CN102100907B - 口服药理活性剂组合物 - Google Patents
口服药理活性剂组合物 Download PDFInfo
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- CN102100907B CN102100907B CN200910259600.9A CN200910259600A CN102100907B CN 102100907 B CN102100907 B CN 102100907B CN 200910259600 A CN200910259600 A CN 200910259600A CN 102100907 B CN102100907 B CN 102100907B
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- calcitonin
- oral
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Abstract
本发明涉及用于口服药理活性剂的组合物，提高口服给药的生物利用度的方法以及通过口服施用本发明的药物组合物治疗和/或预防哺乳动物、尤其是人类疾病的方法。其包括水溶性大分子药物、分散剂、辅助稳定剂、疏水性介质和水以及任选的其他可药用辅料。本发明组合物制备方法简单，并可大大提高药物的口服生物利用度。
Description
技术领域
本发明涉及用于口服药理活性剂的组合物，提高口服给药的生物利用度的方法以及通过口服施用本发明的药物组合物治疗和/或预防哺乳动物、尤其是人类疾病的方法。
背景技术
口服是患者顺应性最好的一种给药途径，但随着生物技术的发展，蛋白多肽类药物在临床上的应用越来越广泛，如降钙素、胰岛素、胸腺素等都是临床常用的多肽药物，目前主要通过注射给药，患者顺应性差。口服剂型易被患者接受，但此类药物口服的最大问题是机体的物理、化学和生物学屏障影响其递送。物理屏障如黏膜以及到达靶点之前必须穿过的各种不同的器官、组织；化学屏障如pH的变化、脂质双层膜和降解酶等；生物学屏障如细胞吞噬、膜转运通道等。因此，降钙素等大部分多肽的生物利用度通常都低于10％。此外，一些难于透过胃肠道粘膜和/或在胃肠道中不稳定的其他药理活性剂的口服吸收很差。为此，目前人们把研究的重点放在克服两个障碍上，即如何提高上述药理活性剂的生物膜透过性和抵抗胃肠道酶的降解。
美国专利No.5773647和5866536、WO 00/59863、CN 03818295.5、CN 01820142.3、CN200480017406.5公开了含有修饰氨基酸的口服递送降钙素的药物组合物，大大提高了降钙素的生物利用度。制剂的制备工艺复杂、成本高。CN 200610097474.8公开了含有吸收促进剂的降钙素口服肠溶组合物及其制备方法，有效提高了降钙素在肠道的吸收。该制剂的制备工艺复杂、成本高。CN 200910052683.4公开了降钙素口服固体脂质纳米粒制剂及其制备方法。该制剂的制备工艺复杂、难于工业化生产且使用了有机溶剂。
因此，仍需要研制出一种制备工艺简单、成本低、具有更高口服生物利用度的药理活性剂如降钙素的组合物。
发明内容
一方面，本发明涉及一种用于口服药理活性剂的组合物，该组合物能大大提高药理活性剂、特别是蛋白多肽类药物的口服生物利用度。其包含药理活性剂及由分散剂、辅助稳定剂、疏水性介质、水及任选其他辅助剂构成的透明溶液。
另一方面，本发明涉及一种提高药理活性剂的口服生物利用度的方法。该方法包括向需要所述药理活性剂的个体施用有效量的本发明组合物。
此外，本发明涉及一种治疗和/或预防骨相关疾病和/或钙失调的方法。该方法包括给患者施用治疗有效量的本发明组合物，其中的药理活性剂是降钙素。
本发明的组合物为稳定的溶液剂形式，其包括作为活性成分的药理活性剂。本发明的组合物不仅解决了药理活性剂在胃肠道中的稳定性问题，足以满足临床使用的剂量要求，而且还显著提高了药理活性剂的胃肠黏膜的透过性，产品稳定性好。该药理活性剂包括但不限于蛋白质、多肽、激素、多糖、碳水化合物，以及它们的混合物。
药理活性剂的例子包括但不限于一切来源的下述活性剂：干扰素、白介素、胰岛素、肝素、降钙素、万古霉素、去甲万古霉素、去铁敏、甲状旁腺激素、蛋白酶抑制剂、超氧化物歧化酶、尿激酶、蚓激酶、链激酶、天冬酰胺酶、尿酸氧化酶、胰蛋白酶、水蛭素、脑啡肽、内啡肽、缓激肽、杆菌肽、短杆菌肽、胸腺肽、胸腺五肽、脑钠肽、奥曲肽、血管作用肠肽、凝血酶抑制剂、抑肽酶、降纤酶、葡糖脑苷酯酶、促红细胞生成素、抗原、单克隆抗体、生长激素、促生长素抑制素、促肾上腺皮质素、促性腺激素释放激素、催产素、促黄体生成激素释放激素、促卵泡激素、促黑激素、催产素、促胃液激素、脂肪肾上腺皮质激素、血管皮质激素、前房促尿钠泄激素、吞噬细胞增强激素、生长激素、分泌素、促胰酶素、缩胆囊素、血管紧张素、胸腺素、胸腺生成素、胸腺刺激素、胃动素、血小板生成素、前列腺素、后叶加压素、血管舒缓素、血管内皮抑制素、抗微生物剂，胰岛素样生长因子、神经生长因子、生长激素释放抑制因子、表皮生长因子、成纤维细胞生长因子、血小板衍生生长因子、干细胞生长因子、转化生长因子、骨形态形成因子、血管形成因子、血管形成抑制因子、胸腺体液因子、血清胸腺因子、肿瘤坏死因子、菌落刺激因子、凝血因子、核酸等，以及上述化合物的类似物、片段、模拟物、衍生物、或聚乙二醇修饰的衍生物，或它们的组合。优选水溶性大分子药物。
在本发明更优选的实施方案中，药理活性剂是蛋白、多肽、多糖类药物，特别是降钙素、低分子肝素。降钙素常用于治疗和预防佩吉特病(变形性骨炎)、高血钙症、骨质疏松症及类风湿性关节炎、神经性营养不良、药物引起的神经营养病、急性胰腺炎等症。各种降钙素，包括鲑、猪、鳗降钙素等。降钙素可以是任意一种降钙素，包括天然的、合成的、重组的降钙素，以及降钙素的衍生物。该组合物可含有单一的降钙素或两种及两种以上降钙素的任意组合。本发明优选的降钙素是合成的鲑降钙素。
本发明的组合物还包括作为分散剂的表面活性剂，该表面活性剂可使含活性剂的盐水均匀地分散在疏水性介质中。典型的表面活性剂包括：
(1)聚氧乙烯化的天然或氢化植物油，如聚氧乙烯化的天然或氢化蓖麻油；
(2)聚氧乙烯失水山梨醇脂肪酸酯，如聚氧乙烯失水山梨醇单油酸酯；
(3)聚氧乙烯脂肪酸酯，如聚氧乙烯硬脂酸酯；
(4)聚氧乙烯脂肪醇醚，如聚氧乙烯月桂醇醚；
(5)聚氧乙烯-聚氧丙烯共聚物，如Pluronic；
(6)聚氧乙烯-聚氧丙烯嵌段共聚物，如Poloxamer；
(7)失水山梨醇脂肪酸酯，如失水山梨醇单油酸酯；
(8)磷脂，如卵磷脂、大豆磷脂、聚氧乙烯化的卵磷脂，以及它们的混合物。
在上述表面活性剂中，本发明优选应用聚氧乙烯失水山梨醇脂肪酸酯分别与失水山梨醇脂肪酸酯、磷脂的混合物。特别优选选自Tween 80和Span 80的混合物、Tween 80和磷脂的混合物。
包含降钙素的本发明组合物还包括辅助稳定剂，它有助于将组合物的各组分混合而配制成均匀、稳定、透明的溶液。可用于本发明的辅助稳定剂包括乙醇、丙二醇、甘油、低分子量的聚乙二醇、二乙二醇单乙醚、四氢糠醇聚乙二醇醚、二甲基异山梨醇或它们的混合物。优选二乙二醇单乙醚、丙二醇、二甲基异山梨醇或它们的混合物。特别优选选自：乙醇、丙二醇，以及它们的混合物。
本发明的组合物还包括与所述分散剂和辅助稳定剂相容的疏水性介质，可用于本发明的典型的疏水性介质包括：
(1)天然的植物油或动物油，如玉米油、豆油、鱼油；
(2)液体脂肪酸，如油酸、亚油酸；
(3)脂肪酸酯，如肉豆蔻酸异丙酯、亚油酸乙酯；
(4)甘油脂肪酸酯，如甘油单、二、三油酸酯，以及
它们的混合物。优选选自脂肪酸酯、甘油脂肪酸酯，以及它们的混合物。特别优选选自：大豆油、中链油、甘油脂肪酸酯，以及它们的混合物。
本发明的组合物还包括促进活性剂透过胃肠粘膜而被吸收的吸收促进剂，其中的吸收促进剂选自生物黏附性高分子聚合物、脂肪酸及脂肪酸盐、非离子表面活性剂、环糊精、螯合剂、氮酮，以及它们的混合物。优选选自：壳聚糖、柠檬酸、水杨酸、癸酸钠、依地酸二钠、Tween80，以及它们的混合物。
可通过简单混合所述组分来制备本发明组合物。本发明组合物外观透明、稳定性好。
可按照本领域公知的常规方法，将本发明组合物制备成口服液、硬胶囊、软胶囊、微丸、片剂等其它多种口服剂型。
此外，本发明的组合物还包括药学上可接受的添加剂，包括但不限于pH调节剂、抗氧剂、矫味剂、防腐剂、黏度调节剂、渗透压调节剂、增塑剂、润滑剂、助流剂、赋形剂、稀释剂等，或是它们的任意组合。
本发明的组合物还可含有转运抑制剂，如p-糖蛋白抑制剂，例如非离子表面活性剂。
为了达到本发明的目的，本发明进行了药代动力学试验和降血钙效应试验。
如上所述，本发明的组合物不仅解决了降钙素在胃肠道中的稳定性问题，而且还显著提高了降钙素的生物膜透过性，提高了降钙素的口服生物利用度。
附图说明 参考附图1和附图2，通过本发明的以下描述，本发明的上述及其它目的和特征将是显而易见的。附图1显示了本发明实施例2和降钙素溶液口服与市售注射剂皮下给药后的生物利用度。附图2显示了本发明实施例2和降钙素溶液口服与市售注射剂皮下给药后的降血钙效应。
如上所述，本发明的组合物使降钙素口服给药的生物利用度显著提高。
以下实施例用于进一步详细说明本发明，但绝对不是对本发明范围的限制。
具体实施方式
实施例1：口服液的制备
将降钙素0.2mg和依地酸二钠1.0mg溶于0.5ml生理盐水中，将Tween801.0mg、Span801.2mg、大豆油1.4mg、乙醇1.1mg等组分混合均匀，加入适量的巴斯甜和苯扎溴铵，混合均匀，得到5ml澄明的混合液，然后将其灌装在西林瓶中，加盖，密封，辐射灭菌即得。
实施例2：软胶囊的制备
将降钙素20mg和水杨酸10mg溶于45ml生理盐水中，将Tween80 91mg、豆磷脂91mg、中链油182mg、丙二醇91mg等组分均匀混合溶解，并加入适量的维生素E、苯扎氯铵，混合均匀后压制成1000粒软胶囊。
实施例3：软胶囊的制备
将低分子肝素19mg和去氧胆酸钠1.6mg溶于48ml生理盐水中，将Tween80 76mg、豆磷脂76mg、辛/癸酸甘油酯228mg、丙二醇76mg等组分均匀混合溶解，并加入适量的维生素E、苯扎氯铵，混合均匀后压制成1000粒软胶囊。
实施例4：硬胶囊的制备
将降钙素20mg、羟丙基纤维素1.5mg、甘露醇2mg溶于45ml生理盐水中得溶液1，将Tween80 60mg、Span20 120mg、中链油90mg、聚乙二醇400 180mg等组分均匀混合溶解得溶液2，将溶液1和2混匀，冷冻干燥或喷雾干燥得含药粉末，以常规制备方法，与稀释剂、崩解剂、粘合剂等混合制粒，直接灌装入肠溶胶囊得1000粒硬胶囊。
实施例5：片剂的制备
将降钙素25mg、壳聚糖2mg、乳糖2.5mg溶于56ml生理盐水中得溶液1，将Tween8056mg、Span20 56mg、椰子油甘油酯224mg、聚乙二醇400 112mg等组分均匀混合溶解得溶液2，将溶液1和2混匀，冷冻干燥或喷雾干燥得含药粉末，以常规制备方法，与稀释剂、崩解剂、粘合剂等混合制粒，，或压制成片剂后外包肠溶衣即得1000粒肠溶片。
试验例1：药代动力学试验
为考察本发明组合物中的鲑鱼降钙素口服给药的生物利用度，如下对实施例2中的本发明制剂和降钙素溶液口服给药，分别进行药代动力学研究，比较鲑鱼降钙素在体内的吸收。
取体重10kg±1kg的雄性健康家犬，随机分为2组，每组4只。试验前24小时禁食，可自由饮水。称重后分别按剂量为5μg/kg(实施例2)和15μg/kg(降钙素溶液)以管饲法给药，并随后给予10ml水。给药后0.25、0.5、1、1.5、2、3、4、6、8小时定时取血，用放射免疫方法测定血中降钙素的含量。测得的药时曲线如图1。
图1的结果表明，与降钙素溶液的相比，本发明的实施例2经口服给药的生物利用度是大大提高，因此本发明的制剂大大提高了降钙素口服的生物利用度。
试验例2：降血钙效应试验
取体重10kg±1kg的雄性健康家犬，随机分为2组，每组4只。试验前24小时禁食，可自由饮水。称重后分别按剂量为5μg/kg(实施例2)和15μg/kg(降钙素溶液)以管饲法给药，分别给予实施例2中的本发明制剂和降钙素溶液，并随后给予10ml水。给药前先取血作为空白对照。给药后0.5、1、1.5、2、3、4、6、8小时定时取血、离心，取上清采用OCPC比色法测定血清钙离子浓度。测得的结果见图2。
图2的结果表明，与降钙素水溶液相比，实施例2的组合物经口服给药，显著地降低了血清中钙离子水平，显示了本发明组合物的优越性。
虽然已利用上述具体的实施方案对本发明进行了描述，但应认识到，本领域的技术人员还可进行各种的改进或改变，而且它们也应在如权利要求书限定的本发明的范围之内。
Claims (1)
1.一种降钙素口服软胶囊，其制备步骤如下：将降钙素20mg和水杨酸10mg溶于45ml生理盐水中，将Tween80 91mg、豆磷脂91mg、中链油182mg、丙二醇91mg均匀混合溶解，并加入适量的维生素E、苯扎氯铵，混合均匀后压制成1000粒软胶囊。
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