CN1304048C - 用于口服递送药理学活性剂的药物组合物 - Google Patents
用于口服递送药理学活性剂的药物组合物 Download PDFInfo
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- CN1304048C CN1304048C CNB018201423A CN01820142A CN1304048C CN 1304048 C CN1304048 C CN 1304048C CN B018201423 A CNB018201423 A CN B018201423A CN 01820142 A CN01820142 A CN 01820142A CN 1304048 C CN1304048 C CN 1304048C
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- calcitonin
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Abstract
本发明公开了适于口服递送药理学活性剂如肽类的固体药物组合物,其含有治疗有效量的药理学活性剂;交联聚维酮或聚维酮;以及所述药理学活性剂的递送试剂。该组合物可使药理学活性剂、特别是降钙素获得优良的口服生物利用度。
Description
发明背景
1.发明领域
本发明涉及用于递送药理学活性剂的口服组合物、提高口服给药的药理学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学活性剂来治疗和/或预防哺乳动物、尤其是人类的疾病的方法。
2.相关领域描述
口服递送药理学活性剂是常选的药物递送途径,因为它很方便、相对容易并少有痛苦,因此与其它递送方式相比具有更高的患者依从性。然而,生物学、化学和物理学屏障,诸如胃肠道pH的变化、强大的消化酶、以及活性剂不可通透的胃肠道粘膜,使得向哺乳动物口服递送某些药理学活性剂是有问题的;例如,口服递送降钙素(一种由哺乳动物体内的甲状腺滤泡旁细胞和鸟及鱼的后腮腺分泌的长链多肽激素)被证明是很困难的,其原因至少部分在于降钙素在胃肠道中不够稳定以及降钙素不能很容易地通过肠壁转运到血液中。
美国专利号5,773,647和5,866,536记载了用于口服递送活性剂诸如肝素和降钙素的组合物,其中含有修饰的氨基酸,例如N-(5-氯代水杨酰)-8-氨基辛酸(5-CNAC)、N-(10-[2-羟基苯甲酰]氨基癸酸(SNAD)以及N-(8-[2-羟基苯甲酰]氨基)辛酸(SNAC)。此外,WO 00/059863公开了式I的二钠盐及其水合物及溶剂化物作为特别有效的用于递送活性剂,诸如降钙素、环孢菌素和肝素的物质;
式I
其中
R1、R2、R3和R4彼此独立地是氢、-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亚链烯基、取代或未取代的C1-C12烷基(亚芳基)或取代或未取代的芳基(C1-C12亚烷基);且
R6和R7彼此独立地是氢、氧或C1-C4烷基。
本发明描述了能为药理学活性剂如降钙素等肽类提供更高的口服生物利用度的药物组合物。
发明概述
相应的,本发明涉及药物组合物,该组合物能出人意料地大大提高活性试剂、特别是肽类的口服生物利用度。具体地讲,本发明提供了适于口服递送药理学活性剂的固体药物组合物,其含有
1.治疗有效量的药理学活性剂;
2.交联聚维酮或聚维酮;和
3.所述药理学活性剂的递送试剂。
在本发明的另一个实施方式中,提供了适于口服递送降钙素的固体药物组合物,其含有
1.治疗有效量的降钙素;和
2.交联聚维酮或聚维酮;
在另一个实施方式中,本发明涉及一种提高药理学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学活性剂的个体施用有效量的本发明的药物组合物。
此外,在另一个实施方式中,本发明涉及一种治疗骨相关疾病和钙失调的方法,该方法包括向需要此治疗的患者施用治疗有效量的本发明的组合物,其中的药理学活性剂是降钙素。
本发明其它的特点和优点将通过如下发明详述而变得显而易见。
发明详述
适用于本发明的药理学活性剂包括治疗性的和预防性的试剂,尤其是那些本身不能穿过或仅有很少量的给药剂量能穿过胃肠道粘膜和/或易于被胃肠道中的酸和酶裂解的试剂。该药理学活性剂包括、但不限于蛋白质;多肽;激素;多糖,包括粘多糖混合物;碳水化合物;脂质;以及它们的组合。
药理学活性剂的具体例子包括、但不限于下述试剂,包括来源于合成的、天然的或重组的试剂: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;白介素-1;白介素-2;胰岛素,包括猪、牛、人和人重组胰岛素,可任选地含有抗衡离子,包括钠、锌、钙和铵;胰岛素样生长因子,包括IGF-1;肝素,包括不分级肝素、类肝素、皮肤素、软骨素、低、极低和超低分子量肝素;降钙素,包括鲑、猪、鳗、鸡和人降钙素;促红细胞生成素;心营养因子(atrial naturetic factor);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;葡糖脑苷脂酶;血小板生成素;非尔司啶;前列腺素;环孢菌素;后叶加压素;色甘酸钠(色甘酸钠或色甘酸二钠);万古霉素;去铁敏(DFO);甲状旁腺激素(PTH),包括其片段;抗微生物剂,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;或它们的组合。
优选的药理学活性剂是药理学活性肽,特别是降钙素。降钙素是一类已知的药理学活性剂,它具有多种药物用途,并常用于治疗如佩吉特病、血钙过高和绝经后骨质疏松症。各种降钙素,包括鲑、猪和鳗降钙素都是可购买到的,并常用于治疗如佩吉特病、恶性血钙过高和骨质疏松症。降钙素可以是任一种降钙素,包括来源于天然的、合成的或重组的降钙素,以及降钙素衍生物,诸如1,7-Asu-鳗降钙素。该组合物可含有单一的降钙素或两种或多种降钙素的任意组合。优选的降钙素是合成的鲑降钙素。
降钙素可以购买到或者可以通过已知方法合成。
药理学活性剂的量通常是可有效达到预期目的的量,如治疗有效量。然而,在施用多个组合物时,该量可以小于上述的有效量,即,总的有效量可以以累积的剂量单元给药。当组合物可以缓释药理学活性剂时,活性试剂的量也可高于有效量。所用的活性试剂总量可通过本领域技术人员公知的方法确定。然而,由于该组合物可比先前的组合物更有效的递送活性试剂,因此可以向个体施用少于先前的剂量单位形式或递送系统的量而仍能获得相同的血液水平和/或治疗效果。
当药理学活性剂是鲑降钙素时,适宜的剂量可根据,例如,给药对象和所治疗病症的性质和严重程度而变化。然而,一般说来,以约0.5μg/kg至约10μg/kg动物体重、优选1μg/kg至约6μg/kg体重的每日剂量全身性给药可获得满意的效果。
药理学活性剂通常占整个药物组合物总重量的0.05%至70%,优选含量为总重量的0.01%至50%,更优选占整个药物组合物总重量的0.3%至30%。
交联聚维酮可以是任一种交联聚维酮。交联聚维酮是一种合成的N-乙烯基-2-吡咯烷酮(也称为1-乙烯基-2-吡咯烷酮)的交联均聚物,具有1,000,000或更高的分子量。可购买到的交联聚维酮包括可从ISP购买的Polyplasdone XL、Polyplasdone XL-10、Polyplasdone INF-10和可从BASF公司购买的Kollidon CL。优选的交联聚维酮是Polyplasdone XL。
聚维酮是一种由线性的1-乙烯基-2-吡咯烷酮基团组成的合成聚合物,分子量通常在2,500和3,000,000之间。可购买到的聚维酮包括可从BASF公司购买的Kollidon K-30、Kollidon K-90F和可从ISP购买的PlasdoneK-30和Plasdone K-29/32。
如上所述,交联聚维酮和聚维酮都是可购买到的。或者,它们也可通过公知的方法合成得到。
交联聚维酮、聚维酮或它们的组合在组合物中通常占整个药物组合物总重量的0.5%至50%,优选2%至25%,更优选占药物组合物总重量的5%至20%。
可用于本发明的递送试剂可以是任一种可用于递送特定的药理学活性剂的试剂。适宜的递送试剂可以是公开于前述美国专利5,866,536中的123种修饰的氨基酸中的任意一种,或者是公开于前述美国专利5,773,647中的193种修饰的氨基酸中的任意一种,或者是它们的任意组合。前述美国专利5,773,647和5,866,536中的内容在此全文引入作为参考。此外,该递送试剂可以是任一种前述的修饰的氨基酸的二钠盐以及它们的乙醇溶剂化物和水合物。适宜的化合物包括以下式I的化合物及其水合物和醇溶剂化物,
式I
其中
R1、R2、R3和R4彼此独立地是氢、-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亚链烯基、取代或未取代的C1-C12烷基(亚芳基)或取代或未取代的芳基(C1-C12亚烷基);且
R6和R7彼此独立地是氢、氧或C1-C4烷基。
式I化合物及其二钠盐和醇溶剂化物和水合物公开于WO 00/059863,此文中还公开了该化合物的制备方法。
二钠盐可从乙醇溶剂化物制备得到:通过本领域公知的方法蒸发或干燥乙醇溶剂化物以形成无水二钠盐。干燥通常在约80至约120℃、优选约85至约90℃、最优选在约85℃的温度下进行。干燥步骤通常在26”Hg或更高的压力下进行。无水二钠盐通常含有少于约5%(重量)的乙醇,优选少于约2%(重量)的乙醇,以无水二钠盐100%总重量计。
递送试剂的二钠盐也可以通过以下方法制备:制备递送试剂在水中的浆液,然后加入两摩尔当量的氢氧化钠水溶液、醇钠等。适宜的醇钠包括、但不限于甲醇钠、乙醇钠以及它们的组合。
另一种制备二钠盐的方法是:将递送试剂与一摩尔当量的氢氧化钠反应以制备二钠盐。
可通过真空蒸馏浓缩含有二钠盐的溶液至浓稠的糊状物以固体的形式分离出二钠盐。该糊状物可在真空烘箱中干燥以得到固体形式的递送试剂的二钠盐。该固体也可以通过喷雾干燥二钠盐的水溶液而得到。
递送试剂可以按本领域公知的,如,按如上所述的,公开于美国专利5,773,647和5,866,536的方法制备。
乙醇溶剂化物,如前述WO 00/059863中所描述的,包括、但不限于乙醇溶剂的分子或离子与递送试剂的二钠盐的分子或离子形成的分子型或离子型的复合物。通常,对于每分子的递送试剂二钠盐而言,乙醇溶剂化物中含有约一个乙醇分子或离子。
递送试剂二钠盐的乙醇溶剂化物可通过将递送试剂溶于乙醇中得到。通常,每克递送试剂可溶于约1至约50mL、通常为约2至约10mL的乙醇中。随后,将递送试剂/乙醇溶液与相对于递送试剂而言一摩尔过量的含钠盐例如含一钠的盐反应(即,对于每摩尔的递送试剂,有多于一摩尔的钠阳离子)得到乙醇溶剂化物。适宜的一钠盐包括、但不限于氢氧化钠;醇钠,诸如甲醇钠和乙醇钠;和它们的任意组合。优选的,向乙醇溶液中加入至少约两摩尔当量的含一钠的盐,即,对于每一摩尔的递送试剂,有至少约两摩尔的钠阳离子。通常,反应于混合物的回流温度下或低于回流温度的温度、诸如室温下进行。随后将乙醇溶剂化物按照本领域公知的方法回收,例如,将所得浆液通过常压蒸馏浓缩,冷却浓缩后的浆液并过滤出固体。回收的固体随后可通过真空干燥得到乙醇溶剂化物。
递送试剂二钠盐的水合物可按如下制备:如前所述干燥乙醇溶剂化物得到无水二钠盐,然后水合该无水二钠盐。优选形成二钠盐的一水合物。由于无水二钠盐极易受潮,因此处于环境湿度下即可形成水合物。通常,水合步骤在约室温至约50℃下、优选室温至约30℃下,在至少50%相对湿度的环境下进行。或者,无水二钠盐也可以用蒸汽水合。
优选的递送试剂是N-(5-氯代水杨酰)-8-氨基辛酸(5-CNAC)、N-(10-[2-羟基苯甲酰]氨基)癸酸(SNAD)、N-(8-[2-羟基苯甲酰]氨基)辛酸(SNAC)以及它们的一钠盐和二钠盐、其钠盐的乙醇溶剂化物及其钠盐的一水合物和它们的任意组合。最优选的递送试剂是5-CNAC的二钠盐及其一水合物。
本发明的药物组合物通常含有递送有效量,即,足以有效递送活性试剂而产生所需效果的量的一种或多种递送试剂。通常,递送试剂的量为2.5%至99.4%(重量),更优选的是25%至50%(重量)。
本发明的药物组合物可以以胶囊(包括软胶囊)、片剂、囊形片剂(caplet)或其它的固体口服剂型提供,所有的这些剂型都可以按本领域公知的方法制备。
该组合物还可含有常规用量的添加剂,包括、但不限于pH调节剂、防腐剂、矫味剂、遮味剂、香料、湿润剂、强度剂(tonicifier)、着色剂、表面活性剂、增塑剂、润滑剂如硬脂酸镁、助流剂、压片助剂、增溶剂、赋形剂、稀释剂如微晶纤维素(如FMC公司提供的Avicel PH 102),或是它们任意组合。其它的添加剂可包括磷酸盐缓冲盐、柠檬酸、乙二醇以及其它分散剂。
组合物中还可以包含一种或多种酶抑制剂,诸如放线酰胺素或表放线酰胺素(epiactinonin)以及它们的衍生物;抑肽酶、Trasylol和Bowman-Birk抑制剂。
此外,在本发明的组合物中还可含有转运抑制剂,即ρ-糖蛋白,诸如Ketoprofin。
优选本发明的固体药物组合物中含有稀释剂,诸如Avicel;及润滑剂,诸如硬脂酸镁。
本发明的固体药物组合物可通过常规方法制备,例如,将一种或多种活性试剂、递送试剂、交联聚维酮或聚维酮和其它成分的混合物混合、揉捏并填入胶囊中,或者不填入胶囊,而在模压后进一步的压片或压模得到片剂。此外,还可以按公知方法制备固体分散体,之后进一步加工成片剂或胶囊。
优选本发明药物组合物中的成分在整个固体剂型中是均匀混合的。
可以向任何需要的动物,包括、但不限于哺乳动物,诸如啮齿类、奶牛、猪、狗、猫和灵长类,特别是人类施用本发明的组合物以向其递送活性试剂。
以下实施例用以进一步的阐明本发明。
实施例1
按照本发明(实施例A)和对比实施例B和C制备片剂,B、C中用Ac-Di-Sol替代交联聚维酮(Ac-Di-Sol是交联羧甲基纤维素钠),并按照对比实施例D制备含有5-CNAC和鲑降钙素的共同冻干的(colyophilized)胶囊。
具体地讲,片剂按照以下方法制备:
制备实施例A
将0.502g预过40目筛的鲑降钙素、120g预过35目筛的5-CNAC二钠盐和20g Polyplasdone XL(交联聚维酮,NF)在500mL广口瓶中混合并用Turbula混合器以46RPM的速度混合2分钟。向广口瓶中补加125.4g预过35目筛的5-CNAC二钠盐和32.5g Avicel PH 102并以46RPM的速度混合物8分钟。再向广口瓶中加入32.5g Avicel并以46RPM的速度混合5分钟。将4.0g硬脂酸镁用35目筛筛入到广口瓶中并以46RPM的速度混合1分钟。将最终的混合物用Manesty B3B压片机压成片剂。片剂重量约为400mg。
对比实施例B
将14g 5-CNAC二钠盐和0.56g CabOSil混合并过40目筛。将0.3g5-CNAC二钠/CabOSil混合物、0.028g预过40目筛的鲑降钙素和0.56g预过30目筛的Ac-Di-Sol在1夸脱的V型混合器中混合。将混合物混合2分钟。将约14.3g 5-CNAC二钠/Cab-O-Sil混合物以几何递增的方式加入到V型搅拌器中并在每次加入后混合2分钟(依次以约0.8、1.7、3.2和8.6g加入)。将12.43g预过40目筛的Avicel PH 102和0.42g预过40目筛的硬脂酸镁加入到V型搅拌器中并混合5分钟。随后将最终的混合物过40目筛并用例如Manesty F3压片机压制成片。片剂重量约为400mg。
对比实施例C
将0.1224g预过40目筛的鲑降钙素、30g预过35目筛的5-CNAC二钠盐和4g Ac-Di-Sol置于500mL Pyrex广口瓶中并用Turbula混合器以46RPM的速度混合2分钟。向广口瓶中补加31.35g预过35目筛的5-CNAC二钠盐和15g Avicel PH 102并以46RPM的速度混合8分钟。将2gCabOSil和16.15g Avicel混合后过18目筛。将CabOSil/Avicel混合物加入到广口瓶中并以46RPM的速度混合5分钟。将1.5g硬脂酸镁用35目筛筛入广口瓶中,并以46RPM的速度混合2分钟。将最终的混合物用Manesty B3B压片机压成片剂。片剂重量约为400mg。
对比实施例D
将18kg注射用水和0.16kg氢氧化钠,NF加入到容器中混合至溶解。将0.800kg 5-CNAC的游离酸加入到容器中并以400-600RPM的速度搅拌至少10分钟。用10N氢氧化钠将容器内的pH调节至约8.5。在每次加入10N氢氧化钠后,将容器搅拌至少10分钟。向100mL注射用水中加入40g氢氧化钠,NF以制备10N氢氧化钠。通过加入注射用水(密度1.016)将混合溶液的最终重量调节到20.320kg。将容器以400-600RPM的速度搅拌至少30分钟。用蠕动泵、有机硅管和DuraPore 0.45μm MPHL膜胶囊式过滤器将混合溶液滤入另一容器中。通过将13.8g磷酸二氢钠一水合物,USP加入到900g注射用水中并用1.0N磷酸溶液将pH调节至4.0制得磷酸盐缓冲液。磷酸溶液是通过将0.96g磷酸,NF加入到25mL注射用水中制备得到的。通过加入注射用水将磷酸盐缓冲液的最终重量调节至1007g(密度1.007)并搅拌5分钟。
缓冲的鲑降钙素溶液可通过将1.6g鲑降钙素加入到660g磷酸盐缓冲液中制得。用磷酸盐缓冲液将该溶液的最终重量调节至806.4g(密度1.008)并以250RPM或更低的速度搅拌至少5分钟。
将0.800kg缓冲的鲑降钙素溶液滴加到20kg 5-CNAC溶液中并以250RPM或更低的速度持续混合至少5分钟。将约0.75L鲑降钙素/5-CNAC溶液填充到不锈钢冷冻干燥盘(30.5×30.5cm)中至最终的溶液深度为0.8-0.9cm。21.75L鲑降钙素/5-CNAC溶液可充满约29个小盘。将小盘置于Edwards冷冻干燥机中并按照以下步骤进行冷冻干燥:
1.放入小盘后密封Reeze干燥器,以1℃/分钟的速度冷却搁板。
2.当搁板温度到达-45℃时,使搁板温度在-45℃下维持至少120分钟。
3.将冷凝器降温至-50℃或更低。
4.排空腔室,当恒定在300微米真空时,将搁板温度以1℃/分钟的速度升至-30℃。
5.将搁板温度在-30℃下维持180分钟。
6.将腔室压力降至200微米,并当真空度维持在200微米时,将搁板温度以1℃/分钟的速度升至-20℃。
7.将搁板温度在-20℃下维持200分钟。
8.以1℃/分钟的速度将搁板温度升高至-10℃。
9.将搁板温度在-10℃下维持360分钟。
10.以1℃/分钟的速度将搁板温度升高至0℃。
11.将搁板温度在0℃下维持720分钟。
12.将腔室压力降至100微米,并当真空度维持在100微米时,将搁板温度以1℃/分钟的速度升至+10℃。
13.将搁板温度在+10℃维持540分钟。
14.将搁板温度以1℃/分钟的速度升至+25℃。
15.将搁板温度在+25℃下维持440分钟。
16.释放真空并取出小盘。
将共同冻干的鲑降钙素/5-CNAC从小盘中取出并在冷藏条件下储存于聚乙烯和箔制小袋中。将约400mg共同冻干的物料填入胶囊(AA型)中用于给药。
实施例2
灵长类动物的给药
将实施例1中所制备的片剂或胶囊按如下方法对恒河猴进行给药:每组4至6只猴子,每只猴子都按照如下方法给予实施例1中制备的胶囊(1粒)或片剂(2片):
使恒河猴在给药前禁食一个晚上,并在研究期间将其意识清醒的固定在椅子上。将胶囊或片剂通过管饲法给药,并随后给予10mL水。
在给药后第0.25、0.5、0.75、1、1.5、2、3、4、5和6小时收集血样。通过放射免疫测定法确定血浆鲑降钙素。将从每组猴子中得到的灵长类动物血浆鲑降钙素(sCT)结果平均,计算最大的平均血浆降钙素浓度和曲线下面积(AUC)并将结果报告于表2中。
表2
剂型 | sCT Cmax(pg/mL) | sCT AUC |
对比实施例D | 415 | 792.4 |
对比实施例B | 457 | 992.5 |
对比实施例C | 329 | 797 |
实施例A | 2420 | 4400 |
从表2中的数据可以看出,含有交联聚维酮的本发明的组合物(实施例A)的鲑降钙素Cmax和鲑降钙素AUC要远远高于不含交联聚维酮的对比组合物,因此本发明的制剂大大提高了口服生物利用度。
实施例3
加速稳定性测试
按照对比实施例C和实施例A分别制备含有0.065mg、0.400mg和2.500mg sCT的片剂,对其中的sCT和Avicel进行调整以获得所需的片剂强度。将片剂和干燥剂一同置于HDPE瓶中,将其感应密封并帽封。加速稳定性测试通过将稳定性样品置于25℃和60%相对湿度的环境模拟箱中进行。在特定的时间点,如在第3、4和6周抽出样品,并通过HPLC分析其中的sCT。所得结果示于表3中。
表3
sCT分析 | 0.065mg片剂 | 0.400mg片剂 | 2.500mg片剂 | |||
25℃/60%RH | 对比实施例C | 实施例A | 对比实施例C | 实施例A | 对比实施例C | 实施例A |
0时间 | 93.5% | 100.9% | 94.3% | 103.0% | 100.3% | 98.0% |
3周 | - | 97.4% | - | 98.8% | - | - |
4周 | 84.2% | - | 88.8% | - | 91.5% | 100.2% |
6周 | - | 95.2% | - | 96.9% | - | - |
在室温下4周后的对比实施例C(sCT分析中有约10%的减少)与室温下6周后的本发明的实施例A(在sCT分析中有约5%的减少)相比,证实了本发明的制剂可以改善按照本发明制备的片剂的稳定性。
实施例4
固体制剂的片剂崩解可通过按照实施例1制备含有60%5-CNAC二钠、29%Avicel、1%硬脂酸镁,但不含sCT的片剂来测定。片剂崩解可按照USP崩解测试<701>的方法测定,片剂硬度可以使用校准后的Vector/Schleuniger 6D片剂硬度测试器测定。所得结果示于表4中。
表4
赋形剂 | 含量 | 硬度 | 崩解 | 硬度 | 崩解 |
Ac-Di-Sol | 10% | 5.7Kp* | 1.1-1.4分钟 | 10.1Kp | 5.6-6.5分钟 |
Explotab | 10% | 6.9Kp | 2.6-3.3分钟 | 10.3Kp | 6.5-7.5分钟 |
Polyplasdone XL | 10% | 7.3Kp | 0.6-0.8分钟 | 10.5Kp | 2.4-2.7分钟 |
Ac-Di-Sol(Cab-O-Sil)* | 10% | 6.3Kp | 4.3-5.3分钟 | 10.3Kp | 7.3-8.0分钟 |
*Kp=千帕斯卡
表4中的结果表明:5-CNAC与Polyplasdone XL(交联聚维酮)结合使用相对于5-CNAC与其它赋形剂结合使用所制备的片剂而言产生了最快的崩解,由此证明本发明的固体制剂改善了药理学活性剂从其中的释放。
实施例5
化学稳定性
通过将片剂(按照与以上实施例1类似的方法制备,使用表5所指定的成分比例)置于帽封的琥珀色瓶子中来准备用于进行极限应力稳定性测试(extreme stress stability testing)的样品。加速稳定性测试可通过将样品置于60℃的校准炉中来进行。通过HPLC分析最初以及3或4天后样品中的sCT。所得结果示于表5中。
表5
赋形剂(0.4mg sCT/200mg 5-CNAC二钠) | 60℃ | 最初sCT分析 | 应力sCT分析 | 变化% |
Ac-Di-Sol,Cab-O-Sil,Avicel,硬脂酸镁(对比实施例C) | 3天 | 94.0% | 12.3% | -81.7% |
10% PolyplasdoneXL-10,Avicel,硬脂酸镁(实施例A) | 4天 | 98.3% | 86.5% | -11.8% |
如表5中所示,含有交联聚维酮(Polyplasdone XL-10)的本发明制剂(实施例A)与不含交联聚维酮的对比制剂相比,其在极限应力条件下sCT的化学稳定性得到了改善。
上文清楚地表明了本发明组合物与其它的口服制剂相比,极大地改善了活性试剂、特别是降钙素的口服生物利用度,并具有良好的崩解速度和优良的稳定性。
上文的具体实施方式和实施例仅供阐明而并非限制本发明。大量的其它实施方式及改变形式都在本发明的范围内,并且是本领域技术人员很容易理解的。
Claims (10)
1.适于口服递送药理学活性剂的固体药物组合物,含有
a.治疗有效量的选自降钙素的药理学活性剂;
b.交联聚维酮或聚维酮;及
c.作为所述药理学活性剂的递送试剂的5-CNAC或其二钠盐。
2.权利要求1的组合物,其中的降钙素是鲑降钙素。
3.权利要求1的组合物,其中含有交联聚维酮。
4.权利要求1的组合物,其中的递送试剂是5-CNAC二钠盐。
5.权利要求1-4任一项所述的组合物,其中还含有稀释剂。
6.权利要求5的组合物,其中的稀释剂是微晶纤维素。
7.权利要求1-4任一项所述的组合物,其中还含有润滑剂。
8.权利要求7的组合物,其中的润滑剂是硬脂酸镁。
9.权利要求1-8任一项所述的药物组合物在制备用于提高降钙素的口服生物利用度的药物中的用途。
10.权利要求1-8任一项所述的药物组合物在制备用于治疗骨相关疾病和钙失调的药物中的用途。
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US5773647A (en) * | 1997-02-07 | 1998-06-30 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
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