TW200800221A - δD-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it - Google Patents
δD-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it Download PDFInfo
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- TW200800221A TW200800221A TW095137029A TW95137029A TW200800221A TW 200800221 A TW200800221 A TW 200800221A TW 095137029 A TW095137029 A TW 095137029A TW 95137029 A TW95137029 A TW 95137029A TW 200800221 A TW200800221 A TW 200800221A
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- 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 claims abstract description 23
- 229960000504 ivabradine hydrochloride Drugs 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000013078 crystal Substances 0.000 claims description 8
- 230000033764 rhythmic process Effects 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 230000000747 cardiac effect Effects 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 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
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229940079593 drug Drugs 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
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000002441 X-ray diffraction Methods 0.000 abstract 1
- 238000010586 diagram Methods 0.000 abstract 1
- 229960003825 ivabradine Drugs 0.000 description 7
- 238000005259 measurement Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 239000007937 lozenge Substances 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
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 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
- 206010036790 Productive cough Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 buccal Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 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
- 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
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 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
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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- 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
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- 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
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- 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)
Description
200800221 九、發明說明： 【發明所屬之技術領域】 本發明係關於式（I)之依伐布雷定（ivabradine)鹽酸鹽之 δ d -結晶型
其製備方法及含其之醫藥組合物。 【先前技術】 依伐布雷定及其與醫藥學上可接受酸之加成鹽，且更尤 其為其鹽酸鹽具有極其重要醫藥及治療特性，尤其為減慢 心率藥特性，使得彼等化合物適用於治療或預防諸如心絞 痛、心肌梗塞及相關心律紊亂之心肌局部缺血之多種臨床 病況，亦及包括心律紊亂、尤其為室上性心律紊亂 (supraventricular rhythm disturbance)之多種病狀，及心臟 衰竭。 依伐布雷定及其與醫藥學上可接受酸之加成鹽，且更尤 其為其鹽酸鹽已於EP 0 534 859歐洲專利說明書中描述。 鑒於此化合物之醫藥價值，最重要的為獲得具有極好鈍 度之該化合物。亦重要的為，可藉助於可易於轉化成工業 規模、尤其呈允許快速過濾且乾燥之形式的方法來合成。 最後，彼形式必須完全可再現、易於調配且足夠穩定以允 許其在對溫度、光或氧含量無特定要求之情況下長期儲 114896.doc 200800221 存。 EP 0 534 859專利說明書描述依伐布雷定及其鹽酸鹽之 合成方法。然而，彼文獻並未說明用於獲得以可再現方式 展示彼等特徵之形式的依伐布雷定之條件。 【發明内容】 該申請案現已發現依伐布雷定之特定鹽，鹽酸鹽，可獲 得展示穩定性及可加工性之重要特徵之定義明確的結晶 型〇
更特定言之，本發明係關於依伐布雷定鹽酸鹽之結 晶型5其特徵為以下粉末X-光繞射圖5該圖使用 PANalytical X’Pert Pro繞射儀連同 X’Celerator偵測器量測 且由線位置（以度表示之布拉格角度（BraggVs angle)20)、線 高（以計數表示）、線面積（以計數X度表示）、半高處之線寬 ("WHM"，以度表示）及晶面間距d(以A表示）表示： 線編號 角度2Θ(度） 高度(計數） 面積(計數X度） FWHM (度） 晶面間距 (A) 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 10305 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 114896.doc 200800221 線編號 角度2Θ(度） 高度(計數） 面積(計數X度） FWHM (度） 晶面間距 (Α) 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 本發明亦係關於一種製備依伐布雷定鹽酸鹽之δ(1-結晶
型之方法，該方法之特徵為：將乙腈或乙腈與水之混合物 預熱，添加依伐布雷定鹽酸鹽，使所得溶液冷卻至室溫， 保持於室溫下直至完全結晶，且使所形成之晶體脫水。 •根據本發明之結晶方法中，可能使用以任何方法獲得之 依伐布雷定鹽酸鹽，例如藉由描述於ΕΡ 0 534 859專利說 明書中之製備方法獲得之依伐布雷定鹽酸鹽。 •溶液可有利地在冷卻步驟中播晶種。 •佳將乙腈或乙腈與水之混合物預熱至介於60°C與回流之 間的溫度，更佳介於65與75°C之間。 •釋液較佳大於15 mg/g，更佳介於5 0與100 ml/g之間。 •佳藉由加熱進行脫水。 本發明亦係關於包含作為活性成份之依伐布雷定鹽酸鹽 的δ(1-結晶型連同一或多種惰性且無毒之適合賦形劑的醫 藥組合物。在根據本發明之醫藥組合物中，更尤其可能提 及為彼等適於口服、非經腸（靜脈内或皮下）或經鼻投與之 114896.doc 200800221 錠劑或糠衣藥丸、舌下錠劑、膠囊、口含劑、栓劑、乳 霜、油膏、皮膚凝膠、可注射製劑及可飲用之懸浮液。 適用劑量可根據病症之性質及嚴重程度、投藥途徑及患 者之年齡及體重而有所不同。該劑量每日自1至500 mg· 化，分一或多次投與。 【實施方式】 以下實例說明本發明。 在下列實驗條件下量測χ_光粉末繞射光譜： -PANalytical X’pert pro繞射儀、x’Celerator>f貞測器、溫 度調節室， -電壓45 kV ’強度40 mA， -安裝Θ-Θ， -鎳（κρ)濾波器， -入射束及繞射束索勒狹縫（S〇ller slit) : 0.04雷得， -自動發散狹縫：輻射長度1 〇 mm， -光罩：1❹mm， -防散射狹縫：1/2。， -量測模式：以0.017。之增量自3。至30。連續量測， -每步驟量測時間：19.7 s， -總時間：4分32秒， -量測速度：0.108°/s。 實例1:依伐布雷定鹽酸鹽之δά-結晶型 將160 ml乙腈預熱至70°C且隨後在攪拌下添加根據Ερ 〇 534 859專利說明書中所述之方法獲得之2 g依伐布雷定鹽 114896.doc 200800221 酸鹽，直至完全溶解。將該溶液於室溫下儲存2天。在真 空下藉由過濾移出晶體且將其散佈於結晶盤上。隨後將該 等晶體以l〇°C/min之速率加熱至85°C之溫度且於該溫度下 保持4小時。 ♦分末X-光繞射圖： 依伐布雷定鹽酸鹽之3d-型之粉末X-光繞射圖概況（繞射 角）藉由於下表中整理之重要線給出：
線編號 角度2Θ(度） 高度(計數） 面積(計數X度） FWHM (度） 晶面間距 (A) 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 114896.doc -10- 200800221 實例2 :醫藥組合物 製備1000個各含有5 mg依伐布雷定鹼之錠劑的配方： 實例 1 之化合物.............··.·.............................................5.39 g 玉米澱粉··.........................................................···.·.........20 g 無水膠狀二氧化矽............................................... 0.2 g 甘露醇..........................................................................63.91 g PVP ...........····.......·····_________......._________________________________10 g 硬脂酸鎂..................................................................0.5 g 114896.doc -11 -
Claims (1)
- 200800221 十、申請專利範圍： 1. 一種式（I)之依伐布雷定（ivabradine)鹽酸鹽的δά-結晶 型，其特徵為以下粉末X-光繞射圖，該圖使用PANalytical X’Pert Pro繞射儀連同X’Celerator偵測器量測且根據線位 置（以度表示之布拉格角度（Bragg’s angle)20)、線高（以 計數表示）、線面積（以計數X度表示）、半高處之線寬 ("FWHM”，以度表示）及晶面間距d(以A表示）表示： 線編號 角度2Θ(度） 高度(計數） 面積(計數X度） FWHM (度） 晶面間距 (Α) 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 3.728114896.doc 200800221 線編號 角度2Θ(度） 高度(計數） 面積(計數X度） FWHM (度） 晶面間距 (A) 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· —種製備如請求項1之依伐布雷定鹽酸鹽之5d-結晶型的 方法，其特徵為：將乙腈或乙腈與水之混合物預熱，添 加依伐布雷定鹽酸鹽，使所得溶液冷卻至室溫，保持於 室溫下直至完全結晶，且使所形成之晶體脫水。 3. 如請求項2之方法，其特徵為在冷卻步驟中於該依伐布 雷定鹽酸鹽溶液中播晶。 4. 一種醫藥組合物，其包含與一或多種醫藥學上可接受之 惰性、無毒載劑相組合之作為活性成份的如請求項1之 依伐布雷定鹽酸鹽的3d·結晶型。 5 · —種如請求項1之依伐布雷定鹽酸鹽之δ(1-結晶型的用 途，其係用於製造用作減慢心率藥之藥物。 6· —種如請求項1之依伐布雷定鹽酸鹽之δ(1-結晶型的用 途，其係用於製造用作治療或預防諸如心絞痛、心肌梗 塞及相關心律紊亂之心肌局部缺血之多種臨床病況，亦 及包括心律紊IL、尤其室上性心律紊|L (supraventricular rhythm disturbance)之多種病狀，及心臟衰竭的藥物。 114896.doc -2- 200800221 七、 指定代表圖·· (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、 本案若有化學式時，請揭示最能顯示發明特徵的化學式：114896.doc
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| 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 |
| 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 |
| 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 |
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| ES2402765T3 (es) | 2008-12-22 | 2013-05-08 | Krka, D.D., Novo Mesto | Procedimiento de preparación de ivabradina |
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| WO2010128525A2 (en) | 2009-05-04 | 2010-11-11 | Dinesh Shantilal Patel | A formulation of ivabradine for treating the cardiovascular disease |
| EA201290772A1 (ru) | 2010-02-12 | 2013-02-28 | КРКА, д.д., НОВО МЕСТО | Новые формы ивабрадина гидрохлорида |
| 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 |
| 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 |
| US9440924B2 (en) | 2011-08-02 | 2016-09-13 | Sandoz Ag | Acetone solvate of ivabradine hydrochloride |
| EP2773621B1 (en) | 2011-11-04 | 2015-12-30 | 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 |
| EP2780327A1 (en) * | 2011-11-14 | 2014-09-24 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
| 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 |
| 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 |
| WO2015001133A1 (en) | 2013-12-12 | 2015-01-08 | Synthon B.V. | Pharmaceutical composition comprising amorphous ivabradine |
| ES2717715T3 (es) | 2014-02-14 | 2019-06-24 | Synthon Bv | Composición farmacéutica que comprende polimorfo IV de clorhidrato de ivabradina |
| CN103880748B (zh) * | 2014-04-03 | 2015-09-16 | 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 |
| CZ2014478A3 (cs) | 2014-07-10 | 2015-09-16 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (R)-mandlové kyseliny a její farmaceutická kompozice |
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| 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 |
| TR201703066A2 (tr) | 2017-02-28 | 2018-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | İvabradi̇ni̇n kati oral farmasöti̇k kompozi̇syonlari |
| EP3366282A1 (en) | 2017-02-28 | 2018-08-29 | Sanovel Ilac Sanayi ve Ticaret A.S. | Solid oral pharmaceutical compositions of ivabradine |
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| IT202000025312A1 (it) | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | Processi per la preparazione di polimorfi di ivabradina hcl |
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| 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 |
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| 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 |
| 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 |
| 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 |
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