CN108289890B - 含有2-{4-[n-(5,6-二苯基吡嗪-2-基)-n-异丙基氨基]丁氧基}-n-(甲磺酰基)乙酰胺的医药组合物 - Google Patents
含有2-{4-[n-(5,6-二苯基吡嗪-2-基)-n-异丙基氨基]丁氧基}-n-(甲磺酰基)乙酰胺的医药组合物 Download PDFInfo
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Abstract
本发明提供稳定化的2‑{4‑[N‑(5,6‑二苯基吡嗪‑2‑基)‑N‑异丙基氨基]丁氧基}‑N‑(甲磺酰基)乙酰胺的固体制剂。该固体制剂包含2‑{4‑[N‑(5,6‑二苯基吡嗪‑2‑基)‑N‑异丙基氨基]丁氧基}‑N‑(甲磺酰基)乙酰胺和比表面积在1.0m2/g以下的D‑甘露糖醇。
Description
技术领域
本发明涉及2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}-N-(甲磺酰基)乙酰胺(以下称为“化合物(I)”)的稳定化固体制剂。
背景技术
已知下述结构式表示的化合物(I)具有优异的前列腺素I2(也称为PGI2)受体激动作用,且显示血小板凝集抑制作用、血管扩张作用、支气管肌肉扩张作用、脂质沉积抑制作用、白血球活化抑制作用等各种药效(专利文献1)。
[化1]
通常,作为固体制剂的赋形剂,使用乳糖、玉米淀粉、结晶纤维素和D-甘露糖醇等糖醇类用于有效成分的稀释。在研究含化合物(I)的固体制剂的处方的过程中,得知化合物(I)自身相对于温度和湿度是稳定的,但随D-甘露糖醇的种类的不同,固体制剂中的化合物(I)发生分解,其含量降低。
现有技术文献
专利文献
专利文献1:国际公开第2002/088084号
专利文献2:国际公开第2009/157396号
专利文献3:国际公开第2009/107736号
专利文献4:国际公开第2009/154246号
专利文献5:国际公开第2009/157397号
专利文献6:国际公开第2009/157398号
专利文献7:国际公开第2009/154246号
专利文献8:国际公开第2009/157397号
非专利文献
非专利文献1:《肝脏病学(Hepatology)》,2007,第45卷,No.1,p159-169.
非专利文献2:《日本药理学杂志(Folia Pharmacologica Japonica)》,第117卷,No.2,p.123-130,2001,简介.
非专利文献3:《国际血管学(International Angiology)》,29,No.2增刊1,p.49-54,2010.
非专利文献4:《日本临床免疫学会会志(Jpn.J.Clin.Immunol.)》,16(5),409-414,1993.
非专利文献5:《日本血栓止血学会志(Jpn.J.Thromb.Hemost.)》,1:2,p.94-105,1990,简介.
非专利文献6:《风湿病学杂志(J.Rheumatol.)》,2009,36(10),2244-2249.
非专利文献7:《日本药理学会志(Japan J.Pharmacol.)》,43,p.81-90,1987.
非专利文献8:《新英格兰医学杂志(New Engl.J.Med.)》,2015,24,2522-2533.
非专利文献9:《胸腔杂志(CHEST)》2003,123,1583-1588.
非专利文献10:《英国心脏杂志(Br.Heart J.)》,53,p.173-179,1985.
非专利文献11:《柳叶刀(The Lancet)》,1,4880,第1部,p.569-572,1981.
非专利文献12:《欧洲药理学杂志(Eur.J.Pharmacol.)》,449,
p.167-176,2002.
非专利文献13:《临床研究杂志(The Journal of Clinical Investigation)》,117,p.464-472,2007.
非专利文献14:《美国生理学杂志-肺细胞和分子生理学(Am.J.Physiol.LungCell Mol.Physiol.)》,296:L648-L656,2009.
发明内容
发明所要解决的技术问题
本发明的目的是提供一种化合物(I)的稳定化固体制剂。这里,“稳定化”是指固体制剂中所含的化合物(I)的分解引起的含量的降低受到抑制。
解决技术问题所采用的技术方案
本发明人为了解决上述技术问题进行了认真研究,结果发现通过使用比表面积在1.0m2/g以下的D-甘露糖醇作为化合物(I)的赋形剂,可改善固体制剂中的化合物(I)的稳定性,从而完成了本发明。
即,本发明如下所述。
(A)
一种固体制剂,其含有化合物(I)和比表面积在1.0m2/g以下的D-甘露糖醇。
(B)
(A)中记载的固体制剂,其中,相对于1重量份的化合物(I),D-甘露糖醇为5~10000重量份。
(C)
(A)或(B)中记载的固体制剂,其中,D-甘露糖醇的含量是固体制剂总重量的10~99重量%。
(D)
(A)~(C)中任一项记载的固体制剂,其中,固体制剂中所含的赋形剂总重量的20重量%以上为D-甘露糖醇。
(E)
(A)中记载的固体制剂,其中,D-甘露糖醇的含量如以下(a)~(c)所述:
(a)相对于1重量份的化合物(I),D-甘露糖醇的重量为5~10000重量份,
(b)是固体制剂总重量的10~99重量%,
(c)是固体制剂中所含的赋形剂总重量的20%以上。
(F)
(A)~(E)中任一项记载的固体制剂,还包含D-甘露糖醇以外的赋形剂和粘合剂。
(G)
(F)中记载的固体制剂,其中,D-甘露糖醇以外的赋形剂是选自玉米淀粉、精制白糖和结晶纤维素的1种或2种。
(H)
(F)中记载的固体制剂,其中,粘合剂是羟丙基纤维素。
(I)
(A)~(E)中任一项记载的固体制剂,还包含:
(a)选自玉米淀粉、精制白糖和结晶纤维素的1种或2种,以及
(b)羟丙基纤维素。
(J)
(I)中记载的固体制剂,其中,
(a)化合物(I)的含量是固体制剂总重量的0.1~2重量%,
(b)D-甘露糖醇的含量是固体制剂总重量的20~80重量%,
(c)玉米淀粉的含量是固体制剂总重量的15~40重量%,
(d)羟丙基纤维素的含量是固体制剂总重量的1~5重量%。
(K)
(J)中记载的固体制剂,其中,化合物(I)是I型的结晶。
(L)
(A)~(K)中记载的固体制剂,其中,固体制剂是片剂或颗粒剂。
(M)
(A)~(L)中任一项记载的固体制剂,其用于治疗下述疾病:糖尿病性神经病变、糖尿病性坏疽、外周循环障碍、慢性动脉阻塞症、间歇性跛行、硬皮病、血栓症、肺高血压症、心肌梗塞、心绞痛、肾小球肾炎、糖尿病性肾病、慢性肾功能衰竭、支气管哮喘、间质性肺炎(肺纤维化)、慢性阻塞性肺疾病、肾小管间质性肾炎、炎性肠病或伴随椎管狭窄症的症状。
(N)
(M)中记载的固体制剂,用于治疗肺高血压症。
(O)
(M)中记载的固体制剂,用于治疗外周循环障碍。
(P)
(M)中记载的固体制剂,用于治疗慢性动脉阻塞症。
(Q)
(M)中记载的固体制剂,用于治疗间歇性跛行。
(R)
(M)中记载的固体制剂,用于治疗伴随椎管狭窄症的症状。
(S)
(M)中记载的固体制剂,用于治疗肺纤维化。
(T)
(M)中记载的固体制剂,用于治疗硬皮病。
(U)
(M)中记载的固体制剂,用于治疗慢性肾功能衰竭。
(V)
(M)中记载的固体制剂,用于治疗肾小管间质性肾炎。
附图说明
图1表示化合物(I)的I型结晶的粉末X射线衍射图谱。纵轴表示峰强度(cps),横轴表示衍射角(2θ[°])。
图2表示化合物(I)的II型结晶的粉末X射线衍射图谱。纵轴表示峰强度(cps),横轴表示衍射角(2θ[°])。
图3表示化合物(I)的III型结晶的粉末X射线衍射图谱。纵轴表示峰强度(cps),横轴表示衍射角(2θ[°])。
具体实施方式
(化合物(I))
化合物(I)可根据例如专利文献1或2中记载的方法来制造,已知以下三种形态的结晶(专利文献2)。
(3)粉末X射线衍射图是使用Cu Kα放射线而得的,在化合物(I)的粉末X射线衍射图谱中,在以下衍射角2θ:9.3度、9.7度、16.8度、20.6度和23.5度显示衍射峰的化合物(I)的III型结晶。
本发明的固体制剂中可使用的化合物(I)可以是上述任一种的结晶,此外,也可以是这些结晶的混合物,或者也可以是非晶系。其中,优选I型结晶。
仅作为参考,在图1~3中显示上述三种形态的结晶的粉末X射线衍射图谱。
这些粉末X射线衍射图谱通过RINT-UltimaIII(理学株式会社((株)リガク)制)(靶:Cu,电压:40kV,电流:40mA,扫描速度:4度/分钟)进行测定。
本发明的固体制剂中所含的化合物(I)优选为固体制剂总重量的0.1~12重量%,更优选0.1~2重量%。
(D-甘露糖醇)
本发明的固体制剂的赋形剂使用比表面积在1.0m2/g以下的D-甘露糖醇。比表面积更优选在0.7m2/g以下,进一步优选大于0.2m2/g且小于0.7m2/g。
本发明中,比表面积是通过BET法测定的值,例如可使用比表面积测定装置Macsorb HM-model 1220(蒙泰科公司(マウンテック社))进行测定。
作为本发明中所用的D-甘露糖醇的例子,可例举例如Mannit C(三菱商事食品科技株式会社(三菱商事フードテック株式会社)、平均粒径:20μm)、Mannit P(三菱商事食品科技株式会社、50μm)、Mannit S(三菱商事食品科技株式会社、平均粒径:150μm)、Pearlitol 25C(罗盖特公司(ROQUETTE社)、平均粒径:25μm)、Pearlitol 50C(罗盖特公司、平均粒径:50μm)、Pearlitol 160C(罗盖特公司、平均粒径:160μm)、Nonpareil 108(100)(弗兰德产业株式会社(フロイント産業株式会社)、平均粒径:100μm)、Nonpareil 108(200)(弗兰德产业株式会社、平均粒径:200μm)。其中,优选Mannit P、Mannit S、Pearlitol 50C、Pearlitol 160C。
本发明的固体制剂的赋形剂使用比表面积在1.0m2/g以下的D-甘露糖醇。该D-甘露糖醇只要在本发明的固体制剂中所含的赋形剂总重量的20重量%以上即可,优选在50重量%以上。赋形剂可以是两种以上的混合物。作为除该D-甘露糖醇以外可使用的赋形剂,可例举玉米淀粉、结晶纤维素、精制白糖、赤藓糖醇、异麦芽酮糖醇等,优选玉米淀粉、精制白糖、结晶纤维素。更优选玉米淀粉。
玉米淀粉的含量优选为固体制剂总重量的0.5~45%,更优选15~40%。
(固体制剂)
本发明的固体制剂是含有化合物(I)和D-甘露糖醇的固体制剂,其特征是,D-甘露糖醇相对于1重量份的化合物(I)为5~10000重量份,更优选为10~9500重量份。
本发明的固体制剂中的D-甘露糖醇的含量通常为固体制剂总重量的10~99重量%。优选15~95重量%,更优选20~80重量%。
本发明中,在没有特别说明的情况下,“固体制剂”是指供于口服给药的一定形状的固体制剂,包括普通片剂、口腔内崩解片剂、咀嚼片剂、锭剂、舌下片剂、泡腾片剂、分散片剂、溶解片剂、散剂、颗粒剂和胶囊剂。本发明的固体制剂包括形成单层结构的单层片剂以及具有两层以上的多层结构的多层片剂。对于由此得到的固体制剂的形状没有特别限制,可以是圆形、椭圆形、囊片型、甜甜圈型等各种形状。为了控制化合物(I)的溶出特性,可利用公知的方法对本发明的固体制剂赋予缓释性和肠溶性。此外,为了光稳定性的提高、外观的改善、识别性的确保或释放控制等目的,可利用各种包衣剂或糖衣剂、通过公知的方法包覆本发明的固体制剂。此外,为了光稳定性的提高、识别性的确保等目的,本发明的固体制剂中可掺合色素,此外,为了改善风味等目的,也可掺合调味剂和香料。
本发明的固体制剂中除掺合上述成分外,可在不妨碍本发明的效果的范围内掺合药学上允许的载体(添加剂)。它们可作为例如粘合剂、崩解剂、流化剂、润滑剂、包衣剂、释放控制剂、增塑剂、着色剂、调味剂和香料而适当适量地掺合。这些添加剂可单独使用,也可将两种以上组合使用。
作为粘合剂,可例举例如明胶、支链淀粉、羟丙基纤维素、甲基纤维素、聚乙烯吡咯烷酮、macrogol(聚乙二醇)、阿拉伯树胶、葡聚糖、聚乙烯醇、预胶化淀粉、羟丙甲基纤维素,优选羟丙基纤维素、聚乙烯醇、羟丙甲基纤维素,进一步优选羟丙基纤维素。
粘合剂优选为固体制剂总重量的0.1~10重量%,更优选1~8重量%,进一步优选1~5%。
羟丙基纤维素优选为固体制剂总重量的0.1~10重量%,更优选1~8重量%,进一步优选1~5重量%。
作为崩解剂,可例举例如羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、交联羧甲基纤维素钠、羟基乙酸淀粉钠、交聚维酮、阳离子交换树脂、部分预胶化淀粉和低取代羟丙基纤维素,优选低取代羟丙基纤维素。
崩解剂优选为固体制剂总重量的0.1~10重量%,更优选1~8重量%。
低取代羟丙基纤维素优选为固体制剂总重量的0.1~10重量%,更优选1~8重量%,进一步优选3~7重量%。
作为流化剂,可例举例如轻质无水硅酸、含水二氧化硅、合成硅酸铝、偏硅酸铝镁。
作为润滑剂,可例举例如硬脂酸、硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠、滑石、石蜡类、DL-亮氨酸、月桂基硫酸钠、月桂基硫酸镁、聚乙二醇、轻质无水硅酸,优选硬脂酸镁。
润滑剂优选为固体制剂总重量的0.1~10重量%,更优选0.2~5重量%。
硬脂酸镁优选为固体制剂总重量的0.1~10重量%,更优选0.2~5重量%,进一步优选0.5~3重量%。
作为包衣剂,可例举乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、甲基丙烯酸共聚物LD、乙酸羟丙甲基纤维素琥珀酸酯等。
作为释放控制剂,可例举例如羟丙基纤维素、乙烯-乙酸乙烯酯共聚物、聚环氧乙烷。
作为增塑剂,可例举例如柠檬酸三乙酯、丙二醇、聚乙二醇,优选丙二醇。
作为着色剂,可例举例如氧化钛、滑石、三氧化二铁、黄色三氧化二铁、食用黄色4号、食用黄色4号铝色淀,优选氧化钛、三氧化二铁、黄色三氧化二铁。
着色剂的含量少于固体制剂总重量的0.1重量%。
作为调味剂,可例举例如果糖、木糖醇、葡萄糖、DL-苹果酸。
作为香料,可例举例如1-薄荷醇、薄荷。
(固体制剂的制造方法)
本发明的固体制剂可通过制剂领域中的常规方法来制造。以下示出该制造方法的一例,但本发明并不受该制造方法的任何限制。
本发明的固体制剂是在作为有效成分的化合物(I)的粉末中,
(1)混合赋形剂等添加物而制成散剂,或者,在该混合粉末中添加崩解剂和粘合剂等添加物,通过公知的各种造粒方法进行造粒而制成颗粒剂。
(2)将得到的混合粉末或颗粒直接、或者与润滑剂和流化剂等添加物混合,填充到胶囊中制成胶囊剂。或者,进行压缩成型(压片)而制成片剂。
(3)根据需要,将所得的混合粉末、颗粒、胶囊或片剂的表面利用包衣剂或糖衣、通过公知的包覆方法进行包覆。
化合物(I)具有优异的PGI2受体激动作用,可用作与PGI2相关的下述疾病的预防剂或治疗剂,例如:短暂性脑缺血发作(TIA)、糖尿病性神经病变(例如,参照非专利文献1)、糖尿病性坏疽(例如,参照非专利文献1)、末梢循环障碍(例如,慢性动脉硬化症、慢性动脉阻塞症(例如,参照非专利文献2)、间歇性跛行(例如,参照非专利文献3)、外周动脉栓塞、雷诺氏病(例如,参照非专利文献4、非专利文献5)、胶原性疾病(例如,系统性红斑狼疮、硬皮病)(例如,参照专利文献3、非专利文献6)、混合性结缔组织病、血管炎综合征、经皮腔内冠状动脉成形术(PTCA)后的再闭塞和再收缩、动脉硬化症、血栓症(例如,急性脑血栓症、肺栓塞症)(例如,参照非专利文献5、非专利文献7)、高血压、肺动脉性高血压症和慢性血栓塞栓性肺高血压症等肺高血压症(例如,非专利文献8、非专利文献9)、缺血性疾病(例如,脑梗塞、心肌梗死(例如,参照非专利文献10))、心绞痛(例如,稳定型心绞痛、不稳定型心绞痛)(例如,参照非专利文献11)、肾小球性肾炎(例如,参照非专利文献12)、糖尿病性肾病(例如,参照非专利文献1)、慢性肾功能衰竭(例如,参照专利文献4)、过敏性反应、支气管哮喘(例如,参照非专利文献13)、溃疡,褥疮、粥样斑块切除和支架植入等冠状动脉介入术后的再狭窄、透析引起的血小板减少、器官或组织的纤维化相关的疾病[例如,肾脏疾病(例如,肾小管间质性肾炎)(例如,参照专利文献3)、呼吸系统疾病(例如,间质性肺炎(肺纤维化)(例如,参照专利文献3)、慢性阻塞性肺疾病(例如,参照非专利文献14)等)、胃肠道疾病(例如,肝硬化、病毒性肝炎、慢性胰腺炎、胃硬癌)、心血管疾病(例如,心肌纤维化)、骨关节疾病(例如,骨髓纤维化、类风湿性关节炎)、皮肤疾病(例如,手术后瘢痕、烧伤瘢痕、瘢痕瘤、肥厚性瘢痕)、产科疾病(例如,子宫肌瘤)、泌尿系统疾病(例如,前列腺肥大症)、其他疾病(例如,阿尔茨海默氏病、硬化性腹膜炎、I型糖尿病、手术后器官粘连)]、勃起功能障碍(例如糖尿病性勃起功能障碍、精神性勃起功能障碍、精神病性勃起功能障碍、由慢性肾衰竭导致的勃起功能障碍、为切除前列腺的盆腔手术后的勃起功能障碍、伴随衰老或动脉硬化的血管性勃起功能障碍)(例如,参照专利文献7)、炎性肠病(例如,溃疡性结肠炎、克罗恩氏病、肠结核、缺血性结肠炎、白塞病相关的肠溃疡)(例如,参照专利文献5)、胃炎、胃溃疡、缺血性眼病(例如,视网膜动脉阻塞、视网膜静脉阻塞、缺血性视神经病变)、突发性耳聋、缺血性骨坏死、与非甾体抗炎药(NSAIDs)(例如,双氯芬酸、美洛昔康、奥沙普秦、萘丁美酮、吲哚美辛、布洛芬、酮洛芬、萘普生或塞来昔布)的给药有关的肠损伤(例如,只要是在十二指肠、小肠、大肠中发生的损伤就没有特别限制,例如在十二指肠、小肠、大肠中发生的糜烂等粘膜损伤和溃疡)(例如,参照专利文献8)、伴随椎管狭窄症(例如,颈部椎管狭窄症、胸部椎管狭窄症、腰部椎管狭窄症、广泛椎管狭窄症、骶骨狭窄症)的症状(例如,麻痹、感觉迟钝、疼痛、麻木、行走能力降低)(例如,参照专利文献6)。此外,本发明的固体制剂也可用作基因治疗或自体骨髓细胞移植等血管新生疗法的促进剂、末梢血管再造术或血管新生疗法中的血管形成促进剂。
实施例
以下,例举比较例、实施例和试验例来对本发明进一步详细说明,但这并不是将本发明限定于此。
本发明中使用的化合物(I)使用上述I型结晶。
在实施例、比较例中没有特别记载的情况下,使用以下的添加剂。玉米淀粉使用日食玉米淀粉W(Nisshoku Cornstarch W,日本食品化工株式会社)。结晶纤维素使用CeolusPH-101(旭化成化学品株式会社(旭化成ケミカルズ株式会社))。羟丙基纤维素使用HPC-SSL(日本曹达株式会社)。低取代羟丙基纤维素使用LH-11(信越化学工业株式会社(信越化学工業株式会社))。硬脂酸镁使用硬脂酸镁植物性(特制)(太平化学产业株式会社)。精制白糖使用T.T.G.H砂糖(东洋精糖株式会社)。黄色三氧化二铁使用黄色三氧化二铁(癸巳化成株式会社)。氧化钛使用Tipaque A-100(石原产业株式会社)。丙二醇使用丙二醇(旭硝子株式会社)。
(实施例1)D-甘露糖醇的种类和稳定性
(1)片剂的制备
将化合物(I)与各种D-甘露糖醇、玉米淀粉、低取代羟丙基纤维素以规定量放入流化床造粒干燥机(MP-01,宝莱科株式会社(株式会社パウレック))中,一边混合一边喷洒5%羟丙基纤维素水溶液,制备了颗粒。在所得的颗粒中混合规定量的硬脂酸镁,使用旋转式压片机(Correct,株式会社菊水制作所)以800kg进行压片,制成片剂(直径7mm,120mg片)。在表1中示出各实施例、比较例中使用的D-甘露糖醇的种类。表1中记载的体积密度(g/mL)是指未经振实(松散)状态的粉体试料的质量与包含粒子间空隙容积的因子的粉体的体积之比,称取25g预先将试料用孔径1000μm的筛进行筛选后的试料,测定并算出将试料通过漏斗投入量筒时的容积。此外,表1记载的振实密度(g/mL)是通过将装有粉体试料的容器机械地振实而得的体积密度,具体而言,进行振实直到确认体积没有变化,测定并算出此时的容积。
片剂的成分及其含量如表2所记载。
[表1]
[表2]
(2)评价方法和结果
将所得的片剂装入塑料瓶中,在不盖盖子的状态下,在40℃/75%RH的开放条件及60℃的开放条件下保存一个月。使用高效液相色谱仪测定保存前后的片剂中的化合物(I)的相关物质,评价了自试验开始时的相关物质的增加量。另外,表中,相关物质的增加量(%)表示保存前后的制剂中所含的化合物(I)的减少量(峰面积)。在表3中示出其结果和使用的各种D-甘露糖醇的比表面积。在实施例1-1至1-5的任一例的片剂中,均显示相关物质的生成量少于3%。这些实施例中使用的D-甘露糖醇的比表面积大约在1.0m2/g以下,在使用具有这些物性的D-甘露糖醇的情况下,确认到制剂的稳定性提高。
[表3]
(实施例2)掺合了D-甘露糖醇和其他赋形剂时的稳定性
(1)片剂的制备
将化合物(I)与D-甘露糖醇(Mannit P,三菱商事食品科技株式会社)、玉米淀粉、结晶纤维素以规定量放入流化床造粒干燥机(MP-01,宝莱科株式会社)中,一边混合一边喷洒10%羟丙基纤维素水溶液,制备了颗粒。在所得的颗粒中混合规定量的低取代羟丙基纤维素和硬脂酸镁,使用旋转式压片机(Correct,株式会社菊水制作所)以1000kg进行压片,制成片剂(直径8mm,190mg片)。各成分的含量如表4所记载。
[表4]
(2)评价方法和结果
将(1)中制备的片剂与干燥剂(Dryern tablet PW 2010,山仁药品株式会社)一起放入塑料瓶中并用盖密封,在40℃/75%RH的条件(加速试验)下保存六个月。此外,将片剂装入塑料瓶中,在不盖盖子的状态下,在40℃/75%RH的条件及60℃的条件下保存一个月。使用高效液相色谱仪测定保存前后的片剂中的化合物(I)的含量,评价了相对于试验开始时的化合物(I)的残存率。
其结果示于表5。作为赋形剂,在仅使用D-甘露糖醇的情况下(实施例2-1)、以及在将玉米淀粉(实施例2-2)或结晶纤维素(实施例2-3)与D-甘露糖醇掺合的情况下都显示出高残存率。
[表5]
(实施例3)颗粒剂的稳定性
(1)颗粒剂的制备
实施例3-1
将规定量的化合物(I)与D-甘露糖醇(Mannit P,三菱商事食品科技株式会社)、玉米淀粉、精制白糖(用样品磨机(AP-S,细川密克朗有限公司(ホソカワミクロン株式会社),孔径3mm)粉碎后的试样)放入流化床造粒干燥机(MP-01,宝莱科株式会社)中,一边混合一边喷洒10%羟丙基纤维素水溶液,制造了颗粒。
实施例3-2
将规定量的化合物(I)与D-甘露糖醇(Mannit P,三菱商事食品科技株式会社)、玉米淀粉放入流化床造粒干燥机(MP-01,宝莱科株式会社)中,一边混合一边喷洒分散有规定量的黄色三氧化二铁的10%羟丙基纤维素水溶液,制造了颗粒。
颗粒剂的成分及其含量如表6所记载。
[表6]
(2)评价方法和结果
将所得的颗粒剂与干燥剂(Dryern tablet PW 2010,山仁药品株式会社)一起放入塑料瓶中并用盖密封,在40℃/75%RH的条件(加速试验)下保存两个月、或在开放的状态下保存一个月。使用高效液相色谱仪测定保存前后的颗粒剂中的化合物(I)的含量,评价了相对于试验开始时的化合物(I)的残存率(%)。其结果示于表7。其结果是,可知在制成颗粒剂时也确保了高稳定性。
[表7]
产业上利用的可能性
根据本发明,可提供化合物(I)的稳定化固体制剂,即作为制剂的保存稳定性得到改善、由有效成分的分解引起的含量降低及有效成分的分解物(相关物质)的生成和增加受到抑制的固体制剂。
Claims (22)
1.一种固体制剂,其包含2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}-N-(甲磺酰基)乙酰胺和比表面积为大于0.2m2/g且小于0.7m2/g的D-甘露糖醇。
2.如权利要求1所述的固体制剂,其特征在于,相对于1重量份的2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}-N-(甲磺酰基)乙酰胺,D-甘露糖醇为5~10000重量份。
3.如权利要求1或2所述的固体制剂,其特征在于,D-甘露糖醇的含量是固体制剂总重量的10~99重量%。
4.如权利要求1~3中任一项所述的固体制剂,其特征在于,固体制剂中所含的赋形剂总重量的20重量%以上为D-甘露糖醇。
5.如权利要求1所述的固体制剂,其特征在于,
D-甘露糖醇的含量如以下(a)~(c)所述:
(a)相对于1重量份的2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}-N-(甲磺酰基)乙酰胺,D-甘露糖醇的重量为5~10000重量份,
(b)是固体制剂总重量的10~99重量%,
(c)是固体制剂中所含的赋形剂总重量的20%以上。
6.如权利要求1~5中任一项所述的固体制剂,其特征在于,还包含D-甘露糖醇以外的赋形剂和粘合剂。
7.如权利要求6所述的固体制剂,其特征在于,D-甘露糖醇以外的赋形剂是选自玉米淀粉、精制白糖和结晶纤维素的1种或2种。
8.如权利要求6所述的固体制剂,其特征在于,粘合剂是羟丙基纤维素。
9.如权利要求1~5中任一项所述的固体制剂,其特征在于,还包含:
(a)选自玉米淀粉、精制白糖和结晶纤维素的1种或2种,以及
(b)羟丙基纤维素。
10.如权利要求9所述的固体制剂,其特征在于,
(a)2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}-N-(甲磺酰基)乙酰胺的含量是固体制剂总重量的0.1~2重量%,
(b)D-甘露糖醇的含量是固体制剂总重量的20~80重量%,
(c)玉米淀粉的含量是固体制剂总重量的15~40重量%,
(d)羟丙基纤维素的含量是固体制剂总重量的1~5重量%。
11.如权利要求10所述的固体制剂,其特征在于,2-{4-[N-(5,6-二苯基吡嗪-2-基)-N-异丙基氨基]丁氧基}-N-(甲磺酰基)乙酰胺是I型的结晶。
12.如权利要求1~11中任一项所述的固体制剂,其特征在于,固体制剂是片剂或颗粒剂。
13.如权利要求1~12中任一项所述的固体制剂,其特征在于,用于治疗下述疾病:糖尿病性神经病变、糖尿病性坏疽、外周循环障碍、慢性动脉阻塞症、间歇性跛行、硬皮病、血栓症、肺高血压症、心肌梗塞、心绞痛、肾小球肾炎、糖尿病性肾病、慢性肾功能衰竭、支气管哮喘、间质性肺炎(肺纤维化)、慢性阻塞性肺疾病、肾小管间质性肾炎、炎性肠病或伴随椎管狭窄症的症状。
14.如权利要求13所述的固体制剂,其特征在于,用于治疗肺高血压症。
15.如权利要求13所述的固体制剂,其特征在于,用于治疗外周循环障碍。
16.如权利要求13所述的固体制剂,其特征在于,用于治疗慢性动脉阻塞症。
17.如权利要求13所述的固体制剂,其特征在于,用于治疗间歇性跛行。
18.如权利要求13所述的固体制剂,其特征在于,用于治疗伴随椎管狭窄症的症状。
19.如权利要求13所述的固体制剂,其特征在于,用于治疗肺纤维化。
20.如权利要求13所述的固体制剂,其特征在于,用于治疗硬皮病。
21.如权利要求13所述的固体制剂,其特征在于,用于治疗慢性肾功能衰竭。
22.如权利要求13所述的固体制剂,其特征在于,用于治疗肾小管间质性肾炎。
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