CN116887815A - 难吸收性药物的吸收性得到改善的组合物 - Google Patents
难吸收性药物的吸收性得到改善的组合物 Download PDFInfo
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Abstract
本发明提供一种组合物,其特征在于:其是包含离子液体和难吸收性药物的组合物,其中,难吸收性药物的吸收性已显著改善,离子液体由阴离子和阳离子构成,阴离子是碳数为3~7的有机酸,阳离子选自精氨酸、葡甲胺、氨丁三醇、二乙醇胺。
Description
技术领域
本发明涉及难吸收性药物的吸收性得到改善的组合物。详细而言,本发明涉及一种组合物,其含有难吸收性药物和离子液体,其中难吸收性药物的消化道吸收性显著改善。
背景技术
药物的口服给药为非侵袭性,容易服用和饮用,作用和效果温和,并且成本低。关于药剂,口服给药制剂是患者最易接受的给药方法,近年来最为广泛使用。
口服给药由于生物体的化学屏障和物理屏障,有时会受到严格限制。存在胃肠道内的过度的pH变化、强效的消化酶和活性剂未渗透至胃肠道等化学和物理屏障。像降钙素、胰岛素等这样的生物药品即使显示药效,也因消化道吸收性低而往往难以以口服给药的形式使用。
这样的消化道难吸收的化合物大部分以注射药的形式开发,但注射与口服给药相比给患者带来的身体、精神负担大。
近年来,运用各种肠道吸收促进技术,进行生物药品的口服给药用制剂的开发,2019年世界上首个生物药品的口服制剂(药物名:索马鲁肽(Semaglutide)、商品名:Rybelsus(注册商标))上市,2020年口服制剂(药物名:奥曲肽(Octreotide)、商品名:Mycapssa(注册商标))上市。
然而,这些口服制剂的肠道吸收性均为1%以下,吸收性低导致成本增加。另外,如果为了弥补药物的低吸收性而制成高剂量的制剂,则担心因副反应等引起的安全性,因此改善吸收性成为大的课题。
为了经粘膜递送这样的低吸收性药物,必须利用DDS技术,该DDS技术可避免药物被消化道酶降解,同时使其通过消化道上皮细胞到达全身循环。其中,对吸收促进剂的期待较高,该吸收促进剂在制剂中用作添加剂,从而可改善生物膜透过性而不损及药效。
吸收促进剂是通过与粘膜直接作用使其结构发生变化、促进药物吸收的化合物。作为吸收促进剂,迄今为止,利用体外和体内试验研究了表面活性剂、胆汁酸盐、细菌毒素、螯合剂或包括中链脂肪酸等在内的多种化合物在改善生物膜透过性低的分子的吸收中的有效性。
然而,对于生物药物这样的生理活性高的药物,在吸收促进剂所产生的生物利用度(生物利用率、以下有时也称为“BA”)改善效果低的情况下,个体间变动增大,无法得到稳定的治疗效果,结果是,导致制剂开发所需的药物量增加,成为药价高涨的主要原因。
最近,调制将由阳离子的胆碱和阴离子的香叶酸(Geranate)的共结晶构成的离子液体和胰岛素混合而得的CAGE-胰岛素,研究了在口服给药中是否在肠内吸收而发挥降血糖作用。另一方面,认为在对除胰岛素以外的药物使用该离子液体上存在课题。
迄今为止,本发明人使用由有机阴离子和有机阳离子构成的、常温下为液体的盐即离子液体(以下,有时称为“ILs”),开发了使小分子药物、中分子核酸、小分子肽等化合物有效地经皮吸收的多种经皮吸收制剂,得到了根据各药物设计最佳离子液体的见解。然而,在经皮吸收和肠道吸收(经粘膜吸收)中,药物的吸收机制大不相同,即使直接使用经皮吸收用离子液体,也无法期待吸收性的改善。为了设计消化道吸收用离子液体,对于离子液体的种类或组成等,从最初起就需要新的制剂设计。
现有技术文献
专利文献
专利文献1:国际公开第2019/09983号小册子;
专利文献2:日本特开第2007-77170号公报;
非专利文献
非专利文献1:Maher S.等人,Pharmaceutics,11,E41(2019)。
发明内容
发明所要解决的课题
本发明的目的在于:开发难吸收性药物的吸收性显著改善的组合物。
用于解决课题的手段
本发明人对用于促进针对难吸收性药物的肠道吸收效果、即药物的被动扩散(Passive Diffusion)作用的新的离子液体组合物进行了研究。
作为难吸收性药物的模型化合物,以作为2型糖尿病治疗药的胰高血糖素样肽-1(GLP-1)激动剂为对象。GLP-1激动剂大部分是以皮下注射制剂的形式使用,因此低服药依从性成为课题。与此相比,口服给药制剂以给药简便、非侵袭性、安全性高为优点,如果可实现口服给药,则可实现高的服药依从性。
GLP-1激动剂虽然是来自消化道的吸收性低的水溶性化合物,但通过使用离子液体(ILs)作为口服基质,期待肠道内的吸收性提高。因此,对于作为GLP-1受体激动剂的利司那肽(Lixisenatide)(以下,有时也称为“Lix.”)(分子量4858.49(4.86KDa))和索马鲁肽(以下,有时也称为“Sem.”)(分子量为4111(4.11KDa)),就与离子液体混合时的肠道中的吸收性进行了评价,对包含各种离子液体的制剂评价了吸收性。另外,作为模型化合物,使用作为水溶性高分子化合物、且主要通过细胞间隙路径吸收的FITC标记葡聚糖(分子量约3000~40000)进行了促进肠道吸收的离子液体的选择。其结果,发现了:通过使用包含离子液体的制剂,难吸收性药物的吸收性显著改善,该离子液体由作为碳数3~7的有机酸的阴离子和选自精氨酸、葡甲胺、氨丁三醇和二乙醇胺的阳离子构成,从而完成了本发明。
即,本发明提供以下的方案。
[项1]组合物,其特征在于:其是包含离子液体和难吸收性药物的组合物,其中,离子液体由阴离子和阳离子构成,阴离子是碳数为3~7的有机酸,阳离子选自精氨酸、葡甲胺、氨丁三醇、二乙醇胺。
[项2]项1所述的组合物,其特征在于:上述难吸收性药物是分子量为3000~20000的水溶性化合物。
[项3]项1或2所述的组合物,其特征在于:上述难吸收性药物为GLP-1激动剂。
[项4]项1~3中任一项所述的组合物,其特征在于:上述有机酸为选自乳酸、柠檬酸、酒石酸、苹果酸、琥珀酸、苯甲酸的1种以上的有机酸。
[项5]项1~4中任一项所述的组合物,其特征在于:进一步包含选自羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮的1种以上的水溶性高分子。
[项6]口服制剂,其包含项1~项5中任一项所述的组合物。
[项7]提高难吸收性药物的消化道吸收性的方法,其特征在于:在包含难吸收性药物的组合物中掺混离子液体,该离子液体由作为碳数3~7的有机酸的阴离子和选自精氨酸、葡甲胺、氨丁三醇和二乙醇胺的阳离子构成。
发明效果
根据本发明,即使是难以口服给药的难吸收性药物,其吸收性也会显著改善,从而可作为口服制剂来调制。另外,还可进行生物利用度较现有的口服制剂优异的制剂设计。
附图说明
[图1]图1显示使用利司那肽作为难吸收性药物的制剂例1、4和5的口服给药和比较例1的皮下给药中的利司那肽的血中浓度(pg/mL)的经时性变化。
[图2]图2显示使用利司那肽作为难吸收性药物的制剂例1的经肠给药和比较例1的皮下给药中的利司那肽的血中浓度(pg/mL)的经时性变化。
[图3-1]图3-1显示使用利司那肽作为难吸收性药物的制剂例1~8和比较例1的经肠给药1小时后的利司那肽的血中浓度(pg/mL)。
[图3-2]图3-2显示使用利司那肽作为难吸收性药物的制剂例9~12的经肠给药1小时后的利司那肽的血中浓度(pg/mL)。
[图3-3]图3-3显示使用利司那肽作为难吸收性药物的制剂例13~21的经肠给药1小时后的利司那肽的血中浓度(pg/mL)。
[图4]图4显示使用索马鲁肽作为难吸收性药物的制剂例1~3和22~23的经肠给药1小时后的索马鲁肽的血中浓度(pg/mL)。
[图5]图5显示使用FTIC标记葡聚糖作为难吸收性药物的制剂例1~5和24~26的口服给药后的血清中FITC标记葡聚糖的荧光强度。
[图6]图6显示使用平均分子量不同的3种(10kDa、20kDa和40kDa)FTIC标记葡聚糖作为难吸收性药物的各制剂例1的口服给药后的血清中FITC标记葡聚糖的荧光强度。在各糊精的条形图中,左侧的条表示制剂例1,右侧的条表示对照。
具体实施方式
本发明涉及含有难吸收性药物和离子液体、且显著改善了难吸收性药物的消化道吸收性的组合物。
本发明中,“难吸收性药物”是指生物膜透过性低的药物,例如可列举:因消化道粘膜上存在的粘液层的透过性差而不易从消化道吸收的药物、通过与存在于粘液层的物质的相互作用而不易被吸收的药物、在消化道粘膜中因透过性差而不易从消化道吸收的药物、因消化道粘液层与粘膜发生相互作用而不易口服吸收的药物、或者通过与胆汁酸形成不溶性复合物而显示难吸收性的药物。通常是指通过口服给药难以递送的药物。
本发明中使用的难吸收性药物例如可列举:肽、蛋白、核酸和它们的衍生物。作为它们的例子,可列举:胰岛素、降钙素、GLP-1激动剂、血管紧张素、加压素、去氨加压素、LH-RH(黄体生成素释放激素)、生长抑素、胰高血糖素、催产素、胃泌素、环孢菌素、生长调节素、促胰液素、h-ANP(人心房利钠肽)、ACTH(促肾上腺皮质激素)、MSH(促黑素细胞激素)、β-内啡肽、胞壁酰二肽、脑啡肽、神经降压素、蛙皮素、VIP(血管活性肠肽)、CCK-8(缩胆囊素-8)、PTH(甲状旁腺激素)、CGRP(降钙素基因相关肽)、TRH(促甲状腺素释放激素)、内皮素、hGH(人生长激素)、特立帕肽或白介素、干扰素、集落刺激因子、肿瘤坏死因子等细胞因子类、以及它们的衍生物等。作为该肽和蛋白,不仅包括天然来源的物质,还包括药理学活性的衍生物和它们的类似物。例如,本发明中成为对象的降钙素不仅包括鲑降钙素、人降钙素、猪降钙素、兔降钙素和鸡降钙素等天然存在的产物,还包括它们的基因重组体等类似物。另外,胰岛素不仅包含人胰岛素、猪胰岛素、牛胰岛素,还包括它们的基因重组体等类似物。
核酸是高分子,并具有由带负电荷的磷酸二酯结构连接而成的聚阴离子结构,因此具有不易透过疏水性细胞膜的特征。作为该核酸,例如包括:作为反义核酸的福米韦生(Fomivirsen)、米泊美生(Mipomersen)、依特立生(Eteplirsen)、诺西那生(Nusinersen)、经RNA适配体进行PEG化的哌加他尼(Macugen)、SiRNA、诱饵(decoy)核酸、CpG低聚物(CpGoligo)和它们的衍生物。
GLP-1激动剂是由生物体分泌的肠降血糖素激素即胰高血糖素样肽-1(GLP-1)的类似物,通过经由GLP-1受体起作用使cAMP增加,葡萄糖浓度依赖性地促进胰岛素分泌。GLP-1激动剂例如包括:索马鲁肽、度拉糖肽(Dulaglutide)、利司那肽、艾塞那肽(Exenatide)、利拉鲁肽(Liraglutide)、以及它们的基因重组体等的类似物。
另外,难吸收性药物还包括除肽、蛋白、核酸以外的难以口服给药的化合物,例如可列举:万古霉素(Vancomycin)、庆大霉素(Gentamicin)、瑞德西韦(Remdesivir)等。
对本发明所涉及的难吸收性药物的口服吸收性的高低不该有特别限定。因在消化道中的吸收性低而无法通过口服给药而获得充分的药理效果的药物,通过提高口服吸收性,可得到期待的药理效果。另外,虽然在消化道中的吸收性低但通过口服给药可得到充分的药理效果的药物,通过进一步提高口服吸收性,可减少药物的给药量,可减轻副作用。
本发明中,“离子液体”是指由阴离子和阳离子形成的常温下为粘稠液态的布朗斯台德(Bronsted)盐,其熔点为100℃以下。阴离子和阳离子可通过将有机酸等的有机阴离子和有机阳离子以等摩尔量或过剩量在室温或加热下混合来调制。有机阴离子/或有机阳离子的过剩量优选为10倍摩尔量以内。
本发明中,“有机酸”是指显示酸性的有机化合物的统称。有机酸中的碳链可以是直链也可以是支链,可以饱和也可以不饱和。适合的是包含羧酸的有机酸,但可以是羧基,除羧基以外,可进一步包含羟基。作为有机酸,例如可列举:碳数为3~7的有机酸,优选乳酸、柠檬酸、酒石酸、琥珀酸、苹果酸、苯甲酸。
本发明中,“阳离子”是指阳离子性有机化合物,例如可列举:有机胺、有机季铵阳离子、碱性氨基酸、氨基糖等。
作为有机阳离子,例如可列举:碳数为4~12的有机胺,优选二乙醇胺、三乙醇胺、精氨酸、赖氨酸、天冬酰胺、葡甲胺、氨丁三醇。特别是优选二乙醇胺、精氨酸、葡甲胺、氨丁三醇。
本发明的离子液体虽然由上述有机阴离子和有机阳离子的组合构成,但可作为2种以上的混合离子液体(也包括仅有机酸或有机胺化合物不同的情况下的离子液体)使用。另外,离子液体例如可包含相对于其量为1~10倍当量的水。
本发明中的组合物(制剂)可与药学上可接受的载体组合使用。作为载体,例如可列举:赋形剂、覆膜剂、粘合剂、增量剂、崩解剂、表面活性剂、润滑剂、稀释剂、分散剂、缓冲剂、渗透压调节剂、pH调节剂、乳化剂、防腐剂、稳定剂、抗氧化剂、着色剂、紫外线吸收剂、保湿剂、增稠剂、活性增强剂、矫味剂、矫臭剂等。
这些载体可各自单独使用,也可将2种以上以适当的量组合使用。
在难吸收性药物为肽、蛋白和核酸的情况下,如果采用使该药物不被降解而送达至消化酶的影响少的空肠、回肠、结肠、大肠等下消化道的制剂技术,则可提供口服用药物组合物。例如,作为这种制剂技术,可列举:缓释制剂、结肠释放制剂控释型或脉冲释放型制剂、片剂、包衣片、颗粒剂、散剂、胶囊剂这样的固体给药形态,以及酏剂、糖浆和悬浮液这样的液体给药形态。
另外,本发明的组合物可制成具有水溶性包围剂的胶囊状。该水溶性包囲剂是指成为胶囊的被膜的物质,通过用该水溶性包囲剂密封内容液,可发挥内容液的抗氧化等品质保持能力,可成型成胶囊。
在将本发明的组合物成型成胶囊时,可使用羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮等水溶性高分子进行成型。
实施例
以下,给出实施例,以更具体地说明本发明。本发明不受以下实施例的任何限定。
在以下的实施例中,试剂等使用从下述制造商获取的产品,但本发明并不限定于这些。
乳酸(日局:健荣制药株式会社);
油酸:Croda Japan株式会社;
苹果酸、硬脂酸、(L+)酒石酸、琥珀酸、柠檬酸、二乙醇胺、氨丁三醇:富士胶片和光纯药株式会社;
纯净水:大冢制药工厂株式会社;
葡甲胺:东京化成工业株式会社。
实施例1:含离子液体的制剂的调制
称取各成分使达到下表1中所示的含量(摩尔比),将它们混合,调制了离子液体配方。然后,将难吸收性药物溶解于所调制的离子液体配方,调制了制剂例1~21的离子液体制剂。另外,调制了将难吸收性药物溶解于生理盐水而得的溶液,以该溶液作为比较例1。
表中的ILs(A)标记为水溶性高的离子液体,ILs(B)标记为与ILs(A)相比脂溶性高的离子液体。括弧内的数字表示各试剂的摩尔比。
[表1]
实施例2:难吸收性药物在口服给药中的血中浓度的评价
本实验中,使用利司那肽(从株式会社Scrum购入)作为难吸收性药物,按照以下的方法对口服给药后的药物的血中浓度进行评价。
按照实施例1的方法,调制了包含利司那肽作为难溶性药物的制剂例1、4和5。具体而言,以上述表1中所示的含量(摩尔比)混合各成分,调制离子液体配方,在所调制的0.5mL该离子液体配方中加入1.4mg利司那肽,在65℃下加热10分钟使其溶解,从而调制了各制剂。
将利司那肽与离子液体混合,在显微镜下确认时,通过加热,利司那肽的晶体消失,由此判断为利司那肽已溶解。
作为比较例,调制了将利司那肽溶解于生理盐水的比较例1。
(试验方法)
使用BALB/c小鼠(5周龄、雄性)(从日本SLC(静冈、日本)购入)作为实验动物。
具体而言,让BALB/c小鼠禁食一夜后,将调节了利司那肽量的制剂例1、4和5(以利司那肽量计为12.5mg/kg)进行口服给药,另外,将比较例1(以利司那肽量计为10μg/kg)进行皮下给药。然后,在给药1、2和4小时后,使用装有肝素钠的注射器从下腔静脉采血,进行离心(4℃、10分钟、3,000×g),之后回收血浆,在-80℃下冷冻保存。用利司那肽EIA试剂盒(Phoenix Pharmaceuticals Inc.、CA、USA)定量该血浆。
将制剂例1、4和5的制剂进行口服给药,测定血液中的利司那肽浓度。以比较例1的血中浓度曲线的AUC为100%,算出各制剂例的相对BA(0-4小时)。
其结果见图1。根据图1显示出:制剂例1和5中,在1小时后血中浓度较高,通过口服给药-离子液体,利司那肽迁移到血中。然而,制剂例4的血中迁移浓度低。需要说明的是,由于利司那肽在胃中降解,所以BA值显示以下的低值:制剂例1(0.046%)、制剂例4(0.032%)、制剂例5(0.058%)。
实施例3:难吸收性药物在经肠给药中的血中浓度的评价
使用BALB/c小鼠(5周龄、雄性)(从日本SLC(静冈、日本)购入)作为实验动物。
具体而言,让BALB/c小鼠禁食一夜后,切开腹部,对十二指肠~空肠之间的肠部经肠给予包含利司那肽作为难溶性药物、且调整了利司那肽量的制剂例1(以利司那肽量计为1mg/kg、制剂例1的离子液体稀释10倍),另外,将包含利司那肽作为难溶性药物的比较例1(以利司那肽量计为10μg/kg)进行皮下给药。在给药1、2、4、6和24小时后,使用装有肝素钠的注射器从下腔静脉采血,进行离心(4℃、10分钟、3,000×g),之后回收血浆,在-80℃下冷冻保存。用利司那肽EIA试剂盒(Phoenix Pharmaceuticals Inc.、CA、USA)定量该血浆。
其结果见图2。根据图2,在调制的制剂例1的经肠给药中,在给药1小时后血中利司那肽浓度达到峰值(5,900pg/mL),之后缓慢减少,在24小时后从血中消失。以比较例1的血中浓度曲线的AUC为100%,算出制剂例1的相对BA值为2.9%左右,大大超过口服给药时的制剂例1的BA值(0.046%)。即,通过对采用了经肠给药的各种离子液体制剂进行血中迁移性的比较研究,显示出可设计适合肠道吸收的离子液体,可用作口服给药制剂。
实施例4:难吸收性药物在经肠给药中的血中迁移性评价(1)
按照实施例1的方法,调制了包含利司那肽作为难溶性药物的制剂例1~21。具体而言,以上述表1中所示的含量(摩尔比)混合各成分,调制离子液体配方,向0.5mL中加入1.4mg利司那肽,在65℃下加热10分钟使其溶解,从而调制了各制剂。使用所调制的制剂例1~21的制剂,就经肠给药中的利司那肽的血中迁移性进行比较研究。使用ICR小鼠(8-9周龄、雄性)(从日本SLC(静冈、日本)购入)作为实验动物。
具体而言,让ICR小鼠禁食一夜后,切开腹部,对十二指肠~空肠之间的肠部经肠给予调整了利司那肽量的制剂例1~21(以利司那肽量计为1mg/kg)。在给药1小时后,使用装有肝素钠的注射器从下腔静脉采血,进行离心(4℃、10分钟、3,000×g),之后回收血浆,在-80℃下冷冻保存。用利司那肽EIA试剂盒(Phoenix Pharmaceuticals Inc.、CA、USA)定量该血浆。
其结果见图3-1~图3-3。如图3-1所示,在包含使用了乳酸的离子液体的制剂例1~3、制剂例5和制剂例7中,利司那肽的血中迁移性高。另一方面,在乳酸比例少的制剂例6、制剂例9~10中,利司那肽的血中迁移性低。因此,由该结果暗示:乳酸的量对难吸收性药物的血中迁移性较为重要。
在包含使用了苹果酸的离子液体的制剂例11、制剂例12中,利司那肽的血中迁移性良好,特别是包含酒石酸的离子液体的制剂例15和16的血中迁移性高。另外,包含苯甲酸的制剂例13和14也显示良好的血中迁移性,包含琥珀酸的制剂例17和18也良好。然而,仅包含油酸的制剂例4的血中迁移性低。
根据以上的结果,通过使用包含一定量的有机酸的离子液体进行经肠给药,难吸收性的利司那肽的血中浓度显著上升,由此暗示这些离子液体促进难吸收性药物的肠道吸收。
实施例5:难吸收性药物在经肠给药中的血中迁移性评价(2)
在本实验中,使用索马鲁肽(从株式会社Scrum购入)作为难吸收性药物,按照以下的方法对药物的血中迁移性进行了评价。
按照实施例1的方法,调制了包含利司那肽作为难溶性药物的制剂例1~3和22~23。具体而言,以下述表2中所示的含量(摩尔比)混合各成分,调制离子液体配方,向所调制的0.5mL该离子液体配方中加入1.44mg索马鲁肽,在65℃下加热10分钟使其溶解,从而调制了各制剂。
将索马鲁肽与离子液体混合,在显微镜下确认到:通过加热,索马鲁肽的晶体消失,判断为索马鲁肽已溶解。
[表2]
使用ICR小鼠(8-9周龄、雄性)(从日本SLC(静冈、日本)购入)作为实验动物。
具体而言,让ICR小鼠禁食一夜后,切开腹部,对十二指肠~空肠之间的肠部经肠给予调整了索马鲁肽量的制剂例1~3和22~23(以索马鲁肽量计为0.4mg/kg)。在给药1小时后,从下腔静脉采血,加入到含有EDTA的管中,充分混合。在进行离心(4℃、10分钟、3,000×g),之后回收血浆,在-80℃下冷冻保存。用索马鲁肽EIA试剂盒(PeninsulaLaboratories International Inc.、CA、USA)定量该血浆。
其结果见图4。根据图4,在制剂例1~3中,血中索马鲁肽浓度高,特别是在制剂例3中显示出高的血中索马鲁肽浓度。另一方面,油酸与葡甲胺、油酸与氨丁三醇的组合制剂例22和23的血中索马鲁肽浓度低。
实施例6:难吸收性药物在口服给药中的血中迁移性评价(1)
本实验中,使用肠道吸收性低的化合物即葡聚糖,按照以下的方法,对药物的血中迁移性进行了研究。葡聚糖是从Sigma-Aldrich(MO、USA)购入FITC标记葡聚糖(平均分子量:3000~5000)。
按照实施例1的方法,调制了包含FITC标记葡聚糖作为难溶性药物的制剂例1~5和24~26。具体而言,以下述表3中所示的含量(摩尔比)混合各成分,调制了离子液体配方,向所调制的1mL该离子液体配方中加入2.5mg FITC标记葡聚糖使其溶解,从而调制了各制剂。
[表3]
使用BALB/c小鼠(7周龄、雄性)(从日本SLC(静冈、日本)购入)作为实验动物。
具体而言,让BALB/c小鼠禁食一夜后,口服给予调整了FITC标记葡聚糖量的制剂例1~5和24~26(以FITC标记葡聚糖量计为12.5mg/kg)。在给药1小时后,从下腔静脉采血,在常温下静置约30分钟,进行离心(4℃、15分钟、1,500×g),从而回收血清,在-80℃下冷冻保存。使用酶标仪(Microplate Reader)(Tecan Infinite F200 pro、Tecan、Mannedorf、Switzerland)测定血清中FITC标记葡聚糖的荧光强度(激发波长:485nm、荧光波长:535nm)。
其结果见图5。根据图5,在制剂例24中显示出最高的荧光强度,其次是制剂例1~3显示出高的荧光强度。另一方面,在仅油酸与精氨酸的组合的制剂例4中,没有显示出良好的荧光强度。
实施例6: 难吸收性药物在口服给药中的血中迁移性评价(2)
在本实验中,使用平均分子量不同的3种葡聚糖,按照以下的方法探讨了药物的血中迁移性。葡聚糖是从Sigma-Aldrich(MO、USA)购入平均分子量为10000(10kDa)、20000(20kDa)和40000(40kDa)的葡聚糖。
按照实施例1的方法,调制了包含平均分子量为10kDa、20kDa或40kDa的葡聚糖作为难溶性药物的制剂例1。具体而言,以下述表3中所示的含量(摩尔比)混合各成分,调制离子液体配方,向所调制的该离子液体配方中加入FITC标记葡聚糖,将浓度调整至0.125M/mL,在65℃下加热10分钟使其溶解,从而调制了各制剂。
使用将各葡聚糖溶解于生理盐水而得的制剂作为对照。
使用BALB/c小鼠(7周龄、雄性)(从日本SLC(静冈、日本)购入)作为实验动物,按照实施例5中记载的试验方法测定血清中FITC标记葡聚糖的荧光强度。
其结果见图6。根据图6,使用了制剂例1的平均分子量为10kDa和20kDa的葡聚糖与对照相比显示出明显的荧光强度,而平均分子量为40kDa的葡聚糖与对照相比没有显示出明显的荧光强度。
产业实用性
根据本发明,即使是难以口服给药的难吸收性药物,其吸收性也会得到显著改善,从而也可调制成口服制剂。另外,可进行生物利用度较现有的口服制剂优异的制剂设计。
Claims (5)
1.组合物,其特征在于:其是包含离子液体和难吸收性药物的组合物,其中,离子液体由阴离子和阳离子构成,阴离子是碳数为3~7的有机酸,阳离子选自精氨酸、葡甲胺、氨丁三醇、二乙醇胺。
2.权利要求1所述的组合物,其特征在于:上述难吸收性药物是分子量为3000~20000的水溶性化合物。
3.权利要求1或2所述的组合物,其特征在于:上述难吸收性药物为GLP-1激动剂。
4.权利要求1~3中任一项所述的组合物,其特征在于:上述有机酸为选自乳酸、柠檬酸、酒石酸、苹果酸、琥珀酸、苯甲酸的1种以上的有机酸。
5.权利要求1~4中任一项所述的组合物,其特征在于:进一步包含选自羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮的1种以上的水溶性高分子。
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