在包衣锅中进行包衣,控制衣膜增重在10%左右,烘箱干燥8h-12h后,在包衣片的一侧进行打孔。由此制得样品1。
实施例2:控释制剂样品2的制备
片芯处方以1000片计,
衣膜处方(对应于100ml包衣液),
制备方法参照实施例1,得到样品2。
实施例3:控释制剂样品3的制备
片芯处方以1000片计,
衣膜处方(对应于100ml包衣液),
制备方法参照实施例1,得到样品3。
实施例4:样品1-3的释放度试验
分别将实施例1-3中所制备的样品1-3放置于900ml含0.5%SDS的水溶液中,50rpm 37℃桨法进行渗透泵片的释放度试验,分别于2、4、8、12、24h取样5ml,并补充5ml的新鲜介质。然后HPLC法测定不同时间点样品的浓度,计算累积释放百分率。所测定的药物浓度-时间曲线分别如附图1-3所示。
由附图1-3可见,本发明的控释制剂中的两种主药美托洛尔和非洛地平能够恒速同步释放。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (11)
1.一种单层渗透泵控释制剂,由片芯和半透性薄膜包衣构成,其中,所述片芯包含如下组分:
其中,
所述增溶剂选自泊洛沙姆、卵磷脂、十二烷基硫酸钠和聚氧乙烯蓖麻油,
所述促渗透剂选自乳糖、甘露醇、果糖、蔗糖、葡萄糖、山梨醇、氯化钾、氯化钠、氯化镁、硫酸钾、硫酸钠、硫酸镁、聚环氧乙烷、聚羟基甲基丙烯酸烷基酯、聚乙烯吡咯烷酮、羧酸聚合物、聚丙烯酸以及聚环氧乙烷聚合物中的一种或多种;
所述半透性薄膜包衣重量为片芯重量的3%-20%,
所述半透性薄膜包衣的包衣液中每100ml包衣液中非挥发性成分组成为:
2.根据权利要求1所述的控释制剂,其中,所述羟丙甲纤维素为HPMC K4M,所述聚维酮为PVP K30,所述羧甲基纤维素钠为低粘度羧甲基纤维素钠。
3.根据权利要求1所述的控释制剂,其中所述增溶剂为泊洛沙姆或十二烷基硫酸钠。
4.根据权利要求1所述的控释制剂,其中所述增溶剂为泊洛沙姆188。
5.根据权利要求1所述的控释制剂,其满足如下的(1)-(6)项中的任一项或多项:
(1)所述促渗透剂是乳糖;
(2)所述控释制剂还包含如下组分:
填充剂 10-20重量份,
其中,所述填充剂选自淀粉、预胶化淀粉、糊精、糖粉、乳糖、甘露醇、微晶纤维素、硫酸钙、碳酸钙以及葡萄糖中的一种或多种;
(3)所述控释制剂还包含如下组分:
润滑剂 5-10重量份,
其中,所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、氢化植物油、滑石粉、微粉硅胶、石蜡中的一种或多种;
(4)所述美托洛尔或其可药用盐选自美托洛尔、酒石酸美托洛尔、琥珀酸美托洛尔以及富马酸美托洛尔;
(5)所述半透性薄膜包衣重量为片芯重量的5%-15%;
(6)所述半透性薄膜包衣上带有一个或多个释药孔,所述释药孔是在片芯的一侧或两侧机械钻孔或激光打孔。
6.根据权利要求1所述的控释制剂,其中,所述半透性薄膜包衣重量为片芯重量的10%。
7.根据权利要求1所述的控释制剂,其满足如下的(1)-(4)项中的任一项或多项:
(1)所述包衣材料选自醋酸纤维素、甲基纤维素、乙基纤维素、丙酸纤维素、琥珀酸酯醋酸羟甲基纤维素、聚邻苯二甲酸乙酸乙烯酯、羟乙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙甲纤维素酯、聚碳酸酯、醋酸纤维素酞酸酯、羟丙甲基纤维素酞酸酯、聚乙烯、聚乙烯醇以及乙烯基乙酸酯中的一种或多种;
(2)所述增塑剂选自邻苯二甲酸甲酯、柠檬酸酯、邻苯二甲酸乙酯、柠檬酸三乙酯、甘油三醋酸酯、蓖麻油、乙酰化甘油酸酯、硅油、司盘、甘油、丙二醇、甘油酯、琥珀酸酯、苯甲酸酯、磷酸酯、己二酸酯、酒石酸酯以及分子量400-10000的聚乙二醇中的一种或多种;
(3)所述致孔剂选自分子量4000-6000的聚乙二醇、羟丙甲基纤维素、聚乙烯醇、尿素、司盘、甘油、丙二醇中的一种或多种;
(4)所述着色剂选自水溶性色素、水不溶性色素、色淀中的一种或多种。
8.根据权利要求1所述的控释制剂,其中,所述着色剂为柠檬黄、或者氢氧化铝、滑石粉或硫酸钙吸附各类色素而成的色淀。
9.根据权利要求1所述的控释制剂,其片芯的组分及含量如下面的(1)-(3)组中的任一组所示:
(1)
(2)
(3)
10.根据权利要求9所述的控释制剂,其中,(1)-(3)组中所述MCC的型号独立地为pH-101。
11.权利要求1至10中任一项所述的控释制剂的制备方法,包括下述步骤:
(1)将美托洛尔、非洛地平、羟丙甲纤维素、聚维酮、羧甲基纤维素钠、增溶剂、促渗透剂、填充剂以等量加减法混和,过筛,充分混匀,用乙醇和水混合溶液制软材,20目制粒,烘干40℃-55℃,加润滑剂,18目整粒,充分混匀,压成片芯;
(2)将包衣材料、致孔剂、着色剂与增塑剂溶于丙酮-水的混合溶媒中,将片芯置于包衣锅或流化床内进行包衣;
(3)将包衣片在30-50℃条件下干燥8-24小时使包衣膜固化;和
(4)使用机械钻孔或激光打孔机在片芯的一侧或者两侧制备一个或多个直径0.05-1.0mm的小孔。
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