CN1193792C - 稳定的口服医药组合物 - Google Patents
稳定的口服医药组合物 Download PDFInfo
- Publication number
- CN1193792C CN1193792C CNB008112517A CN00811251A CN1193792C CN 1193792 C CN1193792 C CN 1193792C CN B008112517 A CNB008112517 A CN B008112517A CN 00811251 A CN00811251 A CN 00811251A CN 1193792 C CN1193792 C CN 1193792C
- Authority
- CN
- China
- Prior art keywords
- weight
- iron sesquioxide
- matrix type
- slow releasing
- releasing preparation
- 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.)
- Expired - Lifetime
Links
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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Abstract
本发明提供了一种稳定的口服医药组合物或制剂，在含有药物、亲水基质和聚环氧乙烷的基质型缓释制剂中，由于加入了黄色三氧化二铁和/或红色三氧化二铁，即使在光照下保存，也可防止其药物释放特性变化。另外，本发明还提供了防止含药物、亲水基质和聚环氧乙烷的基质型缓释制剂在光照下保存后药物释放特性变化的方法。根据本发明，能使制品的保质期变长，制品价格提高。
Description
技术领域
本发明涉及防止含有聚环氧乙烷的基质型缓释制剂中药物释放特性变化的稳定的口服固体医药组合物。本发明还涉及防止含有聚环氧乙烷的基质型缓释制剂中药物释放特性变化的稳定的口服固体医药组合物的制造方法。另外，本发明还涉及防止含有聚环氧乙烷的基质型缓释制剂中药物释放特性变化的方法。
背景技术
在药物领域中，已经开发出各种缓释制剂，患者服用时的药物体内吸收、该制剂释放药物的特性是设计制剂时的重要因素。从药物制剂制造开始到运输、保存、患者服用期间，必须保持从制剂中释放出的药物量是均恒而无变化的，具稳定的释放速率。
然而，本申请公司的研究人员已经制出了各种缓释制剂。尤其在利用形成水凝胶的聚合物作为主要基质的缓释制剂(国际出版物WO94/06414)中，形成水凝胶的聚合物除了能控制药物的释放速度外，还必须和主剂一样稳定，这是不言而喻的。
作为形成水凝胶的高分子物质之一，例如有聚环氧乙烷。该物质是环氧乙烷聚合得到的分子量为数十万到数百万的白色粉末或颗粒状水溶性热塑性树脂，它湿润时有很强的粘性。因此，含有该物质的缓释制剂在消化道内表现出良好的药物释放特性。已知聚合物或用该物质制得的基质的溶蚀(溶解)速度对于该药物的释放速度有很大影响。但是，影响用作缓释制剂基质的聚环氧乙烷稳定性的主要原因，尤其是影响药物释放特性的主要原因还不知道。
本发明者在用聚环氧乙烷作为缓释制剂基质的研究中发现，在光照射下保存后，由聚环氧乙烷制得的基质的溶解(溶出)加快，结果，药物释放速度随时间而加快，药物释放量变化，药物释放特性变化，因此希望防止这些现象的发生。
发明揭示
本发明的目的是提供一种即使在光照下保存、含聚环氧乙烷的基质型缓释制剂中药物释放特性也没有变化的稳定的制剂。本发明的另一个目的是提供一种含有聚环氧乙烷的基质型缓释制剂中药物释放特性没有变化的稳定的制剂的制造方法。本发明的另一个目的是提供一种减少在光照下保存的含有药物和聚环氧乙烷的基质型缓释制剂中药物释放特性变化的方法。
在这些情况下，本发明者作了深入研究，结果发现，在含有聚环氧乙烷的基质型缓释制剂中，如果在药物和聚环氧乙烷中物理混入10％(该用量超过作为着色剂的用量(微量：小于0.1％))的黄色三氧化二铁或红色三氧化二铁(以前用作医药添加物中的着色剂)来制成片剂，则即使在光照下保存，也能防止药物的释放特性变化。本发明者作了进一步研究，发现不仅仅是物理混合，即使对片剂进行包衣，也可减少药物释放特性的变化，从而完成了本发明。关于黄色三氧化二铁和红色三氧化二铁的防止效果的机理还不清楚，但认为不单单是防止聚环氧乙烷的光分解。即，即使在聚环氧乙烷以及聚环氧乙烷制得的基质型片剂中，以10％物理混合入吸收波长400纳米以下的光(UV)、反射波长400纳米以上的光的氧化钛，或是吸收全部(广域)波长的光的药用炭以10％物理混合，也不能减少基质型片剂溶解特性的变化。而且，如果只遮蔽给聚环氧乙烷稳定性带来影响的波长(颜色)，则推测能保持对光的稳定性。然而正相反，即使完全遮蔽了可见光反射或吸收，也不能减少片剂溶解特性的变化。因为聚环氧乙烷水溶液是无色透明的，在可视范围内没能观察到光吸收，因此难以推测在可见光中有影响稳定性的特定波长存在。假设可见光中存在影响稳定性的特定波长，那么如果选择全部反射可见光的添加剂(白色)或全部吸收可见光的添加剂(黑色)，则预计能够得到药物释放特性没有变化的稳定的制剂。然而与之相反，有预想以外的结果。因而，其结果是，尽管关于药物释放特性的变化有光以外的不明原因，但是在至少含有聚环氧乙烷的基质型缓释制剂中将特定量黄色三氧化二铁或红色三氧化二铁混入、或结合包衣等方式制成制剂，对于改变药物释放特性的因素是有效的。因此，1)本发明涉及一种口服的稳定的医药组合物，其特征在于，在含有药物、亲水基质以及聚环氧乙烷的基质型缓冲剂中含有使该制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁。2)本发明还涉及上述1)记载的稳定的口服医药组合物，其中黄色三氧化二铁和/或红色三氧化二铁的合用量为片剂重量的0.3％以上。3)本发明涉及上述1)或2)中记载的稳定的口服医药组合物，其中黄色三氧化二铁的用量为制剂重量的1-20％(重量)。4)本发明还涉及上述1)或2)中记载的稳定的口服医药组合物，其中红色三氧化二铁的用量为制剂重量的5-20％(重量)。5)本发明还涉及一种稳定的口服医药组合物的制备方法，该方法包括在药物、亲水基质和聚环氧乙烷中加入有效量的使基质型缓释制剂稳定的黄色三氧化二铁和/或红色三氧化二铁。6)本发明还涉及上述5)所记载的稳定的口服医药组合物的制备方法，其中用选自薄膜包衣、造粒和混合中的一种或两种以上方法加入黄色三氧化二铁。7)本发明还涉及上述5)或6)所记载的稳定的口服医药组合物的制备方法，其中加入相对于片剂重量为0.3％以上的黄色三氧化二铁和/或红色三氧化二铁。8)本发明还涉及一种通过在含有药物、亲水性制剂和聚环氧乙烷的基质型缓释制剂中加入使上述制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁来防止药物释放特性变化的方法。另外，9)本发明还涉及有效量的黄色三氧化二铁和/或红色三氧化二铁在防止含有药物、亲水基质和聚环氧乙烷的基质型缓释制剂中药物释放特性变化、使制剂稳定中的应用。
具体而言，本发明一方面提供了一种形成水凝胶的稳定的口服医药组合物，其特征在于，它含有使基质型缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁，所述基质型缓释制剂含有
(a)药物，
(b)5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下，和
(c)10-90％重量的聚环氧乙烷，(i)该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或(ii)其粘度平均分子量为2000000或更高，
其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的1-20％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的3-20％重量；或当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.3-2％重量。
本发明另一方面提供了一种制备稳定性有所改善的形成水凝胶的稳定的口服医药组合物的方法，该方法包括将使基质缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁加入基质型缓释制剂中，所述基质型缓释制剂含有：药物；5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下；和，10-90％重量的聚环氧乙烷，该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或其粘度平均分子量为2000000或更高，其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
其中利用造粒或混合的方法，在基质型缓释制剂中加入含量为基质型缓释制剂重量的1-20％重量的所述黄色三氧化二铁或含量为基质型缓释制剂重量的3-20％重量的红色三氧化二铁，或当三氧化二铁在膜包衣中时，加入含量为基质型缓释制剂片剂重量的0.3-2％重量的所述黄色三氧化二铁和/或红色三氧化二铁。
本发明另一方面提供了一种防止药物释放变化的方法，该方法是在基质型缓释制剂中加入使该基质型缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁，
其中所述基质型缓释制剂含有(a)药物，(b)5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下，和(c)10-90％重量的聚环氧乙烷，(i)该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或(ii)其粘度平均分子量为2000000或更高，其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的1-20％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的3-20％重量；或当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.3-2％重量。
本发明还有一个方面涉及一种提高口服组合物的物理稳定性的方法，所述方法包括：混合基质型缓释制剂和使基质型缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁，
其中所述基质型缓释制剂含有(a)药物，(b)5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下，和(c)10-90％重量的聚环氧乙烷，(i)该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或(ii)其粘度平均分子量为2000000或更高，其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的1-20％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的3-20％重量；或当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.3-2％重量。
在本发明中，基质型制剂是指含有聚环氧乙烷作为缓释制剂的基剂、药物和亲水基质分散在聚环氧乙烷中形成的制剂。
作为可用于本发明的药物没有特别限制，只要该药物适用于含有聚环氧乙烷作为基剂成分之一的缓释制剂。这些药物例如有，吲哚美辛、双氯芬酸、双氯芬酸钠、可待因、布洛芬、保泰松、羟布宗、美吡哌唑、阿斯匹林、乙水杨胺、对乙酰氨基酚、氨基比林、非那西丁、丁溴东良菪碱、吗啡、依托多林、喷他佐辛、非诺洛芬钙、萘普生、赛莱奥西(celeoxib)、瓦迪考西(valdecoxib)和反胺苯环醇等消炎、解热、解痉或镇痛药；依托度酸等抗风湿药；异烟肼和盐酸乙胺丁醇等抗结核病药；硝酸异山梨酯、硝化甘油、硝苯啶、盐酸巴尼地平(barnidipine)、盐酸尼卡地平、双嘧达莫、氮力农、盐酸茚诺洛尔、盐酸肼屈嗪、甲基多巴、呋塞米、螺内酯、硝酸胍乙啶、利血平、盐酸氨磺洛尔、赖诺普利、美托洛尔、匹鲁卡品和他尔卡汀(talcaltin)等心血管药；盐酸氯并嗪、盐酸阿米替林、尼蒙普利(nemonapride)、氟哌啶醇、盐酸莫哌隆、奋乃静、地西泮、劳拉西泮、氯氮、阿地唑仑、阿普唑仑、哌醋甲酯、米纳西泮(milnacipran)、培罗西汀(peroxetin)、利培利酮(risperidone)和丙戊酸钠等抗精神病药；甲氧氯普胺、盐酸雷莫特隆(ramosetron)、盐酸格兰思特隆(granisetron)、盐酸奥丹思特隆(ondansetron)和盐酸阿扎思特隆(azasetron)等止吐药；马来那敏、盐酸苯海拉明等抗组胺药；硝酸硫胺、乙酸生育酚、环硫胺、磷酸吡多醛、腺苷钴胺、抗坏血酸和烟酰胺等维生素；别嘌醇、秋水仙碱和丙磺舒等痛风药；左旋多巴和司来吉兰等帕金森药；异戊巴比妥、溴戊酰脲、嘧达唑仑、水合氯醛等催眠镇静药；氟尿嘧啶、卡莫氟、盐酸阿柔比星、环磷酰胺和硫替哌等抗肿瘤药；伪麻黄碱和特非那定等抗变态反应药；苯丙醇胺和麻黄碱等减充血药；醋磺己脲、胰岛素、甲苯磺丁脲、去氮加压素和格列吡嗪等糖尿病药；氢氯噻嗪、泊利噻嗪和氨苯蝶啶等利尿药；氨茶碱、富马酸福莫特罗和茶碱等气管扩张药；磷酸可待因、那可丁、磷酸二甲啡烷和右美沙芬等镇咳药；硝酸喹尼丁、地高辛、盐酸普罗帕酮和普鲁卡因胺等抗心律不齐药；氨基苯甲酸乙酯、利多卡因和盐酸辛可卡因等表面麻醉药；苯妥英、乙琥胺和普里米酮等抗惊厥药；氢化可的松、泼尼松龙、曲安西龙和倍他米松等合成的糖皮质激素类；法莫替丁、盐酸雷尼替丁、西咪替丁、硫糖铝、舒必利、替普瑞酮、谱劳诺托、5-氨基水杨酸、硫氮磺胺吡啶、奥美拉唑和兰索拉唑(lansoprazol)等消化道用药；茚氯秦、艾地苯醌、盐酸硫必利、盐酸二苯美仑和泛酸钙等中枢神经系统药；普伐他汀钠、司伐他汀(simvastatin)、洛伐他汀和阿伐他汀(atorvastatin)等降血脂药；盐酸青霉素、肽磺醋胺、头孢替坦和交沙霉素等抗生素；盐酸他索洛辛(tamsulosin)、甲磺酸多沙唑嗪和盐酸特拉唑嗪等BPH治疗剂；普兰路卡(pranlukast)、扎非路卡(zafirlukast)、沙丁胺醇、氨溴索、布地奈德和瑞普特罗等抗喘药、beraprost钠等前列腺素I诱导代替外周循环改善剂；抗血栓药；降压药；治疗心律失常的药物；糖尿病等各种并发症的治疗剂；消化性溃疡治疗剂；皮肤溃疡治疗剂；高血脂治疗剂；抗喘息药等。药物可以游离体形式或制药上容许的盐形式使用。另外，本发明的药物可单独或两种以上组合使用。
本发明所用药物的配制比例没有特别限制，只要其是药物学上治疗或预防所用的量，较佳的是小于全部制剂的85％(重量)，更好的在80％(重量)以下。
作为本发明中所用的聚环氧乙烷，没有特别限制，只要其能控制制剂的药物释放即可。作为所述聚环氧乙烷(下面简称为PEO)，例如是POLYOXWSR-303(粘度平均分子量为700万，粘度为7500-10000厘泊(1％水溶液25℃))、POLYOXWSRCoagulant(粘度平均分子量为500万，粘度为5500-7500厘泊(1％水溶液25℃))、POLYOXWSR-301(粘度平均分子量为400万，粘度为1650-5500厘泊(1％水溶液25℃))、POLYOXWSR N-60K(粘度平均分子量为200万，粘度为2000-4000厘泊(1％水溶液25℃))(均由Union Carbide制造)、ALKOXE-75(粘度平均分子量为200至250万，粘度为40-70厘泊(0.5％水溶液25℃))、ALKOXE-100(粘度平均分子量为250至300万，粘度为90-110厘泊(0.5％水溶液25℃))、ALKOXE-130(粘度平均分子量为300至350万，粘度为130-140厘泊(0.5％水溶液25℃))、ALKOXE-160(粘度平均分子量为360至400万，粘度为150-160厘泊(0.5％水溶液25℃))、ALKOXE-240(粘度平均分子量为400至500万，粘度为200-240厘泊(0.5％水溶液25℃))(均由明成化学工业公司制得)、PEO-8(粘度平均分子量为170至220万，粘度为20-70厘泊(0.5％水溶液25℃))、PEO-15(粘度平均分子量为330至380万，粘度为130-250厘泊(0.5％水溶液25℃))、PEO-18(粘度平均分子量为430-480万，粘度为250-480厘泊(0.5％水溶液25℃))(均由制铁化学工业公司制造)。另外，作为本发明中采用的PEO，胶凝时粘度高、或粘度平均分子量高的PEO是较好的。上述PEO例如宜表示成在2％水溶液(25℃)中粘度在2000厘泊以上，或平均分子量在200万以上。本发明的PEO可采用分子量、等级等不同的一种或两种以上的组合。
本发明中所用的聚环氧乙烷的配制比例没有特别限制，只要是控制制剂药物释放的用量即可，然而，较佳的是为整个制剂的10-95％(重量)，更佳的为整个制剂的15-90％(重量)。另外，PEO的配制量宜为每单位制剂有约70毫克以上，更好的有100毫克以上。
本发明的口服医药组合物是在含有药物、亲水基质以及聚环氧乙烷的基质型缓释制剂中添加黄色三氧化二铁和/或红色三氧化二铁。该制剂的机理在国际出版物WO94/06414中有所描述。制剂在消化道上部滞留中吸收水分，从而几乎完全凝胶化(有70％以上，较佳有80％以上)，制剂表面受侵蚀溶化并同时向消化道下部移动，通过进一步溶化，药物被持续释放。即使在水分很少的结肠中，药物也可良好而持续的释放吸收，结果实现了持续释放。
作为本发明中采用的亲水基质，没有特别限制，只要其能在本发明所用的聚环氧乙烷凝胶化之前溶解。所述亲水基质宜为使1克该基剂溶解所需的水量为5毫升以下(20±5℃)，更佳的在4毫升(相同温度)以下。所述亲水基质例如是聚乙二醇(例如Macrogol 400、Macrogol 1500、Macrogol 4000、Macrogol 6000、Maerogol 20000(均由日本油脂公司制造))、聚乙烯吡咯烷酮(例如PVPK30(BASF公司制造))等水溶性聚合物；D-山梨糖醇、木糖醇等糖醇；蔗糖、麦芽糖、乳果糖、D-果糖、葡聚糖(例如葡聚糖40)、葡萄糖等糖类；聚氧乙烯氢化蓖麻油(例如CremophorRH40(BASF公司制造))、HCO-40、HCO-60(日光化学公司制造)、聚氧乙烯聚氧化丙二醇(例如，PluronieF68(旭电化公司制造)等)，或是聚氧乙烯脱水山梨糖醇高级脂肪酸酯(例如Tween 80(关东化学公司制造)等)表面活性剂，氯化钠、氯化镁等盐，柠檬酸、酒石酸等有机酸，甘氨酸、β-丙氨酸、盐酸赖氨酸等氨基酸类，甲葡胺等氨基糖类。更佳的是聚乙二醇、蔗糖、聚乙烯吡咯烷酮，还要佳的是聚乙二醇(尤其是Macrogol 6000)。另外，本发明的亲水基质可采用1种或2种以上的组合。
在本发明中，当添加亲水基质时，其配制比例宜为整个制剂的5-80％(重量)，更佳的为整个制剂的5-60％(重量)。
本发明中所用的黄色三氧化二铁或红色三氧化二铁可单独或混合使用。
本发明中所用的黄色三氧化二铁和/或红色三氧化二铁的配制比例没有特别限制，只要其用量使基质型缓释制剂稳定且使药物释放特性不改变即可。该配制比例因种类或添加方法而异，当在基质中物理混合时，该比例宜为制剂总量的1-20％(重量)，更佳的为3-15％(重量)。例如，红色三氧化二铁宜为制剂总量的5-20％(重量)，更佳的为10-15％(重量)。黄色三氧化二铁宜为1-20％(重量)，更佳的为3-10％(重量)。当用薄膜包衣进行配制时，宜为片剂重量的0.3-2％，更佳的为0.5-1.5％。此时，黄色三氧化二铁或红色三氧化二铁在薄膜中的浓度宜为5-50％，更佳的为10-20％。这里所说的“在基质中物理混合”，例如意味着将药物、聚环氧乙烷以及上述三氧化二铁均匀地分散，结果使药物和上述三氧化二铁均匀地分散在作为缓释制剂主要基剂的PEO中的方法。另外，“薄膜包衣”例如是指，例如将上述三氧化二铁溶解或悬浮在羟丙基甲基纤维素等水溶性聚合物溶液中，在制得的片剂上包覆薄膜。本发明的黄色三氧化二铁和/或红色三氧化二铁能存在任何通常的制剂中。例如，可在薄膜包衣的薄膜中、造粒等的颗粒物中或基质中(例如聚环氧乙烷周围)。
作为本发明的减少含有聚环氧乙烷的口服医药组合物的药物释放特性变化的方法，没有特别限制，只要加入上述黄色三氧化二铁和/或红色三氧化二铁即可。例如，可采用薄膜包衣、造粒(颗粒成型)、混合等手段。可采用这些手段中的一种或两种的组合。
在本发明的医药组合物中可根据需要加入其它药学上容许的添加剂。这些添加剂例如是乳糖、甘露糖醇、土豆淀粉、小麦淀粉、水稻淀粉、玉米淀粉、结晶纤维素等赋形剂，羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、阿拉伯胶等粘合剂，羧甲基纤维素、羧甲基纤维素钙、交联的羧甲基纤维素钠等溶胀剂，硬脂酸、硬脂酸钙、硬脂酸镁、滑石、硅铝酸镁、磷酸氢钙、无水磷酸氢钙等润滑剂，水合二氧化硅、轻质无水硅酸、干燥的氢氧化铝凝胶等流化剂，黄色三氧化二铁、三氧化二铁等着色剂，月桂基硫酸钠、蔗糖脂肪酸酯等表面活性剂，玉米蛋白、羟丙基甲基纤维素、羟丙基纤维素等包衣剂，1-薄荷醇、薄荷油、茴香油等香料，山梨酸钠、山梨酸钙、对苯甲酸甲酯、对苯甲酸乙酯等防腐剂，柠檬酸、琥珀酸、富马酸、酒石酸、抗坏血酸及其盐、谷氨酸、谷氨酰胺、甘氨酸、天冬氨酸、丙氨酸、精氨酸及其盐、氧化镁、氧化锌、氢氧化镁、磷酸、硼酸及其盐等缓冲剂，必要时可按需加入1种或2种以上的适量添加剂来配制。
含有本发明医药组合物的医药制剂的制造方法没有特别限制，只要该方法是通常的适合水凝胶制剂的方法。例如，将药物和PEO与黄色三氧化二铁和/或红色三氧化二铁、所希望的亲水基质等各种添加剂配制在一起，压制成形压片，胶囊压制充填，或使混合物溶融后固化挤出成型、喷射成型等。另外，也能在成形后进行通常的糖衣、薄膜包衣等包衣处理。或者，也可以在成形后充填到胶囊中。
实施发明的最佳方式
下面列举比较例、实施例和试验例来进一步详细说明本发明，然而本发明不局限于这些内容。
[比较例]
聚环氧乙烷(PolyoxWSR303) 150(重量份)
Macrogol 6000 30
在研钵中混合聚环氧乙烷和Marcogol 6000，用油压在1吨/冲压下压片，得到直径为8毫米、片剂重量为180毫克的未包衣的片剂。
[实施例1]
聚环氧乙烷(PolyoxWSR303) 150(重量份)
Macrogol 6000 30
在研钵中混合聚环氧乙烷和Marcogol 6000，采用油压在1吨/冲压下压片，得到直径8毫米、重180毫克的片剂。
在88.5克纯化水中溶解8.0克羟丙基甲基纤维素2910(TC-5R)、1.5克Macrogol6000，然后使2.0克黄色三氧化二铁分散在其中，获得包衣液。用薄膜包衣机(HCT-mini，Freund产业公司制造)，在所得未包衣的片剂上以相对于片剂重量为3％的量进行包衣，获得本发明的片剂。
[实施例2]
在实施例1得到的未包衣片剂上用下列包衣液进行薄膜包衣。
在88.5克纯化水中溶解8.0克羟丙基甲基纤维素2910(TC-5R)，1.5克Macrogol6000，然后使2.0克红色三氧化二铁分散在其中，获得包衣液。用薄膜包衣机(HCT-mini，Freund产业公司制造)，在实施例1得到的未包衣的片剂上以相对于片剂重量为3％的量进行包衣，获得本发明的片剂。
[实施例3]
在实施例1得到的未包衣片剂上用下列包衣液进行薄膜包衣。
在88.5克纯化水中溶解8.0克羟丙基甲基纤维素2910(TC-5R)，1.5克Macrogol6000，然后使2.0克黄色三氧化二铁、0.5克氧化钛分散在其中，获得包衣液。用薄膜包衣机(HCT-mini，Freund产业公司制造)，在所得未包衣片剂上以相对于片剂重量为3％的量进行包膜，获得本发明的片剂。
[实施例4]
在实施例1得到的未包衣片剂上用下列包衣液进行薄膜包衣。
在88.5克纯化水中溶解8.0克羟丙基甲基纤维素2910(TC-5R)，1.5克Macrogol6000，然后使2.0克红色三氧化二铁、0.5克氧化钛分散在其中，获得包衣液。用薄膜包衣机(HCT-mini，Freund产业公司制造)，在所得未包衣片剂上以相对于片剂重量为3％的量进行包衣，获得本发明的片剂。
[实施例5]
聚环氧乙烷(PolyoxWSR303) 150(重量份)
Macrogol 6000 30
红色三氧化二铁 20
在研钵中混合聚环氧乙烷、Macrogol 6000和红色三氧化二铁，用油压在1吨/冲压下压片，获得直径8毫米、片剂重量为200毫克的本发明片剂。
[实施例6]
聚环氧乙烷(PolyoxWSR303) 150(重量份)
Macrogol 6000 30
黄色三氧化二铁 20
在研钵中混合聚环氧乙烷、Macrogol 6000和黄色三氧化二铁，用油压在1吨/冲压下压片，获得直径8毫米、片剂重量为200毫克的本发明片剂。
[实施例7]
聚环氧乙烷(PolyoxWSR303) 150(重量份)
Macrogol 6000 30
黄色三氧化二铁 9.5
在研钵中混合聚环氧乙烷、Macrogol 6000和黄色三氧化二铁，用油压在1吨/冲压下压片，获得直径8毫米、片剂重量为189.5毫克的本发明片剂。
[试验例](在光照下的保存稳定性)
将比较例、实施例1-7所得的片剂放入塑料表面皿中，进行光照射。光照射采用ICH指南中提示的选项1(ISO10977中规定的屋外光国际标准D65)，照度总量为120万勒克斯·小时，曝光8周。采用经曝光的片剂以及在遮光条件下保存相同时间的片剂进行以下试验。
基质溶出试验
采用500毫升纯化水作为试验液，根据日本药典溶出试验方法中的方法2(叶片法)，在叶片为200rpm下进行试验。在试验开始6小时后，从瓶中取出片剂，在40℃干燥器中干燥4日，使基质片剂所含水分蒸发。用式(I)从片剂的最初重量与干燥重量的差计算出基质的溶出率(表1)。
基质溶出率＝(最初重量-干燥重量)/最初重量×100 式(I)
表1基质溶出试验结果
溶出率(％)
制剂 遮光 120万勒克斯·小时
比较例1 39.7±0.4 57.4±2.1
实施例1 42.0±0.3 42.6±0.0
实施例2 42.3±1.0 41.5±0.1
实施例3 42.4±0.5 42.8±0.4
实施例4 42.4±0.5 42.8±0.1
实施例5 42.8±0.5 47.7±0.3
实施例6 41.8±0.2 41.6±0.2
实施例7 41.5±0.4 42.8±0.2
(n＝3，平均值±SD)
<结果和讨论>
如表1所示，在不含黄色三氧化二铁和/或红色三氧化二铁的比较例中，预计光照射下基质溶出率增加，药物的溶出速度加快。由于施加了含有黄色三氧化二铁或红色三氧化二铁的薄膜包衣，基质溶出率与遮光条件下保存时达到相同水平。另外，当与黄色三氧化二铁或红色三氧化二铁进行物理混合时，防止了基质溶出率的升高，黄色三氧化二铁的添加尤其显示出有高的防止效果。因此，这些结果暗示，配制了黄色三氧化二铁或红色三氧化二铁的本发明口服医药组合物是稳定制剂，即使在光照射下保存，其药物释放特性也不会变化。
工业上的实用性
本发明的口服医药组合物以及该组合物的制备方法提供了一种稳定的制剂以及制备该稳定制剂的方法，其中在含有聚环氧乙烷的基质型缓释制剂中，即使在光照下保存它的药物溶出特性也不会改变。
由于在本发明的口服医药组合物中通过包衣或物理混合加入了黄色三氧化二铁和/或红色三氧化二铁，因此可防止含有聚环氧乙烷的基质型缓释制剂中药物释放特性发生改变，从而能提供稳定的口服医药组合物及其制造方法。还有，在用混合添加的方法来制备稳定的药物制剂时，由于可在聚环氧乙烷与赋形剂造粒成型的同时添加上述物质，从而能简化生产过程。
另外，本发明的方法能提供防止含有药物、亲水基质和聚环氧乙烷的基质型缓释制剂中药物释放特性变化的方法。
因此，由于缓释制剂的稳定，预计制品的保质期变长，制品价值提高。
Claims (18)
1.一种形成水凝胶的稳定的口服医药组合物，其特征在于，它含有使基质型缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁，所述基质型缓释制剂含有
(a)药物，
(b)5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下，和
(c)10-90％重量的聚环氧乙烷，(i)该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或(ii)其粘度平均分子量为2000000或更高，
其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的1-20％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的3-20％重量；或当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.3-2％重量。
2.根据权利要求1所述的形成水凝胶的稳定的口服医药组合物，其中当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的3-10％重量，所述红色三氧化二铁的含量为基质型缓释制剂重量的5-20％重量。
3.根据权利要求2所述的形成水凝胶的稳定的口服医药组合物，其中所述红色三氧化二铁的含量为基质型缓释制剂重量的10-15％重量。
4.根据权利要求1所述的形成水凝胶的稳定的口服医药组合物，其中当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.5-1.5％重量。
5.根据权利要求4所述的形成水凝胶的稳定的口服医药组合物，其中膜包衣中黄色三氧化二铁和/或红色三氧化二铁的浓度为5-50％。
6.一种制备稳定性有所改善的形成水凝胶的稳定的口服医药组合物的方法，该方法包括将使基质缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁加入基质型缓释制剂中，所述基质型缓释制剂含有：药物；5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下；和，10-90％重量的聚环氧乙烷，该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或其粘度平均分子量为2000000或更高，其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
其中利用造粒或混合的方法，在基质型缓释制剂中加入含量为基质型缓释制剂重量的1-20％重量的所述黄色三氧化二铁或含量为基质型缓释制剂重量的3-20％重量的红色三氧化二铁，或当三氧化二铁在膜包衣中时，加入含量为基质型缓释制剂片剂重量的0.3-2％重量的所述黄色三氧化二铁和/或红色三氧化二铁。
7.根据权利要求6所述的制备稳定性有所改善的形成水凝胶的稳定的口服医药组合物的方法，其中当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的3-10％重量，所述红色三氧化二铁的含量为基质型缓释制剂重量的5-20％重量。
8.根据权利要求7所述的制备稳定性有所改善的形成水凝胶的稳定的口服医药组合物的方法，其中所述红色三氧化二铁的含量为基质型缓释制剂重量的10-15％重量。
9.根据权利要求6所述的制备稳定性有所改善的形成水凝胶的稳定的口服医药组合物的方法，其中当三氧化二铁在膜包衣中，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.5-1.5％重量。
10.根据权利要求9所述的制备稳定性有所改善的形成水凝胶的稳定的口服医药组合物的方法，其中膜包衣中黄色三氧化二铁和/或红色三氧化二铁的浓度为5-50％。
11.一种防止药物释放变化的方法，该方法是在基质型缓释制剂中加入使该基质型缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁，
其中所述基质型缓释制剂含有(a)药物，(b)5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下，和(c)10-90％重量的聚环氧乙烷，(i)该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或(ii)其粘度平均分子量为2000000或更高，其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的1-20％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的3-20％重量；或当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.3-2％重量。
12.根据权利要求11所述的防止药物释放变化的方法，其中当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.5-1.5％重量。
13.根据权利要求11所述的防止药物释放变化的方法，其中膜包衣中黄色三氧化二铁和/或红色三氧化二铁的浓度为5-50％。
14.一种提高口服组合物的物理稳定性的方法，所述方法包括：混合基质型缓释制剂和使基质型缓释制剂稳定的有效量的黄色三氧化二铁和/或红色三氧化二铁，
其中所述基质型缓释制剂含有(a)药物，(b)5-80％重量的亲水基剂，该基剂的溶解度是在20±5℃下使1克所述亲水基剂溶解所需的水量为5毫升或以下，和(c)10-90％重量的聚环氧乙烷，(i)该聚环氧乙烷的2％水溶液在25℃下的粘度为2000cP或更高，或(ii)其粘度平均分子量为2000000或更高，其中所述药物和所述亲水性基剂分散在聚环氧乙烷中，
当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的1-20％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的3-20％重量；或当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.3-2％重量。
15.根据权利要求14所述的提高口服组合物的物理稳定性的方法，其中当三氧化二铁在基质型缓释制剂中物理混合时，所述黄色三氧化二铁的含量为基质型缓释制剂重量的3-10％重量或所述红色三氧化二铁的含量为基质型缓释制剂重量的5-20％重量。
16.根据权利要求15所述的提高口服组合物的物理稳定性的方法，其中所述红色三氧化二铁的含量为基质型缓释制剂重量的10-15％重量。
17.根据权利要求14所述的提高口服组合物的物理稳定性的方法，其中当三氧化二铁在膜包衣中时，所述黄色三氧化二铁和/或红色三氧化二铁的含量为基质型缓释制剂片剂重量的0.5-1.5％重量。
18.根据权利要求14所述的提高口服组合物的物理稳定性的方法，其中膜包衣中黄色三氧化二铁和/或红色三氧化二铁的浓度为5-50％。
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| US14722299P | 1999-08-04 | 1999-08-04 | |
| US60/147,222 | 1999-08-04 |
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| JP (1) | JP3462490B2 (zh) |
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| JP2005162736A (ja) * | 2003-11-10 | 2005-06-23 | Astellas Pharma Inc | 徐放性医薬組成物 |
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| DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
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| JP5849947B2 (ja) | 2010-03-29 | 2016-02-03 | アステラス製薬株式会社 | 放出制御医薬組成物 |
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| KR102027912B1 (ko) | 2011-02-15 | 2019-10-02 | 지엘팜텍주식회사 | 경구투여용 탐술로신 또는 이의 약제학적으로 허용되는 염을 포함하는 서방성 삼중정제 |
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| AR087360A1 (es) | 2011-07-29 | 2014-03-19 | Gruenenthal Gmbh | Tableta a prueba de manipulacion que proporciona liberacion de farmaco inmediato |
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| US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
| BR112015026549A2 (pt) | 2013-05-29 | 2017-07-25 | Gruenenthal Gmbh | forma de dosagem à prova de violação contendo uma ou mais partículas |
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| CA2931553C (en) | 2013-11-26 | 2022-01-18 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
| AU2015261060A1 (en) | 2014-05-12 | 2016-11-03 | Grunenthal Gmbh | Tamper resistant immediate release capsule formulation comprising Tapentadol |
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| AU5652796A (en) * | 1995-04-14 | 1996-10-30 | Pharma Pass Llc | Solid compositions containing polyethyleneoxide and a non-am orphous active principle |
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| Publication number | Publication date |
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| NO20020516L (no) | 2002-02-01 |
| ES2262528T3 (es) | 2006-12-01 |
| HUP0202495A2 (hu) | 2002-11-28 |
| AU769807B2 (en) | 2004-02-05 |
| HUP0202495A3 (en) | 2004-05-28 |
| EP1205190A4 (en) | 2004-01-21 |
| CN1373673A (zh) | 2002-10-09 |
| CA2387705A1 (en) | 2001-02-15 |
| PT1205190E (pt) | 2006-09-29 |
| DE60027728T2 (de) | 2007-04-26 |
| JP3462490B2 (ja) | 2003-11-05 |
| RU2220715C2 (ru) | 2004-01-10 |
| DK1205190T3 (da) | 2006-08-14 |
| PL353154A1 (en) | 2003-10-20 |
| HU229295B1 (en) | 2013-10-28 |
| EP1205190B1 (en) | 2006-05-03 |
| DE60027728D1 (de) | 2006-06-08 |
| NO20020516D0 (no) | 2002-02-01 |
| CA2387705C (en) | 2009-06-30 |
| MXPA02001267A (es) | 2002-08-12 |
| EP1205190A1 (en) | 2002-05-15 |
| WO2001010466A1 (fr) | 2001-02-15 |
| ATE324909T1 (de) | 2006-06-15 |
| NO331834B1 (no) | 2012-04-16 |
| PL200645B1 (pl) | 2009-01-30 |
| KR20020046277A (ko) | 2002-06-20 |
| AU6182100A (en) | 2001-03-05 |
| KR100507400B1 (ko) | 2005-08-10 |
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