CN1183050A - 口服用组合物 - Google Patents
口服用组合物 Download PDFInfo
- Publication number
- CN1183050A CN1183050A CN96193634A CN96193634A CN1183050A CN 1183050 A CN1183050 A CN 1183050A CN 96193634 A CN96193634 A CN 96193634A CN 96193634 A CN96193634 A CN 96193634A CN 1183050 A CN1183050 A CN 1183050A
- Authority
- CN
- China
- Prior art keywords
- monoglyceride
- oral administration
- composition
- mixture
- taste
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
一种口服用组合物,它能出色地掩盖药物的令人讨厌的味道并且具有良好的生物利用度。本发明的口服用组合物由具有令人讨厌味道的药物、胃溶性高分子化合物以及β结晶的单酸甘油酯所组成。
Description
本发明涉及用于具有讨厌味道的药物制剂的组合物，详细地说是涉及出色掩盖药物的令人讨厌的味道、而且具有良好生物利用度的口服用组合物。
过去，一直在寻求为掩盖具有讨厌味道药物的味道而用的各种制剂化方法。
例如，在特开昭49-81526公报中公开了了一种方法，将大环内酯的抗生物质溶解并分散在惰性挥发性有机溶剂中，该惰性挥发性有机溶剂溶解有选自聚乙烯缩乙醛二乙基氨基乙酸酯(以下简称为AEA)、乙酸纤维素二丁基氨基羟丙醚、氨基烷基甲基丙烯酸酯共聚物-E[商品名为奥伊道拉基特E(オイドラギット)]和乙基纤维素的被覆材料聚合物以及选自蜡、高级脂肪酸、高级脂肪酸不溶性盐中的一种或一种以上而制成的，随后将其喷雾干燥，由此生成被覆的大环内酯物系抗生物质颗粒。
另一方面，从药物稳定性的改善、含量均匀均匀性方面来看，有EP 37740专利，它公开一种用于掩盖令人讨厌的味道，但其缺点是仅用蜡掩盖，因此，其溶解性低劣。
作为用于掩盖有令人讨厌味道的碱性药物的味道的药用混合物，例如在EP 69097中所公开的，含有讨厌味道的药物的药物混合物制剂是干燥粉末，这种制剂是制成以含有碱性药物为特征的，高pH下呈不溶解性形态的胶囊。
又，在EP 101418中公开了掩盖其令人讨厌的味道并使其活性物质稳定地控制释放的药物混合物制剂，该药物混合物制剂的特征是含有包覆层的活性物质和以总混合物量的40～90％的碳水化合物、与碳水化合物相关的化合物或它们的化合物混合物控制释放物质并组合而成。
然而，为了溶解包覆剂，例如使用二氯甲烷、氯仿、环己烷、四氯化碳、甲乙酮、丙酮、甲醇、异丙醇等惰性挥发性有机溶剂，因此，必须有除去溶剂的干燥工序。结果，包覆层膜成为多孔，而且在干燥工序中要求时间长，设备、劳动力和费用都大。并且在这种工序中，操作中会有起火和爆炸的危险性，而且，在产品中残留有惰性挥发性有机溶剂，有危害人体健康的影响，在安全性方面有问题。
因此，本申请发明人为了不用惰性挥发性有机溶剂来掩盖碱性药物所具有的令人讨厌的味道，在EP 630233上公开一种由分散或溶解的胃溶性高分子化合物的、40℃～120℃的低熔点物质所构成的复合体、和糖醇以及碱性氯化物所组成的口服用组合物。
本发明人为了获得掩盖具有含有讨厌味道药物的味道、而且具有良好生物利用度的口服用组合物、作了各种研究。作为低熔点物质的单酸甘油酯能出色地形成致密的包膜，而且在肠内易于分解，因此是用于制剂化的良好材料。
又，作为在口内(pH5～8)并不溶解、或难以溶解的材料性质，而在胃内(pH1～4)则快速溶解的材料，胃溶性高分子化合物是有用的。
已知单酸甘油酯具有几种熔点不同的结晶形态，通常，刚制造后的口服用制剂的单酸甘油酯是α-结晶。本发明人发现，当使用α-结晶的单酸甘油酯时，不能长时间充分地掩盖药物的令人讨厌的味道；而意外地发出，当使用β结晶的单酸甘油酯时，能够长时间充分地掩盖药物的令人讨厌的味道，而且发现，由于把β结晶的单酸甘油和胃溶性高分子化合物共同使用时，不仅能极有效地掩盖具有含人讨厌味道的药物的苦味，而且，在胃内能迅速溶解药物，具有良好的生物利用度，基于这种见解而完成本发明。也就是，本发明是由具有令人讨厌味道的药物、胃溶性高分子化合物和β结晶的单酸甘油酯所构成的口服用组合物。
将单酸甘油酯的结晶形态从α结晶转化为β结晶的方法有，例如，将含有单酸甘油酯的造粒物在25℃～60℃，最好35℃～45℃的温度条件下转动和振动的方法。
在本发明中，作为所使用的呈苦味的药物有：红霉素、库拉里斯罗霉素(クラリスロマイシン)、北里霉素、交沙霉素、麦迪霉素、罗西霉素(ロキシスタマイシン)和阿基斯罗霉素(アジスロマイシン)等大环内酯系抗生物质、青霉素衍生物、头孢菌素衍生物等的β-内酰胺系抗生物质、四环素系抗生物质、氯丙嗪等的抗精神药物、洋地黄毒甙等强心剂、安乃近等解热剂、西梅其肼(シメチジン)等抗溃疡剂等。药物的配合量在口服用组合物中1～90重量％，最好占1～60重量％。
在本发明中所使用的单酸甘油酯有例如单甘油硬脂酸酯、单甘油棕榈酸酯、单甘油油酸酯、单甘油辛酸酯、单甘油癸酸酯、单甘油月桂酸酯，最好的是单甘油硬脂酸酯。
在本发明中作为所使用的胃溶性高分子化合物有奥伊道拉基特E(オイドラギットE)、AEA、或它们的混合物，特别优选的是奥伊道拉基特E。
在口服用组合物中的单酸甘油酯的配合量是1～95重量％，最好是20～90重量％。单酸甘油酯和胃溶性高分子化合物的配合比例是99∶1～30∶70，特别优选是90∶10～50∶50。
作为本发明口服用组合物的制造方法如下述。使用在熔点以上加热的单酸甘油酯中分散和溶解胃溶性高分子化合所形成的混合物，将具有令人讨厌味道的药物在高温下造粒后冷却。随后，通过在25℃～60℃、最好35℃～45℃温度条件下转动或振动，即可在短时间内使单酸甘油脂的结晶形从α结晶转化为β结晶。
这里所述造粒方法例如熔融造粒法、加热造粒法或喷雾造粒法。
本发明的口服用组合物可制成单位服用形态例如粒剂、散剂、胶囊剂、片剂、干糖浆剂等口服用制剂，特别以制成干糖浆剂最好。
这样所得的口服用组合物作为医药品使用时按照需要可使用一般制剂所用的其它添加剂。作为添加剂有：赋形剂、崩解剂、粘合剂、润滑剂、抗氧化剂、包衣剂、着色剂、矫味矫臭剂、表面活性剂、增塑剂等。
作为赋形剂有，例如：甘露醇、本糖醇、山梨糖醇、麦芽糖醇、葡萄糖、白糖、乳糖、结晶纤维素、结晶纤维素·羧甲基纤维素钠、磷酸氢钙、小麦淀粉、米淀粉、玉米淀粉、马铃薯淀粉、羧甲基淀粉钠、糊精、α-环糊精、β-环糊精、羧基乙烯聚合物、轻质无水硅酸、氧化钛、氧化镁、氧化铝、氢氧化镁、氢氧化铝、碳酸氢钠、硅酸铝酸镁、聚乙二醇、中链脂肪酸三甘油酯等。
作为崩解剂有：低取代度的羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、克罗斯卡尔梅罗斯钠(トロスカルメロ-ス)·A型(阿克疾早尔)、淀粉、结晶纤维素、羟丙基淀粉、部分α化淀粉等。
作为粘合剂有，例如：甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、明胶、阿拉伯胶、乙基纤维素、聚乙烯醇、普卢兰(プルラン)、α化淀粉、琼脂、塔拉甘特(タラガント)、藻酸钠藻酸丙二醇酯等。
作为润滑剂有，例如：硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酸聚氧(ステア リ ン酸ポリオキシル)、鲸蜡醇、滑石、硬化油、蔗糖脂肪酸酯、二甲基聚硅氧烷、微晶蜡、蜂蜡、白蜡等。
作为抗氧化剂有，例如：二丁基羟基甲苯(BHT)、五倍子酸丙酯、丁基羟基茴香醚(BHA)、α-生育酚、柠檬酸等。
作为包衣剂有，例如：羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素苯二甲酸酯、羟丙基甲基纤维素乙酸盐琥珀酸酯、羧甲基乙基纤维素、乙酸苯二甲酸纤维素、聚乙烯乙缩醛二乙基氨基乙酸酯、氨基烷基甲基丙烯酸酯共聚物、羟丙基甲基纤维素乙酸盐琥珀酸酯、甲基丙烯酸共聚物、纤维素乙酸盐偏苯三酸酯(CAT)、聚乙烯乙酸盐邻苯二甲酸酯、虫胶等。
作为着色剂有，例如，焦油色素(tarchrome)、氧化钛等。
作为矫味矫臭剂有：柠檬酸、己二酸、抗坏血酸、薄荷醇等。
作为表面活性剂有，例如：聚氧乙烯硬化蓖麻油、单硬脂酸甘油酯、单硬脂酸脱水山梨醇、单棕榈酸脱水山梨醇、单月桂酸脱水山梨醇、聚氧乙烯聚氧丙烯嵌段共聚物、聚山梨酸酯类、月桂基硅酸钠、聚乙二醇类、蔗糖脂肪酸酯等。
作为增塑剂有：柠檬酸三乙酯、三醋精、鲸蜡醇等。
利用本发明可制得长时间而持续地掩盖令人讨厌的味道、而且其生物利用度优越的具有令人讨厌味道的药物的口服用制剂。
而且，根据本发明所得的具有令人讨厌味道的药物口服用制剂即使悬浮于水中、在室温下连续保存14天也没有令人讨厌的味道，而且，其生物利用度优越，因此，作为儿童用的干糖浆剂等口服用制剂也很容易服用。
以下列举实施例和试验例，以对本发明具体说明。
实施例1
将单甘油硬脂酸酯600g在约100℃溶解，在其中分散并溶解奥伊道拉基特E100g。而且在该混合物中分散红霉素300g，用喷雾干燥装置在入口温度为80℃、旋转盘转速20000rpm条件下进行了喷雾冷却造粒。其次，将该造粒物用VG涂布机(菊水制作所产品)在夹套温度40℃、旋转数15rpm下转动和振动2小时，得到散剂约950g。在该散剂中，单甘油硬脂酸酯的结晶形态是β结晶。
实施例2
使单甘油硬脂酸酸600g在约100℃溶解，在其中分散溶解奥伊道拉基特E100g。而且在该混合物中分散库拉里斯罗霉素300g，使用喷雾装置，在入口温度80℃、旋转盘转速20000rpm条件下喷雾冷却造粒。然后，将该造粒物用VG涂布机(菊水制作所产品)在夹套温度40℃、旋转数15rpm下转动及振动2小时，得到散剂约950g。在该散剂中，单甘油硬脂酸酯的结晶形态是β结晶。
实施例3
实施例1的散剂333g中加入山梨醇300g、氧化镁20g、淀粉347g，均匀混合。将该混合物在水流化床造粒，得到颗粒剂。
实施例4
实施例1的散剂333g中加入甘露醇500g、氧化镁15g、淀粉152g，均匀混合，将该混合物在水流化床造粒，得到颗粒剂。
实施例5
在实施例1的散剂333g中加入木糖醇450g、氧化镁10g、淀粉162g，均匀混合，将该混合物在水流化床造粒，得到颗粒剂。
实施例6
在实施例2的散剂333g中加入山梨醇300g、甘露醇300g、氧化镁5g、羧甲基纤维素钠10g、结晶纤维素52g，均匀混合，将该混合物在水流化床造粒，得到颗粒剂。
实施例7
在实施例1的散剂333g中加入山梨糖醇300g、甘露醇300g、羧甲基纤维钠10g、淀粉47g，均匀混合。另外，将氧化镁10g悬浮于水中，以此作为粘合溶剂，将上述混合物流化造粒，得到颗粒剂。
实施例8
在实施例2的散剂333g中加入山梨糖醇300g、羧甲基纤维素钠10g、淀粉347g，均匀混合。另外，将氧化镁10g悬浮于水中，以此作为粘合溶剂，将上述混合物流化造粒，得到颗粒剂。
实施例9
在实施例2的散剂333g中加入山梨糖醇400g、木糖醇229g、羧甲基纤维素钠10g、氧化镁5g、羟丙基纤维素20g、糖精钠3g，均匀混合，以水作为造粒溶剂，将上述混合物流化床造粒，得到粒剂。取该粒剂1g，悬浮于约5ml水中，即得到糖浆剂。
实施例10
在实施例2的散剂333g中，加入山梨糖醇300g、甘露醇100g、木糖醇100g、麦芽糖醇100g、羧甲基纤维素钠10g、氧化镁20g、淀粉14g、羟丙基纤维素20g、糖精钠3g，均匀混合，以水作为造粒溶剂，将上述混合物流化造粒，得到库拉里斯罗霉素干糖浆剂。
实施例11
在实施例1的散剂333g中加入甘露醇500g、氧化镁20g、淀粉125g、羟丙基纤维素20g、羧甲基纤维素钠2g，均匀混合，将该混合物在水中流化造粒，得到粒剂。
实施例12
将单甘油硬脂酸酯600g在约100℃溶解，在其中，分散溶解奥伊道拉基特E100g。而且在该混合物中分散红霉素300g，使用喷雾干燥装置，在入口温度80℃，旋转盘转速20000rpm的条件下喷雾冷却造粒。然后，将该造粒物用VG涂布机(菊水制作所产品)，在夹套温度45℃、旋转数15rpm下转动和振动1小时，得到散剂约950g。在这散剂中，单甘油硬酸酯的结晶形态是β结晶，在该散剂333g中加入山梨糖醇300g、甘露醇300g、羧甲基纤维素钠10g、淀粉47g，均匀混合。另外，将氧化镁10g悬浮于水中，以此作为粘合溶剂，将上述混合物进行流化造粒，得到粒剂。
实施例13
将单甘油硬脂酸酯600g在约100℃溶解，在其中分散溶解奥伊道拉基特E100g，而且在该混合物中分散红霉素300g，用喷雾干燥装置，在入口温度70℃、旋转盘转速15000rpm条件下进行喷雾冷却造粒。然后，将该造粒物用VG涂布机(菊水制作所产品)在夹套温度35℃、旋转数15rpm下转动和振动3小时，得到散剂约950g。在该散剂中，单甘油硬脂酸酯的结晶形态是β结晶。然后，在该散剂333g中加入甘露醇300g、羧甲基纤维素钠10g、淀粉347g，均匀混合。另外，将氧化镁10g悬浮于水中，以作为粘合溶剂，将上述混合物进行流化造粒，得到粒剂。
对照例1
使单油硬脂酸酯600g在约100℃下溶解，在其中分散溶解奥伊道拉基特E100g，而且在该混合物中分散红霉素300g，将该混合物使用喷雾干燥装置，在入口温度80℃。旋转盘转速20000rpm条件下进行喷雾冷却造粒，得到散剂约950g，在该散剂中单甘油硬脂酸酯的结晶形态是α结晶。
对照例2
在对照例1的散剂333g中加入山梨糖醇300g、氧化镁20g、淀粉347g，均匀混合，将该混合物在水流化床造粒，得到粒剂。
试验例1
测试样品；实施例1、3～13、对照例1和对照例2所得的口服用制剂。
测试方法：将各测试样品中2g悬浮于5ml水中，将其室温保存的样品给10名健康成人服用，进行苦味评价试验。测定点是：刚调配好、3天后、7天后和14天后。评价时间是：刚服后、1分钟后和10分钟后。作为评价基准有5级：0：完全不感到苦味；1：感到有苦味；2：稍微有些苦；3：苦；4：可忍的苦味；5不可忍的苦味。
结果：结果10人的平均评价，示于表1。各实施例也与对照例相比较，表明它们能极长时间地持续掩盖苦味。
表1
| 调配后 | 3日后 | 7日后 | 14日后 | |||||||||
| 立即 | 1分钟后 | 3分钟后 | 立即 | 1分钟后 | 3分钟后 | 立即 | 1分钟后 | 3分钟后 | 立即 | 1分钟后 | 3分钟后 | |
| 对照例1 | 0 | 0 | 0 | 2 | 2 | 1 | 4 | 4 | 3 | 5 | 5 | 5 |
| 对照例2 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 3 | 2 | 4 | 4 | 4 |
| 实施例1 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 2 | 1 | 1 | 2 | 1 |
| 实施例2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例8 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例11 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例12 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 实施例13 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
试验例2
测试样品：实施例1、3～13所得口服用制剂。
测试方法：对各测试样品进行溶出试验。试验方法按日本11局的溶出试验方法进行。使用的溶出液是pH4.0的乙酸缓冲液。搅拌转速为100rpm，测定其10分钟后的溶出率。
结果如表2所示，各实施例均有良好的溶出率。
表2
| 10分钟 | |
| 实施例1 | 100 |
| 实施例2 | 100 |
| 实施例3 | 100 |
| 实施例4 | 100 |
| 实施例5 | 100 |
| 实施例6 | 100 |
| 实施例7 | 100 |
| 实施例8 | 100 |
| 实施例9 | 100 |
| 实施例10 | 100 |
| 实施例11 | 100 |
| 实施例12 | 100 |
| 实施例13 | 100 |
Claims (5)
1.口服用组合物，其特征在于，由具有令人讨厌味道的药物、胃溶性高分子化合物以及β结晶的单酸甘油酯所组成。
2.按照权利要求1所记载的口服组合物，其特征特在于，在所述的口服用组合物中的单酸甘油酯的配合量是1～95重量％，单酸甘油酯对胃溶性高分子化合物的比例是99∶1～30∶70。
3.按照权利要求1所记载的口服组合物，其特征在于，胃溶性高分子化合物是聚乙烯乙缩醛二乙基氨基乙酸酯、氨基烷基甲基丙烯酸酯共聚物E或它们的混合物，单酸甘油酯是单甘油硬脂酸酯。
4.按照权利要求1所记载的口服组合物，其特征在于，该口服用组合物的单位服用形态是干糖浆剂。
5.使用胃溶性高分子化合物和β结晶形态的单酸甘油酯掩盖具有令人讨厌味道药物的方法。
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| JP108338/1995 | 1995-05-02 | ||
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| CN1183050A true CN1183050A (zh) | 1998-05-27 |
| CN1170596C CN1170596C (zh) | 2004-10-13 |
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| CNB961936347A Expired - Fee Related CN1170596C (zh) | 1995-05-02 | 1996-04-30 | 口服用组合物 |
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| EP (1) | EP0826376B1 (zh) |
| JP (1) | JP3470198B2 (zh) |
| KR (1) | KR100404293B1 (zh) |
| CN (1) | CN1170596C (zh) |
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| AU (1) | AU694655B2 (zh) |
| CA (1) | CA2219991C (zh) |
| DE (1) | DE69636864T2 (zh) |
| DK (1) | DK0826376T3 (zh) |
| ES (1) | ES2279519T3 (zh) |
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-
1996
- 1996-04-30 KR KR1019970707775A patent/KR100404293B1/ko not_active IP Right Cessation
- 1996-04-30 CA CA002219991A patent/CA2219991C/en not_active Expired - Fee Related
- 1996-04-30 EP EP96912281A patent/EP0826376B1/en not_active Expired - Lifetime
- 1996-04-30 DK DK96912281T patent/DK0826376T3/da active
- 1996-04-30 DE DE69636864T patent/DE69636864T2/de not_active Expired - Lifetime
- 1996-04-30 AT AT96912281T patent/ATE352289T1/de active
- 1996-04-30 JP JP53317096A patent/JP3470198B2/ja not_active Expired - Lifetime
- 1996-04-30 ES ES96912281T patent/ES2279519T3/es not_active Expired - Lifetime
- 1996-04-30 CN CNB961936347A patent/CN1170596C/zh not_active Expired - Fee Related
- 1996-04-30 WO PCT/JP1996/001179 patent/WO1996034628A1/ja active IP Right Grant
- 1996-04-30 AU AU55152/96A patent/AU694655B2/en not_active Ceased
- 1996-04-30 US US08/945,822 patent/US5972373A/en not_active Expired - Lifetime
-
1998
- 1998-04-29 HK HK98103648A patent/HK1004372A1/xx not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1343128B (zh) * | 1999-03-17 | 2010-04-21 | 第一制药株式会社 | 药物组合物 |
| CN105142633A (zh) * | 2013-03-26 | 2015-12-09 | 橘生药品工业株式会社 | 西洛多辛苦味被掩蔽的口服给药制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU694655B2 (en) | 1998-07-23 |
| HK1004372A1 (en) | 1998-11-27 |
| WO1996034628A1 (fr) | 1996-11-07 |
| EP0826376A4 (en) | 2004-06-09 |
| DE69636864D1 (de) | 2007-03-15 |
| ES2279519T3 (es) | 2007-08-16 |
| EP0826376A1 (en) | 1998-03-04 |
| CA2219991C (en) | 2007-10-30 |
| CN1170596C (zh) | 2004-10-13 |
| DK0826376T3 (da) | 2007-04-16 |
| EP0826376B1 (en) | 2007-01-24 |
| CA2219991A1 (en) | 1996-11-07 |
| KR19990008249A (ko) | 1999-01-25 |
| JP3470198B2 (ja) | 2003-11-25 |
| KR100404293B1 (ko) | 2004-02-18 |
| US5972373A (en) | 1999-10-26 |
| ATE352289T1 (de) | 2007-02-15 |
| DE69636864T2 (de) | 2007-05-31 |
| AU5515296A (en) | 1996-11-21 |
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