CN101160126A - 血管紧张肽ⅱ受体拮抗剂 - Google Patents
血管紧张肽ⅱ受体拮抗剂 Download PDFInfo
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- CN101160126A CN101160126A CNA2006800127256A CN200680012725A CN101160126A CN 101160126 A CN101160126 A CN 101160126A CN A2006800127256 A CNA2006800127256 A CN A2006800127256A CN 200680012725 A CN200680012725 A CN 200680012725A CN 101160126 A CN101160126 A CN 101160126A
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- Prior art keywords
- chloro
- butyl
- imidazole
- biphenyl
- methyl
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Abstract
本发明的化合物是具有结构(I)的化合物2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸的多晶型物。具体讲，本发明的化合物选自权利要求3的2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸，而后者则选自I型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸盐酸盐、II型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸盐酸盐、III型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸盐酸盐、以及IV型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸一水合物、V型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸一水合物、VI型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸一水合物、VII型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸一水合物、和VIII型2－丁基－4－氯－1－[(2＇－(1－H－四唑－5－基)联苯－4－基)甲基]－咪唑－5－羧酸一水合物。
Description
发明背景
美国专利5136069不仅从类别上而且还具体描述了2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]咪唑-5-甲醇钾盐以及无水形式的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐。美国专利5136069第261-263栏记载了将该专利中所述化合物制剂化的通用方法，这些制剂包括胶囊剂、片剂、注射剂、以及混悬剂。美国专利5153197记载了这些化合物单独或与其他利尿剂联合治疗高血压患者的用途。美国专利5310929描述了5-咪唑羧酸酯血管紧张肽II受体拮抗剂前药。
2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸是2-丁基-4-氯-1-[对-(邻-1-H-四唑-5-基苯基)苄基]-咪唑-5-羧酸钾盐(亦称为氯沙坦(losartan)钾盐)的活性代谢物。
发明概述
本发明包括血管紧张肽II受体拮抗剂2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物[包括这些多晶型物的各种可药用盐和水合物在内]，以及用于将这些多晶型物以控缓释方式给药于患者的药物制剂。
本发明的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸多晶型物的盐包括无毒盐，例如由无机酸(像盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等)生成的盐，或者是由例如无机酸碱或有机酸碱形成的季铵盐。例如，酸加成盐包括乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、葡糖酸庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、和十一烷酸盐。碱盐包括铵盐、碱金属盐如钠与钾盐、碱土金属盐如钙与镁盐，与有机碱形成的盐如二环己基胺盐、N-甲基-D-葡糖胺盐，以及与氨基酸如精氨酸、赖氨酸等形成的盐。还有，含氮基团例如可以用下列试剂季铵化：低级烷基卤化物，如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊基酯，长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物，芳烷基卤化物，譬如苄基和苯乙基的溴化物等等。
本发明包括选自以下的血管紧张肽II受体拮抗剂多晶型物：I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。
本发明还包括治疗下列疾病的方法：高血压，充血性心力衰竭，肺动脉高血压，肾机能不全，肾缺血，肾衰竭，肾性纤维变性，心肌机能不全，心肥大，心肌纤维变性，心肌缺血，心肌病，肾小球性肾炎，肾绞痛，糖尿病并发症如肾病、血管病和神经病，青光眼，高眼内压，动脉粥样硬化，血管成形术后再狭窄，血管或心脏手术后的并发症，勃起机能障碍，醛甾酮过多症，肺纤维变性，硬皮病，焦虑症，认知障碍，免疫抑制剂治疗并发症，以及已知与血管紧张肽系统相关的其他疾病，该方法包括对患有一种或多种这些疾病的患者给药本发明的血管紧张肽II受体拮抗剂多晶型物。
附图简述
图1是I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐的X-射线粉末衍射图案。
图2是II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐的X-射线粉末衍射图案。
图3是III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐的X-射线粉末衍射图案。
图4是IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物的X-射线粉末衍射图案。
图5是V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物的X-射线粉末衍射图案。
图6是VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物的X-射线粉末衍射图案。
图7是VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物的X-射线粉末衍射图案。
图8是VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物的X-射线粉末衍射图案。
发明详述与优选实施方案
本发明化合物是具有下式结构的化合物2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的血管紧张肽II受体拮抗剂多晶型物：
在本发明的一个实施方案中，本发明化合物为具有选自以下X-射线粉末衍射图案d间距值的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的晶型：
a)约12.9，约4.8，约4.0，约3.79，约3.77，约3.7，和约3.7，
b)约8.6，约6.5，约5.7，约3.9，和约3.7，
c)约18.8，约9.5，约9.3，约6.2，和约4.2，
d)约8.6，约5.0，约3.7，和约3.6，
e)约6.44，约6.39，约6.3，和约4.2，
f)约7.4，约6.8，和约6.7，
g)约15.9，和
h)约9.1，约8.1，约6.6，约4.2，约3.7，和约3.7。
在本发明的优选实施方案中，本发明化合物为具有选自以下X-射线粉末衍射图案d间距值的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的晶型：
a)约12.96，约4.75，约3.97，约3.79，约3.77，约3.71，和约3.44，
b)约8.55，约6.54，约5.68，约3.90，和约3.71，
c)约18.78，约9.49，约9.34，约6.22，和约4.20，
d)约8.57，约5.01，约3.66，和约3.63，
e)约6.44，约6.39，约6.34，和约4.20，
f)约7.38，约6.75，和约6.69，
g)约15.91，和
h)约9.13，约8.09，约6.61，约4.18，约3.70，和约3.65。
在本发明更优选的实施方案中，本发明化合物为具有选自以下X-射线粉末衍射图案d间距值的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的晶型：
a)12.96，8.32，8.13，7.06，5.18，4.75，4.64，4.45，4.41，4.33，4.19，3.97，3.86，3.79，3.77，3.71，3.59，3.44，3,15，和2.92，
b)10.09，8.55，7.42，7.26，6.54，6.43，5.68，4.39，4.26，4.17，4.12，4.10，4.02，3.90，3.85，3.71，3.67，3.63，3.59，3.44，3.37，3.35，3.12，和3.02，
c)18.78，9.49，9.34，6.22，6.18，4.85，4.67，4.46，4.20，3.97，3.68，3.66，3.63，和3.50，
d)10.52，8.57，7.46，6.60，5.45，5.37，5.01，4.91，4.65，3.80，3.66，3.63，3.29，3.23，3.22，3.19，3.02，
e)7.34，6.90，6.44，6.39，6.34，5.69，5.64，4.54，4.26，4.24，4.20，3.91，3.90，3.77和3.59，
f)7.38，7.32，6.75，6.69，4.38，4.03，3.76，3.70，和3.42，
g)15.91，9.99，8.37，和7.59，和
h)10.99，9.13，8.69，8.09，6.61，6.32，6.24，5.39，4.37，4.23，4.18，3.96，3.93，3.80，3.70，3.65，3.24，3.17和3.13。
这些实施方案中，代表性的血管紧张肽II受体拮抗剂多晶型物为选自以下的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的晶型：I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、和IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。本说明书中提供了制备这些晶型的方法以及与这些晶型有关的衍射图。
血管紧张肽II受体拮抗剂-治疗用途-使用方法
本发明的血管紧张肽II受体拮抗剂多晶型物可用于多种疾病的治疗和/或预防，这些疾病涉及高血压，充血性心力衰竭，肺动脉高血压，肾机能不全，肾缺血，肾衰竭，肾性纤维变性，心肌机能不全，心肥大，心肌纤维变性，心肌缺血，心肌病，肾小球性肾炎，肾绞痛，糖尿病并发症如肾病、血管病和神经病，青光眼，高眼内压，动脉粥样硬化，血管成形术后再狭窄，血管或心脏手术后的并发症，勃起机能障碍，醛甾酮过多症，肺纤维变性，硬皮病，焦虑症，认知障碍，免疫抑制剂治疗引起的并发症，以及已知与血管紧张肽系统相关的其他疾病。
本发明的血管紧张肽II受体拮抗剂多晶型物特别适用于以下疾病的治疗和/或预防，这些疾病涉及高血压，充血性心力衰竭，肺动脉高血压，肾机能不全，肾缺血，肾衰竭，肾性纤维变性，心肌机能不全，心肥大，心肌纤维变性，心肌缺血，心肌病，糖尿病并发症如肾病、血管病和神经病。
在一个实施方案中，本发明涉及治疗和/预防与肾素-血管紧张肽系统的调节异常相关的疾病的方法，特别是治疗或预防上述疾病的方法，所述方法包括对患者施用药物活性量的本发明的血管紧张肽II受体拮抗剂。
本发明还涉及本发明的血管紧张肽II受体拮抗剂多晶型物在制备治疗和/或预防上述疾病的药物中的应用。
本发明的上述血管紧张肽II受体拮抗剂多晶型物还能够与其他药物活性化合物联合应用，这些活性化合物包括血管紧张肽转化酶抑制剂(例如阿拉普利，贝那普利，卡托普利，西洛普利，西拉普利，地拉普利，依那普利，依那普利拉，福辛普利，咪哒普利，赖诺普利，莫替普利，哌道普利，喹那普利，雷米普利，螺普利，替莫普利，或川道普利)，中性内肽酶抑制剂(例如塞奥吩和磷酰二肽(phosphoramidon))，醛固酮拮抗剂，肾素抑制剂(例如二肽与三肽的脲衍生物(参见美国专利5116835)，氨基酸及其衍生物(美国专利5095119和5,104,869)，经由非肽键连接的氨基酸链(美国专利5114937)，二-及三-肽衍生物(美国专利5106835)，肽基氨基二醇(美国专利5063208和4845079)以及肽基β-氨基酰基氨基二醇氨基甲酸酯(美国专利5089471)；同样也包括如美国专利5071837、5,064,965、5,063,207、5036054、5036053、5034512和4894437中记载的各种其他肽类似物，以及小分子肾素抑制剂(包括二醇磺酰胺与亚磺酰基物(美国专利5098924)，N-吗啉代衍生物(美国专利5055466)，N-杂环醇(美国专利4885292)，和吡咯并咪唑酮类(pyrolimidazolones)(美国专利5075451)；以及抑肽素衍生物(美国专利4980283)和statone肽的氟与氯衍生物(美国专利5066643)，enalkrein，RO 42-5892，A 65317，CP 80794，ES 1005，ES 8891，SO 34017，阿利克仑(2(S)，4(S)，5(S)，7(S)-N-(2-氨基甲酰基-2-甲基丙基)-5-氨基-4-羟基-2，7-二异丙基-8-[4-甲氧基-3-(3-甲氧基丙氧基)苯基]-辛酰胺半富马酸盐)，SPP600，SPP630和SPP635)，内皮素受体拮抗剂，血管扩张剂，钙通道阻断剂(例如氨氯地平、硝苯地平、维拉帕米、地尔硫卓、加洛帕米、尼鲁地平、尼莫地平、尼卡地平)，钾通道激活剂(例如尼可地尔、吡那地尔、克罗卡林、米诺地尔、阿普卡林、氯普唑纶)，利尿剂(例如氢氯噻嗪)，抗交感神经药，β-肾上腺素能阻滞药(例如普萘洛尔、阿替洛尔、比索洛尔、卡维地洛、美托洛尔、或酒石酸盐甲氧乙心胺)，α-肾上腺素能阻滞药(例如多沙唑嗪、哌唑嗪、或α-甲基多巴)，中枢β-肾上腺素能激动剂，外周血管扩张剂(例如肼屈嗪)，降脂剂(如辛伐他汀、洛伐他汀、ezetamibe、阿托他汀(atorvastatin)、普伐他汀)，代谢改变剂包括胰岛素增敏剂及相关化合物(例如英格列扎、格列吡嗪、甲福明、罗格列酮))或与有助于预防或治疗上述疾病的其他药物(包括硝普和二氮嗪)联合应用。
使用本发明血管紧张肽II受体拮抗剂多晶型物的给药方案依各种因素而变，这些因素包括病人类型、人种、年龄、体重、性别和健康状况；要治疗病症的严重程度；给药途径；患者的肾功与肝功情况；以及所使用的具体化合物或其盐。普通专业医师或兽医能够很容易地确定并处方预防、对抗或阻止所述疾病进展所需要的药物有效量。
当用于预定效果时，本发明的血管紧张肽II受体拮抗剂多晶型物的口服剂量在每天每千克体重约0.0125mg(mg/kg/天)至约7.5mg/kg/天之间变化，优选0.0125mg/kg/天-3.75mg/kg/天，更优选0.3125mg/kg/天-1.875mg/kg/天。例如，80kg的患者每天可以接受的剂量为约1mg/天-600mg/天，优选1mg/天-300mg/天，且更优选25mg/天-150mg/天。这样，适合每天给药一次的特制药物可以含有1mg-600mg，优选1mg-300mg，更优选25mg-300mg，例如25mg，50mg，100mg，150，200，250和300mg。有利的是，本发明的血管紧张肽II受体拮抗剂可以以每天两次、三次或四次的分剂量给药。对于每天两次的给药，适宜的特制药物含有0.5mg-300mg，优选0.5mg-150mg，更优选12.5mg-150mg，例如12.5mg，25mg，50mg，75mg，100mg，125mg和150mg。
本发明组合物中各成分的量由加入到制剂中的特定成分的重量表示，例如加到制剂中的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐的量包括2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐的游离碱和盐成分。例如，对于2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐，含108.5mg 2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐的制剂提供100mg游离碱成分和8.5mg盐酸盐成分。
本发明的血管紧张肽II受体拮抗剂多晶型物可以以诸如片剂、胶囊剂和颗粒剂之类口服剂型给用。本发明的血管紧张肽II受体拮抗剂通常是作为活性成分与适当的药用粘合剂(如下文所述)混合给用。％w/w表示与组合物总量相比指出的组合物组分的百分重量。
用于给药本发明血管紧张肽II受体拮抗剂多晶型物的适当药物组合物的一个实施方案为包括以下组分的药物颗粒基质组合物：
a)约1-75％w/w的具有选自以下X-射线粉末衍射图案d间距值的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物：
i)约12.9，约4.8，约4.0，约3.79，约3.77，约3.7，和约3.4，
ii)约8.6，约6.5，约5.7，约3.9，和约3.7，
iii)约18.8，约9.5，约9.3，约6.2，和约4.2，
iv)约8.6，约5.0，约3.7，和约3.6，
v)约6.44，约6.39，约6.3，和约4.2，
vi)约7.4，约6.8，和约6.7，
vii)约15.9，和
viii)约9.1，约8.1，约6.6，约4.2，约3.7，和约3.7；
b)约2.5-90％w/w的至少一种水溶胀性聚合物；
c)约2.5-90％w/w的至少一种填充剂；和
d)约0.5-10％w/w的至少一种润滑剂，
其中颗粒的粒度为约150-1200μm。
本发明的颗粒基质组合物任选包括2.5-15％w/w的增溶剂。
优选本发明的血管紧张肽II受体拮抗剂多晶型物选自I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、和IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。
在本实施方案中，一种或多种的水溶胀性聚合物优选选自聚环氧乙烷和羟丙基甲基纤维素，填充剂优选为磷酸氢钙和微晶纤维素的混合物，并且所述润滑剂优选为硬脂酸镁。这些颗粒可以以单一的活性成分制剂形式给药于患者，或者以1∶10-10∶1的比例与血管紧张肽II受体拮抗剂的即释性颗粒混合，该比例适于获得需要的总释放速率。
用于给药本发明血管紧张肽II受体拮抗剂多晶型物的适当药物组合物的另一个实施方案是包括以下组成的可侵蚀基质组合物：
a)约1-90％w/w的具有选自以下X-射线粉末衍射图案d间距值的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物：
i)约12.9，约4.8，约4.0，约3.79，约3.77，约3.7，和约3.4，
ii)约8.6，约6.5，约5.7，约3.9，和约3.7，
iii)约18.8，约9.5，约9.3，约6.2，和约4.2，
iv)约8.6，约5.0，约3.7，和约3.6，
v)约6.44，约6.39，约6.3，和约4.2，
vi)约7.4，约6.8，和约6.7，
vii)约15.9，和
viii)约9.1，约8.1，约6.6，约4.2，约3.7，和约3.7；
b)约2.5-25％w/w的至少一种水溶胀性聚合物；
c)约2.5-15％w/w的至少一种增溶剂；和
d)约2.5-90％w/w的至少一种填充剂。
本发明的可侵蚀基质组合物任选包括多达15％w/w的水溶性填充剂。
优选本发明的血管紧张肽II受体拮抗剂多晶型物选自I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、以及IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。
在本实施方案中，一种或多种的水溶胀性聚合物优选选自聚环氧乙烷和羟丙基甲基纤维素，填充剂为磷酸氢钙、微晶纤维素和乳糖的混合物，并且所述增溶剂选自环氧乙烷与环氧丙烷的嵌段共聚物(例如，泊咯沙姆(Poloxamers))。
用于给药本发明血管紧张肽II受体拮抗剂多晶型物的适宜药物组合物的另一个实施方案是颗粒和包衣该颗粒的包衣材料，其中
a)该颗粒包括：
1)约5-50％w/w的具有选自以下X-射线粉末衍射图案d间距值的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物：
i)约12.9，约4.8，约4.0，约3.79，约3.77，约3.7，和约3.4，
ii)约8.6，约6.5，约5.7，约3.9，和约3.7，
iii)约18.8，约9.5，约9.3，约6.2，和约4.2，
iv)约8.6，约5.0，约3.7，和约3.6，
v)约6.44，约6.39，约6.3，和约4.2，
vi)约7.4，约6.8，和约6.7，
vii)约15.9，和
viii)约9.1，约8.1，约6.6，约4.2，约3.7，和约3.7；
2)约5-50％w/w的至少一种中和剂；
3)约1-25％w/w的至少一种粘合剂；和
4)约5-75％w/w的至少一种填充剂，
其中该颗粒的粒度为约100-1200μm；和
b)所述包衣材料包括：
1)在以后蒸发分散液溶剂时能以水分散液或有机溶液的形式沉积的聚合物，其中包衣材料中聚合物的量应使得沉积在颗粒上的聚合物量为颗粒重量的约5-40％w/w；
2)增塑剂，其量最多达聚合物重量的40％；和
3)防粘着剂，其量最多达聚合物重量的10％。
优选本发明的血管紧张肽II受体拮抗剂多晶型物选自I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、以及IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。
所述包衣材料为颗粒重量的约5-约60％，亦即包含100mg颗粒的组合物进一步包括约5mg-约60mg的包衣材料。
所述颗粒任选包含2.5-15％w/w量的增溶剂，并且还任选包含最多达15％w/w量的水溶性填充剂。
在本实施方案中，中和剂为磷酸氢二钠七水合物，填充剂为微晶纤维素，粘合剂为羟丙基纤维素，并且水分散液包含乙基纤维素、柠檬酸三乙酯和高岭土。这些包衣颗粒可以作为单一的活性成分制剂给药于患者，或者以1∶10-10∶1的比例与血管紧张肽II受体拮抗剂的即释性颗粒混合，该比例适于获得需要的总释放速率。
这些剂型中使用的适宜填充剂包括微晶纤维素，硅化微晶纤维素，磷酸氢钙，乳糖，甘露糖醇和淀粉，优选微晶纤维素、磷酸氢钙、乳糖或其混合物。
合适的粘合剂包括羟丙基纤维素，羟丙基甲基纤维素，淀粉，明胶，天然糖如葡萄糖或β-乳糖，玉米甜料，天然和合成胶如阿拉伯胶、黄耆胶或藻酸钠，羧甲基纤维素，以及聚乙烯吡咯烷酮。
这些剂型中使用的润滑剂包括油酸钠，硬脂酸钠，硬脂酸镁，苯甲酸钠，乙酸钠，氯化钠，十八烷基富马酸钠，硬脂酸等，优选硬脂酸镁。
水溶胀聚合物是指水合时能溶胀的聚合物。术语“可溶胀的”表示聚合物处于非水合状态，而术语“溶胀”则表示聚合物处于水合状态。这些聚合物通常具有25,000-10,000,000的高分子量，在水合态时相应地具有高的粘度。可溶胀聚合物的代表性实例为纤维素聚合物如羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙，以及非纤维素类如聚环氧乙烷、聚乙烯醇、瓜尔胶、阿拉伯胶、角叉菜胶、黄耆胶、藻酸盐、果胶、和黄原胶。同样具代表性的还有“AQUAKEEP J-550”、“AQUAKEEP J-400”，它们是日本Seitetsu Kagaku有限公司(Hyogo)生产的丙烯酸钠聚合物的商品名称。“AQUAKEEP”聚合物种类记载在美国专利4340706中。同样，此类聚合物的代表例还包括通过丙烯酸与蔗糖或季戊四醇的烯丙基醚交联制得的羧基聚亚甲基，它们以“CARBOPOL 934P”和“CARBOPOL974P”商品名出售，此二者为B.F.Goodrich化学公司(Cleveland，Ohio)生产的两种氨基甲酸酯(carbamer)类聚合物的商品名。关于氨基甲酸酯聚合物的种类见美国专利2909462和National Formulary XVII的第1911，CAS登记号9003-01-4中所述。所有上述参考文献在此都引入作为参考。在干态下，“CARBOPOL 974P”和“CARBOPOL 934P”颗粒的大小为2-7微米。当这些干燥颗粒发生水合时，生成20微米的微观凝胶颗粒。当“AQUAKEEP J-550”或“AQUAKEEP J-400”干颗粒发生水合时，微观凝胶颗粒的直径大小可以在100-1000微米范围内。优选的水溶胀性聚合物为聚环氧乙烷和羟丙基甲基纤维素。
合适的增溶剂包括泊咯沙姆(poloxamers)和脂肪酸大分子缩水甘油酯(fatty acid macrogolglycerides)。泊咯沙姆是环氧乙烷与环氧丙烷的嵌段共聚物。例如，合适的泊咯沙姆包括具有约1000-约20,000平均分子量和约40-约90wt.％氧乙烯含量的这类物质。适合本发明使用的代表性泊咯沙姆包括泊咯沙姆188，泊咯沙姆237，泊咯沙姆338，和泊咯沙姆407。合适的脂肪酸大分子缩水甘油醚为硬脂酰基大分子缩水甘油酯，例如GELUCIRE50/13(购自Gattefosse，Paramus，NJ)，它为单-、二-和三-缩水甘油酯与聚乙二醇的单-和二-脂肪酸酯的混合物，其熔点范围为46.0-51.0℃，HLB值为13。
合适的包衣组合物包括不溶聚合物的水分散液或有机溶液，这类聚合物如乙基纤维素、乙酸纤维素，乙酸丁酸纤维素以及在市场上以Eudragit为人们所知的丙烯酸酯共聚物。增塑剂包括柠檬酸三乙酯、癸二酸二丁酯、邻苯二甲酸二丁酯、甘油三乙酸酯和蓖麻油。
防粘着剂包括滑石、高岭土、胶态二氧化硅或其混合物。
“给药装置”是指剂型，它能提供将药物活性成分或药物传递给需要的受治疗者的简便方式。受治疗者可以是需要这类药物活性成分的人或任何其他动物。这种装置设计成可用于通过任何药学上可接受的方式来传递药物活性成分，这些方式如吞咽、保留在嘴内直至有效成分完成分配，置于口腔前庭内等方式。
“控制”表示药物活性成分从装置释放到使用环境的速率不是即速性的，而是按照预定方式释放。因此，可以在指定的时间周期内相对恒定或按预定可变量分配有效成分。
“多晶型物”是指相同物质的不同结晶形式，即其中分子具有不同的排列和/或不同的分子构型。它们显示出不同的物理性质，例如包括一种或多种下列性质：堆积所致的物理性质，各种热动力学、光谱学、界面和机械性质。
在下面的实施例中，“活性成分”是选自以下的化合物中的任何一种：I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、以及IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物和VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。
2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联笨-4-基)甲基]-咪唑-5-羧酸是2-丁基-4-氯-1-[对-(邻-1H-四唑-5-基苯基)苄基]-咪唑-5-甲醇的活性代谢物，后者以单钾盐的形式获得(也称为芦沙坦钾盐)。作为活性成分，芦沙坦钾盐在市场上以COZAAR(Merck&Co.，Inc.(Whitehouse Station，NJ))商品名获得。芦沙坦钾盐的制备见美国专利5136069，5130439和5310928中的描述。在芦沙坦钾盐合成中有用的四唑基苯硼酸中间体记载在美国专利5206374中。记载了可用于制备芦沙坦钾盐方法的其他专利包括美国专利4820843，4870186，4874867，5039814和5859258。
实施例I
I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸
盐的制备
向配置有热电偶、氮气入口管和机械搅拌器的22升烧瓶内加入14升水。向该溶液中加入1197克(86％)片状氢氧化钾和700克芦沙坦钾(2-丁基-4-氯-1-[对-(邻-1H-四唑-5-基苯基)苄基]-咪唑-5-甲醇)，用500ml水冲洗。在使用激冷器装置进行冷却的异丙醇浴中冷却所得溶液到2℃。冷却进行2小时。在此期间有白色浆体形成。向该浆体中顺序加入775克高碘酸钠和16.9克氯化钌(III)水合物，用100ml水冲洗。升温到6-6.5℃。在4-6℃老化所得浆体。老化19小时后，反应完成。在滤除固体和用700ml水洗涤之后，向滤液中加入130ml异丙醇，在18-23℃老化2.5小时。混合物通过Solka Floc滤垫过滤，用600ml水洗涤。在保持温度低于31℃的同时将滤液用1.68L磷酸酸化。老化30分钟后，过滤所得浆体，用2×4L水洗涤。干燥固体随后脱色，浓缩产生白色浆体，过滤，继用500ml冷甲醇洗涤，风干。
将460克游离酸溶于5升冰乙酸并将所得溶液通过玻璃料过滤。于1小时内将滤液加到6升1.1N HCl冰乙酸溶液中。正好在滤液加入结束前开始发生结晶，老化所得批料1小时。添加冰水浴来冷却该批料，并且老化该批料1小时。在1小时内加入12.5升乙酸异丙酯，在3-4℃老化所生成的物质1小时，过滤所得物质，用1升乙酸异丙酯置换洗涤，2×1升乙酸异丙酯淤浆洗涤，再用2.5升乙酸异丙酯置换洗涤。风干所得物质45分钟，然后通过引导氮气通过滤饼，接着在真空箱中35℃干燥至恒重来进行干燥。所得盐酸盐为I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐。随后采用X-射线粉末衍射法分析该固体。I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐衍射图的特征在于具有以下的主要d-间距值：12.96，4.75，3.97，3.79，3.77，和3.44，更准确地说是具有以下的主要d-间距值：12.96，8.32，8.13，7.06，5.18，4.75，4.64，4.45，4.41，4.33，4.19，3.97，3.86，3.79，3.77，3.71，3.59，3.44，3.15和2.92。
实施例2
II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸
盐的制备
在离心管中，在大约0.5mL甲醇中淤浆50mgs实施例1中生成的晶型I。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并且移去上清液。自然干燥残留固体过夜，再真空干燥(50℃)24小时。随后采用X-射线粉末衍射法分析所得固体。II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐衍射图的特征在于具有以下的主要d-间距值：8.55，6.54，5.68，3.90，3.71；更准确地说是具有以下的主要d-间距值：10.09，8.55，7.42，7.26，6.54，6.43，5.68，4.39，4.26，4.17，4.12，4.10，4.02，3.90，3.85，3.71，3.67，3.63，3.59，3.44，3.37，3.35，3.12和3.02。
实施例3
III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐
酸盐的制备
在离心管中，在大约0.5mL乙醇中淤浆50mgs实施例1中生成的晶型I。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并且移去上清液。自然干燥残留的固体过夜，进而再真空干燥(50℃)24小时。随后采用X-射线粉末衍射法分析所得固体。III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐衍射图的特征在于具有以下的主要d-间距值：18.78，9.49，9.34，6.22，和4.20；更准确地说是具有以下的主要d-间距值：18.78，9.49，6.22，6.18，4.85，4.67，4.46，4.20，3.97，3.68，3.66，3.63和3.50。
实施例4
IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一
水合物的制备
在分离离心管中放入25mgs实施例2中生成的晶型II和实施例3中形成的晶型III。向包含晶型II和晶型III的各离心管内加入约25mg实施例1中生成的晶型I。向各离心管中加入0.5mL水。在旋转蒸发器上旋转样品约72小时。72小时后，离心样品并且移去上清液。真空干燥(40℃)残留固体24小时。随后采用X-射线粉末衍射法分析该固体。IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物衍射图的特征在于具有以下的主要d-间距值：8.57，5.01，3.66，和3.63；更准确地说是具有以下的主要d-间距值：10.52，8.57，7.46，6.60，5.45，5.37，5.01，4.91，4.65，3.80，3.66，3.63，3.29，3.23，3.22，3.19，3.02。
实施例5
IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一
水合物的另一种制法
在离心管中，在大约0.5mL水中淤浆50mgs实施例1中生成的晶型I。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并且移去上清液。自然干燥残留的固体过夜，进而再真空干燥(50℃)24小时。随后采用X-射线粉末衍射法分析所得固体。IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物衍射图的特征在于具有以下的主要d-间距值：8.57，5.01，3.66，和3.63；更准确地说是具有以下的主要d-间距值：10.52，8.57，7.46，6.60，5.45，5.37，5.01，4.91，4.65，3.80，3.66，3.63，3.29，3.23，3.22，3.19，3.02。
实施例6
V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水
合物的制备
在离心管中，在大约0.5mL水中淤浆50mgs实施例5中生成的晶型IV。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并且移去上清液。自然干燥残留的固体过夜，进而再真空干燥(50℃)24小时。随后采用X-射线粉末衍射法分析所得固体。V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物衍射图的特征在于具有以下的主要d-间距值：6.44，6.39，6.34，和4.20；更准确地说是具有以下的主要d-间距值：7.34，6.90，6.44，6.34，5.69，5.64，4.54，4.26，4.24，4.20，3.91，3.90，3.77和3.59。
实施例7
VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一
水合物的制备
在离心管中，在大约0.5mL乙醇中淤浆50mgs实施例5中生成的晶型IV。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并且移去上清液。自然干燥残留的固体过夜，再真空干燥(50℃)24小时。随后采用X-射线粉末衍射法分析所得固体。VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物衍射图的特征在于具有以下的主要d-间距值：7.38，6.75，和6.69；更准确地说是具有以下的主要d-间距值：7.38，7.32，6.75，6.69，4.38，4.03，3.76，3.70，和3.42。
实施例8
VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一
水合物的制备
在离心管中，在大约0.5mL乙腈中淤浆50mgs实施例5中生成的晶型IV。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并且移去上清液。自然干燥残留的固体过夜，再真空干燥(50℃)24小时。随后采用X-射线粉末衍射法分析所得固体。VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物衍射图的特征在于具有15.91的主要d-间距值；更准确地说是具有以下的主要d-间距值：15.91，9.99，8.37和7.59。
实施例9
VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一
水合物的制备
在离心管中，在大约0.5mL水中淤浆50mgs实施例7中生成的晶型VI。在旋转蒸发器上旋转该样品约72小时。72小时后，离心样品并移去上清液。真空干燥(40℃)残留的固体24小时。随后采用X-射线粉末衍射法分析所得固体。VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物衍射图的特征在于具有以下的主要d-间距值：9.13，8.09，6.61，4.18，3.70和3.65；更准确地说是具有以下的主要d-间距值：10.99，9.13，8.69，8.09，6.61，6.24，5.39，4.37，4.23，4.18，3.96，3.93，3.80，3.70，3.65，3.24，3.17和3.13。
实施例10
基于亲水性溶胀聚合物的多微粒
以亲水性溶胀聚合物HPMC和聚(环氧乙烷)为基质的控释多微粒控制包埋在基质中的药物的释放。为获得4-6小时的释放分布图，这些控释多微粒可以与下文描述的即释性颗粒联用。
控释多微粒制剂10A，10B和10C
| 组分 | 10A | 10B | 10C | ％范围w/w |
| 活性成分 | 25 | 25 | 25 | 1-75 |
| HPMC(Methocel K4M) | 10 | 25 | - | 2.5-90 |
| 聚(环氧乙烷)(Polyox WSR N60K) | 10 | 25 | - | 2.5-90 |
| HPMC(Methocel K15M) | - | - | 15 | 2.5-90 |
| 聚(环氧乙烷)(Polyox WSR Coagulant) | - | - | 15 | 2.5-90 |
| 磷酸氢钙(ATAB) | 27 | 12 | 22 | 2.5-90 |
| Avicel PH 102(微晶纤维素) | 27 | 12 | 22 | 2.5-90 |
| 硬脂酸镁 | 1 | 1 | 1 | 0.5＝5 |
数量以％w/w为单位。
制备控释多微粒制剂的方法
精确称取各组分，在Turbula捏合机中捏合5分钟。使用1”圆扁型工具，在自动Carver压力机上以4000kg的压力(77MPa)将上述共混物压制成2g的块状物。将这些块状物人工破碎，利用#35和#80号筛筛分成500-180μm颗粒。上述这些颗粒也可以利用辊式压制法或湿制粒法工业制备。
即释性颗粒制剂10D
| 组分 | 10D |
| 活性成分 | 25 |
| 乳糖 | 35.5 |
| Avicel PH 102(微晶纤维素) | 35.5 |
| 交联羧甲基纤维素钠 | 3 |
| 硬脂酸镁 | 1 |
数量以％w/w为单位。
制备即释性颗粒制剂的方法
精确称取所述各组分，在Turbula捏合机中捏合5分钟。使用1”圆扁型工具，在自动Carver压力机上以4000kg的压力(77MPa)将上述共混物压制成2g的块状物。然后将这些块状物共研磨成颗粒。
上述这些颗粒也可以利用辊式压制法或湿制粒法工业制备。
控释多微粒与即释性颗粒的联合制剂
将控释多微粒单独或与即释性颗粒一起填充到胶囊内，以获得具有需要释放速率的制剂。药物的释放取决于药物/聚合物的比值，聚合物总含量，聚合物的等级(高分子量对低分子量)，HPMC与聚环氧乙烷Polyox的比值。此外，释放速率还取决于控释多微粒的量与即释性颗粒的量之比。
制备上述这些颗粒的其他可供选择的方法采用辊式压制法替代成块法，随后通过研磨获得具有需要粒度范围的多微粒和颗粒。
实施例11
可侵蚀基质片剂
HPMC K4M和用于控制释放速率的可侵蚀聚合物一样是溶胀剂。Poloxamer 407是作为增溶剂加入到制剂中的。此外假设它也能调控片剂的侵蚀情况。
可侵蚀基质片剂11A，11B和11C
| 组分 | 11A | 11B | 11C |
| 活性成分 | 25 | 25 | 25 |
| HPMC(Methocel K) | 2.5 | 5 | 7.5 |
| Poloxamer 407 | 12 | 12 | 12 |
| 磷酸氢钙(ATAB) | 27 | 27 | 27 |
| Avicel PH 102(微晶纤维素) | 29.5 | 27 | 24.5 |
| Fast flo乳糖 | 3 | 3 | 3 |
| 硬脂酸镁 | 1 | 1 | 1 |
速率以％w/w为单位。
制备可侵蚀基质片剂的方法
在Turbula捏合机中干法捏合上述各组分，使用19/32”标准圆凹性工具在自动Carver压力机中压制成200mg的片剂。药物的释放受制剂中HPMC的含量控制。2.5％HPMC含量的制剂在期望的6小时内释放药物。
制备该制剂的方法可以是直接压片法、辊式压制法、高剪切湿制粒法或流化床制粒法。
实施例12
包衣多微粒系统
控释多微粒系统由乙基纤维素水分散液(Aquacoat)包衣的药物颗粒组成(采用高剪切湿制粒法和团球技术制备，药物填充量为15％w/w)，这种乙基纤维素水分散液用作速率控制阻挡层，并且包衣采用流化床包衣方法。
包衣颗粒剂12A
包衣颗粒制剂包括干燥颗粒组分和包衣组分。
包衣组分组成
| 组分 | ％w/w |
| 活性成分 | 15 |
| 磷酸氢二钠七水合物 | 15 |
| Avicel RC 591(含羧甲基纤维素钠的微晶纤维素) | 20 |
| 羟丙基纤维素(EXF级) | 2 |
| Avicel PH 101(微晶纤维素) | 48 |
数量以％w/w为单位。
颗粒组分配制方法
在Turbula捏合机中捏合规定量的E3174、磷酸氢二钠七水合物、Avicel RC 591、Avicel PH 101以及一半规定量的羟丙基纤维素。将这些内容物转移到Bohle高剪切造粒机中，用10％w/v HPC EXF溶液造粒。然后将颗粒化物在Caleva团球机(120型)中以3mts的中等速率团成球状，在盘架干燥器中35℃干燥14小时。然后筛分这种干燥颗粒，得到粒度范围为180-355μm的颗粒。
包衣组分组成
| 组分 | ％w/w固体组分 |
| Aquacot | 68.8 |
| 柠檬酸三乙酯 | 24.1 |
| 高岭土 | 6.88 |
| FD&C兰色淀(blue lake) | 0.28 |
上述组成列出的各成分的量以％重量固体为基准。在水中制成20％固体含量的包衣溶液。
包衣组分组成和包衣方法
将筛分过的颗粒转移到Miniglatt流化床包衣机中，用20％w/w固含量的Aquacoat分散液包衣，增加8％的重量。Aquacoat分散液还含有柠檬酸三乙酯(增塑剂)、高岭土和FD&C兰色淀(blue lake)，其含量相应地为固体乙基纤维素的35％w/w，10％w/w和0.4％w/w。包衣使用顶端喷雾结构，并且使用气动振动器来减轻静态效应。包衣颗粒在盘架干燥器中60℃老化4小时，将相当于500mg游离碱的包衣颗粒包封在00号胶囊内。另一方面，这些包衣多微粒可以借助用于保护控速聚合物衣膜的缓冲角钉(cushioning brads)轻轻地压制成片剂。
实施例13
溶出分布图
在USP溶出装置II中(桨式法(paddle method))，在pH 6.8磷酸盐缓冲液中以100rpm评价上面实施例中制备的各种制剂，在14小时时期内例如0.5，1，2，3，4，6，8，10，12和14小时测定各样品。
Claims (11)
1.2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物，或其药学上可接受的盐或水合物。
2.权利要求1的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物，其具有选自以下的X-射线粉末衍射图案d间距值：
a)约12.9，约4.8，约4.0，约3.79，约3.77，约3.7和约3.4，
b)约8.6，约6.5，约5.7，约3.9，和约3.7，
c)约18.8，约9.5，约9.3，约6.2，和约4.2，
d)约8.6，约5.0，约3.7，和约3.6，
e)约6.44，约6.39，约6.3，和约4.2，
f)约7.4，约6.8，和约6.7，
g)约15.9，和
h)约9.1，约8.1，约6.6，约4.2，约3.7，和约3.7。
3.权利要求2的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物，其具有选自以下的X-射线粉末衍射图案d间距值：
a)约12.96，约4.75，约3.97，约3.79，约3.77，约3.71，和约3.44，
b)约8.55，约6.54，约5.68，约3.90，和约3.71，
c)约18.78，约9.49，约9.34，约6.22，和约4.20，
d)约8.57，约5.01，约3.66，和约3.63，
e)约6.44，约6.39，约6.34，和约4.20，
f)约7.38，约6.75，和约6.69，
g)约15.91，和
h)约9.13，约8.09，约6.61，约4.18，约3.70，和约3.65。
4.权利要求2的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物，其具有选自以下的X-射线粉末衍射图案d间距值：
a)12.96，8.32，8.13，7.06，5.18，4.75，4.64，4.45，4.41，4.33，4.19，3.97，3.86，3.79，3.77，3.71，3.59，3.44，3,15，和2.92，
b)10.09，8.55，7.42，7.26，6.54，6.43，5.68，4.39，4.26，4.17，4.12，4.10，4.02，3.90，3.85，3.71，3.67，3.63，3.59，3.44，3.37，3.35，3.12，和3.02，
c)18.78，9.49，9.34，6.22，6.18，4.85，4.67，4.46，4.20，3.97，3.68，3.66，3.63，和3.50，
d)10.52，8.57，7.46，6.60，5.45，5.37，5.01，4.91，4.65，3.80，3.66，3.63，3.29，3.23，3.22，3.19，3.02，
e)7.34，6.90，6.44，6.39，6.34，5.69，5.64，4.54，4.26，4.24，4.20，3.91，3.90，3.77和3.59，
f)7.38，7.32，6.75，6.69，4.38，4.03，3.76，3.70，和3.42，
g)15.91，9.99，8.37，和7.59，以及
h)10.99，9.13，8.69，8.09，6.61，6.32，6.24，5.39，4.37，4.23，4.18，3.96，3.93，3.80，3.70，3.65，3.24，3.17和3.13。
5.权利要求3的2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸的多晶型物，其选自I型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、II型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、III型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸盐酸盐、以及IV型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、V型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VI型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、VII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物、和VIII型2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸一水合物。
6.一种药物颗粒基质组合物，其包括：
a)约1-75％w/w的权利要求2的结晶2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸；
b)约2.5-90％w/w的至少一种水溶胀性聚合物；
c)约2.5-90％w/w的至少一种填充剂；和
d)约0.5-10％w/w的至少一种润滑剂，
其中颗粒的粒度为约150-1200μm。
7.权利要求5的组合物，其中所述溶胀性聚合物优选选自聚环氧乙烷和羟丙基甲基纤维素，填充剂优选为磷酸氢钙和微晶纤维素的混合物，并且润滑剂优选为硬脂酸镁。水溶胀性聚合物选自聚环氧乙烷和羟丙基甲基纤维素。
8.一种可侵蚀的基质组合物药物片剂，其包括：
a)约1-75％w/w的权利要求2的结晶2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸；
b)约2.5-25％w/w的至少一种水溶胀性聚合物；
c)约2.5-15％w/w的至少一种增溶剂；和
d)约2.5-90％w/w的至少一种填充剂。
9.权利要求7的组合物，其中所述的水溶胀性聚合物选自聚环氧乙烷和羟丙基甲基纤维素，所述填充剂为磷酸氢钙、微晶纤维素与乳糖的混合物，并且增溶剂选自环氧乙烷与环氧丙烷的嵌段共聚物。
10.一种药物组合物，其包括颗粒和用于包衣该颗粒的包衣材料，其中
a)所述颗粒包括
1)约1-75％w/w的权利要求2的结晶2-丁基-4-氯-1-[(2’-(1-H-四唑-5-基)联苯-4-基)甲基]-咪唑-5-羧酸；
2)约5-50％w/w的至少一种中和剂；
3)约1-25％w/w的至少一种粘合剂；和
4)约5-75％w/w的至少一种填充剂，
其中所述颗粒的粒度为约100-1200μm；和
b)所述包衣材料包括：
1)在以后蒸发分散液溶剂时能以水分散液或有机溶液的形式沉积的聚合物，其中包衣材料中聚合物的量应使得沉积在颗粒上的聚合物量为颗粒重量的约5-40％w/w；
2)增塑剂，其量最多达聚合物重量的40％；和
3)防粘着剂，其量最多达聚合物重量的10％。
11.权利要求9的组合物，其中所述中和剂选自磷酸氢二钠七水合物，填充剂为微晶纤维素，粘合剂为羟丙基纤维素，并且水分散液包含乙基纤维素、柠檬酸三乙酯和高岭土。
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| SI2774925T1 (sl) | 2005-11-08 | 2017-04-26 | Vertex Pharmaceuticals Incorporated | Heterociklični modulatorji prenašalcev z ATP-vezavno kaseto |
| TWI399223B (zh) * | 2006-09-15 | 2013-06-21 | Daiichi Sankyo Co Ltd | 奧美沙坦酯及氨氯地平之固體劑型 |
| NZ702159A (en) * | 2007-12-07 | 2016-03-31 | Vertex Pharma | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
| NZ602838A (en) | 2010-04-07 | 2015-06-26 | Vertex Pharma | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof |
| MX2016006118A (es) | 2013-11-12 | 2016-07-21 | Vertex Pharma | Proceso para preparar composiciones farmaceuticas para el tratamiento de enfermedades mediadas por regulador de la conductancia transmembrana de la fibrosis quistica (cftr). |
| RU2016147009A (ru) | 2014-05-01 | 2018-06-04 | Сан Фармасьютикал Индастриз Лимитед | Композиции с пролонгированным высвобождением в виде суспензии |
| US10258583B2 (en) | 2014-05-01 | 2019-04-16 | Sun Pharmaceutical Industries Limited | Extended release liquid compositions of guanfacine |
| US9962336B2 (en) | 2014-05-01 | 2018-05-08 | Sun Pharmaceutical Industries Limited | Extended release suspension compositions |
| AU2015254874A1 (en) * | 2014-05-01 | 2016-11-17 | Sun Pharmaceutical Industries Limited | Extended release liquid compositions of metformin |
| US20180104197A9 (en) | 2014-05-01 | 2018-04-19 | Sun Pharmaceutical Industries Limited | Extended release liquid compositions of metformin |
| CA2956902A1 (en) | 2014-07-30 | 2016-02-04 | Sun Pharmaceutical Industries Limited | Dual-chamber pack |
| MA41124A (fr) * | 2014-12-05 | 2017-10-10 | Sun Pharmaceutical Ind Ltd | Compositions en suspension à libération prolongée à rétention gastrique |
| US10238803B2 (en) | 2016-05-02 | 2019-03-26 | Sun Pharmaceutical Industries Limited | Drug delivery device for pharmaceutical compositions |
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| EP1874302A1 (en) | 2008-01-09 |
| CA2604190A1 (en) | 2006-11-02 |
| US20090123538A1 (en) | 2009-05-14 |
| AU2006240247A1 (en) | 2006-11-02 |
| JP2008538561A (ja) | 2008-10-30 |
| WO2006115834A1 (en) | 2006-11-02 |
| EP1874302A4 (en) | 2009-12-16 |
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