TWI406678B - 藥物錠劑或錠劑層及其製法 - Google Patents
藥物錠劑或錠劑層及其製法 Download PDFInfo
- Publication number
- TWI406678B TWI406678B TW097108903A TW97108903A TWI406678B TW I406678 B TWI406678 B TW I406678B TW 097108903 A TW097108903 A TW 097108903A TW 97108903 A TW97108903 A TW 97108903A TW I406678 B TWI406678 B TW I406678B
- Authority
- TW
- Taiwan
- Prior art keywords
- tablet
- lozenge
- layer
- telmisartan
- sorbitol
- Prior art date
Links
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Classifications
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Description
本發明係關於一種藥物錠劑或錠劑層,其包含活性成份替米沙坦、鹼性試劑及山梨糖醇。
如EP-A-502314中所揭示替米沙坦為開發用以治療高血壓及其他醫學病症之血管收縮素II受體拮抗劑。其化學名稱為4'-[2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)-苯并咪唑-1-基甲基]-聯苯-2-甲酸,其具有以下結構:
替米沙坦係以游離酸形式製造且提供。其特徵為在pH值介於1至7之間的胃腸道之生理pH範圍內在水性系統中之溶解度極差。如WO 00/43370中所揭示,結晶替米沙坦以具有不同熔點之兩種多晶形存在。在熱及濕度之影響下,較低熔點之多晶型物B不可逆轉地轉化為較高熔點之多晶型物A。此外,替米沙坦可以非晶形來製備,亦即以一種具有>50℃或較佳>80℃之玻璃轉移溫度Tg
之固化溶液或玻璃形式製備。
替米沙坦可以劑量20 mg、40 mg及80 mg之錠劑形式購
得。20 mg錠劑為圓形的,經測量其直徑為7 mm且高度為約2.5 mm。40 mg及80 mg錠劑為橢圓形,含有氫氯噻嗪(HCTZ)作為第二活性成份之市售雙層錠劑亦為橢圓形。橢圓形產品之長度介於12 mm與16.2 mm之間,寬度在5.8 mm至7.9 mm之範圍內且厚度為3.8 mm至6.2 mm。
在錠劑中替米沙坦之藥理學效能需要使用稀釋劑。除用以吞服之立即釋放製劑外,可能進一步需要類似"歐洲藥典(European Pharmacopeia)"之專論'口服用錠劑(Tablets for Use in the Mouth')中之說明,調配含有替米沙坦之錠劑或錠劑層。如WO 03/059327中所揭示,此意謂其係藉由侵蝕過程而非基質之崩解而決定其溶解特性且需要合適的水溶性稀釋劑。WO 03/059327揭示山梨糖醇作為用於替米沙坦之較佳稀釋劑,且替米沙坦之註冊之醫藥組合物係包含山梨糖醇作為填充劑。此外,與諸如木糖醇之替代性填充劑相比,山梨糖醇通常為較廉價之賦形劑。
另外,替米沙坦之不良溶解度及親脂性特徵分別需要特殊手段以便由錠劑或錠劑層達成所註冊之替米沙坦溶解速率。根據USP專論之定義,Q必須大於75%,較佳大於85%。因此,根據本發明,必須確保30 min之後溶解至少75%且通常至少85%之替米沙坦藥物負載。
根據WO 03/059327,該等手段為在錠劑中含有鹼性試劑,此舉有助於替米沙坦在水性介質中溶解,且所使用之非晶形替米沙坦可藉由噴霧乾燥獲得。
將D(0.5)定義為其中50體積%之所用物質顆粒之粒度在
相應數字D(0.5)值以下,用以製備替米沙坦之註冊之組合物之非晶形替米沙坦之粒度D(0.5)係在20-55 μm之範圍內,而山梨糖醇之粒度D(0.5)在160-190 μm之範圍內,亦即超過150 μm。較小粒度之山梨糖醇將提高穩定性以抵抗填充劑山梨糖醇、活性劑替米沙坦及醫藥組合物之其他組份之分層且將使醫藥組合物具有改良及更易於重現之均質性。然而,150 μm以下之山梨糖醇粒度無法產生所要硬度之錠劑,實例1之80 mg替米沙坦錠劑之硬度必須大於100 N,較佳大於130 N,該硬度用Erweka TBH30儀器測定為抗壓強度。對於圓形、平面錠劑(諸如實例2之錠劑),如Newton等人(J. Pharm. Pharmac.增刊23,195S-201S(1971))所述表示為拉伸強度,此等於至少1.6 N/mm2
,較佳>2.1 N/mm2
。
藥劑師知曉若一方面活性成份與另一方面稀釋劑之粒度相差大於因子2,如包含替米沙坦及山梨糖醇之註冊之組合物之情況(通常175 μm(山梨糖醇):38 μn(替米沙坦)=4.6),則組份之分層為一般觀測到之技術問題。此顯著尺寸差異最終產生因為不匹配註冊之技術規格故必須消除之組合物。
在藥物製備中,通常經由適當調節壓實壓力獲得錠劑之指定硬度。可達該加工所允許之最大應變,此程序可補償批與批之間的壓實性差異,此又歸因於成份之物理參數之自然差異。舉例而言,由WO 03/059327中所揭示之方法製造之經噴霧乾燥之非晶形替米沙坦可具有介於0.4與0.6
g/ml之間的容積密度。
此外,已知壓縮至較高硬度等級可導致削弱之溶解。因此,先前不可能始終獲得顯示溶解速率與硬度等級均在最佳等級之包含替米沙坦之錠劑或錠劑層。
申請人現驚奇地發現並非用於製備包含替米沙坦之錠劑或錠劑層之山梨糖醇之粒度而是比表面積主要確定錠劑或錠劑層之硬度及活性成份替米沙坦之溶解速率。因此,本發明教示使用具有介於0.75-3.5 m2
/g之間的比表面積之山梨糖醇來製備替米沙坦錠劑或錠劑層。而先前所用之山梨糖醇具有介於0.3-0.7 m2
/g之間的比表面積。
比表面積在77 K下及氮氣中慮及USP專論<846>,方法2,使用合適的經校準BET儀器(Micromeritics ASAP 2400或等效物)來測定。樣品重量為3 g至5 g。將樣品在40℃下在真空中除氣2小時。在p/p0=0.07-0.22下進行6點測定。
根據本發明所製造之錠劑顯示在<60%之最大加工強度之壓實壓力之較佳範圍內經改良之硬度以及較高溶解速率,此外,顯著改良溶解及硬度參數之重現性,從而產生較低同批內差異及異批間差異。此最小化註冊之規格不一致之風險。
亦可將本發明中所述之醫藥組合物在結合替米沙坦及一或多種其他活性成份之固定劑量組合中,例如在雙層或三層錠劑中用作分隔錠劑層。與包含替米沙坦之層相結合之
分隔層中之該等其他活性成份之實例為利尿劑,諸如氫氯噻嗪;鈣受體拮抗劑,諸如胺氯地平(amlodipine);ACE抑制劑,諸如依那普利(enalapril)、賴諾普利(lisinopril)、雷米普利(ramipril)等;HMG-CoA還原酶抑制劑,諸如斯伐他汀(simvastatin)或阿托伐他汀(atorvastatin);抗糖尿病劑,諸如二甲雙胍(metformin)、格列酮(glitazones)及DPP-IV抑制劑。
因此,本發明之一實施例為血管收縮素II受體拮抗劑替米沙坦、鹼性試劑及作為稀釋劑之山梨糖醇包含於(例如)溶解錠劑基質中之藥物錠劑或錠劑層,其特徵在於山梨糖醇具有0.75-3.5 m2
/g之比表面積。山梨糖醇之比表面積之較佳範圍為1.4-3.0 m2
/g且最佳範圍為2.0-2.5 m2
/g。
另外,用於本發明之製劑之山梨糖醇的特徵可為D(0.5)粒度在100-350 μm之範圍內,而較佳尺寸在120-300 μm之範圍內且最佳尺寸係介於150-250 μm之間。
為獲得活性劑替米沙坦之所要註冊之溶解速率,較佳以具有尺寸小於80 μm,較佳20-55 μm之顆粒之非晶形來使用。替米沙坦之該非晶形可藉由熟習此項技術者已知之任何合適方法,例如藉由冷凍乾燥水溶液、在流化床中塗佈載劑顆粒及在糖丸粒或其他載劑上之溶劑沈積來製備。然而,非晶形替米沙坦較佳大體上藉由WO 03/059327中所述之噴霧乾燥方法來製備,其中替米沙坦係藉由藉助於如氫氧化鈉及/或葡甲胺之一或多種鹼性試劑使其溶解於純水中來製備。可視情況添加增溶劑及/或再結晶延遲劑。起
始水溶液之乾物質含量一般為10至50重量%,較佳20至40重量%。隨後在室溫下或較佳在(例如)50℃與100℃之間的高溫下,在平行流或逆流噴霧乾燥器中,在(例如)1至5巴之噴霧壓力下噴霧乾燥水溶液。一般而言,較佳以一定方式選擇噴霧乾燥條件以便在分離旋風器中獲得具有5重量%,較佳3.5重量%之殘餘濕度之經噴霧乾燥顆粒。為此,噴霧乾燥器之出口氣溫較佳維持在介於約80℃與90℃之間的值,而相應地調節其他過程參數,諸如噴霧壓力、噴射率、入口氣溫等。所獲得之噴霧乾燥顆粒較佳為具有以下粒度分布之細粉:d10
:20 μm,較佳10 μm d50
:80 μm,較佳20至55 μm d90
:350 μm,較佳50至150 μm。
在噴霧乾燥之後,活性成份替米沙坦以及包含於噴霧乾燥顆粒中之賦形劑大體上處於無法偵測到結晶度之非晶形狀態。可區分所獲得之低密度(0.4-0.5 g/ml)與高密度(0.5-0.6 g/ml)替米沙坦顆粒。
以100重量份之替米沙坦計,噴霧乾燥顆粒較佳含有5至200重量份之鹼性試劑及(視情況)增溶劑及/或結晶延遲劑。合適鹼性試劑之特定實例為鹼金屬氫氧化物,諸如NaOH及KOH;鹼性胺基酸,諸如精胺酸及離胺酸;及葡甲胺(N-甲基-D-葡糖胺),較佳為NaOH及葡甲胺。
本發明之錠劑一般含有介於10至160 mg,較佳20至80 mg或40至80 mg之間的替米沙坦。替米沙坦之較佳劑量濃
度為20 mg,40 mg及80 mg。
在另一實施例中,包含替米沙坦、山梨糖醇及鹼性試劑之錠劑或錠劑層另外包含賦形劑及/或佐劑,諸如黏合劑、載劑、崩解劑、填充劑、潤滑劑、流動控制劑、結晶延遲劑,增溶劑、著色劑、pH值控制劑、界面活性劑及乳化劑。較佳選擇用於錠劑或錠劑層組合物之賦形劑及/或佐劑以便獲得非酸性、速溶錠劑基質。
本發明之錠劑或錠劑層一般包含3至50重量%,較佳5至35重量%之替米沙坦;0.25至20重量%,較佳0.40至15重量%之鹼性試劑;及30至95重量%,較佳60至80重量%之山梨糖醇。
以兩個階段進行混合,亦即在第一混合步驟中使用(例如)高剪切混合器或自由下落摻合機混合噴霧乾燥顆粒及稀釋劑,且在第二混合步驟中較佳亦在高剪切之條件下將潤滑劑與預混料摻合。因此,一般添加占錠劑或錠劑層組合物重量計0.1至5重量%,較佳0.3至2重量%之諸如硬脂酸鎂之潤滑劑至預混料中。然而,本發明之方法不限於此混合程序,且一般可在不同加工步驟中採用其他替代混合程序。
可自一或多種以下所示用量之賦形劑及/或佐劑中選擇其他(可選用)組分:10至30重量%,較佳15至25重量%之黏合劑及載劑;0.01-5重量%之崩解劑;0.01至5重量%,較佳0.5至3重量%之潤滑劑;
0.01至5重量%,較佳0.3至2重量%之流動控制劑;0.01至20重量%,較佳2至8重量%之結晶延遲劑;0.01至10重量%,較佳2至8重量%之增溶劑;0.01至1.5重量%,較佳0.1至0.8重量%之著色劑;0.01至10重量%,較佳2至8重量%之pH值控制劑;0.01至5重量%,較佳0.05至1重量%之界面活性劑及乳化劑。
本發明之錠劑略具吸濕性且因此較佳使用防潮包裝材料,諸如鋁箔發泡包裝或聚丙烯管及較佳含有乾燥劑之HDPE瓶來包裝。
製備本發明之錠劑或錠劑層之較佳方法包含a)製備替米沙坦、至少一種鹼性試劑及(視情況)增溶劑及/或結晶延遲劑之水溶液;b)噴霧乾燥該水溶液以獲得經噴霧乾燥顆粒;c)使該經噴霧乾燥顆粒與具有介於0.75-3.5 m2
/g之間的比表面積之山梨糖醇混合以獲得預混料;d)使該預混料與潤滑劑混合以獲得最終摻合物;e)視情況,在步驟a)至d)中之任一者中添加其他賦形劑及/或佐劑;及f)將該最終摻合物壓縮為錠劑或錠劑層。
可將該方法用以製造本發明之錠劑或錠劑層以單獨治療高血壓或協同治療或預防選自由以下各病組成之群的病況:慢性穩定型心絞痛、血管痙攣性心絞痛、中風、心肌梗塞、短暫性缺血性發作、充血性心力衰竭、心血管疾
病、糖尿病、胰島素抗性、葡萄糖耐受不良、糖尿病前期、2型糖尿病、糖尿病性腎病、新陳代謝症候群(症候群X)、肥胖、血脂異常、高甘油三酯血症、C-反應蛋白之血清濃度升高、脂蛋白(a)之血清濃度升高、高半胱胺酸之血清濃度升高、低密度脂蛋白(LDL)-膽固醇之血清濃度升高、脂蛋白相關之磷脂酶(A2)之血清濃度升高、高密度脂蛋白(HDL)-膽固醇之血清濃度減小、HDL(2b)-膽固醇之血清濃度減小、脂聯素之血清濃度減小、認知能力下降及癡呆。
尤其較佳為額外治療或預防之慢性穩定型心絞痛、血管痙攣性心絞痛、中風、心肌梗塞、充血性心力衰竭、糖尿病、血脂異常或癡呆。
最終,可使用適當製錠機將本發明之錠劑層與一或多種包含其他活性成份之錠劑層組合物壓縮至具有適當尺寸及抗壓強度之目標錠劑重量之多層錠劑中,諸如雙層錠劑及三層錠劑中。為改善潤滑可在製造該等錠劑期間使用用於沖模與衝壓機之可選適當外部潤滑劑噴霧系統。
為進一步說明本發明,給出以下非限制性實例。
錠劑形狀為橢圓形,16.2 mm×7.9 mm×4.6 mm(L×W×H)
錠劑形狀為圓形,直徑為7 mm,厚度為2.5 mm
(80 mg替米沙坦加上12.5 mg氫氯噻嗪雙層錠劑)
(80 mg替米沙坦加上12.5 mg氫氯噻嗪雙層錠劑)
(錠劑形狀為橢圓形,12.0 mm×5.8 mm×3.8 mm(L×W×H))
(40 mg替米沙坦加上12.5 mg氫氯噻嗪雙層錠劑;錠劑形狀為椭圓形,14.0 mm×6.8 mm×5.2 mm(L×W×H))
Claims (13)
- 一種藥物錠劑或錠劑層,其包含呈非晶形之血管收縮素II受體拮抗劑替米沙坦(telmisartan)、鹼性試劑及山梨糖醇,其特徵在於該山梨糖醇具有1.4-3.0 m2 /g之比表面積及D(0.5)平均粒度為100-350 μm。
- 如請求項1之錠劑或錠劑層,其包含D(0.5)平均粒度為120-300 μm之山梨糖醇。
- 如請求項1之錠劑或錠劑層,其包含D(0.5)平均粒度為150-200 μm之山梨糖醇。
- 如請求項1之錠劑或錠劑層,其中該鹼性試劑係選自鹼金屬氫氧化物、鹼性胺基酸及葡甲胺。
- 如請求項1之錠劑或錠劑層,其含有10-160 mg替米沙坦。
- 如請求項5之錠劑或錠劑層,其含有20-80 mg替米沙坦。
- 如請求項5之錠劑或錠劑層,其含有40-80 mg替米沙坦。
- 如請求項1之錠劑或錠劑層,其中該山梨糖醇具有2.0-2.5 m2 /g之比表面積,且包含平均粒度<80 μm之非晶形替米沙坦。
- 如請求項8之錠劑或錠劑層,其中該非晶形替米沙坦具有20-55 μm之平均粒度。
- 如請求項1之錠劑或錠劑層,其另外包含其他賦形劑或佐劑。
- 如請求項10之錠劑或錠劑層,其中該等其他賦形劑及佐劑係選自黏合劑、載劑、崩解劑、填充劑、潤滑劑、流 動控制劑、結晶延遲劑、增溶劑、著色劑、pH值控制劑、界面活性劑及乳化劑。
- 如請求項1之錠劑或錠劑層,其係藉由以下步驟來製備:噴霧乾燥包含替米沙坦及鹼性試劑之水溶液,以獲得噴霧乾燥顆粒,混合該經噴霧乾燥顆粒與山梨糖醇,以獲得預混料,且混合該預混料與潤滑劑,以獲得最終摻合物。
- 如請求項1之錠劑或錠劑層,其係由防潮包裝材料,諸如鋁箔發泡包裝或聚丙烯管及HDPE瓶來包裝。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07104157A EP1970053A1 (en) | 2007-03-14 | 2007-03-14 | Pharmaceutical composition |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200900095A TW200900095A (en) | 2009-01-01 |
TWI406678B true TWI406678B (zh) | 2013-09-01 |
Family
ID=38179677
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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TW097108903A TWI406678B (zh) | 2007-03-14 | 2008-03-13 | 藥物錠劑或錠劑層及其製法 |
Country Status (36)
Country | Link |
---|---|
US (1) | US20100143465A1 (zh) |
EP (2) | EP1970053A1 (zh) |
JP (1) | JP5742045B2 (zh) |
KR (1) | KR101503674B1 (zh) |
CN (1) | CN101641084B (zh) |
AR (1) | AR065726A1 (zh) |
AT (1) | ATE493119T1 (zh) |
AU (1) | AU2008225754B2 (zh) |
BR (1) | BRPI0808797A2 (zh) |
CA (1) | CA2680608C (zh) |
CL (1) | CL2008000733A1 (zh) |
CO (1) | CO6220927A2 (zh) |
CY (1) | CY1111350T1 (zh) |
DE (1) | DE602008004217D1 (zh) |
DK (1) | DK2120884T3 (zh) |
EA (1) | EA018574B1 (zh) |
EC (1) | ECSP099629A (zh) |
ES (1) | ES2358770T3 (zh) |
HK (1) | HK1140692A1 (zh) |
HR (1) | HRP20110012T1 (zh) |
IL (1) | IL200125A (zh) |
MA (1) | MA31251B1 (zh) |
MX (1) | MX2009009201A (zh) |
MY (1) | MY145089A (zh) |
NZ (1) | NZ580185A (zh) |
PE (1) | PE20090165A1 (zh) |
PL (1) | PL2120884T3 (zh) |
PT (1) | PT2120884E (zh) |
RS (1) | RS51584B (zh) |
SI (1) | SI2120884T1 (zh) |
TN (1) | TN2009000371A1 (zh) |
TW (1) | TWI406678B (zh) |
UA (1) | UA96982C2 (zh) |
UY (1) | UY30961A1 (zh) |
WO (1) | WO2008110599A1 (zh) |
ZA (1) | ZA200905224B (zh) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1908469A1 (en) | 2006-10-06 | 2008-04-09 | Boehringer Ingelheim Vetmedica Gmbh | Angiotensin II receptor antagonist for the treatment of systemic diseases in cats |
WO2009058950A2 (en) * | 2007-10-30 | 2009-05-07 | Dr. Reddy's Laboratories Ltd. | Pharmaceutical formulations comprising telmisartan and hydrochlorothiazide |
EP2291177A2 (en) | 2008-05-05 | 2011-03-09 | Farmaprojects, S.A. | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
CZ2008469A3 (cs) * | 2008-07-31 | 2009-10-29 | Zentiva, A. S. | Telmisartan tablety |
GB0822171D0 (en) * | 2008-12-04 | 2009-01-14 | Arrow Int Ltd | Temisartan formulations |
WO2010133638A1 (de) | 2009-05-20 | 2010-11-25 | Boehringer Ingelheim Vetmedica Gmbh | Pharmazeutische telmisartan-trinklösung |
WO2013142314A1 (en) * | 2012-03-19 | 2013-09-26 | Althera Life Sciences, Llc | Oral tablet formulation consisting of immediate release rosuv astatin and extended release metformin |
JP6344678B2 (ja) * | 2013-09-27 | 2018-06-20 | キョーリンリメディオ株式会社 | テルミサルタン含有製剤及びその製造方法 |
JP6096328B2 (ja) * | 2014-02-10 | 2017-03-15 | 富士フイルム株式会社 | 口腔内崩壊錠 |
BE1021954B1 (nl) * | 2014-06-05 | 2016-01-28 | Syral Belgium Nv | Samenstelling van sorbitol met lage friabiliteit |
FR3023128B1 (fr) | 2014-07-01 | 2017-11-10 | Roquette Freres | Nouvelle composition edulcorante |
JP5871294B1 (ja) * | 2015-02-27 | 2016-03-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 即時放出経口錠剤 |
KR20170001921A (ko) | 2015-06-26 | 2017-01-05 | 대원제약주식회사 | 안정성이 개선된 텔미사르탄을 함유하는 약제학적 조성물 및 이의 제조방법 |
CN106420739A (zh) * | 2016-10-31 | 2017-02-22 | 扬子江药业集团四川海蓉药业有限公司 | 一种替米沙坦氨氯地平双层片及其制备方法 |
CN106800537B (zh) | 2017-01-18 | 2019-02-01 | 广东隆赋药业股份有限公司 | 丁苯酞-替米沙坦杂合物及其制备方法和用途 |
CN109316451B (zh) * | 2017-07-31 | 2022-07-01 | 武汉朗来科技发展有限公司 | 治疗高血压和相关疾病的口服固体制剂 |
EP3787596A1 (en) | 2018-05-02 | 2021-03-10 | Ferring B.V. | Improved pharmaceutical formulations |
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WO2003059327A1 (en) * | 2002-01-16 | 2003-07-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof |
US20060159747A1 (en) * | 2004-12-17 | 2006-07-20 | Boehringer Ingelheim International Gmbh | Telmisartan and hydrochlorothiazide combination therapy |
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DE3245170A1 (de) * | 1982-12-07 | 1984-06-07 | Merck Patent Gmbh, 6100 Darmstadt | Verbesserter sorbit, verfahren zur herstellung und verwendung |
AU1042199A (en) * | 1998-11-06 | 2000-05-29 | Boehringer Ingelheim International Gmbh | Antihypertensive medicaments containing lacidipine and telmisartan |
FR2787110B1 (fr) * | 1998-12-11 | 2001-02-16 | Roquette Freres | Sorbitol pulverulent et son procede de preparation |
DE10244681A1 (de) * | 2002-09-24 | 2004-04-08 | Boehringer Ingelheim International Gmbh | Neue feste Telmisartan enthaltende pharmazeutische Formulierungen und deren Herstellung |
DE102004008804A1 (de) * | 2004-02-20 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Mehrschichttablette |
US20060078615A1 (en) * | 2004-10-12 | 2006-04-13 | Boehringer Ingelheim International Gmbh | Bilayer tablet of telmisartan and simvastatin |
ES2452019T5 (es) * | 2004-11-05 | 2021-06-28 | Boehringer Ingelheim Int | Comprimido bicapa que comprende telmisartán y amlodipino |
EA200701159A1 (ru) * | 2004-12-17 | 2007-12-28 | Бёрингер Ингельхайм Интернациональ Гмбх | Комбинированное лекарственное средство, включающее телмисартан и гидрохлортиазид |
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2007
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2008
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- 2008-03-13 ES ES08717753T patent/ES2358770T3/es active Active
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- 2008-03-13 UA UAA200910184A patent/UA96982C2/ru unknown
- 2008-03-13 KR KR1020097021453A patent/KR101503674B1/ko active IP Right Review Request
- 2008-03-13 AU AU2008225754A patent/AU2008225754B2/en active Active
- 2008-03-13 JP JP2009553147A patent/JP5742045B2/ja active Active
- 2008-03-13 UY UY30961A patent/UY30961A1/es not_active Application Discontinuation
- 2008-03-13 AT AT08717753T patent/ATE493119T1/de active
- 2008-03-13 WO PCT/EP2008/053009 patent/WO2008110599A1/en active Application Filing
- 2008-03-13 SI SI200830179T patent/SI2120884T1/sl unknown
- 2008-03-13 MX MX2009009201A patent/MX2009009201A/es active IP Right Grant
- 2008-03-13 CN CN2008800075975A patent/CN101641084B/zh active Active
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- 2008-03-13 CA CA2680608A patent/CA2680608C/en not_active Expired - Fee Related
- 2008-03-13 EP EP08717753A patent/EP2120884B1/en not_active Revoked
- 2008-03-13 TW TW097108903A patent/TWI406678B/zh not_active IP Right Cessation
- 2008-03-13 DK DK08717753.1T patent/DK2120884T3/da active
- 2008-03-13 PL PL08717753T patent/PL2120884T3/pl unknown
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- 2008-03-13 US US12/530,489 patent/US20100143465A1/en not_active Abandoned
- 2008-03-13 MY MYPI20093767A patent/MY145089A/en unknown
- 2008-03-13 BR BRPI0808797-0A patent/BRPI0808797A2/pt not_active Application Discontinuation
- 2008-03-13 AR ARP080101038A patent/AR065726A1/es active Pending
- 2008-03-13 PT PT08717753T patent/PT2120884E/pt unknown
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2009
- 2009-07-27 ZA ZA200905224A patent/ZA200905224B/xx unknown
- 2009-07-28 IL IL200125A patent/IL200125A/en active IP Right Grant
- 2009-09-09 CO CO09096619A patent/CO6220927A2/es not_active Application Discontinuation
- 2009-09-11 EC EC2009009629A patent/ECSP099629A/es unknown
- 2009-09-11 MA MA32218A patent/MA31251B1/fr unknown
- 2009-09-11 TN TNP2009000371A patent/TN2009000371A1/fr unknown
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2010
- 2010-07-28 HK HK10107229.6A patent/HK1140692A1/xx not_active IP Right Cessation
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- 2011-01-10 HR HR20110012T patent/HRP20110012T1/hr unknown
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WO2003059327A1 (en) * | 2002-01-16 | 2003-07-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof |
US20060159747A1 (en) * | 2004-12-17 | 2006-07-20 | Boehringer Ingelheim International Gmbh | Telmisartan and hydrochlorothiazide combination therapy |
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