CN1809377B - 包含微粉化形式的传送剂的口服给药药物组合物 - Google Patents
包含微粉化形式的传送剂的口服给药药物组合物 Download PDFInfo
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- CN1809377B CN1809377B CN2004800174065A CN200480017406A CN1809377B CN 1809377 B CN1809377 B CN 1809377B CN 2004800174065 A CN2004800174065 A CN 2004800174065A CN 200480017406 A CN200480017406 A CN 200480017406A CN 1809377 B CN1809377 B CN 1809377B
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Abstract
公开了固体药物组合物以及它们适用于口服传送药理活性剂如肽的方法，所述的组合物包含治疗有效量的药理活性剂；交聚维酮或聚维酮；以及用于药理活性剂的传送剂。该组合物采用微粉化形式的传送剂，所述传送剂使药理活性剂、特别是降钙素的生物利用度提高。
Description
发明背景
1.本发明的领域
本发明涉及用于传送药理活性剂的口服组合物，增加口服施用的药理活性剂的生物利用度的方法，以及通过口服施用本发明的药理活性剂来治疗和/或预防哺乳动物、特别是人类疾病的方法。
2.相关技术的描述
口服传送药理活性剂是通常选用的传送途径，因为它与其它传送途径相比方便、相对容易并且通常无痛，以致患者的顺从性更好。然而，生物屏障、化学屏障及物理屏障，如胃肠道内pH变化、强效消化酶以及活性剂不可穿透的胃肠道膜，使得某些药理活性剂对哺乳动物口服传送存在问题，例如降钙素的口服传送，它是由哺乳动物甲状腺滤泡旁细胞和由鸟类与鱼类的后腮腺分泌的长链多肽激素，其口服传送被证明是困难的，这至少部分由于降钙素在胃肠道内的不稳定性以及不能轻易穿过肠壁进入血流。
美国专利US 5,773,647和5,866,536描述了口服传送活性剂如肝素和降钙素以及改性氨基酸如N-(5-氯水杨酰基)-8-氨基辛酸(5-CNAC)、N-(10-[2-羟基苯甲酰基]氨基)癸酸(SNAD)和N-(8-[2-羟基苯甲酰基]氨基)辛酸(SNAC)的组合物。此外，WO 00/059863公开了式I的二钠盐及其水合物和溶剂化物，
其中：
R1、R2、R3和R4独立地是氢、-OH、-NR6R7、卤素、C1-C4烷基或C1-C4烷氧基；
R5是取代或未取代的C2-C16亚烷基、取代或未取代的C2-C16亚烯基、取代或未取代的C1-C12烷基(亚芳基)或者取代或未取代的芳基(C1-C12亚烷基)；并且
R6和R7独立地是氢、氧或C1-C4烷基；
对口服传送活性剂如降钙素、环孢素和肝素特别有效。
本发明描述了一种药物组合物，该组合物提供了口服生物利用度更好的药理活性剂，例如象降钙素这样的肽。
发明概述
因此，本发明涉及一种药物组合物，该组合物非常令人惊讶地极大提高了活性成分、特别是肽的口服生物利用度。具体而言，本发明提供了适于口服传送药理活性剂的固体药物组合物，该组合物包含：
1.治疗有效量的药理活性剂；
2.可药用的非活性赋形剂；以及
3.用于所述药理活性剂的传送剂，其中所述传送剂为微粉化形式。
在另一实施方案中，本发明提供了适于口服传送降钙素的固体药物组合物，该组合物包含：
1.治疗有效量的降钙素；以及
2.可药用的非活性赋形剂，以及
3.用于所述降钙素的传送剂，其中该传送剂为微粉化形式。
在本发明的另一实施方案中，可药用的非活性赋形剂可以是聚合物交聚维酮或聚维酮之一或之二。
在本发明的另一实施方案中，适于口服传送的固体药物组合物还可包含稀释剂。
此外，在本发明的另一实施方案中，适于口服传送的固体药物组合物还可包含润滑剂。
在另一实施方案中，本发明涉及增加药理活性剂的口服生物利用度的方法，该方法包括给需要所述药理活性剂的受治疗者施用有效量的本发明的药物组合物。
在另一实施方案中，本发明涉及治疗骨相关疾病和钙紊乱的方法，该方法包括给需要该治疗的患者施用治疗有效量的本发明的组合物，其中所述药理活性剂为降钙素。
本发明的其它特征与优点将从下述发明详述而变得显而易见。
发明详述
适用于本发明的药理活性剂包括治疗剂和预防剂两者，特别指自身不穿过或仅少量所施用剂量穿过胃肠粘膜的那些和/或易于被胃肠道的酸和酶裂解的那些。药理活性剂包括但不限于蛋白质；多肽；激素；多糖且包括粘多糖混合物；碳水化合物；脂类；以及它们的组合。
药理活性剂的具体实例包括但不限于下述活性剂，包括它们的合成、天然或重组来源：生长激素，包括人生长激素(hGH)、重组人生长激素(rhGH)、牛生长激素及猪生长激素；生长激素释放激素；干扰素，包括α-、β-、和γ-干扰素；白细胞介素-1；白细胞介素-2；胰岛素，包括猪、牛、人及人重组胰岛素，任选含有抗衡离子，包括钠、锌、钙和铵；胰岛素样生长因子，包括IGF-1；肝素，包括未级分肝素、类肝素、皮肤素、软骨素、低分子量、极低分子量及超低分子量肝素；降钙素，包括鲑、猪、鳗、鸡和人降钙素；促红细胞生成素(erythopoietein)；心钠素；抗原；单克隆抗体；促生长素抑制素；蛋白酶抑制剂；促肾上腺皮质激素、促性腺素释放激素；催产素；促黄体生成素释放激素；促卵泡激素；葡糖脑苷脂酶；血小板生成素；非格司亭；前列腺素；环孢素；血管加压素；色甘酸钠(色甘酸钠或二钠)；万古霉素；去铁敏(DFO)；甲状旁腺素(PTH)，包括其片段；抗菌剂，包括抗真菌剂；维生素；这些化合物的类似物、片段、模拟物或聚乙二醇(PEG)修饰的衍生物；或它们的任意组合。
一种感兴趣的药理活性剂是药理活性肽，特别是骨活性剂，甚至更特别是降钙素。
骨活性剂包括在动物体内表现出药理活性的活性剂类别，例如使骨稳定、愈合或生长，减速或抑制骨转化，减速或抑制骨吸收，抑制破骨细胞活性，以及激活成骨细胞活性。某些骨活性剂可以是肽类，例如降钙素、甲状腺旁素(PTH)、PTH片段、类似物或释放者以及转化生长因子(TGF)片段、类似物和释放者。骨活性剂还可具有表现出如本段落上述的体内骨药理活性的小分子非肽类结构。
一类已知的该药理活性剂——降钙素——具有多种药物用途，通常用于治疗如佩吉特氏病、高钙血症以及绝经后骨质疏松症。各种降钙素，包括鲑、猪和鳗降钙素可自商业途径获得，通常用于治疗例如佩吉特氏病、恶性高钙血症以及骨质疏松症。降钙素可以是任何降钙素，包括其天然、合成或重组来源，以及降钙素衍生物如1，7-Asu-鳗降钙素。组合物可包含单一降钙素或者两种或多种降钙素的组合。优选的降钙素是合成的鲑降钙素。
降钙素可自商业途径获得或通过已知方法合成。
药理活性剂的量通常是达到预期目标的有效量，例如，治疗有效量。然而，当施用多个组合物时该量可以有所减少，即总有效量可通过累加剂量单位来施用。当组合物的药理活性剂被缓释时，活性剂的量也可高于有效量。活性剂的总用量可通过本领域技术人员已知的方法来确定。然而，由于该组合物可以比现有组合物更有效地传送活性剂，因此可以给受治疗者施用比现有剂量单位形式或传送系统少的活性剂量，而仍然达到相同的血药浓度和/或疗效。
当药理活性剂是鲑降钙素时，适宜的剂量当然根据例如宿主和所治疗病症的性质和严重程度而有所变化。但是通常而言，以约0.5μg/kg至约10μg/kg动物体重、优选1μg/kg至6μg/kg体重的日剂量全身施用可获得令人满意的结果。
药理活性剂通常占相对于整个药物组合物总重量的0.05-70％重量，优选相对于整个药物组合物总重量的0.01-50％重量、更优选0.3-30％重量。
可药用的非活性赋形剂可包括聚合物和例如帮助配制或制备本发明的固体口服剂型或者帮助固体口服组合物在胃肠环境内的释放非活性化合物。
上文所指出的非药理活性成分例如任选包含交聚维酮和聚维酮，它可以是任何交聚维酮和聚维酮。交聚维酮是N-乙烯基-2-吡咯烷酮(还称为1-乙烯基-2-吡咯烷酮)的合成交联均聚物，分子量为1,000,000或更高。市售交聚维酮包括得自ISP的Polyplasdone XL、Polyplasdone XL-10及Polyplasdone INF-10和得自BASF公司的Kollidon CL。优选的交聚维酮是Polyplasdone XL。
聚维酮是由线性1-乙烯基-2-吡咯烷酮基团组成的合成聚合物，分子量通常为2,500至3,000,000。市售聚维酮包括得自BASF公司的KollidonK-30及Kollidon K-90F和得自ISP的Plasdone K-30及Plasdone K-29/32。
如上所述，交聚维酮和聚维酮可自商业途径获得。或者，它们可通过已知方法合成。
交聚维酮、聚维酮或它们的组合通常在组合物中存在的量为相对于整个药物组合物总重量的0.5％至50％重量，优选相对于整个药物组合物总重量的2至25％重量、更优选5至20％重量。
可用于本发明的传送剂是任何可用于传送特定药理活性剂的试剂。适宜的传送剂是前述美国专利US 5,866,536中公开的123种改性氨基酸中的任一种或者前述美国专利US 5,773,647中描述的193种改性氨基酸中的任一种，或者是它们的任意组合。上述美国专利US 5,773,647和5,866,536的内容全文引入本文作为参考。此外，传送剂可以是上述任意一种改性氨基酸的二钠盐以及它们的乙醇溶剂化物或水合物。适宜的化合物包括式I化合物以及它们的水合物或乙醇溶剂化物：
其中：
R1、R2、R3和R4独立地是氢、-OH、-NR6R7、卤素、C1-C4烷基或C1-C4烷氧基；
R5是取代或未取代的C2-C16亚烷基、取代或未取代的C2-C16亚烯基、取代或未取代的C1-C12烷基(亚芳基)或者取代或未取代的芳基(C1-C12亚烷基)；且
R6和R7独立地是氢、氧或C1-C4烷基。式I化合物及其二钠盐和乙醇溶剂化物和水合物以及它们的制备方法在专利WO 00/059863中有描述。
二钠盐可如下制备：从乙醇溶剂化物按照本领域已知的方法通过蒸发或干燥乙醇溶剂化物来形成无水二钠盐。干燥通常在约80至120℃、优选约85至约90℃、最优选约85℃下进行。干燥步骤通常在26”Hg或更高压力下进行。无水二钠盐通常含有低于基于无水二钠盐100％总重量计的约5％重量的乙醇，优选低于约2％重量的乙醇。
传送剂的二钠盐还可如下制备：将传送剂在水中制成浆状，加入2摩尔当量的氢氧化钠、醇钠等的水溶液。适宜的醇钠包括但不限于甲醇钠、乙醇钠和它们的组合。
另一种制备二钠盐的方法是使传送剂与1摩尔当量的氢氧化钠反应得到二钠盐。
二钠盐可如下作为固体被分离：通过真空蒸馏使含有二钠盐的溶液浓缩至粘稠糊状。将该糊状物在真空烤箱中干燥，得到固态的传送剂二钠盐。还可通过喷雾干燥二钠盐水溶液得到该固体。
传送剂可通过本领域已知的方法制备，例如如前所述，通过美国专利US 5,773,647和5,866,536中描述的方法来制备。
如前述WO 00/059863中所述，乙醇溶剂化物包括但不限于乙醇溶剂分子或离子与传送剂二钠盐的分子或离子的分子或离子复合物。通常而言，乙醇溶剂化物含有约1个乙醇分子或离子对应1个传送剂二钠盐的分子。
传送剂二钠盐的乙醇溶剂化物可通过将传送剂溶解在乙醇中制备。通常，每克传送剂溶于约1至约50ml乙醇中，通常约2至约10ml乙醇中。然后使传送剂/乙醇溶液与相对于传送剂摩尔过量的含钠盐、如单钠盐反应，即每摩尔传送剂相对于多于1摩尔的钠阳离子，得到乙醇溶剂化物。适宜的单钠盐包括但不限于氢氧化钠；醇钠如甲醇钠和乙醇钠；以及上述钠盐的任意组合。优选将至少约2摩尔当量的单钠盐加入乙醇溶液中，即每摩尔传送剂相对于至少约2摩尔的钠阳离子。反应通常在混合物的回流温度或低于回流温度下进行，例如在环境温度下进行。然后通过本领域已知的方法回收乙醇溶剂化物，例如常压蒸馏浓缩所得的浆状物、冷却所浓缩的浆状物并滤出固体。然后将所回收的固体真空干燥，得到乙醇溶剂化物。
传送剂二钠盐的水合物可如下制备：如前所述，干燥乙醇溶剂化物得到无水二钠盐，使无水二钠盐吸水。优选形成二钠盐的一水合物。由于无水二钠盐具有很强的吸湿性，因此水合物通过与大气湿气接触而形成。通常，吸水步骤在约环境温度至约50℃、优选环境温度至约30℃和环境相对湿度为至少50％下进行。或者，无水二钠盐可通过用蒸汽使之吸水。
优选的传送剂是N-(5-氯水杨酰基)-8-氨基辛酸(5-CNAC)、N-(10-[2-羟基苯甲酰基]氨基)癸酸(SNAD)、N-(8-[2-羟基苯甲酰基]氨基)辛酸(SNAC)、它们的单钠盐和二钠盐以及这些钠盐的乙醇溶剂化物、一水合物以及它们的任意组合。最优选的传送剂是5-CNAC的二钠盐及其一水合物。
传送剂5-CNAC、SNAD和SNAC具有很好的水溶性，并且无论以微粉化形式还是粗形式被摄取，几乎全部(即超过90％)被胃肠道吸收。然而，已经出人意料地发现：当这些传输剂之一以微粉化形式用于组合物时，该组合物的药理活性剂被更彻底地吸收入血流。因此，使用微粉化的传送剂是本发明的一个要素。
用于制备本发明的固体口服剂型的微粉化形式的传送剂被定义这样的传送剂：当该传送剂被加入药理活性剂和非药理活性剂的组合混合物中时，平均粒径低于40微米。期望本发明的传送剂是平均粒径低于20微米的微粉化形式。更感兴趣的是，本发明的传送剂是平均粒径低于10微米的微粉化形式。
微粉化形式的本发明的传送剂可以通过在研磨机中研磨来制备，所述的研磨机可用于研磨药理成分并能将药理成分和/或传送剂研磨成细小均匀的微粒。该研磨机的实例是Air Jet Mill Gem T(Copley Scientific，Ltd，诺丁汉，英国)。然后使单独的研细传送剂或者研细传送剂与研细的本发明其它成分的任意组合一起过筛，例如，通过具有适宜筛孔的网筛，以仅允许具有所要求粒径的成分通过并收集以供本发明使用。
本发明的药物组合物通常含有传送有效量、即足以传送活性剂达到所要求作用的量的一种或多种传送剂。通常，传送剂存在的量为2.5％至99.4％重量，更优选为25％至50％重量。
本发明的药物组合物可作为胶囊且包括软明胶胶囊、片剂、胶囊形片剂或其它固体口服剂型提供，所有这些剂型可通过本领域已知的方法制备。
组合物可另外包含常规用量的添加剂，包括但不限于pH调节剂、防腐剂、调味剂、掩味剂、香料、保湿剂、增强剂(tonicifier)、着色剂、表面活性剂、增塑剂、润滑剂如硬脂酸镁、助流剂、助压缩剂、增溶剂、赋形剂、稀释剂如微晶纤维素如Avicel PH 102
(FMC公司提供，1735 MarketStreet，费城，PA 19103，USA)，或它们的任意组合。其它添加剂可包括磷酸缓冲盐、柠檬酸、乙二醇及其它分散剂。
组合物还可包括一种或多种酶抑制剂，如放线酰胺素或表放线酰胺素及其衍生物；抑肽酶、Trasylol和Bowman-Birk抑制剂。
此外，本发明的药物组合物中可以存在传输抑制剂，即ρ-糖蛋白，如Ketoprofin。
本发明的固体药物组合物优选包括稀释剂如Avicel
和润滑剂如硬脂酸镁。
本发明的固体药物组合物可如下制备：首先将传送剂或者传送剂与该组合物其它成分的任意组合一起研磨成微粉粒径。然后，将微粉化传送剂或者微粉化传送剂加上本发明的微粉化其它成分通过常规方法进一步加工，例如将活性剂、传送剂、交聚维酮或聚维酮以及其它成分的混合物混合、捏合并填入胶囊中，或者不是填入胶囊，而是模制并进一步压片或模压成片。此外，可通过已知方法形成固体分散体，然后进一步加工形成片剂或胶囊。
本发明的药物组合物中的成分优选是完全均匀或均一混合的固体剂型。
可以对任何需要其的动物施用本发明的组合物来传送活性剂，所述动物包括但不限于哺乳动物，如啮齿动物、牛、猪、狗、猫及灵长类动物，特别是人。
下述实施例用于进一步解释本发明，并易于被本领域普通技术人员理解。这些实施例不意欲以任何方式限制本发明。
实施例1
根据本发明，如下制备微粉化5-CNAC以及鲑降钙素加上微粉化5-CNAC的片剂：
微粉化5-CNAC的制备
将欲被微粉化的粗5-CNAC加入气流粉碎机(Air Jet Mill Gem TCopley Scientific.Ltd.，诺丁汉，UK)中，采用80陶瓷底盘气流粉碎机，直径8cm，6巴N2，0.5mm喷嘴，手工进料约700克/小时。将粗5-CNAC气流粉碎并定时取样，在显微镜下用参照标尺测量法确定何时获得所需的平均微粉化粒径。将三个不同批次研磨成6μm、35μm、46μm。然后用锥形筛磨(Quadro Comil，Quadro Engineering Incorporated 613Colby Drive，滑铁卢，安大略省，加拿大N2V 1A1)分别筛出各微粉化批次，该筛磨采用U10，813μm锥形筛、圆形搅拌器，在1500upm下以约150kg/h产量工作。
制剂I：含不同粒径5-CNAC的鲑降钙素制剂
制剂I的制备
利用三个不同批次的微粉化5-CNAC二钠制备三个不同批次的片剂，第一批片剂含有平均粒径为46μm的5-CNAC二钠(批次A)，第二批片剂含有平均粒径为6μm的5-CNAC二钠(批次B)，第三批片剂含有平均粒径为35μm的5-CNAC二钠(批次C)。
将0.50g预过40目筛的鲑降钙素、57.g过35目筛的微粉化5-CNAC二钠和10g Polyplasdone XL(交聚维酮，NF，国际专有产品，1361AlpsRoad，Wayne，新泽西，07470，USA)在500ml罐中合并，用Turbula搅拌器以46RPM的速度搅拌100转。向罐中加入另外的57.g过35目筛的微粉化5-CNAC二钠和36.75g Avicel PH 102，以46RPM的速度搅拌500转。再向罐中加入36.75g Avicel PH 102，以46RPM的速度另外搅拌100转。将4.0g硬脂酸镁通过35目筛筛入罐中，以46RPM的速度混合1分钟。最终混合物用Manesty B3B压片机压制成片。片重约400mg。
实施例1中制成的片剂的生物利用度可以如下检测：
实施例2
灵长类动物的给药
采用三个不同批次的微粉化5-CNAC二钠按照实施例1制备三批片剂，第一批片剂含有平均粒径为46μm的5-CNAC二钠(批次A)，第二批片剂含有平均粒径为6μm的5-CNAC二钠(批次B)，第三批片剂含有平均粒径为35μm的5-CNAC二钠(批次C)。将由这三个批次的每一批制备的片剂在不同天数如下分别施用于相同的四只恒河猴。
在给药前使恒河猴禁食过夜，并在研究期间将其束缚在椅子上并保持完全清醒。通过强饲管给药给每只猴子施用一片批次A或批次B或批次C的片剂，然后给予10ml水。
在给药前及给药后0.25、0.5、0.75、1、1.5、2、3、4、5、6小时迅速采集恒河猴血样。以相似方式给予其余两批片剂批次各自的片剂并采集血样，但剩余两批的片剂批次在不同天进行。通过放射免疫分析法测定每只恒河猴每一剂量所得的血浆鲑降钙素。计算每只恒河猴一个批次和一个时间段的灵长动物血浆鲑降钙素(SCt)、所有恒河猴一个批次和一个时间段的平均血浆SCt、一个批次和一个时间段的血浆SCt浓度的标准偏差(SD)以及所有恒河猴一个批次和一个时间段的血浆SCt浓度的平均标准误差(SEM)，报导见于下表1、2和3。
表1批次A：5-CNAC平均粒径为46微米
鲑降钙素(SCt)血浆浓度[pg/mL]
(给恒河猴施用单片口服片剂(200mg 5-CNAC+1mg SCt))
定量下限(LLOQ)＝2.5pg/mL，低于LLOQ的浓度在表1中设为0。
表2批次B：5-CNAC平均粒径为6微米
鲑降钙素(SCt)血浆浓度(pg/mL)
(给恒河猴施用单片口服片剂(200mg 5-CNAC+1mg SCt))
定量下限(LLOQ)＝2.5pg/mL，低于LLOQ的浓度在表2中设为0。
表3批次C：5-CNAC平均粒径为35微米
鲑降钙素(SCt)血浆浓度(pg/mL)
(给恒河猴施用单片口服片剂(200mg 5-CNAC+1mg SCt))
定量下限(LLOQ)＝2.5pg/mL，低于LLOQ的浓度在表3中设为0。
上文清楚地表明：本发明的组合物使相当大地改善活性剂的口服生物利用度成为可能。改善的生物利用度导致可通过口服传送获得活性剂、特别是降钙素的高体内浓度，并且与实施例中口服制剂的5-CNAC粒径相关。
上述实施方案和实施例仅用于解释而非限制本发明。大量其它实施例和变通方法在本发明的范围之内，并且容易被本领域技术人员达到。
Claims (13)
1.适于口服传送药理活性剂的固体药物组合物，包含：
a.治疗有效量的降钙素；
b.可药用的非活性赋形剂；以及
c.选自N-(5-氯水杨酰基)-8-氨基辛酸的传送剂，其中所述传送剂被微粉化至平均粒径低于20μm。
2.根据权利要求1的组合物，其中所述的平均粒径低于10μm。
3.根据权利要求1的组合物，其中的降钙素为鲑降钙素。
4.根据权利要求1的组合物，其中所述的非活性赋形剂选自交聚维酮和聚维酮。
5.根据权利要求1的组合物，其中的传送剂选自N-(5-氯水杨酰基)-8-氨基辛酸二钠盐。
6.根据权利要求1的组合物，其还包括稀释剂。
7.根据权利要求6的组合物，其中的稀释剂为微晶纤维素。
8.根据权利要求1的组合物，其还包括润滑剂。
9.根据权利要求8的组合物，其中的润滑剂为硬脂酸镁。
10.根据权利要求1至9任一项的药物组合物在制备具有提高的降钙素的口服生物利用度的药物中的用途。
11.根据权利要求1至9任一项的组合物在制备用于治疗骨相关疾病和钙紊乱的药物中的用途。
12.根据权利要求11的用途，其中所述的降钙素是鲑降钙素。
13.根据权利要求1至9任一项的药物组合物在制备用于治疗骨相关疾病的药物中的用途。
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| US20060078622A1 (en) * | 2004-08-13 | 2006-04-13 | Emisphere Technologies, Inc. | Pharmaceutical formulations containing microparticles or nanoparticles of a delivery agent |
| KR20080049128A (ko) | 2005-09-19 | 2008-06-03 | 에미스페어 테크놀로지스, 인코포레이티드 | Ｎ-(5-클로로살리실로일)-8-아미노카프릴산 이나트륨염의결정형 |
| GB0522566D0 (en) * | 2005-11-04 | 2005-12-14 | Novartis Ag | Organic compounds |
| ES2426485T3 (es) * | 2006-08-31 | 2013-10-23 | Novartis Ag | Composiciones farmacéuticas que comprenden hGH para administración oral |
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| PL2215047T3 (pl) * | 2007-11-02 | 2014-05-30 | Emisphere Tech Inc | Sposób leczenia niedoborów witaminy b12 |
| RU2576511C2 (ru) * | 2010-02-24 | 2016-03-10 | Эмисфире Текнолоджис, Инк. | Пероральная терапия недостаточности витамина в12 |
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| CN111494324B (zh) | 2012-03-22 | 2023-05-16 | 诺和诺德股份有限公司 | 包含递送剂的组合物及其制备 |
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| CN104487056A (zh) | 2012-06-20 | 2015-04-01 | 诺和诺德A/S（股份有限公司） | 包含肽和递送剂的片剂制剂 |
| CN104095828A (zh) * | 2014-07-29 | 2014-10-15 | 中国药科大学 | 一种降钙素口服肠溶组合物及其制备方法 |
| WO2019149880A1 (en) | 2018-02-02 | 2019-08-08 | Novo Nordisk A/S | Solid compositions comprising a glp-1 agonist, a salt of n-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant |
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| ES2330638T3 (es) | 2009-12-14 |
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| US8748383B2 (en) | 2014-06-10 |
| CA2529604A1 (en) | 2005-01-20 |
| US20130230593A1 (en) | 2013-09-05 |
| ATE442158T1 (de) | 2009-09-15 |
| CA2529604C (en) | 2012-05-08 |
| BRPI0412458A (pt) | 2006-10-17 |
| MXPA06000446A (es) | 2006-04-07 |
| DE602004023093D1 (de) | 2009-10-22 |
| HK1089950A1 (en) | 2006-12-15 |
| PL1651248T3 (pl) | 2010-02-26 |
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