CN101272777B - 螺和二螺1,2,4-三氧戊环抗疟药的稳定剂型 - Google Patents
螺和二螺1,2,4-三氧戊环抗疟药的稳定剂型 Download PDFInfo
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Abstract
本发明涉及含有螺和二螺1，2，4-三氧戊环抗疟药，或其药学上可接受的盐、前药和类似物的稳定剂型，以及其制备方法。该剂型的含水量不超过6.5％w/w。
Description
发明领域
本发明领域涉及含有螺和二螺1，2，4-三氧戊环(trioxolane)抗疟药，或其药学上可接受的盐、前药和类似物的稳定剂型，以及其制备方法。
发明背景
疟疾，这种人类最常见的寄生虫病，在大多数热带国家仍然是主要的健康和经济负担。中南美洲的广阔区域，伊斯帕尼奥拉岛(海地和多米尼加共和国)、非洲、中东、印度次大陆、东南亚和大洋洲被认为是疟疾危险地区。这导致疾病和死亡(尤其是在孩子和孕妇中)的沉重代价。根据世界卫生组织，据估计每年有4亿人感染该疾病，并且每年有大约两到三百万人死于疟疾。有四类感染人类的疟疾寄生虫：恶性疟原虫(Plasmodium falciparum)、间日疟原虫(Plasmodium vivax)、卵形疟原虫(Plasmodium ovale)和三日疟原虫(Plasmodium malariae)。
疟疾通过蚊子的叮咬从一个人传播到另一个人，冈比亚按蚊(Anophelesgambiae)可作为昆虫媒介。当蚊子吸人血时，子孢子与蚊子的唾液一起转移进人血中。子孢子进入肝细胞，进行无性繁殖，最后进入血流。寄生虫在红细胞中继续繁殖，直到红细胞破裂并释放大量的裂殖子。这一过程持续进行，破坏大量的血细胞并引起伴随疾病的特征性阵发(“寒战和发烧”)。在红细胞中，部分裂殖子变为雄性或雌性的配子母细胞。这些配子母细胞在蚊子吸血时被它们所摄取。配子母细胞在该昆虫媒介的消化道内融合；产生子孢子并迁移至昆虫媒介的唾液腺。
疟疾的临床症状一般与红细胞破裂所导致的伴随寒战的高烧有关，这可能使受感染的个体疲惫和卧床不起。与重复感染和/或恶性疟原虫(Plasmodiumfalciparum)感染有关的更严重的症状包含贫血、严重头痛、抽搐、谵妄、和某些情况下的死亡。
奎宁，一种从金鸡纳树的树皮中提取的抗疟化合物，是现存的最古老和最有效的药物之一。氯喹和甲氟喹是20世纪40年代开发出的奎宁的合成类似物，由于它们有效、容易制备和一般不具有副作用，成为可选的药物。奎宁及其衍生物的不足是作用时间短并具有苦味。此外，其未能防治疾病复发，而且通常是认为与“金鸡纳反应综合症(Chinchonism syndrome)”的副作用相关，表现为恶心、呕吐、头晕、眩晕和耳聋。然而近些年来，伴随着寄生虫的药物抗性株和昆虫媒介的杀虫剂抗性株的出现，使这些常规药物对疟疾的治疗和/或控制变得困难。
疟疾治疗的进一步发展是发现青蒿素，一种从植物黄花蒿(Artemisis annua)中分离出的天然存在的内过氧化物倍半萜内酯(Meshnick，S.R.等人，Microbiol.Rev.1996，60，301-315；Vroman J.A.等人，Curr.Pharm.Design，1999，5，101-138；Dhingra V.K.等人，2000，66，279-300)，和大量其前药、代谢产物和半合成衍生物，它们显示出抗疟疾性质。青蒿素的抗疟作用是由于其与疟疾寄生虫的游离血红素分子中的铁反应，随着自由基的产生导致细胞破坏。经过大量的努力以阐明其作用的分子机理(Jefford，C.，Adv.Drug Res.1997，29，271-325；Cumming，J.N.等人，Adv.Pharmacol.1997，37，254-297)并鉴定新的抗疟过氧化物(Dong，Y.和Vennerstrom，J.L.，expert Opin.Ther.Patents2001，11，1753-1760)。
虽然临床上有用的半合成青蒿素衍生物是快速作用和有效的抗疟药物，但它们具有数个缺点，包含复发性、神经毒性(Wesche，D.L.等人，Antimicrob.Agent.Chemother.1994，38，1813-1819)和代谢不稳定(White，N.J.，Trans.R.Soc.Trop.Med.Hyg.，1994，88，41-43)。相当数量的这些化合物在体外颇具活性，但大部分的口服活性较低(White，N.J.，Trans.R.Soc.Trop.Med.Hyg.，1994，88，41-43和van Agtmael等人，Trends Pharmacol.Sci.，1999，20，199-205)。
因此，现有技术中仍然需要鉴定新的过氧化物抗疟药，特别是易于合成、没有神经毒性，以及具有改善的溶解性、稳定性和药代动力学的性质的那些。据此，已制备了许多合成的抗疟药1，2，4-三噁烷(Jefford，C.，Adv.Drug Res.1997，29，271-325；Cumming，J.N.等人，Adv.Pharmacol.1997，37，254-297)，1，2，4，5-四噁烷(Vennerstrom，J.L等人，J.Med.Chem.，2000，43，2753-2758)，和其它内过氧化物。多个专利/申请公开了使用螺或二螺1，2，4-三氧戊环治疗疟疾的手段和方法，例如在美国专利申请2004/0186168、美国专利No.6,486,199和6,825,230中。本申请涉及在这些专利/申请中公开的各种螺或二螺1，2，4-三氧戊环抗疟药化合物的固体剂型，并且将这些专利/申请在此引入作为参考。
活性化合物表示多种螺和二螺1，2，4-三氧戊环衍生物，除了结构简单并易于合成之后，它们具有极好的抗疟原虫属寄生虫的效力和功效，以及低水平的神经毒性们的。此外，与其它青蒿素类药物相比，这些化合物有利地具有据信可允许短期治疗方案的半衰期(half live)。一般而言，三氧戊环衍生物的治疗剂量范围可以为约0.1-1000mg/kg/天，尤其是约1-100mg/kg/天。前述剂量可以作为单一剂量给药或者可以分成多个剂量给药。对于疟疾预防而言，例如典型的给药方案可以是2.0-1000mg/kg/周，从疟疾暴露之前1-2周开始，直至暴露后1-2周。
可是，尽管三氧戊环有很多优点，但对于配制者开发含三氧戊环的制剂时也有一定局限，首先是在水分的存在下，它们的降解易感性导致保存期限的缩短。第二个是它们的苦味，这导致在给药时的顺应性差或者选择另外的、可能较低效果的治疗制剂。
我们现在发现可以通过将含水量控制在低于某一个临界范围可以制备含有螺和二螺1，2，4-三氧戊环稳定的抗疟口服固体制剂。此外，苦味可以通过对固体制剂使用薄膜包衣层来掩饰。
发明概述
在一个总的方面，提供了一种稳定的口服固体剂型，其包含治疗有效量具有式I结构的化合物，及其对映异构体、非对映体、多晶型物、药学上可接受的盐和药学上可接受的溶剂合物；及一种或多种药学上可接受的赋形剂，其中在40±2℃和相对湿度为75±5％下贮藏超过6个月下，该固体剂型形成不超过5％w/w的总有关物质，
式I
其中：
R1、R2可以是相同或不同的，选自氢、取代或未取代的直链或支链烷基、芳基和烷芳基、以及任选地插入一个或多个氧、硫或氮原子的取代或未取代的脂环族基团、可以插入一个或多个氧、硫或氮原子的取代或未取代的芳香族基团或杂环基、羟基或卤素，以及进一步的条件是螺环己基环相连R1、R2可任意插入一个或多个氧、硫或氮原子。
口服固体剂型的实施方案可以包含一个或多个下面的特征。例如，该剂型可以包含一种或多种其它的抗疟药。其它抗疟药可包含奎宁、甲氟喹、本芴醇、磺胺多辛-乙胺嘧啶、二氢青蒿素、喹哌、氯奎、阿莫地喹、白乐君、阿托伐醌、氯白乐君(chloroproguanil)、氨苯砜、膦胺霉素、四环素、DB289(马来酸帕福米定，pafuramidine maleate)、氯林肯霉素、它们的盐及其衍生物。特别地，可以使用喹哌、本芴醇和DB289。
药学上可接受的赋形剂可以包含一种或多种粘合剂、稀释剂、助流剂/润滑剂、崩解剂、表面活性剂和着色剂。
另一方面，提供了治疗有效量具有式I结构的化合物的稳定口服固体剂型，它是通过使用干燥或非水的方法来制备。
固体剂型可以是片剂，而且片剂可以包衣。
在另一个总的方面中，提供了制备稳定的口服固体剂型的方法。该方法包括混合具有式I结构的化合物及一种或多种颗粒内赋形剂；对混合物进行造粒以形成颗粒；将该颗粒与一种或多种颗粒外赋形剂混合；然后压缩混合物成片剂或填入胶囊。
方法的实施方案可以包含一个或多个下面的特征。例如，制粒可以是湿法制粒，而湿法制粒可以包含选自乙醇、异丙醇、丙酮、二氯甲烷和粘合剂溶液的非水制粒液体。制粒也可以是干法制粒，而干法制粒可以是压实或压制。特别地，干法制粒可以是压制，例如干碾压(roller compaction)。
片剂可以被一层或多层薄膜包衣层包衣。
在另一个总的方面中，提供了制备稳定的口服固体剂型的方法。该方法包括混合具有式I结构的化合物及一种或多种药学上可接受的赋形剂；直接压缩混合物成片剂或填入胶囊；在片剂上任选地施用一层或多层薄膜包衣层。
在另一个总的方面中，提供了制备稳定的口服固体剂型的方法。该方法包括对一种或多种赋形剂的混合物进行造粒；干燥赋形剂颗粒；把赋形剂颗粒和具有式I结构的化合物，或包含具有式I结构的化合物的颗粒混合；压缩混合物成片剂或填入胶囊；在片剂上任选施用一层或多层薄膜包衣层。
该方法的实施方案可以包含一个或多个下面的特征。例如，制粒可以是湿法制粒，湿法制粒可以包含选自水、乙醇、异丙醇、丙酮、二氯甲烷和粘合剂溶液的制粒液体。制粒也可以是干法制粒，干法制粒可以是压实或压制。特别地，干法制粒可以是压制法，例如干燥辊子压制法。
在另一个总的方面，提供了预防或治疗疟疾的方法。该方法包括给予一固体剂型，其包含治疗有效量的具有式I结构的化合物及一种或多种药学上可接受的赋形剂，其中该剂型在40±2℃和相对湿度为75±5％下贮藏超过6个月的，产生不超过5％w/w的总的有关物质。
口服固体剂型的实施方案可以包含一个或多个下面的特征。例如，该剂型可以包含一种或多种其它抗疟药。其它抗疟药可包括：奎宁、甲氟喹、本芴醇、磺胺多辛-乙胺嘧啶、二氢青蒿素、喹哌、氯奎、阿莫地喹、白乐君、阿托伐醌、氯白乐君、氨苯砜、膦胺霉素、四环素、DB289(pafuramidine maleate)、氯林肯霉素、它们的盐及其衍生物。特别地，可以使用喹哌、本芴醇和DB289。
在另一个方面中，提供了预防或治疗疟疾的方法。该方法包括给予一固体剂型，其包含治疗有效量的具有式I结构的化合物，该剂型使用干燥或非水的方法制备。
在另一个方面中，提供了稳定的口服固体剂型。该剂型包含治疗有效量的具有式I结构的化合物；至少一种选自本芴醇、喹哌或DB289的其它抗疟药；以及一种或多种药学上可接受的赋形剂。
口服剂型的实施方案可以包含一个或多个下面的特征。例如，剂型的含水量可以至多为6.5％w/w。
在另一个总的方面中，提供了稳定的口服固体剂型。该剂型包含顺式-金刚烷-2-螺-3’-8’[[[(2’-氨基-2’-甲基丙基)氨基]羰基]甲基]-1’，2’，4’-三氧杂螺[4.5]癸烷马来酸氢盐/酯(hydrogen maleate)；喹哌；以及一种或多种药学上可接受的赋形剂。
一个或多个实施方案的详述由下面的说明书给出。本发明的其它特征、目的和益处通过说明书和权利要求将很明显。
发明详述
我们已经发现可以制得螺和二螺1，2，4-三氧戊环抗疟药的稳定口服固体剂型，其不会显著降解并提供可接受的保存期限。
这里使用的术语“稳定的”是指固体剂型中活性化合物对抗保存期限内由于水解发生的分解的化学稳定性，其中在40±2℃和相对湿度为75±5％下贮藏超过6个月，产生不超过5％w/w的总的有关物质。
这里使用的术语“固体剂型”包括片剂或包衣片剂、胶囊、小药丸、丸剂、颗粒、粉末等等。特别合适的固体剂型是片剂。
本发明提供活性化合物的稳定的口服固体剂型，通过使用低水含量的赋形剂和使用干燥或非水制剂方法来制造。
这里使用的术语“活性化合物”包括式I的螺和二螺1，2，4-三氧戊环化合物
式I
其中R1、R2可以是相同或不同，并选自氢、取代或未取代的直链或支链烷基、芳基和烷芳基、以及任选地插入一个或多个氧、硫或氮原子的取代或未取代的脂环基团、插入一个或多个氧、硫或氮原子的取代或未取代的芳香族基团或杂环基、羟基或卤素，以及进一步的条件为螺环己基环相连R1、R2可任意插入一个或多个氧、硫或氮原子。特别地，其包含式I的化合物，其中R1为氢，例如具有式II结构的化合物。
式II
活性化合物包括在美国申请No.2004/0186168、美国专利No.6,486,199和6,825,230中公开的一种或多种不同的螺和二螺三氧戊环衍生物，并在此引入作为参考。这些三氧戊环由于在三氧戊环杂环的至少一侧有相对的空间位阻而提供更好的体内活性，尤其是考虑到口服给药。特别的，螺和二螺1，2，4-三氧戊环衍生物，具有极好的抗疟原虫属寄生虫的效力和功效，以及低水平的神经毒性。
活性化合物包括在此涉及的化合物的游离形式，以及其药学上可接受盐、溶剂合物、酯、对映异构体、非对映体、多晶型物、代谢产物、前药和类似物。特别地，活性化合物为顺式-金刚烷-2-螺-3’-8’[[[(2’-氨基-2’-甲基丙基)氨基]羰基]甲基]-1’，2’，4’-三氧杂螺[4.5]癸烷马来酸氢盐/酯。
通过详尽的试验已经观察到，当将活性化合物制成包括液体和固体剂型在内的剂型时，其通过水解而降解。降解作用可能是由与赋形剂在一起的水或制备过程中添加的水引起的。因而，不能成功制得具有想要的贮存期限的液体口服剂型例如水性糖浆、悬浮液或溶液。此外，采用涉及使用水的技术例如湿法制粒、喷雾干燥、或挤出滚圆方法来制备活性化合物的固体口服剂型，所得到的剂型具有摇摆不定的稳定性结果。可是，当固体制剂使用适当的低含水量赋形剂和诸如干法制粒、直接压缩或非水制粒方法的无水方法来制备时，获得了可接受的稳定性结果。在使用水对赋形剂进行制粒时，赋形剂颗粒可以在与活性化合物或包含活性化合物的颗粒混合前适当地干燥，加工成具有可接受稳定性的固体剂型。
赋形剂和含水量的作用是通过不同比例的活性化合物与各种赋形剂的相容性试验来评估，以及通过在60℃超过2周和50℃的4周的强制降解评估降解程度来评估的。含水量使用卡尔费舍(Karl Fisher)方法来分析以及通过HPLC方法来测定全部有关物质(％w/w)。试验的结果在下面的表1中表示。
表1：活性化合物与各种赋形剂的相容性试验
试验清楚地表明在活性化合物的稳定固体剂型中使用低含水量或湿气量的赋形剂的重要性。在本发明中，我们发现使用含水量少于6.5％w/w的赋形剂令人惊奇地增加了活性化合物的稳定性，以及提供了适当长的贮存期限。当使用较高含量的淀粉时，发现其与活性化合物是不相容的。此外，乳糖也被发现是不相容的，这是由于其通过其它机理例如麦拉德反应(Maillard reaction)所引起的降解作用，并且磷酸二钙也不是优选的，这是由于其在60℃时相关物质增加。然而，微晶纤维素得到最令人满意的结果。
本发明的稳定的口服固体剂型可以进一步包含一种或多种药学上可接受的赋形剂，其包括在制备固体剂型的领域所用的全部生理学上惰性的赋形剂。实例包括粘合剂、稀释剂、助流剂/润滑剂、崩解剂、表面活性剂和着色剂等等。赋形剂可以在微粒内或微粒外使用，或两者都可以。剂型中活性化合物和赋形剂的重量比可以在约1.5∶1到约1∶30之间变化。
“粘合剂”的实例包括甲基纤维素、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、支链淀粉、琼脂、黄蓍树胶、海藻酸钠等等。
“稀释剂”的实例包括粉末状的纤维素、微晶纤维素、葡萄糖结合剂、糊精、葡萄糖赋形剂、果糖、高岭土、拉克替醇、甘露糖醇、山梨糖醇、蔗糖、可压缩的糖、糖膏剂等等。
“崩解剂”的实例包括粘土、纤维素、海藻酸盐/酯、树胶、交联聚合物(例如交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠)、淀粉乙醇酸钠、低取代羟丙基纤维素、大豆多糖等等。
“润滑剂”或“助流剂”的实例包括滑石、硬脂酸镁、硬脂酸钙、硬脂酸、二氧化硅胶体、碳酸镁、氧化镁、硅酸钙、微晶纤维素、矿物油、蜡、山萮酸甘油酯、聚乙二醇、苯甲酸钠、醋酸钠、氯化钠、十二烷基硫酸钠、硬脂酰醇富马酸钠，和氢化植物油，脂肪酸的蔗糖酯、微晶蜡、黄蜡、白蜡等等。
“表面活性剂”的实例包括适用于增甜剂组合物(sweetener composition)的非离子的和离子的(阳离子、阴离子和两性离子)表面活性剂。这些包括聚氧乙基化的脂肪酸和其衍生物，例如聚乙二醇400二硬脂酸酯、聚乙二醇-20二油酸酯、聚乙二醇4-150单二月桂酸酯、聚乙二醇-20硬脂酸甘油酯；醇-油酯交换产物，例如聚乙二醇-6玉米油；聚甘油化的脂肪酸，例如聚甘油-6戊油酸酯(polyglyceryl-6pentaoleate)；丙二醇脂肪酸酯，例如丙二醇单辛酸酯；单和二甘油酯例如蓖麻油酸甘油酯；甾醇和甾醇衍生物；脱水山梨糖醇脂肪酸酯及其衍生物，例如聚乙二醇-20脱水山梨糖醇单油酸酯、脱水山梨糖醇单月桂酸酯；聚乙二醇烷基醚或酚，例如聚乙二醇-20鲸蜡醚、聚乙二醇-10-100壬基酚；糖酯，例如单棕榈酸蔗糖酯；称为“泊洛沙姆”的聚氧乙烯-聚氧丙烯嵌段共聚物；离子型表面活性剂，例如己酸钠、甘氨胆酸钠、大豆卵磷脂、硬脂酰醇富马酸钠、藻酸丙二醇酯、辛基磺基丁二酸二钠、和棕榈酰卡尼丁(palmitoyl carnitine)。
“着色剂”包括FDA批准口服使用的任何颜料。
固体剂型可以进一步用含有成膜聚合物和其它包衣添加剂的一个或多个功能性和/或非功能层所包衣。
“成膜聚合物”的例子包括纤维素衍生物，例如乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、甲基纤维素、羧甲基纤维素、羟甲基纤维素、羟乙基纤维素、部分水解的聚乙烯醇、醋酸纤维素、邻苯二甲酸羟丙基甲基纤维素、邻苯二甲酸醋酸纤维素、乙酸纤维素1，2，4-偏苯三酸酯(cellulose acetate trimellitate)；蜡例如聚乙二醇；甲基丙烯酸聚合物例如Eudragit
RL和RS；等等。或者，也可将以各种商品名(例如Opadry
)市售获得的含有成膜聚合物的包衣组合物用于包衣。
“包衣添加剂”包含增塑剂、助流剂或流量调节剂(flow regulator)、遮光剂和润滑剂。
可以选择药学上可接受的赋形剂和/或成膜聚合物和包衣添加剂，以提供速释特性或缓释特性。
活性化合物的固体剂型可以通过压实活性化合物和一种或多种赋形剂，然后加工成固体剂型来制备。可以通过使用本领域的任何常规方法来致密化。特别的，可以使用制粒或挤压滚圆方法。
在一个实施方案中，活性化合物的稳定的口服片剂可以通过包括以下步骤的方法制得：混合活性化合物和颗粒内部分的稀释剂、润滑剂与崩解剂；将该混合物通过碾压机以形成压紧的团块(mass)；将压紧物粉碎(reducing)为适合大小的颗粒；在双锥混合器中混合该颗粒和颗粒外部分的润滑剂、崩解剂及稀释剂；最后使用合适的工具加工压成片剂。
在另一个实施方案中，活性化合物的稳定的口服片剂可以通过包括以下步骤的方法制得：混合活性化合物和颗粒内部分的稀释剂、润滑剂与崩解剂；在重型压片机(heavy tabletting press)下将混合物压成坯料；将坯料粉碎成适合大小的颗粒；在双锥混合器中混合颗粒和颗粒外部分的润滑剂、崩解剂及稀释剂；最后使用适合的工具加工压成片剂。
在另一个实施方案中，活性化合物的稳定的口服胶囊剂可以通过包括以下步骤的方法制得：混合活性化合物和颗粒内部分的稀释剂、润滑剂与崩解剂；将混合物通过碾压机以形成压紧的团块；将该压紧物粉碎为适合大小的颗粒；在双锥混合器中混合颗粒和颗粒外部分的润滑剂；最后填装入合适尺寸的胶囊。
在另一个实施方案中，活性化合物的稳定的口服胶囊可以通过包括以下步骤的方法制得：混合活性化合物和颗粒内部分的稀释剂、润滑剂与崩解剂；在重型压片机将混合物压紧形成坯料；将该坯料粉碎为适合大小的颗粒；在双锥混合器中混合颗粒和颗粒外部分的润滑剂；最后填装入合适尺寸的胶囊。
在另一个实施方案中，活性化合物的稳定的口服片剂可以通过包括以下步骤的方法制得：混合活性化合物和稀释剂、润滑剂与崩解剂；使用合适的工具加工直接压制成片剂。
在另一个实施方案中，活性化合物的稳定的口服胶囊可以通过包括以下步骤的方法制备：混合活性化合物和稀释剂、润滑剂与崩解剂；填装入合适尺寸的胶囊。
在另一个实施方案中，活性化合物的稳定的口服片剂可以通过包括以下步骤的方法制得：混合活性化合物和颗粒内部分的稀释剂与崩解剂；用非水制粒液体或药学上可接受的赋形剂的非水制粒液体的溶液/分散液对该混合物进行湿法制粒；干燥并将该颗粒粉碎为合适大小；在双锥混合器中混合颗粒和颗粒外部分的润滑剂、崩解剂及稀释剂；最后使用合适的工具加工压成片剂。
而在另一个实施方案中，活性化合物的稳定的口服胶囊可以通过包括以下步骤的方法制得：混合活性化合物和颗粒内部分的稀释剂与崩解剂；用非水制粒液体或药学上可接受的赋形剂的非水制粒液体的溶液/分散液对该混合物进行湿法制粒；干燥并将该颗粒粉碎成合适大小；在双锥混合器中混合颗粒和颗粒外部分的润滑剂；最后填装入合适尺寸的胶囊。
“非水制粒液体”的实例包括有机溶剂，例如甲醇、乙醇、异丙醇、二氯甲烷、丙酮等等。
还在另一个实施方案中，可对使用上述任一方法制备的片剂进一步用成膜聚合物和一种或多种包衣添加剂进行包衣，包衣可使用本领域已知的技术，例如在常规的包衣锅或流化床处理器上的喷雾包衣；或浸渍包衣。或者，包衣也可使用热熔技术来完成。
片剂上的包衣层可以包衣成分在适合溶剂中的溶液/分散液形式施加。用于制备包衣成分溶液/分散液的溶剂的例子包含甲醇、乙醇、异丙醇、正丁醇、丙酮、乙腈、氯仿、二氯甲烷、水等等，及它们的混合物。
而在另一个实施方案中，可将选自喹哌、本芴醇或DB 289(马来酸帕福米定)的一种或多种其它抗疟药添加到任一上述实施方案中含有活性化合物的混合物中。
在此所述的发明通过下面的实施例进一步阐述，其不应当解释为限制本发明范围。
实施例1：
过程：
1.使活性化合物与颗粒内部分的微晶纤维素过筛子BSS#44筛分，然后在双锥混合器中混合，形成均匀的混合物。
2.向步骤1的混合物中加入筛分过的颗粒内部分的硬脂酸镁，然后混合大约5分钟。
3.使步骤2的混合物在碾压机中压紧，然后过筛BSS#22筛分，形成颗粒。
4.使颗粒外部分的微晶纤维素、交联羧甲基纤维素和硬脂酸镁通过筛BSS#44筛分，然后与步骤3的颗粒混合。
5.使用合适尺寸的冲压压紧步骤4的混合物，获得紧压的片剂。
6.使用常规的包衣技术用Opadry对获自步骤5的片剂进行包衣。
使经实施例1制备的片剂在25℃/相对湿度60％、30℃/相对湿度65％和40℃/相对湿度75％下进行超过6个月的稳定性试验。结果总结在表2中。表3中给出了在预定时间段中的体外药物释放的分析结果。
表2：总的有关物质(％w/w)
*总的有关物质(related substance)％应不超过5％
表3：在USP II装置中的体外药物释放百分比(％)(介质：在水中2％的吐温80，900ml，75rpm，45分钟)
*体外药物释放(％w/w)应不超过45分钟内溶解的标示量的70％(Q)。
从上面的实验明显得出，通过本发明方法制备得到的不含水的片剂，表现出可接受的贮存稳定性。
实施例2：
过程：
1.使活性化合物、微晶纤维素、交联羧甲基纤维素钠和硬脂酸镁过筛BSS#44筛分。
2.在双锥混合器中混合筛过的活性化合物、微晶纤维素和交联羧甲基纤维素钠大约15分钟，形成均匀的混合物。
3.向步骤2的混合物中加入筛过的硬脂酸镁，然后混合大约5分钟。
4.将步骤3获得的混合物直接使用适合尺寸胶囊形冲头挤压以获得压紧的片剂。
实施例3和4：
过程：
1.使活性化合物、磷酸喹哌与颗粒内部分的微晶纤维素及交联聚乙烯吡咯烷酮过筛BSS#44筛分，然后在双锥混合器中混合，形成均匀的混合物。
2.向步骤1的混合物中加入筛过的颗粒内部分的硬脂酸镁，然后混合大约5分钟。
3.使步骤2的混合物在碾压机中压紧，然后过筛BSS#18筛分，形成颗粒。
4.使颗粒外部分的微晶纤维素和交联聚乙烯吡咯烷酮过筛BSS#44筛分，然后与步骤3的颗粒混合。
5.使颗粒外部分的硬脂酸镁过筛BSS#44筛分，并与步骤4的混合物混合，在双锥混合器中混合约5分钟。
6.使用合适尺寸的冲头压紧步骤5的混合物，获得紧压的片剂。
7.用Opadry使用常规的包衣技术对获自步骤6的片剂进行包衣，重量最多增加(weight built of up to)2.5％w/w。
使经实施例3和4制备的片剂在40℃/相对湿度75％进行超过3个月时间的稳定性试验，在表4中表示。
表4：总的有关物质％(％w/w)
*总的有关物质％应不超过5％
虽然已经描述了几个具体的制剂，显然在不背离本发明的精神和范范围的前提下，可以对全文中详细描述的制剂进行多种改变和组合。例如，尽管已经制备了片剂剂型，但其它常规固体剂型如胶囊也可以使用相似的组合物来制备。因此，除了附加的权利要求之外，其并不限制本发明的意图。
Claims (7)
1.一种稳定的口服固体剂型，其含有：
(a)顺式-金刚烷-2-螺-3’-8’[[[(2’-氨基-2’-甲基丙基)氨基]羰基]甲基]-1’，2’，4’-三氧杂螺[4.5]癸烷马来酸氢盐，
(b)喹哌，和
(c)一种或多种药学上可接受的赋形剂，所述赋型剂为含水量不超过6.5％w/w的赋型剂；
所述剂型是使用干燥方法制备的。
2.如权利要求1所述的稳定的固体剂型，所述干燥方法选自直接压缩和干法制粒。
3.如权利要求2所述的稳定的固体剂型，所述干法制粒选自碾压法和压实法。
4.如权利要求1所述的稳定的固体剂型，其特征在于，所述药学上可接受的赋形剂选自粘合剂、稀释剂、助流剂/润滑剂、崩解剂、表面活性剂和着色剂。
5.一种稳定的口服固体剂型，其含有：
(a)顺式-金刚烷-2-螺-3’-8’[[[(2’-氨基-2’-甲基丙基)氨基]羰基]甲基]-1’，2’，4’-三氧杂螺[4.5]癸烷马来酸氢盐，
(b)喹哌，
(c)微晶纤维素，和
(d)一种或多种药学上可接受的赋形剂，所述赋型剂是含水量不超过6.5％w/w的赋型剂，且不是微晶纤维素；
所述剂型是使用干燥方法制备的。
6.如权利要求1或5所述的稳定的固体剂型，其特征在于，所述剂型选自片剂、胶囊、小药丸、颗粒和粉末。
7.如权利要求6所述的稳定的固体剂型，其特征在于，所述片剂是用含有成膜聚合物和包衣添加剂的一个或多个功能和/或非功能包衣层所包衣的。
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| US6486199B1 (en) * | 2001-06-21 | 2002-11-26 | Medicines For Malaria Venture Mmv International Centre Cointrin | Spiro and dispiro 1,2,4-trioxolane antimalarials |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6825230B2 (en) * | 2002-06-21 | 2004-11-30 | Medicines For Malaria Venture Mmv | Spiro and dispiro 1,2,4-trixolane antimalarials |
| US6906205B2 (en) * | 2002-06-21 | 2005-06-14 | Medicines For Malaria Venture Mmv | Spiro and dispiro 1,2,4-trioxolane antimalarials |
-
2006
- 2006-05-18 PL PL06744985T patent/PL1898901T3/pl unknown
- 2006-05-18 ES ES06744985.0T patent/ES2615458T3/es active Active
- 2006-05-18 HU HUE06744985A patent/HUE033191T2/en unknown
- 2006-05-18 US US11/914,867 patent/US20090042821A1/en not_active Abandoned
- 2006-05-18 CN CN2006800171210A patent/CN101272777B/zh active Active
- 2006-05-18 PT PT67449850T patent/PT1898901T/pt unknown
- 2006-05-18 WO PCT/IB2006/051588 patent/WO2006123314A2/en active Application Filing
- 2006-05-18 EP EP06744985.0A patent/EP1898901B1/en active Active
-
2011
- 2011-07-14 US US13/183,119 patent/US8664265B2/en active Active
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2017
- 2017-02-03 CY CY20171100160T patent/CY1118583T1/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6486199B1 (en) * | 2001-06-21 | 2002-11-26 | Medicines For Malaria Venture Mmv International Centre Cointrin | Spiro and dispiro 1,2,4-trioxolane antimalarials |
Also Published As
| Publication number | Publication date |
|---|---|
| HUE033191T2 (en) | 2017-11-28 |
| PL1898901T3 (pl) | 2017-07-31 |
| EP1898901A2 (en) | 2008-03-19 |
| US20120183607A1 (en) | 2012-07-19 |
| ES2615458T3 (es) | 2017-06-07 |
| US8664265B2 (en) | 2014-03-04 |
| WO2006123314A2 (en) | 2006-11-23 |
| CY1118583T1 (el) | 2017-07-12 |
| PT1898901T (pt) | 2017-02-27 |
| WO2006123314A3 (en) | 2008-04-10 |
| US20090042821A1 (en) | 2009-02-12 |
| CN101272777A (zh) | 2008-09-24 |
| EP1898901B1 (en) | 2016-11-23 |
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