CN1948293A - δd-结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 - Google Patents
δd-结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 Download PDFInfo
- Publication number
- CN1948293A CN1948293A CNA2006101322309A CN200610132230A CN1948293A CN 1948293 A CN1948293 A CN 1948293A CN A2006101322309 A CNA2006101322309 A CN A2006101322309A CN 200610132230 A CN200610132230 A CN 200610132230A CN 1948293 A CN1948293 A CN 1948293A
- Authority
- CN
- China
- Prior art keywords
- hydrochloric acid
- delta
- crystalline form
- acid ivabradine
- counting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 6
- 229960000504 ivabradine hydrochloride Drugs 0.000 title abstract 2
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 39
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 229960003825 ivabradine Drugs 0.000 claims description 18
- 206010003119 arrhythmia Diseases 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 230000000059 bradycardiac effect Effects 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 230000007170 pathology Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002441 X-ray diffraction Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- -1 frost Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
δd-结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物δd-结晶形式的式(I)的盐酸伊伐布雷定。其特征在于其粉末X-射线衍射图。药剂。
Description
技术领域
本发明涉及δd-结晶形式的式(I)的盐酸伊伐布雷定(ivabradine),其制备方法以及包含它的药物细合物。
背景技术
伊伐布雷定以及其与药学上可接受的酸形成的加成盐,尤其是其盐酸盐,具有非常有价值的药理学和治疗学特性,尤其减慢心率(bradycardic)的特性,从而使得这些化合物可用于治疗或预防多种心肌缺血性临床状况,如心绞痛、心肌梗塞及有关的心脏节律紊乱,也可用于多种涉及心脏节律紊乱的病理学,特别是室上性心脏节律紊乱,以及心力衰竭。
欧洲专利说明书EP 0 534 859已经描述了伊伐布雷定及其与药学上可接受的酸形成的加成盐,特别是其盐酸盐的制备和治疗学用途。
考虑到该化合物的药学价值,获得高纯度的该化合物非常重要。能够通过非常容易转化为产业规模的方法手段,尤其是允许快速过滤和干燥的形式合成该化合物也是很重要的。最后,该形式也必须能够完美地再生、容易配制,并且足够稳定,以允许长期存储而对温度、光照和氧水平没有特别要求。
专利说明书EP 0 534 859描述了伊伐布雷定及其盐酸盐的合成方法。然而,该文献没有说明获得以可再现的方式显示上述特征的形式的伊伐布雷定的条件。
发明内容
申请人现在已经发现,伊伐布雷定的一种特定的盐,即盐酸盐,可以以完全确定的结晶形式获得,其显示有价值的稳定性和可加工性特征。
更具体地讲,本发明涉及δd-结晶形式的伊伐布雷定的盐酸盐,其特征为以下的粉末X-射线衍射图,该图用PANalytical X′Pert Pro衍射计和X′Celerator探测器测得,以线的位置(布喇格角2θ,以度表示)、线高(以计数表示)、线面积(以计数×度表示)、半高时的线宽(″FWHM″,以度表示)和晶面间距d(以_表示)表示:
线编号 | 角2θ(度) | 高(计数) | 面积(计数×度) | FWHM(度) | 晶面间距(_) |
1 | 4.1 | 414 | 41 | 0.1004 | 21.672 |
2 | 6.8 | 176 | 139 | 0.8029 | 13.078 |
3 | 8.6 | 1020 | 101 | 0.1004 | 10.305 |
4 | 9.1 | 323 | 43 | 0.1338 | 9.687 |
5 | 10.9 | 224 | 30 | 0.1338 | 8.100 |
6 | 11.7 | 354 | 47 | 0.1338 | 7.592 |
7 | 14.6 | 2774 | 458 | 0.1673 | 6.074 |
8 | 15.3 | 1805 | 328 | 0.184 | 5.800 |
9 | 16.6 | 986 | 163 | 0.1673 | 5.345 |
10 | 17.2 | 3821 | 946 | 0.2509 | 5.153 |
11 | 18.1 | 2290 | 378 | 0.1673 | 4.898 |
12 | 19.1 | 440 | 73 | 0.1673 | 4.649 |
13 | 19.6 | 289 | 38 | 0.1338 | 4.526 |
14 | 20.1 | 650 | 86 | 0.1338 | 4.408 |
15 | 20.9 | 887 | 146 | 0.1673 | 4.252 |
16 | 21.4 | 3112 | 565 | 0.184 | 4.147 |
17 | 22.1 | 1708 | 254 | 0.1506 | 4.027 |
18 | 22.5 | 1191 | 275 | 0.2342 | 3.945 |
19 | 23.4 | 619 | 102 | 0.1673 | 3.800 |
20 | 23.9 | 1343 | 222 | 0.1673 | 3.728 |
21 | 24.7 | 256 | 34 | 0.1338 | 3.604 |
22 | 25.6 | 309 | 41 | 0.1338 | 3.482 |
23 | 26.2 | 1899 | 313 | 0.1673 | 3.397 |
24 | 26.9 | 1588 | 183 | 0.1171 | 3.310 |
25 | 27.6 | 1357 | 224 | 0.1673 | 3.231 |
26 | 29.1 | 140 | 37 | 0.2676 | 3.069 |
27 | 29.5 | 145 | 29 | 0.2007 | 3.023 |
本发明还涉及δd-结晶形式的盐酸伊伐布雷定的制备方法,该方法的特征是将乙腈或乙腈与水的混合物预热,加入盐酸伊伐布雷定,将获得的溶液冷却到室温,保持在室温直至结晶完成,将所形成的晶体脱水。
在依据本发明的结晶方法中,可以使用由任何方法获得的盐酸伊伐布雷定,例如由专利说明书EP 0 534 859中所述的制备方法获得的盐酸伊伐布雷定。
有利地,可以在冷却步骤期间向溶液中加入晶种。
优选将乙腈或乙腈与水的混合物预热至60℃和回流温度之间的温度,更优选预热至65和75℃之间。
优选稀释度大于15ml/g,更优选在50和100ml/g之间。
脱水优选通过加热进行。
本发明还涉及药物组合物,所述药物组合物包含作为活性成分的δd-结晶形式的盐酸伊伐布雷定和一种或多种合适的、惰性且无毒的赋形剂。在根据本发明的药物组合物中,可能更特别要提到的是那些适合于口服、肠胃外(静脉内或皮下)或经鼻施用的药片或糖衣丸、舌下用药片、胶囊、锭剂、栓剂、霜、软膏、皮肤凝胶、可注射制剂、可饮用的混悬液。
可用剂量可根据疾病的性质和严重性、施药途径和患者的年龄和体重而有所不同。剂量在每天1至500mg之间变化,可以单次或分多次给药。
下面的实施例阐述了本发明。
在下述实验条件下测量X射线粉末衍射光谱。
-PANalytical X′Pert Pro衍射计,X′Celerator探测器,温控室,
-电压45kV,电流强度40mA,
-设定(mounting)θ-θ,
-镍(Kβ)过滤器,
-入射光和衍射光Soller狭缝:0.04rad,
-自动散射狭缝:10mm辐射长度,
-掩盖:10mm,
-反散射(antiscatter)狭缝:1/2°,
-测量模式:自3°至30°连续测量,增量为0.017°,
-每步的测量时间:19.7秒,
-总时间:4分32秒,
-测量速度:0.108°/s。
实施例1:δd-结晶形式的盐酸伊伐布雷定
将160ml乙腈预热到70℃,然后一部分一部分地加入由专利说明书EP0534859中所述的方法获得的2g盐酸伊伐布雷定,同时搅拌,直至完全溶解。然后将所述溶液于周围温度下保存2天。真空过滤出晶体并在结晶盘上铺展。然后以10℃/min的速率将晶体加热到85℃并在85℃保持4小时。
粉末X-射线衍射图:
在下表中用明显的线给出了δd-形式的盐酸伊伐布雷定的粉末X-射线衍射图型(衍射角):
线编号 | 角2θ(度) | 高(计数) | 面积(计数×度) | FWHM(度) | 晶面间距(_) |
1 | 4.1 | 414 | 41 | 0.1004 | 21.672 |
2 | 6.8 | 176 | 139 | 0.8029 | 13.078 |
3 | 8.6 | 1020 | 101 | 0.1004 | 10.305 |
4 | 9.1 | 323 | 43 | 0.1338 | 9.687 |
5 | 10.9 | 224 | 30 | 0.1338 | 8.100 |
6 | 11.7 | 354 | 47 | 0.1338 | 7.592 |
7 | 14.6 | 2774 | 458 | 0.1673 | 6.074 |
8 | 15.3 | 1805 | 328 | 0.184 | 5.800 |
9 | 16.6 | 986 | 163 | 0.1673 | 5.345 |
10 | 17.2 | 3821 | 946 | 0.2509 | 5.153 |
11 | 18.1 | 2290 | 378 | 0.1673 | 4.898 |
12 | 19.1 | 440 | 73 | 0.1673 | 4.649 |
13 | 19.6 | 289 | 38 | 0.1338 | 4.526 |
14 | 20.1 | 650 | 86 | 0.1338 | 4.408 |
15 | 20.9 | 887 | 146 | 0.1673 | 4.252 |
16 | 21.4 | 3112 | 565 | 0.184 | 4.147 |
17 | 22.1 | 1708 | 254 | 0.1506 | 4.027 |
18 | 22.5 | 1191 | 275 | 0.2342 | 3.945 |
19 | 23.4 | 619 | 102 | 0.1673 | 3.800 |
20 | 23.9 | 1343 | 222 | 0.1673 | 3.728 |
21 | 24.7 | 256 | 34 | 0.1338 | 3.604 |
22 | 25.6 | 309 | 41 | 0.1338 | 3.482 |
23 | 26.2 | 1899 | 313 | 0.1673 | 3.397 |
24 | 26.9 | 1588 | 183 | 0.1171 | 3.310 |
25 | 27.6 | 1357 | 224 | 0.1673 | 3.231 |
26 | 29.1 | 140 | 37 | 0.2676 | 3.069 |
27 | 29.5 | 145 | 29 | 0.2007 | 3.023 |
实施例2:药物组合物
用于制备1000片药片、其中每片药片含5mg伊伐布雷定碱的配方:
实施例1的化合物........................................5.39g
玉米淀粉.................................................20g
无水胶态二氧化硅........................................0.2g
甘露醇................................................63.91g
PVP......................................................10g
硬脂酸镁................................................0.5g
Claims (6)
1.δd-结晶形式的式(I)的盐酸伊伐布雷定:
其特征在于下述的粉末X-射线衍射图,该图用PANalytical X′Pert Pro衍射计和X′Celerator探测器测得,以线的位置(布喇格角2θ,以度表示)、线高(以计数表示)、线面积(以计数×度表示)、半高时的线宽(″FWHM″,以度表示)和晶面间距d(以_表示)表示: 线编号
角2θ(度)
高(计数)
面积(计数×度)
FWHM(度)
晶面间距(_)
1
4.1
414
41
0.1004
21.672
2
6.8
176
139
0.8029
13.078
3
8.6
1020
101
0.1004
10.305
4
9.1
323
43
0.1338
9.687
5
10.9
224
30
0.1338
8.100
6
11.7
354
47
0.1338
7.592
7
14.6
2774
458
0.1673
6.074
8
15.3
1805
328
0.184
5.800
9
16.6
986
163
0.1673
5.345
10
17.2
3821
946
0.2509
5.153
11
18.1
2290
378
0.1673
4.898
12
19.1
440
73
0.1673
4.649
13
19.6
289
38
0.1338
4.526
14
20.1
650
86
0.1338
4.408
15
20.9
887
146
0.1673
4.252
16
21.4
3112
565
0.184
4.147
17
22.1
1708
254
0.1506
4.027
18
22.5
1191
275
0.2342
3.945
19
23.4
619
102
0.1673
3.800
20
23.9
1343
222
0.1673
3.728
21
24.7
256
34
0.1338
3.604
22
25.6
309
41
0.1338
3.482
23
26.2
1899
313
0.1673
3.397
24
26.9
1588
183
0.1171
3.310
25
27.6
1357
224
0.1673
3.231
26
29.1
140
37
0.2676
3.069
27
29.5
145
29
0.2007
3.023
。
2.根据权利要求1的δd-结晶形式的盐酸伊伐布雷定的制备方法,其特征在于将乙腈或乙腈与水的混合物预热,加入盐酸伊伐布雷定,将获得的溶液冷却到室温,保持在室温直至结晶完成,将所形成的晶体脱水。
3.根据权利要求2的方法,其特征在于在冷却步骤期间向所述盐酸伊伐布雷定的溶液中加入晶种。
4.药物组合物,其包含作为活性成分的根据权要求1的δd-结晶形式的盐酸伊伐布雷定,和一种或多种药学上可接受的、惰性、无毒载体。
5.根据权利要求1的δd-结晶形式的盐酸伊伐布雷定在生产用作减慢心率药的药物中的用途。
6.根据权利要求1的δd-结晶形式的盐酸伊伐布雷定在生产用于治疗或预防各种心肌缺血性临床状况,例如心绞痛、心肌梗塞及有关的心脏节律紊乱,以及用于多种涉及心脏节律紊乱的病理学,特别是室上性心脏节律紊乱,以及心力衰竭的药物中的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0510354 | 2005-10-11 | ||
FR0510354A FR2891827B1 (fr) | 2005-10-11 | 2005-10-11 | Forme cristalline deltad du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1948293A true CN1948293A (zh) | 2007-04-18 |
Family
ID=36588996
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006101322309A Pending CN1948293A (zh) | 2005-10-11 | 2006-10-11 | δd-结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 |
Country Status (32)
Country | Link |
---|---|
US (3) | US7384932B2 (zh) |
EP (2) | EP1775287A1 (zh) |
JP (1) | JP2007112797A (zh) |
KR (1) | KR20070040310A (zh) |
CN (1) | CN1948293A (zh) |
AP (1) | AP2185A (zh) |
AR (1) | AR056573A1 (zh) |
AU (1) | AU2006228028B2 (zh) |
BR (1) | BRPI0604253A (zh) |
CA (1) | CA2564369C (zh) |
CO (1) | CO5840253A1 (zh) |
CR (1) | CR8647A (zh) |
EA (1) | EA010286B1 (zh) |
EC (1) | ECSP066914A (zh) |
FR (1) | FR2891827B1 (zh) |
GE (1) | GEP20094654B (zh) |
GT (1) | GT200600448A (zh) |
IL (1) | IL178545A (zh) |
MA (1) | MA28625B1 (zh) |
MX (1) | MXPA06011767A (zh) |
MY (1) | MY140490A (zh) |
NI (1) | NI200600240A (zh) |
NO (1) | NO20064588L (zh) |
NZ (1) | NZ550436A (zh) |
PE (1) | PE20070547A1 (zh) |
SA (1) | SA06270371B1 (zh) |
SG (1) | SG131857A1 (zh) |
TW (1) | TW200800221A (zh) |
UA (1) | UA90266C2 (zh) |
UY (1) | UY29856A1 (zh) |
WO (1) | WO2007042657A1 (zh) |
ZA (1) | ZA200608404B (zh) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010081342A1 (zh) | 2009-01-13 | 2010-07-22 | 江苏恒瑞医药股份有限公司 | 硫酸伊伐布雷定及其i型结晶的制备方法 |
CN101353325B (zh) * | 2007-07-27 | 2011-11-09 | 上海优拓医药科技有限公司 | 稳定型盐酸伊伐布雷定结晶及其制备方法 |
CN102731400A (zh) * | 2011-04-11 | 2012-10-17 | 山东新时代药业有限公司 | 一种盐酸伊伐布雷定的新晶型、制备方法及其在制备药物组合物中的用途 |
CN103012269A (zh) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | 一种盐酸伊伐布雷定新晶型c及其制备方法 |
CN101768117B (zh) * | 2008-12-29 | 2014-05-07 | 北京德众万全药物技术开发有限公司 | 一种盐酸伊伐布雷定晶型及其制备方法 |
CN103880748A (zh) * | 2014-04-03 | 2014-06-25 | 南京正大天晴制药有限公司 | 一种盐酸伊伐布雷定结构类似物及其制备方法和应用 |
CN105503726A (zh) * | 2015-12-30 | 2016-04-20 | 浙江美诺华药物化学有限公司 | 伊伐布雷定盐酸盐晶型变体delta-d的制备方法 |
CN107200710A (zh) * | 2017-05-22 | 2017-09-26 | 苏州华健瑞达医药技术有限公司 | 盐酸伊伐布雷定新晶型、制备方法及含有其的组合物 |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2882556B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882553B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882555B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882554B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
EP2097383B1 (en) | 2006-11-30 | 2012-02-08 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
US8212026B2 (en) | 2007-05-30 | 2012-07-03 | Ind-Swift Laboratories Limited | Process for the preparation of ivabradine hydrochloride and polymorph thereof |
WO2010072409A1 (en) | 2008-12-22 | 2010-07-01 | Krka, D. D., Novo Mesto | Process for preparation of ivabradine |
US8270169B2 (en) | 2009-03-24 | 2012-09-18 | Raytheon Company | Translating hinge |
WO2010128525A2 (en) | 2009-05-04 | 2010-11-11 | Dinesh Shantilal Patel | A formulation of ivabradine for treating the cardiovascular disease |
EP2902384B1 (en) | 2010-02-12 | 2017-11-08 | KRKA, D.D., Novo Mesto | Form of ivabradine hydrochloride |
HUP1000245A2 (en) | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
WO2012025940A1 (en) * | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Polymorphic form of ivabradine hydrochloride and process for preparation thereof |
EP2726462B1 (en) | 2011-08-02 | 2017-03-22 | Sandoz AG | Acetone solvate of ivabradine hydrochloride |
WO2013064427A1 (en) | 2011-11-04 | 2013-05-10 | Synthon Bv | A process for making crystalline delta-form of ivabradine hydrochloride |
EP2589594A1 (en) | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
US9120755B2 (en) * | 2011-11-14 | 2015-09-01 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
WO2014114341A1 (en) | 2013-01-24 | 2014-07-31 | Synthon Bv | Process for making ivabradine |
EP2781509B2 (en) | 2013-03-19 | 2023-06-14 | Chemo Research, S.L. | New polymorph of ivabradine hydrochloride and method for its preparation |
CZ305096B6 (cs) * | 2013-10-02 | 2015-04-29 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (S)-mandlové kyseliny a její farmaceutická kompozice |
ES2672472T3 (es) | 2013-12-12 | 2018-06-14 | Synthon Bv | Composición farmacéutica que comprende ivabradina amorfa |
EP2774606B1 (en) | 2014-02-14 | 2019-01-30 | Synthon B.V. | Pharmaceutical composition comprising ivabradine hydrochloride polymorph IV |
CZ305436B6 (cs) | 2014-07-10 | 2015-09-16 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (R)-mandlové kyseliny a její farmaceutická kompozice |
WO2016102423A1 (en) | 2014-12-22 | 2016-06-30 | Ratiopharm Gmbh | Composition comprising ivabradine in a dissolved form |
EP3366282A1 (en) | 2017-02-28 | 2018-08-29 | Sanovel Ilac Sanayi ve Ticaret A.S. | Solid oral pharmaceutical compositions of ivabradine |
TR201703066A2 (tr) | 2017-02-28 | 2018-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | İvabradi̇ni̇n kati oral farmasöti̇k kompozi̇syonlari |
IT202000025312A1 (it) * | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | Processi per la preparazione di polimorfi di ivabradina hcl |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3119874A1 (de) * | 1981-05-19 | 1982-12-09 | Dr. Karl Thomae Gmbh, 7950 Biberach | "benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel" |
DE3418270A1 (de) * | 1984-05-17 | 1985-11-21 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue aminotetralinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
GB9017453D0 (en) | 1990-08-09 | 1990-09-26 | Mcivor Robert C | Fluid additive regulating apparatus |
FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2882554B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882556B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882555B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2882553B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
FR2891826B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
-
2005
- 2005-10-11 FR FR0510354A patent/FR2891827B1/fr not_active Expired - Fee Related
-
2006
- 2006-09-21 CR CR8647A patent/CR8647A/es not_active Application Discontinuation
- 2006-09-22 MA MA29339A patent/MA28625B1/fr unknown
- 2006-09-27 AP AP2006003757A patent/AP2185A/xx active
- 2006-09-29 SG SG200606817-5A patent/SG131857A1/en unknown
- 2006-10-02 PE PE2006001193A patent/PE20070547A1/es not_active Application Discontinuation
- 2006-10-05 TW TW095137029A patent/TW200800221A/zh unknown
- 2006-10-05 GT GT200600448A patent/GT200600448A/es unknown
- 2006-10-09 AR ARP060104434A patent/AR056573A1/es not_active Application Discontinuation
- 2006-10-09 ZA ZA200608404A patent/ZA200608404B/xx unknown
- 2006-10-09 SA SA06270371A patent/SA06270371B1/ar unknown
- 2006-10-09 NI NI200600240A patent/NI200600240A/es unknown
- 2006-10-09 CO CO06101550A patent/CO5840253A1/es not_active Application Discontinuation
- 2006-10-10 GE GEAP20069655A patent/GEP20094654B/en unknown
- 2006-10-10 NO NO20064588A patent/NO20064588L/no not_active Application Discontinuation
- 2006-10-10 EP EP06291572A patent/EP1775287A1/fr not_active Ceased
- 2006-10-10 BR BRPI0604253-8A patent/BRPI0604253A/pt not_active Application Discontinuation
- 2006-10-10 EP EP08009939A patent/EP1958937A1/fr not_active Withdrawn
- 2006-10-10 KR KR1020060098444A patent/KR20070040310A/ko not_active Application Discontinuation
- 2006-10-10 US US11/545,362 patent/US7384932B2/en not_active Expired - Fee Related
- 2006-10-10 UA UAA200610732A patent/UA90266C2/ru unknown
- 2006-10-10 NZ NZ550436A patent/NZ550436A/en not_active IP Right Cessation
- 2006-10-10 MY MYPI20064301A patent/MY140490A/en unknown
- 2006-10-10 EA EA200601661A patent/EA010286B1/ru not_active IP Right Cessation
- 2006-10-10 EC EC2006006914A patent/ECSP066914A/es unknown
- 2006-10-10 WO PCT/FR2006/002266 patent/WO2007042657A1/fr active Application Filing
- 2006-10-11 UY UY29856A patent/UY29856A1/es not_active Application Discontinuation
- 2006-10-11 CN CNA2006101322309A patent/CN1948293A/zh active Pending
- 2006-10-11 JP JP2006277131A patent/JP2007112797A/ja active Pending
- 2006-10-11 MX MXPA06011767A patent/MXPA06011767A/es active IP Right Grant
- 2006-10-11 AU AU2006228028A patent/AU2006228028B2/en not_active Ceased
- 2006-10-11 CA CA2564369A patent/CA2564369C/fr not_active Expired - Fee Related
- 2006-10-15 IL IL178545A patent/IL178545A/en not_active IP Right Cessation
-
2008
- 2008-05-07 US US12/151,545 patent/US20080227771A1/en not_active Abandoned
-
2009
- 2009-08-27 US US12/583,914 patent/US7879841B2/en not_active Expired - Fee Related
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101353325B (zh) * | 2007-07-27 | 2011-11-09 | 上海优拓医药科技有限公司 | 稳定型盐酸伊伐布雷定结晶及其制备方法 |
CN101768117B (zh) * | 2008-12-29 | 2014-05-07 | 北京德众万全药物技术开发有限公司 | 一种盐酸伊伐布雷定晶型及其制备方法 |
WO2010081342A1 (zh) | 2009-01-13 | 2010-07-22 | 江苏恒瑞医药股份有限公司 | 硫酸伊伐布雷定及其i型结晶的制备方法 |
CN102731400A (zh) * | 2011-04-11 | 2012-10-17 | 山东新时代药业有限公司 | 一种盐酸伊伐布雷定的新晶型、制备方法及其在制备药物组合物中的用途 |
CN103012269A (zh) * | 2013-01-05 | 2013-04-03 | 江苏宇田生物医药科技有限公司 | 一种盐酸伊伐布雷定新晶型c及其制备方法 |
CN103012269B (zh) * | 2013-01-05 | 2014-08-13 | 江苏宇田生物医药科技有限公司 | 一种盐酸伊伐布雷定晶型c及其制备方法 |
CN103880748A (zh) * | 2014-04-03 | 2014-06-25 | 南京正大天晴制药有限公司 | 一种盐酸伊伐布雷定结构类似物及其制备方法和应用 |
CN105503726A (zh) * | 2015-12-30 | 2016-04-20 | 浙江美诺华药物化学有限公司 | 伊伐布雷定盐酸盐晶型变体delta-d的制备方法 |
CN105503726B (zh) * | 2015-12-30 | 2019-07-30 | 浙江美诺华药物化学有限公司 | 伊伐布雷定盐酸盐晶型变体delta-d的制备方法 |
CN107200710A (zh) * | 2017-05-22 | 2017-09-26 | 苏州华健瑞达医药技术有限公司 | 盐酸伊伐布雷定新晶型、制备方法及含有其的组合物 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1948293A (zh) | δd-结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 | |
CN1948292A (zh) | δ-结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 | |
CN1827601A (zh) | 盐酸伊伐布雷定的γd-晶形、其制备方法和含有它的药物组合物 | |
CN1827602A (zh) | 盐酸伊伐布雷定的γ-晶形、其制备方法和含有它的药物组合物 | |
CN1827599A (zh) | 盐酸伊伐布雷定的βd-晶形、其制备方法和含有它的药物组合物 | |
CN1827600A (zh) | 盐酸伊伐布雷定的β-晶形、其制备方法和含有它的药物组合物 | |
CN1754878A (zh) | α晶形的雷奈酸锶、其制备方法和含有它的药物组合物 | |
CN101805289A (zh) | 伊伐布雷定盐酸盐的ω-晶型、其制备方法和药物组合物 | |
EP3694843A1 (en) | New salt and solid state forms of escitalopram | |
MX2014009086A (es) | Polimorfos anhidros de nitrato de [ (2r,3s,4r,5r) -5- (6- (ciclopentilamino) -9h-purin-9-il) -3,4-dihidroxitetra-hidrofuran- 2-il) ] metilo y procesos para su preparación. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1102386 Country of ref document: HK |
|
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1102386 Country of ref document: HK |