CN1205629A - 一种难溶碱性药物的控释制剂 - Google Patents
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Abstract
一种用于减少每日服用次数的口服,固体,控释药物组合物,其治疗成分是一种难溶的碱性药物。该制剂使用了一种水溶性藻酸盐,藻酸复盐和有机羧酸与本治疗药物混合物。也描述了具体实施方案,该方案包括克拉霉素一日一次的剂型。
Description
发明领域
本发明涉及一种用于减少每日服用次数的、控制缓释制剂的口服剂型,它至少由一种难溶碱性药物组成的。更具体地说,本发明涉及服法为一日一次的克拉霉素制剂。发明背景
控释制剂的出现给制药工业带来了效益。控释制剂使减少药物服用次数成为可能,尤其是口服给药的门诊病人。
对于门诊病人来说,减少药物服用次数的优点在于方便,更重要的是更好地保证了病人按医嘱服药。举例来说,药物服用次数的减少从一天四次(q.i.d.)到一天三次(t.i.d.),为使得病人能够在清醒时间服药。药物服用次数减少至一日两次(b.i.d.)允许病人早晚服药,这带来了很大的方便,例如,病人离家在外就不必另外再带药了。当然,最方便服用形式是一日一次。遗憾的是,大多数药物的药代动力学性质(例如,吸收,清除和代谢)使它们不易被制成单一的口服制剂,不能24小时保持有效的控释并且具有重现性的生物利用度。
一种用于改进控制缓释固体制剂的方法指包含一种藻酸盐凝胶的改良制剂。典型的是,这种水溶性藻酸盐例如藻酸钠和钙盐中的钙离子,它们通过反应与藻酸盐交联变成一种不溶的藻酸钙凝胶。将强酸加入藻酸钠和钙盐的混合物,钙盐将缓慢离子化产生钙离子。接着钙离子与可溶性藻酸盐反应形成一种不溶性藻酸钙凝胶。凝胶化作用通过钙盐缓慢离子化完成。对于这些制剂成分,藻酸盐凝胶控释性质随藻酸盐分子量,藻酸盐浓度,多价阳离子交联剂类型或阳离子浓度的不同而不同。
欧洲专利188040-B1和它的同族美国专利4,842,866描述了一种改良凝胶型藻酸盐组合物,它能缓慢溶解于体液,例如胃肠道液体,包括至少一种治疗活性药物的有效剂量,它能以藻酸盐水合物的形式缓慢释放,其特征在于制剂中不仅有水溶性藻酸盐,尤其是藻酸钠的参与,也有藻酸复盐,尤其是藻酸钙钠的参与,这种复盐中一种阳离子单独存在产生可溶性藻酸盐,另一种阳离子单独存在产生不可溶性藻酸盐。将该U.S.专利的公开内容,U.S.4,842,866,全文引做参考。
然而,上述专利中改良技术末被发现用于水溶性差的药物。例如,药物体外释放研究中观察到克拉霉素藻酸盐制剂的体外释放较慢,类似地,红霉素体内动物实验表明具有重现性生物利用度的控释制剂不可能用藻酸盐或其他任何整体水凝胶片剂。由此可得出结论大环内酯类药物例如红霉素的单体水凝胶片剂不会产生合适的控释剂量,这是由于该药物的酸不稳定性,难溶性和可变性胃肠道转运作用。
日本公开专利163823/1985报道了一种生物利用度得到改善的口服制剂,该制剂包括6-O-甲基红霉素A和柠檬酸,在WPI登记号85-247033/40有摘要。
本发明的目的是用控释制剂减少水溶性差的碱性药物每日服用次数。
本发明通过将有机酸和药物结合制成藻酸盐制剂克服了难溶碱性药物释放慢和潜在难吸收及可变吸收的问题。
发明概述
本发明通过将有机酸掺入藻酸盐骨架减少了难溶碱性药物每日服用次数。进入大肠远端(pH8.0)时,碱性药物溶解度降低;而它在胃中及小肠上部或近端是可溶的。因此难溶碱性药物会导致更少的药物可被用于肠的低端和远端吸收。该制剂中有机酸的存在解决了这个问题。只要不被特定的理论约束,可以认为含有有机酸的该制剂造成了一种低pH值的微环境,从而在药物到达胃肠道时增加该制剂中药物溶解度。
本发明包括一种适用于口服给药的固体控释药物组合物,它包括:
至少一种碱性药物的有效治疗剂量,该碱性药物水中的溶解度少于1∶30;
水溶性藻酸盐;
藻酸复盐和用于促进碱性药物溶解的适量有机羧酸。
本发明特殊的方面在于服法为一日一次的克拉霉素制剂,而目前根据细菌感染类型不同每天服用两次250mg或500mg片剂。体内吸收克拉霉素的确切部位还不确定。然而,众所周知克拉霉素在胃部(pH=1.2)易溶,在小肠上部(pH=5.0)最易吸收的部位也有一定的溶解度。由于该药物在肠的下端pH6至8溶解度降低,这会减少药物吸收。本发明提供了一种解决该问题的途径,即使用含有机酸的藻酸盐制剂,尤其是,例如使用柠檬酸。
本发明的另一特殊方面在于该组合物的组成,该组合物是一种适用于口服每天一次的固体控释制剂,它包括:
约500mg克拉霉素;
约75~400mg藻酸钠;
约10~400mg藻酸钠钙,约128mg柠檬酸。优选实施方案详述
本发明的目的是提供一种控释药物组合物,该组合物中难溶碱性药物在通过胃肠道时能持续释放。
本发明提供了一天服用一次的药物的给药方案,该组合物中至少有一种难溶碱性药物,对于需要的病人来说,该固体控释制剂适于口服。优选该药物组合物片剂形式。
难溶性或少量水溶性碱性药物的溶解度少于1∶30。本发明使用了更低溶解度的药物,例如,溶解度最高到1∶10,000。
少量水溶性碱性药物可能包括下列抗生素,例如,磺胺甲噁唑水中溶解度为1∶3,400;四环素,1∶2,500;甲硝唑和西米替丁(组胺H2受体阻滞剂,治疗溃疡),约1∶100~1∶1000;吲达帕胺(抗高血压药/利尿药),小于1∶10,000;阿替洛尔(抗高血压药),约1∶30~1∶100;安定(镇静药),1∶1,000~1∶10,000。
作为优选碱性药物,本发明包括难溶于水的大环内酯类药物。例如,红霉素,溶解度为1∶1,000;地红霉素,溶解性与红霉素相似;交沙霉素,麦迪霉素,吉他霉素,三者在水中溶解度很小,约1;1,000~1∶10,000;泰洛星,兽药,溶解度为约1∶100到1∶1,000。其他的大环内酯类药物包括例如罗红霉素,罗他霉素,竹桃霉素,美地霉素,氟红霉素,罗沙米星,阿奇霉素,及化合物ABT-229和ABT-269。本发明首选的大环内酯类药物是克拉霉素,它的溶解度约为1∶1,000。
本发明的药物组合物包括其他与难溶碱性药物结合的药物,不论这种联合治疗是必需的还是有益的。
因此,举例来说,大环内酯类药物,红霉素或克拉霉素可以与常规治疗胃炎,溃疡,胃食管返流疾病(GERD)的药物结合做成制剂,像包括抗溃疡和抗胃炎的药剂;例如,从抑制胃分泌的药物中选择,如奥美拉唑、西米替丁、雷尼替丁、兰索拉唑、泮托拉唑、硫糖铝、法莫替丁、尼扎替丁、或抗酸剂,像氢氧化镁、氢氧化铝、碳酸钠、碳酸氢钠、二甲硅油、氢氧化镁铝或其水合物(像其-水合物,即镁加铝)。
本发明药物组合物中另一些大环内酯类药物,尤其是红霉素或克拉霉素,它们适合与一种制剂联合服用,这种制剂包括铋盐,像碱式柠檬酸铋、碱式水杨酸铋、碱式碳酸铋、碱式硝酸铋、碱式棒酸铋。
该药物组合物中药物占总组合物或片剂的约40~75%。对于克拉霉素,该数值优选超过50%,最高达到75%(重量)。
该制剂的释放速度由以一种水溶性藻酸盐和藻酸复盐为基础制成的骨架控制。
尽管本发明中正常情况下使用藻酸钠,也可用其他阳离子代替钠离子;例如,钾离子或其他碱金属离子,镁离子,铵离子,它们均可产生可溶性藻酸盐。因此藻酸盐也可以是例如藻酸钾或藻酸铵。
该藻酸复盐是藻酸钠钙,其中钙的量应精确控制,不需与胃酸反应或另加钙离子就能自身凝胶化。尽管本发明中正常情况下使用藻酸钠钙,也可用其他阳离子代替钠离子产生可溶性藻酸盐;例如,钾离子或其他碱金属离子,镁离子,铵根离子,也可用其他多价阳离子(镁离子除外)代替钙离子产生不溶性藻酸盐;例如,锶离子、铁离子、钡离子。优选制剂包括藻酸钠,例如由英国Alginate Industries有限公司出品,商标为“Manucol”,藻酸钠钙,由美国圣地亚哥、加利福尼亚Merk公司Kelco部出品,商标为“Kelset”,
可溶性藻酸盐与藻酸复盐的重量比例范围是约16∶1~1∶1,优选约8∶1~2∶1,藻酸钠与藻酸钠钙的重量比例与此相同。上述可溶性藻酸盐与复盐结合形成不溶性盐用来做控释制剂,这项技术在欧洲专利188040中有描述。
本发明控释制剂中所需有机酸的量用于在水合物周围产生pH值低于7.0的低pH值微环境。从另一角度来看,适量有机酸促进碱性药物经过胃肠道时溶解。对于本领域的技术人员来说,酸量的多少由所选酸和碱性药物而定。该比例为克分子比例,酸与药物的比例范围是约0.2∶1~5∶1,优选1∶1。
本发明所用有机酸包括任何有机酸羧酸,优选C3~C20脂肪族羧酸,例如,优选酒石酸、苹果酸、琥珀酸、戊二酸、谷氨酸、马来酸、扁桃酸、柠檬酸。最优选柠檬酸。
本发明具体优选实施方案是适合于口服的固体控释制剂,服法为一日一次,它包括:
约500mg克拉霉素;
约75~400mg藻酸钠;
约10~400mg藻酸钠钙,约128mg柠檬酸。
该组合物优选约80~200mg藻酸钠和约10~40mg藻酸钠钙。首选约120mg藻酸钠和15mg藻酸钠钙。
该组合物在剂型方面优选片剂,也可选胶囊或丸剂/颗粒剂。
根据本发明制剂中其他成分通常包括药用赋形剂,如防腐剂、稀释剂;例如,淀粉或微晶纤维素;粘合剂如淀粉、聚乙烯吡咯烷酮(povidone)、羧甲基纤维素钠;助流剂或润滑剂,如滑石粉和硬脂酸镁;填充剂如乳糖;着色剂。制剂也可包衣,包衣材料不特别为药物释放的控制和改进而设计。
该药物可被制成片剂、栓剂或用于填充胶囊。该制剂可能应需要被包衣,例如为了掩盖一种苦味制剂。
通过实例,对于一种成功的服法为一日一次的制剂来说含500mg克拉霉素本发明代表制剂的生物利用度达到了可接受的标准。这意味着它的曲线下面积AUC0-24至少相当于250mg一日两次(BII)服法的曲线下面积,克拉霉素的24小时血浆浓度与250mgBID服法相似。实施例
实施例1
片剂制备详述1a.控释颗粒
所有片剂都按下述常规制备方法制备。将主药、聚合物、粘合剂和剩余赋形剂通过850微米孔的筛,除去大的附聚物。然后将过筛的原料放入行星式搅和机最低速干燥搅拌5分钟。向混合后的原料中加入少量50/50(v/v)乙醇溶液和水使原料颗粒化直到获得合适的颗粒为止。将湿粒通过4.0mm孔筛到衬着纸的盘子里,放入50℃热气加热炉中干燥直到颗粒中水分含量少于4%(w/w)(用Sartorious IR balance测量。型号:YTC01L。条件:98℃,15分钟)。最后干粒通过850微米孔筛,用行星式搅和机将干粒与片剂润滑剂混合,最低速,5分钟。1b.压片
用旋转压片机压片,使片适合卵形冲头。制剂A,B,C分别被压缩达到能产生合适厚度和脆碎度的片剂抗碎强度。片剂组合物的组成见下表1。
表1
制剂 A B C成分 mg/片 mg/片 mg/片克拉霉素 500 500 500无水柠檬酸(美国药典标准) 128 128 128藻酸钠 80 120 180藻酸钠钙 10 15 22.5乳糖300目 100 100 100Providonc K(29-32) 30 30 30纯净滑石粉 30 30 30硬脂酸 21 21 21硬脂酸镁 10 10 10
实施例2
生物利用度研究2a.原料和设备
上述制剂A,B,C每天服用一次(QD),每次500mg,将这三种制剂的稳态血浆浓度与市场出售的BIAXINR 250mg片剂作比较,这种片剂每天服用两次作为对照(即250mg一日两次,本文指制剂D)。成功的QD制剂的可接受标准是:
至少与一日两次(BID)每次250mg的AUC0-24相等。
克拉霉素24小时的血浆浓度与250mg,BID相等。2b.实验设计与结果
本实验为工期临床多剂量给药、随机分布、分四步进行、平衡、交叉实验。合适的病人根据其完整的病史、物理检查和化验指标包括血液学、肾脏、肝脏参数评价结果筛选。
年龄在18~50岁的男性志愿者8名,在四个试验期的每一期的第1,2,3天的早晨服药。制剂D(BIAXINR克拉霉素250mg)也在四个试验期的每一期的第1,2,3天的晚上服用实验结束前每个被试者都服用了所有的制剂。
收集服药第三天(0小时)以前的血样,及服药后1,2,3,4,6,8,10,12,16,24小时的血样。所有的样品转移到肝素化的收集管里,离心。将分离出的血浆分流成相同的体积转移到相应标记的试管中,立即冷冻。血浆样品保持冰冻直到检测为止。
利用大型薄层生物分析法分析血浆样品。这种方法测定总抗生素活性,以克拉霉素,mcg/mg的形式表示结果。2c.数据与统计学分析
上述三种服法为一日一次的制剂的常规片剂的生物等值通过两个单侧-t-检验来评价。用24小时的AUC、Cmax、血药浓度的自然对数计算90%置信区域。通过将平均对数差的90%置信限的终点指数化获得这些数据。如果界限值位于0.80~1.25的范围内,就可推出制剂之间的生物等值。另外,通过分析未转换的AUC和24小时血药浓度获得平均数比率的90%置信限。分析结果见表3,4,5。药代动力学数据见表2。表2药代动力学数据
*由于血浆抽样不足以监测第二种常规片剂,因此将AUC0-12值乘以2得到AUC0-24。
参数 | 制剂D(250mg BID) | 制剂A | 制剂B | 制剂C |
AUC0-24mcg.h/ml(范围) | 32.16*(25.66-42.70) | 31.44(21.16-38.50) | 32.32(24.65-40.78) | 28.69(24.61-32.74) |
Cmaxmcg/ml(范围) | 2.28(1.49-3.34) | 2.42(1.53-3.26) | 2.41(1.81-3.07) | 2.00(1.62-2.40) |
Tmax小时(范围) | 2(1-4) | 6(3-8) | 6(3-8) | 6(4-10) |
24小时浓度mcg/ml(范围) | 0.72(0.53-1.05) | 0.57(0.33-0.91) | 0.65(0.30-0.87) | 0.66(0.37-0.91) |
表3统计学分析/AUC结果
制剂 | AUC0-24(mcg.h/ml) | 相对生物利用度(90%置信限) | |
未转换数据 | Ln转换数据 | ||
A | 31.44 | 0.98(0.86-1.10) | 0.98(0.84-1.14) |
B | 32.32 | 1.01(0.88-1.14) | 1.01(0.88-1.16) |
C | 28.29 | 0.89(0.80-0.98) | 0.90(0.80-1.02) |
表4统计学分析/Cmax结果
制剂 | AUCmaxmcg/ml | 相对生物利用度(90%置信限) | |
未转换数据 | Ln转换数据 | ||
A | 2.42 | 1.06(0.86-1.26) | 1.07(0.87-1.32) |
B | 2.41 | 1.06(0.86-1.26) | 1.08(0.90-1.31) |
C | 2.00 | 0.88(0.75-1.01) | 0.90(0.76-1.06) |
表5统计学分析/24小时浓度结果
2d.讨论
制剂 | AUCmaxmcg/ml | 相对生物利用度(90%置信限) | |
未转换数据 | Ln转换数据 | ||
A | 0.57 | 0.79(0.62-0.99) | 0.79(0.63-0.99) |
B | 0.65 | 0.90(0.79-1.01) | 0.89(0.68-1.15) |
C | 0.66 | 0.92(0.76-1.08) | 0.90(0.71-1.15) |
90%置信限的平均AUC比率表明与常规用法相比服用制剂A,B,C是生物等效的。所有三种制剂表明了C24小时的治疗水平。对于大多数制剂来说Cmax极限(未转换)是可接受的。与常规制剂相比所有三种一日一次制剂证明了克拉霉素的吸收延迟了。
制剂A和B,尽管包含不同数量的藻酸盐,但产生相似的体内特征。然而,以前的研究表明通过增加藻酸盐的数量来改善释放特征的重现性。因此制剂B的总结果最好。
上述说明、实施例、数据提供了本发明组合物完整的制备和用途。因为本发明中的许多具体实施例在不违反本发明的性质和范围情况下可以做到,因而本发明范围见后面的权利要求。
Claims (19)
1.一种适合于口服的控释、固体药物组合物,包括:
至少一种水中溶解度小于1∶30的碱性药物的有效治疗剂量;
一种水溶性藻酸盐;
一种藻酸复盐,和
一种有效剂量的有机羧酸以促进碱性药物的溶解。
2.权利要求1的组合物,是片剂形式。
3.权利要求1的组合物,为一日一次服法的剂型。
4.权利要求1的组合物,其中该碱性药物是大环内酯类。
5.权利要求4的组合物,其中该大环内酯类药物是克拉霉素。
6.权利要求1的组合物,其中该水溶性藻酸盐是藻酸钠。
7.权利要求1的组合物,其中该藻酸复盐是藻酸钠钙。
8.权利要求1的组合物,其中该有机羧酸选自酒石酸、苹果酸、琥珀酸、戊二酸、谷氨酸、马来酸、扁桃酸、柠檬酸。
9.权利要求8的组合物,其中有机羧酸是柠檬酸。
10.权利要求1的组合物,其中可溶性藻酸盐与藻酸复盐的重量比例约为16∶1~1∶1。
11.权利要求10的组合物,其中藻酸钠与藻酸钠钙的重量比例约为16∶1~1∶1。
12.权利要求11的组合物,其中藻酸钠与藻酸钠钙的重量比例约为8∶1~2∶1。
13.权利要求1的组合物,其中有机羧酸与碱性药物的克分子比例约为0.2∶1~5∶1。
14.权利要求1的组合物,其中有机羧酸与碱性药物的克分子比例约为1∶1。
15.权利要求1的组合物,其中碱性药物选自磺胺异恶唑、甲硝唑、西米替丁、吲达帕胺、阿替洛尔、安定。
16.权利要求4的组合物,其中大环内酯类药物选自红霉素、地红霉素、阿其霉素、罗红霉素、ABT-229。
17.一种适合于口服的服法为一日一次的控释、固体药物组合物,包括:
约500mg克拉霉素;
约75~400mg藻酸钠钙和约128mg柠檬酸。
18.权利要求17的组合物,包括:
约80~200mg藻酸钠,约10~40mg藻酸钠钙。
19.权利要求18的组合物,包括:
约120mg藻酸钠,和约15mg藻酸钠钙。
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- 1996-11-25 DE DE69600620T patent/DE69600620T2/de not_active Revoked
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