TW200900095A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- TW200900095A TW200900095A TW097108903A TW97108903A TW200900095A TW 200900095 A TW200900095 A TW 200900095A TW 097108903 A TW097108903 A TW 097108903A TW 97108903 A TW97108903 A TW 97108903A TW 200900095 A TW200900095 A TW 200900095A
- Authority
- TW
- Taiwan
- Prior art keywords
- layer
- telmisartan
- lozenge
- sorbitol
- agent
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 4
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims abstract description 139
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims abstract description 70
- 229960005187 telmisartan Drugs 0.000 claims abstract description 70
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 43
- 239000000600 sorbitol Substances 0.000 claims abstract description 43
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims abstract 2
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 claims abstract 2
- 239000003826 tablet Substances 0.000 claims description 41
- 239000007937 lozenge Substances 0.000 claims description 26
- 239000002245 particle Substances 0.000 claims description 14
- 210000002966 serum Anatomy 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- 239000007921 spray Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 206010002383 Angina Pectoris Diseases 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
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- 108090001030 Lipoproteins Proteins 0.000 claims description 4
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 4
- 229960003194 meglumine Drugs 0.000 claims description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
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- 206010020772 Hypertension Diseases 0.000 claims description 3
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- 208000006011 Stroke Diseases 0.000 claims description 3
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- 239000008280 blood Substances 0.000 claims description 3
- 239000003086 colorant Substances 0.000 claims description 3
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- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
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- 108010074051 C-Reactive Protein Proteins 0.000 claims description 2
- 102100032752 C-reactive protein Human genes 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 206010061216 Infarction Diseases 0.000 claims description 2
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- 208000001280 Prediabetic State Diseases 0.000 claims description 2
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- 108010007622 LDL Lipoproteins Proteins 0.000 claims 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- 206010020565 Hyperaemia Diseases 0.000 claims 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims 1
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 6
- -1 imidazol-1-ylindenyl Chemical group 0.000 description 6
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
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- 229960005370 atorvastatin Drugs 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 239000007767 bonding agent Substances 0.000 description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
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- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
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- 229940123613 Calcium receptor antagonist Drugs 0.000 description 1
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- 208000002705 Glucose Intolerance Diseases 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
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- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 241000276707 Tilapia Species 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
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- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
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- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
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- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
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- 239000011159 matrix material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
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- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- RSGAIWOEJXRYRV-UHFFFAOYSA-M sodium;2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoate Chemical compound [Na+].CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C([O-])=O RSGAIWOEJXRYRV-UHFFFAOYSA-M 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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Description
200900095 九、發明說明: 【發明所屬之技術領域】 本發明係關於一種藥物旋劑或錠劑層,其包人、、舌丨生成1八 替米沙坦、鹼性試劑及山梨糖醇。 【先前技術】
如EP-A-5023 14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Π受體拮抗劑。其化學名 稱為4,-[2-正丙基-4-曱基_6_(1_曱基苯并咪唑基I苯=咪 唑-1-基曱基]-聯苯-2-甲酸,其具有以下結構:
替米/y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範圍内在水性系統中之溶 解度極差。如W0 〇()/4337()中所揭示,結晶替米沙坦以具 有不同炼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 C或較佳>8〇χ:之玻璃轉移溫度&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 128721.doc 200900095 得。20 mg錠劑為圓形的,經測量其直徑為7麵且高度為 約2.5醜。40 mg80 mg旋劑為擴圓形,含有氣氯嘆嘻 (HCTZ)作為第二活性成份之市售雙層錠劑亦為橢_ 1 圓形產品之長度介於12 _與162職之間,寬度在58 mm至7.9 mm之範圍内且厚度為3 8随至以麵。 在鍵劑中替米沙坦之藥理學效能f要❹㈣_。除用 以吞服之立即釋放製劑外,可能進一步需要類似”歐洲荦 典啊寧抓PhamaC〇Peia)”之專論'口服用錠劑(Tablets for ^ ^ M〇Uth)’中之說明’調配含有替米沙坦之鍵劑或 旋劑層。如W〇 _59327中所揭示,此意謂其係藉由侵韻 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。W〇 〇3/〇59327揭示山梨糖醇作為用於替米沙括 之較佳稀釋劑,且替米沙坦之註冊之醫藥組合物係包含山- 裂搪醇作為填充劑。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。 殊==坦之不良溶解度及親脂性特徵分別需要特 率㈣Γ 錠劑層達成所註冊之替米沙坦溶解速 率。根據USP專論夕中装 ^ 寻_之疋義,Q必須大於75%,較佳 85 /〇。因此,根據本發 . 、 75%0、s ^ s , 乂 /員確保30 mm之後溶解至少 75/。且通…85%之替米沙坦藥物負載。 根據wo 03/059327,該等手段 劑,此舉有助於替 有驗性式 非晶形替米沙括可藉由γΓ 貝中溶解,且所使用之 丁 "t 了猎由賀霧乾燥獲得。 將0(0.5)定義為其中 體積/〇之所用物質顆粒之粒度在 128721.doc 200900095
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 μηι之範圍 内,而山梨糖醇之粒度D(0.5)在160-190 μπι之範圍内,亦 即超過150 μπι。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 μηι以下之山梨糖醇粒度無法產生所要硬度 之鍵劑’實例1之80 mg替米沙坦錠劑之硬度必須大於1 〇〇 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、平面鍵劑(諸如實例2之鍵劑),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16 N/mm2,較佳>2 ι 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 μηι(山梨糖醇):38 μιη(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”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。 匕=藥物製備中’㉟常經由適當調節壓實壓力獲得鍵劑之 指定硬度。可達該加項允許之最大應變,此程序可補償 批’、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w〇議59327中所揭示之方 造之經喷霧乾燥之非晶形替米沙坦可具有介於〇·4與“ 128721.doc 200900095 g/rnl之間的容積密度。 此外火已知壓縮至較高硬度等級可導致削弱之溶解。因 此先剛不可此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旋劑或錠劑層。 【發明内容】 、申請人現驚奇地發現並非用於製備包含替㈣坦之鍵劑 或錠劑層之山梨糖醇之粒度而是比表面積主要確^鍵劑或 _劑層之硬度及/¾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鍵劑或鍵劑層,而先前所用之山梨 糖醇具有介於0.3-0.7 m、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 24〇〇 或等放物)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/P〇 = 〇.〇7 - 0.22下進行6點測 定。 根據本發明所製造之旋劑顯示在< 60%之最大加工強度 ^壓κ壓力之較佳範圍内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 較低同批内差異及異批間差異。此最小化註冊之規格不^ 致之風險。 亦可將本發明中所述之醫藥、组合物在結合替米沙坦及〆 或多種其他活性成份之固定劑量組合中,例如在雙層或三 層鍵劑中用作分隔_層。肖包含㈣沙坦之層相結合之 128721.doc 200900095 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(aml〇dipine) ; ACE抑 制劑,諸如依那普利(enalapril)、賴諾普利(lisin〇pril)、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,諸如二曱雙胍(metformin)、格列酮(glitaz〇nes:^ Dpp_ IV抑制劑。
因此,本發明之一實施例為血管收縮素π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 〇_2 5 m2/g。 另外,用於本發明之製劑之山梨糖醇的特徵可gD(〇 5) 粒度在100-350㈣之範圍内,而較佳尺寸在12〇_3〇〇 _之 範圍内且最佳尺寸係介於15〇_25〇μιη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 _,較佳20_55 μιη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;東乾燥水溶液、在流化床中塗佈 载劑顆粒及在糖丸粒或其他載劑上之溶劑沈積來製備。缺 而’非晶形替米沙坦較佳大體上藉由w〇g3/q593 之喷霧乾燥方法來製借,i 现 l備八中替米沙坦係藉由藉助於如氫 乳化鈉及/或葡甲胳之― ^ 中來势借 種驗^劑使其溶解於純水 又 可視情況添加增溶劑及/或再結晶延遲劑。起 128721 .doc -20- 200900095
始水洛液之乾物質含量一般為10至5〇重量%,較佳μ至仂 隨後在室溫下或較佳在(例如)5n^iG(rc之間的 °下在平行流或逆流噴霧乾燥器中,在(例如)1至5巴 之喷霧壓力下噴霧乾燥水溶液…般而言,較佳以_定方 式選擇喷霧乾燥條件讀在分離旋風器巾獲得具有$ 5重量 % ’較佳认5重量%之殘餘濕度之經噴霧乾燥顆粒。為 此,喷霧乾燥器之出口氣溫較佳維持在介於約帆與㈣ 之間的值,而相應地調節其他過程參數, 喷射率…氣溫等。所獲得之喷霧乾燥顆粒=有 以下粒度分布之細粉: di〇 : $20 μιη,較佳 $1〇 μιη dso : $80 μιη,較佳 20至 55 μπι d9〇 : $350 μιη,較佳 50至 150 μιη。 在喷霧乾燥之後,活性成份替米沙坦以及包含於喷霧乾 燥顆粒中之賦形劑大體上處於無法偵測到結晶度之非晶开^ 狀態。可區分所獲得之低密度(〇.4_〇,5 g/m丨)與高密度⑼^ 〇_6 g/ml)替米沙坦顆粒。 以1〇〇重量份之替米沙坦計,喷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驗金屬氫氧化物,諸如 NaOH及KOH ;驗性胺基酸,諸如精胺酸及離胺酸;及— 甲胺(N-曱基_D_葡糖胺),較佳為Na〇H及葡甲胺。 匍 本發明之錠劑-般含有介於1〇至16〇 mg,較佳2〇至8〇 8或4〇至80 mg之間的替米沙坦。替米沙坦之較佳劑量濃 128721.doc 11 200900095 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 之旋劑或鍵: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5〇重量。4,較佳5至 35重量%之替米沙坦;〇.25至2〇重量%,較佳〇.40至15重量 〇/〇之驗性試劑;及30至95重量%,較佳6〇至8〇重量。/❶之山 梨糖醇。 以二個階段進行混合,亦即在第—混合步驟中使用(例 々)门剪刀犯°③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。+ A b,一般添加占錠劑或錠劑層組 5物重1計0.1至5重量%, ^ ^ 钗仫〇·3至2重置之諸如硬脂酸 鱗之U至預混料中1而,本發 合程序,且一般可 ’不限於此混 序。 不同加工步驟中採用其他替代混合程 可自一或多種以下所千田旦 其他(可選用)組分: 1之賦形劑及/或佐劑中選擇 =0重量%’較佳15至25重量%之 0·01-5重量%之崩解劑; ㈣’ 〇·01至5重量% ’較佳〇_5至3重量%之潤滑劑; 128721.doc 200900095 0.01至5重量%,較佳〇.3至2重量%之流動控制劑; 〇.01至2〇重量%,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。/❶之增溶劑; 0·01至1.5重量%,較佳〇丨至〇 8重量%之著色劑; 〇·01至1〇重量%,較佳2至8重量%tpH值控制劑; 0.01至5重量%,較佳〇 〇5至1重量%之界面活性劑及乳化 劑。
C 本發月之叙刈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"坦、至少—種驗性試劑及(視情況)增溶劑及/ 或結晶延遲劑之水溶液; b) 喷霧乾燥該水溶液以獲得經喷霧乾燥顆粒; c) 使忒經噴霧乾燥顆粒與具有介於〇75_35 之間的比 表面積之山梨糖醇混合以獲得預混料; d) 使该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—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太發日只夕兔丨4 & +知明之紅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 128721.doc -13- 200900095 f糖尿病、胰島素抗性、葡萄糖耐受不良、糖尿病前 』2型糖尿病、糖尿病,ϊ·生腎病、新陳代謝症候群(症候群 J肥胖、血脂異常、高甘油三酯血症、c-反應蛋白之血 二度升@、脂蛋白⑷之血清濃度升高、高半胱胺酸之血 /月/辰度升间、低密度脂蛋白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 ^白(HDL)-膽固醇之血清濃度減小、h叫叫-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 几〜肌梗塞、充血性心力衰竭、糖尿 病、血脂異常或癡呆。 最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M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料錠劑㈣使用用於 沖模與衝壓機之可選適當外部潤滑劑噴霧系统。 【實施方式】 為進-步說明本發明’給出以下非限制性實例。 128721.doc 14- 200900095 實例1 :包含80 11^替米沙垣之鍵劑(層)
組分 替米沙坦~~~~ 氫氧化鈉 聚乙烯吡咯ig 葡甲胺 山梨糖醇2 m2/g 硬脂酸鎮 純水* 總替米沙^~ *揮發性組吞~,在最終產物 實例2 :包含4 0 m
mg/狡劑 替米沙坦層之% 80.000 16.667 6.720 1.400 24.000 5.000 24.000 5.000 337.280 70.267 8.000 1.667 480.000_ 100.000 g替米沙坦之錠劑(層)
組分 ~~ 替米沙坦~~" ^~~~ 氫氧化鈉 聚乙稀D比洛酮 葡曱胺 山梨糖醇2 m2/g 硬脂酸鎂 純水* 總替籴沙ϋ ^-- *揮發性組 1,在最終 mg/疑劑 替米沙坦層之% 40.000 16.667 3.360 1.400 12.000 5.000 12.000 5.000 168.640 70.267 4.000 1.667 木 氺 240.000_ 100.000 實例3.包含2〇 mg替米沙坦之鍵劑(層) mg/疑劑 替米沙坦層之% 20.000 16.667 1.680 1.400 6.000 5.000 6.000 5.000 84.320 70.267 2.000 —--- 1.667 * -__ 120.000 *松找/— /入 100.000 揮發性組份,在最終產物中不殘留 組分___ 替米沙坦 氫氧化納 聚乙烯°比"各朗] 葡曱胺 山梨糖醇(2 m2/g> 硬脂酸鎂 純水$ 總替朵沙gj~~ 128721.doc *15· 200900095 實例4 : 8〇 m 錠劑 /V--—— ig替米沙坦及12, •5 mg氫氣噻嗪(HCTZ)雙層 組分 mg/鍵劑 替米沙坦層之 朁米沙垣 80.000 16.667 氫氧化鈉 6.720 1.400 聚乙烯吡咯_| 24.000 5.000 葡甲胺 24.000 5.000 山梨糖醇2m2/g 337.280 70,267 硬脂酸鎂 8.000 1.667 純水* 氺 氺 總替米沙 480.000 100.000 里1l!Lw塞嗓 12.500 6.250 乳糖單水合物 112.170 56.085 微晶纖維素 64.000 32.000 氧化鐵紅 0.330 0.165 羥基乙酸澱粉鈉 4.000 2.000 乾玉米源:粉 6.000 3.000 硬脂酸鎂 1.000 0.500 總HCTZ層 200.000 100.000 總雙層旋劑 680.000 *揮發性組份,在最終產物中不殘留 128721.doc 16- 200900095 實例5:比較80 mg替米沙坦錠劑(層)硬度 旋劑形狀為橢圓形,16.2 mmX7.9 mmX4.6 mm (LxWxH) a.使用具有0.5-0.7 m2/g之比表面積之山梨糖醇 1071379122 0 0 18 3 2 2 3 5 3 4 1 27201935
6. A 值%值值 均D(小大 平Is最最 替米沙坦 鍵劑 硬度 壓實力 壓實壓力 壓實壓力/硬度之比 密度組 批號 (N) (kN) (Mpa) (MPa/N) LD1 204348 122 21 194 1.6 204349 114 32 295 2.6 204350 114 32 295 2.6 HD2 508489 109 24 222 2.0 508490 109 25 231 2.1 508491 122 28 259 2.1 510280 107 30 277 2.6 602146 79 38 351 4.4 602147 90 38 351 3.9 b.使用具有2 m2/g之比表面積之山梨糖醇 替米沙坦 錠劑 硬度 壓實力 壓實壓力 壓實壓力/硬度之比 密度組 批號 (N) _) (MPa) (MPa/N) LD1 #75 222 20 185 0.8 HD2 #72 216 20 185 0.9 #73 211 20 185 0.9 #74 215 20 185 0.9 606035 190 20 185 1.0 606036 189 20 185 1.0 606037 191 20 185 1.0 702619 198 24 222 1.1 204 21 189 0.9 平均值 7 7 7 1.0 RSD(%) 189 20 185 0.8 最小值 222 24 222 1.1 最大值
128721.doc •17· 1 LD =低密度 0.4 - 0.5 g/ml 2 HD =高密度 0.5 - 0.6 g/ml 200900095
實例6:比較80 mg替米沙坦錠劑(層)溶解速率 a·使用具有0.5-0.7 m2/g之比表面積之山梨糖醇 替米沙坦 密度組 錠劑 批號 溶解 平均值 (%) 溶解 單一最小值 (%) 溶解值之差異 (平均值·最小值) (%) LD 204348 88 83 5 204349 82 74 8 204350 83 78 5 HD 508489 88 76 12 508490 86 82 4 508491 91 79 12 510280 91 85 6 602146 88 81 7 602147 85 72 13 87 79 8 平均值 82 72 4 最小值 91 85 12 最大值 2 S75⑻ b.使用具有2 m 2/g之比表面積之山梨糖醇 替米沙坦 密度組 錠劑 批號 溶解 平均值 (%) 溶解單一最小 值 (%) 溶解值之差異(平 均值-最小值) (%) LD #75 95 95 0 HD #72 93 84 9 #73 95 91 4 #74 94 93 1 606035 87 84 3 606036 84 78 6 606037 87 83 4 702619 94 93 1 91 87 4 平均值 84 78 0 最小值 95 95 9 最大值 0 575⑻ 128721.doc 18 200900095 實例7:比較20 mg替米沙坦錠劑(層)硬度 錠劑形狀為圓形,直徑為7 mm,厚度為2.5 mm
a.使用具有0.5-0.7 m2/g之比表面積之山梨糖醇 替米 沙坦 密度組 錠劑 批號 硬度 (N) 壓實力 (_ 拉伸 強度 (N/mm2) 壓實 壓力 (MPa) 壓實壓力/ 硬度之比 拉伸強度 (MPa/N) 之比 HD 509997 58 11 2.1 286 4.9 135 509998 56 11 2.0 286 5.1 140 509999 59 10 2.1 260 4.4 121 602786 72 11 2.6 286 4.0 109 603693 52 10 1.9 260 5.0 137 603733 71 12 2.6 312 4.4 121 604178 47 22 1.7 571 12.2 334 59 12 2.2 323 5.7 157 b.使用具有2 m2/g之比表面積之山梨糖醇 替米 沙坦 密度組 旋劑 批號 硬度 (N) 壓實力 (kN) 拉伸 強度 (N/mm2) 壓實 壓力 (MPa) 壓實壓力/ 硬度之比 拉伸強度 (MPa/N) 之比 HD 702914 67 9.5 2.4 247 3.7 101 平均值
128721.doc •19- 200900095 實例8 ··比較替米沙坦錠劑層硬度 (80 mg替米沙坦加上12.5 mg氫氯嗟σ秦雙層錄:劑) a.使用具有0· 5-0.7 m2/g之比表面積之山梨糖醇
替米沙坦 密度組 錠劑 批號 硬度 (N) 壓實力 (kN) 壓實壓力 (MPa) 壓實壓力/ 硬度之比 (MPa/N) HD 506918 133 16 148 1.1 506919 135 16 148 1.1 506920 131 15 139 1.1 509994 129 19 175 1.4 509995 127 19 175 1.4 509996 125 17 157 1.3 130 17 157 1.2 平均值 b.使用具有2 m2/g之比表面積之山梨糖醇 替米沙坦 錠劑 硬度 壓實力 壓實壓力讎力/ 魘1佺刀硬度之比 密度組 批號 (N) _ (MPa) (MPa/N) HD 609031 180 14 129 0.7 128721.doc 20- 200900095 實例9 :比較替米沙坦溶解速率 (8 0 mg替米沙坦加上12.5 mg氫氣嗟嗉雙層錠劑) a.使用具有0.5-0.7 m2/g之比表面積之山梨糖醇
替米沙坦 密度组 錠劑 批號 溶解平均值 (%) 溶解單一 最小值 (%) 溶解值之差異 (平均值-最小值) (%) HD 506918 102 99 3 506919 94 92 2 506920 100 97 3 509994 97 95 2 509995 94 88 6 509996 98 96 2 98 94 3 平均值 94 88 2 最小值 102 99 6 最大值 b.使用具有2 m2 /g之比表面積之山梨糖醇 替米沙坦 密度組 鍵劑 批號 溶解平均值 (%) 溶解單一 最小值 (%) 溶解值之差異 (平均值-最小值) (%) HD 609031 97 94 3 128721.doc -21 - 200900095 實例10:比較40 mg替米沙坦錠劑(層)硬度 mm (錠劑形狀為橢圓形,12.0 mm><5.8 mm><3.8 (LxWxH)) a.使用具有0.5-0.7 m2/g之比表面積之山梨糖醇 替米沙坦 密度組 錠劑 批號 硬度 (N) 壓實力 (kN) 壓實壓力 (MPa) 壓實壓力/ 硬度之比 (MPa/N) HD 603199 77 22 382 5.0 603200 80 21 354 4.4 603201 66 24 410 6.2 603202 91 21 363 4.0 603203 67 22 366 5.5 603204 68 22 377 5.5 75 22 375 5.1 b.使用具有1.3 ! n 2/g之比表面積之山梨糖醇 替米沙坦 錠劑 硬度 壓實力 壓實壓力 壓實壓力/ 硬度之比 密度組 批號 (N) _ (MPa) (MPa/N) HD 710507 83 18 306 3.7 c.使用具有1.8 m2/g之比表面積之山梨糖醇 替米沙坦 錠劑 硬度 壓實力 壓實壓力 壓實壓力/ 硬度之比 密度組 批號 (N) _ (MPa) (MPa/N) HD 710508 113 16 270 2.4 平均值 128721.doc 22- 200900095 d.使用具有2 m2/g之比表面積之山梨糖醇 替米沙坦 密度組 旋劑 批號 硬度 (N) 壓實力 _ 壓實壓力 (MPa) 壓實壓力/ 硬度之比 (MPa/N) HD 708400 143 17 295 2.1 708401 147 18 302 2.1 708402 143 17 295 2.1 708403 147 18 305 2.1 708407 144 20 338 2.4 709123 160 16 268 1.7 147 18 300 2.1 平均值 實例11 : 比較40 mg替米沙坦鍵劑層硬度 (40 mg替米沙坦加上12.5 mg氫氣°塞°秦雙層鍵劑; 鍵:劑形狀為橢圓形,14.0 mm X 6.8 mm><5.2 mm(LxWxH)) a.使用具有0.5-0.7 m2 /g之比表面積之山梨糖醇 替米沙坦 錠劑 硬度 壓實力 壓實壓力 壓實壓力/ 硬度之比 密度組 批號 (N) (MPa) (MPa/N) HD 608690 117 16 201 1.7 608691 125 15 190 1.5 608692 115 15 189 1.6 608693 122 15 185 1.5 608694 114 16 195 1.7 608695 123 16 192 1.6 119 16 192 1.6 平均值 b.使用具有1.4 m2/g之比表面積之山梨糖醇 替米沙坦 錠劑 硬度 壓實力 壓實壓力 壓實壓力/ 錄麼之fcb 密度組 批號 (N) (kN) (MPa) (MPa/N) HD 709569 134 14 173 1.3 128721.doc 23- 200900095 C.使用具有2 m2/g之比表面積之山梨糖醇 f 替米沙坦 錠劑 硬度 壓實力 壓實壓力 密度組 批號 (N) _ (MPa) HD 609030/24 152 15 185 壓實壓力/ 硬度之比 (MPa/N)1,2 128721.doc -24-
Claims (1)
- 200900095 十、申請專利範圍: 1. 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#沙坦⑽misartan)、驗性試劑及山梨糖 醇,其特徵在於該山梨糖醇具有0.75-3.5 m2/g,較佳1 4 3.0 m2/g且最佳2·0_2.5 m2/g之比表面積。 2. 如清求項1之錠劑或錠劑層,其包含D(0.5)平均粒度為 100-350 μιη,較佳 12〇_3〇〇 μηι且最佳 15〇 2〇〇 之二二 糖醇。 本 月求項1之劑或鏡劑層,其中該驗性試劑係選自驗 金屬氫氧化物、鹼性胺基酸及葡甲胺。 4.如明求項1之錠劑或錠劑層,其含有i〇_i6〇 ,較佳 80 mg或40-80 mg替米沙坦。 月求員1之錠劑或錠劑層,其包含平均粒度 < ⑽, 較佳20-55 μΐη之非晶形替米沙坦。 &如請求们之錠劑或錠劑層’其另外包含其 佐劑。 扪或 月长項6之旋劑或旋劑層,其中該等其他 =選自黏合劑、載劑、崩解劑、填充劑、潤滑及: :控::卜結晶延遲劑、增溶劑、著色劑、。Η值控: Α 界面活性劑及乳化劑。 如叫求項1之鍵劑或 備:喳* 处釗層其係糟由以下步驟來製 、務乾燥包含替米沙坦及鹼性 得喷霧乾燥顆粒,混合該經嗔霧乾崎=,以獲 以獲得 乾各顆粒與山梨糖醇, 預此枓,且混合該預混料與潤滑劑,以獲得最終 128721.doc 200900095 掺合物。 青长項1之錠劑或錠劑層,其係由防潮包裝材料,諸 ι &包裝或聚两稀管及HDpE瓶來包裝。 1〇·種製造如請求項t之錢劑或鍵劑層之方法,該鍊劑或 w層係m u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 攣性心絞痛、中風、㈣梗塞、短暫性缺血性發作、充 血I"生、力衰竭、心血管疾病、糖尿病、胰島素抗性、葡 萄糖耐文不良、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 酉曰血症、C-反應蛋白之血清濃度升高、脂蛋白(&)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)-膽固醇之血清滚度升高、脂蛋白相關之碎脂 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。 η.如:求項H)之方法’其中所治療或預防之該病況為慢性 穩疋型心絞痛、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。 12· 一種製備如請求項丨之藥物錠劑或錠劑層之方法’其包 括: ' 噴霧乾燥包含替米沙坦及鹼性試劑之水溶液,以獲得 喷霧乾燥顆粒; 混合該喷霧乾燥顆粒與比表面積介於〇·75_3 5 ^仏之 128721.doc 200900095 間的山梨糖醇,獲得預混料; 混合該預混料與潤滑劑,以獲得最終摻合物 將該最終摻合物壓縮為錠劑或錠劑層。128721.doc 200900095 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:128721.doc
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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 |
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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 |
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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 |
DK1854454T3 (da) * | 2002-01-16 | 2014-01-13 | Boehringer Ingelheim Pharma | Fremgangsmåde til fremstilling af amorf telmisartan |
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 |
US20060159747A1 (en) * | 2004-12-17 | 2006-07-20 | Boehringer Ingelheim International Gmbh | Telmisartan and hydrochlorothiazide combination therapy |
EA200701159A1 (ru) * | 2004-12-17 | 2007-12-28 | Бёрингер Ингельхайм Интернациональ Гмбх | Комбинированное лекарственное средство, включающее телмисартан и гидрохлортиазид |
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