CA2801020A1 - A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide - Google Patents
A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide Download PDFInfo
- Publication number
- CA2801020A1 CA2801020A1 CA2801020A CA2801020A CA2801020A1 CA 2801020 A1 CA2801020 A1 CA 2801020A1 CA 2801020 A CA2801020 A CA 2801020A CA 2801020 A CA2801020 A CA 2801020A CA 2801020 A1 CA2801020 A1 CA 2801020A1
- Authority
- CA
- Canada
- Prior art keywords
- telmisartan
- formulation according
- diuretic
- formulation
- stable pharmaceutical
- 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.)
- Abandoned
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- OZCVMXDGSSXWFT-UHFFFAOYSA-N 6-chloro-1,1-dioxo-3,4-dihydro-2h-1$l^{6},2,4-benzothiadiazine-7-sulfonamide;2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoic acid Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O.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 OZCVMXDGSSXWFT-UHFFFAOYSA-N 0.000 title 1
- 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 146
- 239000005537 C09CA07 - Telmisartan Substances 0.000 claims abstract description 77
- 229960005187 telmisartan Drugs 0.000 claims abstract description 70
- 238000004090 dissolution Methods 0.000 claims abstract description 41
- 239000002934 diuretic Substances 0.000 claims abstract description 27
- 230000001882 diuretic effect Effects 0.000 claims abstract description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 26
- 239000011159 matrix material Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 230000002708 enhancing effect Effects 0.000 claims abstract description 13
- 239000007884 disintegrant Substances 0.000 claims abstract description 11
- 239000003085 diluting agent Substances 0.000 claims abstract description 9
- 239000002671 adjuvant Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 107
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 61
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 61
- 238000009472 formulation Methods 0.000 claims description 59
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 26
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 23
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 23
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 21
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 21
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 21
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 21
- 238000002156 mixing Methods 0.000 claims description 19
- 239000008363 phosphate buffer Substances 0.000 claims description 19
- 239000010410 layer Substances 0.000 claims description 18
- 239000001913 cellulose Substances 0.000 claims description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 14
- 238000005469 granulation Methods 0.000 claims description 14
- 230000003179 granulation Effects 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 235000010980 cellulose Nutrition 0.000 claims description 13
- 229920002678 cellulose Polymers 0.000 claims description 13
- CPLXHLVBOLITMK-UHFFFAOYSA-N Magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 11
- 239000000395 magnesium oxide Substances 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 229920000881 Modified starch Polymers 0.000 claims description 10
- 238000007906 compression Methods 0.000 claims description 9
- 230000006835 compression Effects 0.000 claims description 9
- 238000007580 dry-mixing Methods 0.000 claims description 9
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000002356 single layer Substances 0.000 claims description 9
- 229920003081 Povidone K 30 Polymers 0.000 claims description 8
- -1 hydroxyl propyl Chemical class 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 239000000391 magnesium silicate Substances 0.000 claims description 7
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 7
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 235000019426 modified starch Nutrition 0.000 claims description 6
- 229940068196 placebo Drugs 0.000 claims description 6
- 239000000902 placebo Substances 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 229940032147 starch Drugs 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 5
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 claims description 5
- 238000005461 lubrication Methods 0.000 claims description 5
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 5
- 235000012239 silicon dioxide Nutrition 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- IHJCXVZDYSXXFT-UHFFFAOYSA-N chloraminophenamide Chemical compound NC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O IHJCXVZDYSXXFT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910000386 magnesium trisilicate Inorganic materials 0.000 claims description 4
- 235000019793 magnesium trisilicate Nutrition 0.000 claims description 4
- 229940099273 magnesium trisilicate Drugs 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000005995 Aluminium silicate Substances 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 235000019759 Maize starch Nutrition 0.000 claims description 3
- 239000004411 aluminium Substances 0.000 claims description 3
- 235000012211 aluminium silicate Nutrition 0.000 claims description 3
- 230000000181 anti-adherent effect Effects 0.000 claims description 3
- 239000003911 antiadherent Substances 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- 239000001175 calcium sulphate Substances 0.000 claims description 3
- 235000011132 calcium sulphate Nutrition 0.000 claims description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000829 kaolin Drugs 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 235000001055 magnesium Nutrition 0.000 claims description 3
- 235000019792 magnesium silicate Nutrition 0.000 claims description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 3
- 235000019814 powdered cellulose Nutrition 0.000 claims description 3
- 229920003124 powdered cellulose Polymers 0.000 claims description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 239000004368 Modified starch Substances 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 238000007907 direct compression Methods 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 238000009476 low shear granulation Methods 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- 239000008187 granular material Substances 0.000 description 21
- 239000003826 tablet Substances 0.000 description 19
- 229940097420 Diuretic Drugs 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 17
- 238000012216 screening Methods 0.000 description 14
- 229940057948 magnesium stearate Drugs 0.000 description 10
- 229910002012 Aerosil® Inorganic materials 0.000 description 9
- 230000015556 catabolic process Effects 0.000 description 9
- 238000006731 degradation reaction Methods 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 7
- 235000019700 dicalcium phosphate Nutrition 0.000 description 7
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 7
- 229940101564 micardis Drugs 0.000 description 7
- 239000013543 active substance Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229920001903 high density polyethylene Polymers 0.000 description 6
- 239000004700 high-density polyethylene Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 102000005862 Angiotensin II Human genes 0.000 description 5
- 101800000733 Angiotensin-2 Proteins 0.000 description 5
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 5
- 229950006323 angiotensin ii Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 108010064733 Angiotensins Proteins 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 101150059573 AGTR1 gene Proteins 0.000 description 3
- 101150116411 AGTR2 gene Proteins 0.000 description 3
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- 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 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 235000013980 iron oxide Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
- 108090000783 Renin Proteins 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 229960005191 ferric oxide Drugs 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229940033134 talc Drugs 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 102400000967 Bradykinin Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 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
- 102000004310 Ion Channels Human genes 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940121792 Thiazide diuretic Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 235000010210 aluminium Nutrition 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229920001531 copovidone Chemical class 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 229920013819 hydroxyethyl ethylcellulose Polymers 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000002210 silicon-based material Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 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
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- 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
- A61P9/12—Antihypertensives
Abstract
The present invention is directed to a stable pharmaceutical formulation comprising telmisartan, or a pharmaceutically acceptable salt thereof/ and a diuretic dispersed in a matrix. The matrix comprises at least one disinte grant in an amount ranging from 0.5 % to 20% by weight; a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from 1:1 to 10:1; a water-insoluble diluent in an amount ranging from 15%-75% by weight and at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from 0 - 25% by weight,
Description
A STABLE PHARMACEUTICAL FORMULATION COMPRISING
TELMISARTAN AND RYDROCHLOROTHIAZIDE
FIELD OF TIDE INVENTION
The present invention relates to a pharmaceutical t Wet formulation comprising two active ingredients. More specifically the present invention relates to a formulation comprising telmisartan, which is an angiotenl II receptor antagonist and hydrochlorothiazide, which is a diuretic, and method of manufacturing thereof.
BACKGROUND OF THE INVENTION
Telmisartan was first disclosed in European Patent No. 0,502,314 (issued on May 20, 1998 to Dr. Karl Thomae GmbH) as angiotensin II receptor antagonist and is indicated for treatment of mild to moderate essential hypertension in patients, Its chemical name is 4'-[[4-methyl-6.(1-methyl-2 benzixnidazolyl) 2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid, with molecular formula CsH3QN4O2, having following structure:
Tehnisartan is a white to off-white, odorless crystalline powder. It is practically insoluble in water and in the pH range of 3 to 7, sparingly soluble in strong acid (except HC1) and soluble in strong base.
As disclosed in PCT Publication W020000/43370 (corresponding to Canadian Patent No. 2,352,436, issued on March 23, 2010 to Boehringer Ingelheim Pharma KG) crystalline telmisartan exists in two polymorphic forms having different melting points.
Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.
Telmisartan is an orally active, AT1 selective angiotensin 11 receptor antagonist. By selectively blocking the binding of angiotensin II to the AT1 receptors, telmisartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II.
Telmisartan blocks AT1 receptors, and has essentially no affinity for the AT2 receptors.
AT2 receptors have been found in many tissues; to date, they have not been found to be associated with cardiovascular homeostasis. Telmisartan does not inhibit angiotensin converting enzyme (ACE, also known as kininase II), the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis. In hypertensive patients, antagonism of angiotensin II AT1 receptors results in two to three-fold increases in plasma renin and angiotensin 11 plasma concentrations. Long term effects of increased AT2 receptor stimulation by angiotensin II are unknown. Telmisartan is known on the market under the trade name Mieardis by Boehringer Irtgelheirn Corporation.
Hydrochlorothiazide (HCTZ) is an orally administered thiazide diuretic which was first disclosed in United States Patent No. 3,163,645 (issued on December 29, 1964 to Ciba Corporation) and is indicated in the treatment of edema and hypertension. The chemical name for HCTZ is 6-chloro-3,4-dihydro>-2H-1,2,4-beznzothiadiazine-7-sulfonamide 1,1-dioxide, molecular formula is C7H8C1N304S2 with following structure:
TELMISARTAN AND RYDROCHLOROTHIAZIDE
FIELD OF TIDE INVENTION
The present invention relates to a pharmaceutical t Wet formulation comprising two active ingredients. More specifically the present invention relates to a formulation comprising telmisartan, which is an angiotenl II receptor antagonist and hydrochlorothiazide, which is a diuretic, and method of manufacturing thereof.
BACKGROUND OF THE INVENTION
Telmisartan was first disclosed in European Patent No. 0,502,314 (issued on May 20, 1998 to Dr. Karl Thomae GmbH) as angiotensin II receptor antagonist and is indicated for treatment of mild to moderate essential hypertension in patients, Its chemical name is 4'-[[4-methyl-6.(1-methyl-2 benzixnidazolyl) 2-propyl-1-benzimidazolyl]methyl]-2-biphenylcarboxylic acid, with molecular formula CsH3QN4O2, having following structure:
Tehnisartan is a white to off-white, odorless crystalline powder. It is practically insoluble in water and in the pH range of 3 to 7, sparingly soluble in strong acid (except HC1) and soluble in strong base.
As disclosed in PCT Publication W020000/43370 (corresponding to Canadian Patent No. 2,352,436, issued on March 23, 2010 to Boehringer Ingelheim Pharma KG) crystalline telmisartan exists in two polymorphic forms having different melting points.
Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.
Telmisartan is an orally active, AT1 selective angiotensin 11 receptor antagonist. By selectively blocking the binding of angiotensin II to the AT1 receptors, telmisartan inhibits the vasoconstrictor and aldosterone-secreting effects of angiotensin II.
Telmisartan blocks AT1 receptors, and has essentially no affinity for the AT2 receptors.
AT2 receptors have been found in many tissues; to date, they have not been found to be associated with cardiovascular homeostasis. Telmisartan does not inhibit angiotensin converting enzyme (ACE, also known as kininase II), the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cardiovascular regulation of blood pressure and sodium homeostasis. In hypertensive patients, antagonism of angiotensin II AT1 receptors results in two to three-fold increases in plasma renin and angiotensin 11 plasma concentrations. Long term effects of increased AT2 receptor stimulation by angiotensin II are unknown. Telmisartan is known on the market under the trade name Mieardis by Boehringer Irtgelheirn Corporation.
Hydrochlorothiazide (HCTZ) is an orally administered thiazide diuretic which was first disclosed in United States Patent No. 3,163,645 (issued on December 29, 1964 to Ciba Corporation) and is indicated in the treatment of edema and hypertension. The chemical name for HCTZ is 6-chloro-3,4-dihydro>-2H-1,2,4-beznzothiadiazine-7-sulfonamide 1,1-dioxide, molecular formula is C7H8C1N304S2 with following structure:
2 NVO
HCTZ is a white to practically white, crystalline powder which is slightly soluble in water and freely soluble in sodium hydroxide solution.
Combination of telmisartan and HCTZ is commercially available under the trade name Micardis Plus and is indicated for use in the treatment of hypertension, However, particularly with a combination of telmisartan or a pharmaceutically acceptable salt thereof, and HCTZ, this approach was not feasible due to the incompatibility of HCTZ with basic compounds such as, e.g., meglumine (N-methyl-D-glucamine) which is a component of conventional telmisartan formulations and the reduced dissolution rate of HCTZ from the dissolving matrix as compared with dissolution from a disintegrating tablet.
Formulations using a combination of these two drugs are described in the following patents; W02003/059327 (CA2472392), WO2004/096215 (CA2524091), W02006063737 (CA2589493), W02007/060170 (CA2625404), W02007/144175 (CA2654890), W02009/058950, and W02009/115301.
PCT Publication No. W02003/059327 (corresponds to Canadian Patent No.
2,472,392, issued to Boehringer Ingeiheim Pharma on July 14, 2009) discloses a bilayer pharmaceutical tablet comprising a first layer containing telmisartart in substantially amorphous form in a dissolving tablet matrix and a second layer containing a diuretic in a disintegrating tablet matrix. This bilayer tablet structure overcomes the stability problem caused by the incompatibility of a diuretic like HCTZ with basic constituents of the telrnisartan formulation. At the same time such a formulation provides for immediate release of the diuretic from the fast disintegrating matrix. However bilayer tablets as per PCT Publication No. W02003/059327 tend to be slightly hygroscopic and,
HCTZ is a white to practically white, crystalline powder which is slightly soluble in water and freely soluble in sodium hydroxide solution.
Combination of telmisartan and HCTZ is commercially available under the trade name Micardis Plus and is indicated for use in the treatment of hypertension, However, particularly with a combination of telmisartan or a pharmaceutically acceptable salt thereof, and HCTZ, this approach was not feasible due to the incompatibility of HCTZ with basic compounds such as, e.g., meglumine (N-methyl-D-glucamine) which is a component of conventional telmisartan formulations and the reduced dissolution rate of HCTZ from the dissolving matrix as compared with dissolution from a disintegrating tablet.
Formulations using a combination of these two drugs are described in the following patents; W02003/059327 (CA2472392), WO2004/096215 (CA2524091), W02006063737 (CA2589493), W02007/060170 (CA2625404), W02007/144175 (CA2654890), W02009/058950, and W02009/115301.
PCT Publication No. W02003/059327 (corresponds to Canadian Patent No.
2,472,392, issued to Boehringer Ingeiheim Pharma on July 14, 2009) discloses a bilayer pharmaceutical tablet comprising a first layer containing telmisartart in substantially amorphous form in a dissolving tablet matrix and a second layer containing a diuretic in a disintegrating tablet matrix. This bilayer tablet structure overcomes the stability problem caused by the incompatibility of a diuretic like HCTZ with basic constituents of the telrnisartan formulation. At the same time such a formulation provides for immediate release of the diuretic from the fast disintegrating matrix. However bilayer tablets as per PCT Publication No. W02003/059327 tend to be slightly hygroscopic and,
3 therefore, need to be packaged using a moisture-proof packaging material such as aluminium foil blister packs, or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
Several approaches to overcome the incompatibility problem have been reported in PCT
Publication No. W02003/059327. In one approach HCTZ particle was coated in a fluidized-bed granulator with a polymer solution containing water soluble polymers like hydroxypropylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone, thereby reducing the contact surface area of the HCTZ particles with the teimisartan formulation during mixing and compressing. However, by this means it was not possible to reduce the surface contact area of HCTZ with the telmisartan formulation in a compressed tablet to a degree sufficient to achieve the desired prolonged shelf life, PCT Publication No. W02004/096215 (corresponds to Canadian Patent Application No.
2,524,091, filed April 27, 2004 by Boehringer Ingelheim Pharma) relates to a medicament formulation of the crystalline sodium salt of 4'-[2-n propyl-4-methyl-6-(1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid (i.e., tehuisartan) and methods for production thereof. The patent discloses pharmaceutical composition containing the telmisartan sodium salt and a diuretic.
PCT Publication No. W02006/063737 (corresponds to Canadian Patent Application No.
2,589,493, filed December 9, 2005 by Boehringer Ingelheim Pharma) discloses a pharmaceutical composition comprising telmisartan and HCTZ for the treatment of hypertension in patients with an insufficient blood pressure reduction upon treatment either with an angiotensin 11 receptor antagonist, or a pharmaceutical composition of an angiotensin II receptor antagonist and a low dose of HCTZ, wherein the pharmaceutical composition contains the component telmisartan in a dissolving tablet matrix having instant release characteristics and wherein the diuretic HCTZ is in a separate layer in a disintegrating pharmaceutical matrix.
FCT Publication No, W02007/144175 (corresponds to Canadian Patent Application No.
2,654,890, filed June 14, 2007 be Lek Pharmaceuticals D.D.) discloses a stable formulation
Several approaches to overcome the incompatibility problem have been reported in PCT
Publication No. W02003/059327. In one approach HCTZ particle was coated in a fluidized-bed granulator with a polymer solution containing water soluble polymers like hydroxypropylcellulose, hydroxypropylmethylcellulose or polyvinylpyrrolidone, thereby reducing the contact surface area of the HCTZ particles with the teimisartan formulation during mixing and compressing. However, by this means it was not possible to reduce the surface contact area of HCTZ with the telmisartan formulation in a compressed tablet to a degree sufficient to achieve the desired prolonged shelf life, PCT Publication No. W02004/096215 (corresponds to Canadian Patent Application No.
2,524,091, filed April 27, 2004 by Boehringer Ingelheim Pharma) relates to a medicament formulation of the crystalline sodium salt of 4'-[2-n propyl-4-methyl-6-(1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid (i.e., tehuisartan) and methods for production thereof. The patent discloses pharmaceutical composition containing the telmisartan sodium salt and a diuretic.
PCT Publication No. W02006/063737 (corresponds to Canadian Patent Application No.
2,589,493, filed December 9, 2005 by Boehringer Ingelheim Pharma) discloses a pharmaceutical composition comprising telmisartan and HCTZ for the treatment of hypertension in patients with an insufficient blood pressure reduction upon treatment either with an angiotensin 11 receptor antagonist, or a pharmaceutical composition of an angiotensin II receptor antagonist and a low dose of HCTZ, wherein the pharmaceutical composition contains the component telmisartan in a dissolving tablet matrix having instant release characteristics and wherein the diuretic HCTZ is in a separate layer in a disintegrating pharmaceutical matrix.
FCT Publication No, W02007/144175 (corresponds to Canadian Patent Application No.
2,654,890, filed June 14, 2007 be Lek Pharmaceuticals D.D.) discloses a stable formulation
4 of telmisartan and HCTZ having both substances in separate units is prepared, exhibiting exceptiorkal stability when subjecting to stress conditions.
PCT Publication No. W02009/058950 (filed October 30, 2008 by Dr. Reddy's Laboratories Ltd.) discloses the pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of HCTZ from a dissolving matrix, methods for producing tablets and methods of use for treating hypertension.
PCT Publication No. W02009/115301 discloses a solid pharmaceutical composition comprising at least two layers, wherein the first layer contains a non-peptide angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof in a dissolving matrix and the second layer contains a diuretic or a pharmaceutically acceptable salt thereof, characterized in that the second layer contains the diuretic or the pharmaceutically acceptable salt thereof in a dissolving matrix and the pharmaceutical composition is substantially free of disintegrants.
It is often desirable to combine multiple active ingredients in a single pharmaceutical composition. Inclusion of multiple ingredients in a single composition generally reduces costs and provides the convenience of consuming a single medication rather than multiple medications for treating individual symptoms. However, a combination of ingredients might compromise the stability of a composition due to incompatibility between two active ingredients.
The solid pharmaceutical composition according to the present invention, preferably in the form of a tablet, provides an immediate release of the non peptide angiotensin Il receptor antagonist, in particular of the poorly water soluble telmisartan or pharmaceutically acceptable salts thereof, and also provides an immediate release of a diuretic from the tablet matrix. At the same time the tablet structure overcomes the stability problem caused by the incompatibility of diuretics, like HC z, with basic excipients of conventional telmisartan formulations, e.g. meglumine.
PCT Publication No. W02009/058950 (filed October 30, 2008 by Dr. Reddy's Laboratories Ltd.) discloses the pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of HCTZ from a dissolving matrix, methods for producing tablets and methods of use for treating hypertension.
PCT Publication No. W02009/115301 discloses a solid pharmaceutical composition comprising at least two layers, wherein the first layer contains a non-peptide angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof in a dissolving matrix and the second layer contains a diuretic or a pharmaceutically acceptable salt thereof, characterized in that the second layer contains the diuretic or the pharmaceutically acceptable salt thereof in a dissolving matrix and the pharmaceutical composition is substantially free of disintegrants.
It is often desirable to combine multiple active ingredients in a single pharmaceutical composition. Inclusion of multiple ingredients in a single composition generally reduces costs and provides the convenience of consuming a single medication rather than multiple medications for treating individual symptoms. However, a combination of ingredients might compromise the stability of a composition due to incompatibility between two active ingredients.
The solid pharmaceutical composition according to the present invention, preferably in the form of a tablet, provides an immediate release of the non peptide angiotensin Il receptor antagonist, in particular of the poorly water soluble telmisartan or pharmaceutically acceptable salts thereof, and also provides an immediate release of a diuretic from the tablet matrix. At the same time the tablet structure overcomes the stability problem caused by the incompatibility of diuretics, like HC z, with basic excipients of conventional telmisartan formulations, e.g. meglumine.
5
6 PCT/CA2011/000621 It is known from the literature that telmisartan has very poor aqueous solubility in the physiological p1 i range of the gastrointestinal tract between pH 1 and 7, and is soluble in strong base. On the other hand, HCTZ degrades in alkaline conditions i.e undergoes alkaline hydrolysis in the presence of heat and moisture. The major degradation product of HCTZ is 4-amino-6-chloro-1,3-benzenesulfonamide ("DSA") It is advantageous to administer both drugs concomitantly or even better to administer a composition comprising both, to treat hypertension.
Difficulty results from the fact that both active substances need to be released from the composition substantially simultaneously. Preparation of fixed dose combinations of telmisartan and HCTZ with adequate stability poses a challenge to formulators.
Hence there is need for simple and stable fixed dose compositions containing telmisartan and HCTZ.
SUMMARY OF TEE INVENTION
The present invention provides a stable pharmaceutical formulation comprising telntisartan or a pharmaceutically acceptable salt and a diuretic dispersed in a matrix, said matrix comprising - at least one disintegrant in an amount ranging from about 0.5 % to about 20%
by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from about 1:1 to about 10:1;
- a water-insoluble diluent in an amount ranging from about 15% to about 76%
by weight; and - at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from about 0 to about 25% by weight The preferred diuretic of the present invention is HCTZ.
In a further aspect of the present invention, there is provided a stable pharmaceutical formulation wherein the in vitro dissolution rate of said formulation is at least about 80 % by weight of telmisartan dissolved within 30 minutes and at least about 80%
of the diuretic dissolved within 30 minutes as measured by using USP type II
apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.
In a further aspect of the present invention, there is provided a process for the preparation of a stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt thereof, and a diuretic dispersed in a matrix, wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.
According to another aspect of the present invention, there is provided a use of a stable pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form, for the treatment or prevention of hypertension.
According to another aspect of the present invention further relates to stable formulations comprising telmisartan, or acceptable salts, and HCTZ, wherein the telmisartan or acceptable salt is in substantially amorphoous form.
DETAILED DESCRIPTION OF THE INVENTION
In the present application, the terms or expressions "active agent", "active ingredient", "active pharmaceutical ingredient", "drug", "pharmacologically active agent", "pharmaceutically acceptable active agent" and/or "pharmaceutically acceptable active substance" are used interchangeably to refer to a chemical material, compound, agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a pharmaceutically significant or effective amount. The active agent can be a therapeutic, a prophylactic, or a diagnostic agent These terms of art are well-known in the pharmaceutical and medicinal arts.
Difficulty results from the fact that both active substances need to be released from the composition substantially simultaneously. Preparation of fixed dose combinations of telmisartan and HCTZ with adequate stability poses a challenge to formulators.
Hence there is need for simple and stable fixed dose compositions containing telmisartan and HCTZ.
SUMMARY OF TEE INVENTION
The present invention provides a stable pharmaceutical formulation comprising telntisartan or a pharmaceutically acceptable salt and a diuretic dispersed in a matrix, said matrix comprising - at least one disintegrant in an amount ranging from about 0.5 % to about 20%
by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from about 1:1 to about 10:1;
- a water-insoluble diluent in an amount ranging from about 15% to about 76%
by weight; and - at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from about 0 to about 25% by weight The preferred diuretic of the present invention is HCTZ.
In a further aspect of the present invention, there is provided a stable pharmaceutical formulation wherein the in vitro dissolution rate of said formulation is at least about 80 % by weight of telmisartan dissolved within 30 minutes and at least about 80%
of the diuretic dissolved within 30 minutes as measured by using USP type II
apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.
In a further aspect of the present invention, there is provided a process for the preparation of a stable pharmaceutical formulation comprising telmisartan or a pharmaceutically acceptable salt thereof, and a diuretic dispersed in a matrix, wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.
According to another aspect of the present invention, there is provided a use of a stable pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form, for the treatment or prevention of hypertension.
According to another aspect of the present invention further relates to stable formulations comprising telmisartan, or acceptable salts, and HCTZ, wherein the telmisartan or acceptable salt is in substantially amorphoous form.
DETAILED DESCRIPTION OF THE INVENTION
In the present application, the terms or expressions "active agent", "active ingredient", "active pharmaceutical ingredient", "drug", "pharmacologically active agent", "pharmaceutically acceptable active agent" and/or "pharmaceutically acceptable active substance" are used interchangeably to refer to a chemical material, compound, agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a pharmaceutically significant or effective amount. The active agent can be a therapeutic, a prophylactic, or a diagnostic agent These terms of art are well-known in the pharmaceutical and medicinal arts.
7 The term "stability" refers to the extent to which a product retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture. There are five general types of stability defined by the United States Pharmacopoeia: chemical, physical, microbiological, therapeutic and toxicological.
The present invention discloses a pharmaceutical formulation comprising a combination of telmisartan and HCTZ in a single layer, preferably with magnesium oxide, that does not degrade or contribute to degradation of HCTZ, and a manufacturing process in order to get suitable stability properties without the need of expensive packing. For example, the active ingredients are present in a monolithic tablet or a single layer tablet.
In a preferred embodiment of the invention, there is provided bilayer pharmaceutical formulation comprising two active ingredients, wherein the first active ingredient is telmisartan or a pharmaceutically acceptable salt thereof, which is practically insoluble in water (pH 3- 9), though soluble in strong base. Preferably, according to the present invention the second active ingredient is HCTZ, which is slightly soluble in water, though soluble in sodium hydroxide solution. In the bilayer tablet, the first layer is a placebo layer and the second layer comprises telmisartan, or a pharmaceutically acceptable salt thereof, and the diuretic (e.g., HCTZ).
The formulation of the present invention further comprise pharmaceutically acceptable excipients. Such excipients are added to the formulations for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, such as for example diluents, binders, lubricants, disintegrants, glidants, and acidifying agents.
Some of the preferred pharmaceutically acceptable excipients of the formulations of the present invention include: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90 (Prosolv ), colloidal silicon dioxide (Aerosil 0), dibasic calcium phosphate hydrous, croscarmellose sodium, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose and iron oxides.
The present invention discloses a pharmaceutical formulation comprising a combination of telmisartan and HCTZ in a single layer, preferably with magnesium oxide, that does not degrade or contribute to degradation of HCTZ, and a manufacturing process in order to get suitable stability properties without the need of expensive packing. For example, the active ingredients are present in a monolithic tablet or a single layer tablet.
In a preferred embodiment of the invention, there is provided bilayer pharmaceutical formulation comprising two active ingredients, wherein the first active ingredient is telmisartan or a pharmaceutically acceptable salt thereof, which is practically insoluble in water (pH 3- 9), though soluble in strong base. Preferably, according to the present invention the second active ingredient is HCTZ, which is slightly soluble in water, though soluble in sodium hydroxide solution. In the bilayer tablet, the first layer is a placebo layer and the second layer comprises telmisartan, or a pharmaceutically acceptable salt thereof, and the diuretic (e.g., HCTZ).
The formulation of the present invention further comprise pharmaceutically acceptable excipients. Such excipients are added to the formulations for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, such as for example diluents, binders, lubricants, disintegrants, glidants, and acidifying agents.
Some of the preferred pharmaceutically acceptable excipients of the formulations of the present invention include: povidone, sodium hydroxide, isopropyl alcohol, silicified MCC90 (Prosolv ), colloidal silicon dioxide (Aerosil 0), dibasic calcium phosphate hydrous, croscarmellose sodium, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose and iron oxides.
8 Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing.
Suitable binders include, for example, the following: povidone; copovidone;
alginic acid;
sodium alginate; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methylcellulose and ethyl cellulose; gelatin starch or starch derivatives; and mixtures thereof.
Suitable lubricants include, for example, the following- magnesium-, aluminum or calcium-stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate hydrogenated vegetable oil, polyethylene glycol, and mixtures thereof.
Suitable disintegrants include, for example, the following: croscarmellose sodium, sodium starch glycolate, maize starch, CMC-Ca, CMC-Na, microc ryystalline cellulose, cross-linked PVP, alginic acid, sodium alginate, pregelatinized starch and low-substituted hydroxy propyl cellulose, Suitable anti-adherents include, for example, one or more compounds that are capable of preventing stickiness to surfaces of the punches. Examples of anti-adherents include silicon-containing compounds such as colloidal silicon dioxide, magnesium trisilicate and talc.
The stable pharmaceutical formulations of the present invention can be used to treat or prevent hypertension. For example, the pharmaceutical formulations of the present invention containing the two active ingredients in a single layer, in an immediate release form, can be used to treat or prevent hypertension.
Illustrated Embodiments of the Formulations of the Present Invention According to an embodiment of the present invention, the stable pharmaceutical formulations comprise telmisartan, or a pharmaceutically acceptable salt, and a diuretic (preferably HCTZ), dispersed in a matrix. The matrix comprises:
Suitable binders include, for example, the following: povidone; copovidone;
alginic acid;
sodium alginate; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methylcellulose and ethyl cellulose; gelatin starch or starch derivatives; and mixtures thereof.
Suitable lubricants include, for example, the following- magnesium-, aluminum or calcium-stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, glyceryl mono fatty acid, glyceryl monostearate hydrogenated vegetable oil, polyethylene glycol, and mixtures thereof.
Suitable disintegrants include, for example, the following: croscarmellose sodium, sodium starch glycolate, maize starch, CMC-Ca, CMC-Na, microc ryystalline cellulose, cross-linked PVP, alginic acid, sodium alginate, pregelatinized starch and low-substituted hydroxy propyl cellulose, Suitable anti-adherents include, for example, one or more compounds that are capable of preventing stickiness to surfaces of the punches. Examples of anti-adherents include silicon-containing compounds such as colloidal silicon dioxide, magnesium trisilicate and talc.
The stable pharmaceutical formulations of the present invention can be used to treat or prevent hypertension. For example, the pharmaceutical formulations of the present invention containing the two active ingredients in a single layer, in an immediate release form, can be used to treat or prevent hypertension.
Illustrated Embodiments of the Formulations of the Present Invention According to an embodiment of the present invention, the stable pharmaceutical formulations comprise telmisartan, or a pharmaceutically acceptable salt, and a diuretic (preferably HCTZ), dispersed in a matrix. The matrix comprises:
9 o at least one disintegrant in an amount ranging from about 0.5% to about 20%
by weight;
o a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to tehuisartan of from about 1:1 to about 10:1;
o a water-insoluble diluent in an amount ranging from about 15% to about 75%
by weight; and o at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from about 0% to about 25% by weight.
The disintegrant in the formulations of the present invention include, for example, the following: crospovidone, croscarmellose sodium, sodium starch glycolate, starch, modified starch, maize starch, microcrystalline cellulose, cross-linked polyvinylpolypyrrolidone (PVP), alginic acid, sodium alginate, pregelatinized starch, carboxymethyl cellulose (CMC), CMC-calcium, CMC-sodium, low-substituted hydroxyl propyl cellulose, and combinations thereof. Preferably, the disintegrant is croscarmellose sodium, The dissolution enhancing agent in the formulations of the present invention include, for example, the following: NaHCO3s KHCO3, NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO, and MgCO3. Preferably, the dissolution enhancing agent is MgO.
The water insoluble diluent in the formulations of the present inventions include, for example, the following; microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin(V), kaolin, starch, starch derivatives, and co-processed excipients.
The co-processed excipient is preferably Ludipress( (mixture of lactose and 3.2%
Povidone K30), Cellactose (mixture of lactose and cellulose), and Silicified MCC
Prosolv (mixture of microcrystalline cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified microcrystalline cellulose Prosoly().
Preferably, the formulation further comprises a solubilizing agent selected from the group consisting of alkali metal hydroxide such as NaOH and KOH. More preferably, the solubilizing agent is NaOH_ Preferably, the formulation according to the present invention further comprises a surfactant or emulsifier present in an amount ranging from about 0.5% to about
by weight;
o a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to tehuisartan of from about 1:1 to about 10:1;
o a water-insoluble diluent in an amount ranging from about 15% to about 75%
by weight; and o at least one other pharmaceutically acceptable excipient /or adjuvant in an amount ranging from about 0% to about 25% by weight.
The disintegrant in the formulations of the present invention include, for example, the following: crospovidone, croscarmellose sodium, sodium starch glycolate, starch, modified starch, maize starch, microcrystalline cellulose, cross-linked polyvinylpolypyrrolidone (PVP), alginic acid, sodium alginate, pregelatinized starch, carboxymethyl cellulose (CMC), CMC-calcium, CMC-sodium, low-substituted hydroxyl propyl cellulose, and combinations thereof. Preferably, the disintegrant is croscarmellose sodium, The dissolution enhancing agent in the formulations of the present invention include, for example, the following: NaHCO3s KHCO3, NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO, and MgCO3. Preferably, the dissolution enhancing agent is MgO.
The water insoluble diluent in the formulations of the present inventions include, for example, the following; microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin(V), kaolin, starch, starch derivatives, and co-processed excipients.
The co-processed excipient is preferably Ludipress( (mixture of lactose and 3.2%
Povidone K30), Cellactose (mixture of lactose and cellulose), and Silicified MCC
Prosolv (mixture of microcrystalline cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified microcrystalline cellulose Prosoly().
Preferably, the formulation further comprises a solubilizing agent selected from the group consisting of alkali metal hydroxide such as NaOH and KOH. More preferably, the solubilizing agent is NaOH_ Preferably, the formulation according to the present invention further comprises a surfactant or emulsifier present in an amount ranging from about 0.5% to about
10% by weight.
Preferably, the water insoluble diluent is selected from the group consisting of.
microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin), kaolin, starch, starch derivatives, and co-processed excipients.
Also preferably, the co-processed excipient is selected from the group consisting of:
Ludipress( (mixture of lactose and 3.2% Povidone K30), Cellactose( (mixture of lactose and cellulose), and Silicified MCC ProsolvO (mixture of microcrystalline cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified microcrystalline cellulose Prosoly .
In the preferred embodiments of the present invention, the in vitro dissolution rate of the formulation is at least 80% w/w of telmisartan dissolved within 30 minutes and at least 80% of the diuretic dissolved within 30 minutes as measured by using USP type II
apparatus at 75 rpm in 900m1 of pH 7.5 phosphate buffer.
More preferably, the in vitro dissolution rate of the formulations of the present invention is at least about 60% of telmisartan is dissolved within 5 minutes as measured by USP
Paddle Method at 75 rpm at pI4 7.5 dissolution phosphate buffer at 37 C; at least about 80% of telmisartan is dissolved within 10 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C; and at least about 90%
of telmisartan is dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C.
Furthermore, the in vitro dissolution rate of the HCTZ in the formulations of the present invention is at least about 55% dissolved within 5 minutes as measured by USP
Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 370C; at least about 75%
Preferably, the water insoluble diluent is selected from the group consisting of.
microcrystalline cellulose, di- or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate (Neusilin), kaolin, starch, starch derivatives, and co-processed excipients.
Also preferably, the co-processed excipient is selected from the group consisting of:
Ludipress( (mixture of lactose and 3.2% Povidone K30), Cellactose( (mixture of lactose and cellulose), and Silicified MCC ProsolvO (mixture of microcrystalline cellulose and silicon dioxide). More preferably, the co-processed excipient is silicified microcrystalline cellulose Prosoly .
In the preferred embodiments of the present invention, the in vitro dissolution rate of the formulation is at least 80% w/w of telmisartan dissolved within 30 minutes and at least 80% of the diuretic dissolved within 30 minutes as measured by using USP type II
apparatus at 75 rpm in 900m1 of pH 7.5 phosphate buffer.
More preferably, the in vitro dissolution rate of the formulations of the present invention is at least about 60% of telmisartan is dissolved within 5 minutes as measured by USP
Paddle Method at 75 rpm at pI4 7.5 dissolution phosphate buffer at 37 C; at least about 80% of telmisartan is dissolved within 10 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C; and at least about 90%
of telmisartan is dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C.
Furthermore, the in vitro dissolution rate of the HCTZ in the formulations of the present invention is at least about 55% dissolved within 5 minutes as measured by USP
Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 370C; at least about 75%
11 dissolved within 10 minutes as measured by USP Paddle Method at 75 rpm at pH
7.5 dissolution phosphate buffer at 37 C; at least about 80% dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C; and at least about 85% dissolved within 60 minutes as measured by USP
Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C.
Preferably, the formulations of the present invention comprise less than about 0.5% by weight of 4--amino-6-chloro-1,3 benzenedisulfonamide (DSA) impurity in comparison to the initial HCTZ content when exposed to 40 C /75% RH conditions in Blister as well as HDPE pack. Also preferably, the in vitro dissolution rate remains similar to the initial value for telmisartan and for the diuretic on stabiliy as measured by using USP type II
apparatus at 75 rpm in 900m1 of pH 7, 5 phosphate buffer.
Illustrated Processes for Preparing the Formulations of the Present Invention A wet granulation process, preferably a low shear granulation process, is preferred for preparing the stable pharmaceutical formulations of the present invention.
When the process has for starting material a salt form of an angiotensin II receptor antagonist (i.e.
telmisartan) the process comprises a dry mixing step and direct compression.
For example, the following process can be used to prepare a formulation of the present invention wherein the two active ingredients are in a single layer:
1) preparation of granulation solution;
2) dry mixing;
3) granulation;
4) lubrication; and 5) compression.
Preferably, the step of preparation of a granulation solution (step (1)) further comprises dissolving telmisartan under stirring in purified water with sodium hydroxide.
Preferably, step (1) further comprises dissolving povidone (K-30) in isopropyl alcohol.
7.5 dissolution phosphate buffer at 37 C; at least about 80% dissolved within 30 minutes as measured by USP Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C; and at least about 85% dissolved within 60 minutes as measured by USP
Paddle Method at 75 rpm at pH 7.5 dissolution phosphate buffer at 37 C.
Preferably, the formulations of the present invention comprise less than about 0.5% by weight of 4--amino-6-chloro-1,3 benzenedisulfonamide (DSA) impurity in comparison to the initial HCTZ content when exposed to 40 C /75% RH conditions in Blister as well as HDPE pack. Also preferably, the in vitro dissolution rate remains similar to the initial value for telmisartan and for the diuretic on stabiliy as measured by using USP type II
apparatus at 75 rpm in 900m1 of pH 7, 5 phosphate buffer.
Illustrated Processes for Preparing the Formulations of the Present Invention A wet granulation process, preferably a low shear granulation process, is preferred for preparing the stable pharmaceutical formulations of the present invention.
When the process has for starting material a salt form of an angiotensin II receptor antagonist (i.e.
telmisartan) the process comprises a dry mixing step and direct compression.
For example, the following process can be used to prepare a formulation of the present invention wherein the two active ingredients are in a single layer:
1) preparation of granulation solution;
2) dry mixing;
3) granulation;
4) lubrication; and 5) compression.
Preferably, the step of preparation of a granulation solution (step (1)) further comprises dissolving telmisartan under stirring in purified water with sodium hydroxide.
Preferably, step (1) further comprises dissolving povidone (K-30) in isopropyl alcohol.
12 Furthermore, the process preferably further comprises mixing the content of step (1) with the content of step (2) for 15 minutes.
Preferably, the step of dry mixing (step (2)) further comprises dry mixing silicified MCC
90 (Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide in a ribbon blender for 5 min.
Preferably, step (2) further comprises screening the content obtained from step (2) through a comill equipped with 0.045R screen (1190 m) and then mix for 5 minutes to yield a telmisartan blend.
Preferably, the step of granulation (step (3)) further comprises adding to the blend obtained from step (2) (the dry mixing step) the granulation solution.
Preferably, step (3) further comprises drying the wet granules in a fluid bed drier at an inlet temperature of 50 C 5 C until a loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes.
Preferably, the step (3) further comprises screening the dried granules through a comill equipped with 0.039R screen (1000 m).
Preferably, the step of lubrication (step (4)) comprises mixing magnesium oxide heavy and the colloidal silicon dioxide (Aerosil(g) and screening through #30 sieve (600 m).
Preferably, step (4) further comprises screening HCTZ, microcrystalline cellulose PHI 02 (Avicel ) and croscarmellose sodium through #40 sieve (400 m) and adding to the granules of telmisartan and blending to yield a HCTZ blend.
Preferably, step (4) further comprises dispersing a portion of the HCTZ blend with magnesium stearate and screening the obtained content through #40 sieve (400 m) to yield a lubricated HCTZ blend.
Preferably, step (4) further comprises adding the lubricated HCTZ blend to the telmisartan granules and blending for 3 minutes to yield the actives blend.
Preferably, the process comprises a step of blending placebo involving screening microcrystalline cellulose, yellow or red iron oxide, colloidal silicon dioxide and croscarmellose sodium, through #40 sieve (400 m) and blending the content for minutes to obtain an excipient placebo blend.
Preferably, the step of dry mixing (step (2)) further comprises dry mixing silicified MCC
90 (Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide in a ribbon blender for 5 min.
Preferably, step (2) further comprises screening the content obtained from step (2) through a comill equipped with 0.045R screen (1190 m) and then mix for 5 minutes to yield a telmisartan blend.
Preferably, the step of granulation (step (3)) further comprises adding to the blend obtained from step (2) (the dry mixing step) the granulation solution.
Preferably, step (3) further comprises drying the wet granules in a fluid bed drier at an inlet temperature of 50 C 5 C until a loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes.
Preferably, the step (3) further comprises screening the dried granules through a comill equipped with 0.039R screen (1000 m).
Preferably, the step of lubrication (step (4)) comprises mixing magnesium oxide heavy and the colloidal silicon dioxide (Aerosil(g) and screening through #30 sieve (600 m).
Preferably, step (4) further comprises screening HCTZ, microcrystalline cellulose PHI 02 (Avicel ) and croscarmellose sodium through #40 sieve (400 m) and adding to the granules of telmisartan and blending to yield a HCTZ blend.
Preferably, step (4) further comprises dispersing a portion of the HCTZ blend with magnesium stearate and screening the obtained content through #40 sieve (400 m) to yield a lubricated HCTZ blend.
Preferably, step (4) further comprises adding the lubricated HCTZ blend to the telmisartan granules and blending for 3 minutes to yield the actives blend.
Preferably, the process comprises a step of blending placebo involving screening microcrystalline cellulose, yellow or red iron oxide, colloidal silicon dioxide and croscarmellose sodium, through #40 sieve (400 m) and blending the content for minutes to obtain an excipient placebo blend.
13 Preferably, the step of compression (step (5)) further comprises compressing the excipient blend and actives blend, to form a bilayer pharmaceutical formulation.
The present invention provides a process for the preparation of a pharmaceutical formulation containing two active ingredients in a monolithic tablet comprising the following steps:
1) dissolving telmisartara in purified water with sodium hydroxide;
2) dissolving a binder in isopropyl alcohol;
3) mixing the content of step (1) with the content of step (2);
4) blending pharmaceutical acceptable excipients;
5) granulating the blend of step (4) with the content of step (3);
6) drying the wet granules obtained from step (5);
7) screening the dried granules obtained from step (6);
8) mixing the granules of step (7) with additional pharmaceutically acceptable excipients;
9) preparing a mixture of the diuretic (HCTZ) and pharmaceutically acceptable excipients;
10) adding the content of step (9) to the content of step (8); and 11) compressing the blend of step (10).
The following process can be used to prepare a formulation of the present invention wherein the two active ingredients are in a single layer of a bi-layer tablet:
1) dissolving telmisartan in purified water with sodium hydroxide;
2) dissolving, povidone (K-30) in isopropyl alcohol;
3) mixing the solution of step (1) with the solution of step (2);
4) dry mixing the following pharmaceutical excipients: silicified MCC 90 (Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide;
The present invention provides a process for the preparation of a pharmaceutical formulation containing two active ingredients in a monolithic tablet comprising the following steps:
1) dissolving telmisartara in purified water with sodium hydroxide;
2) dissolving a binder in isopropyl alcohol;
3) mixing the content of step (1) with the content of step (2);
4) blending pharmaceutical acceptable excipients;
5) granulating the blend of step (4) with the content of step (3);
6) drying the wet granules obtained from step (5);
7) screening the dried granules obtained from step (6);
8) mixing the granules of step (7) with additional pharmaceutically acceptable excipients;
9) preparing a mixture of the diuretic (HCTZ) and pharmaceutically acceptable excipients;
10) adding the content of step (9) to the content of step (8); and 11) compressing the blend of step (10).
The following process can be used to prepare a formulation of the present invention wherein the two active ingredients are in a single layer of a bi-layer tablet:
1) dissolving telmisartan in purified water with sodium hydroxide;
2) dissolving, povidone (K-30) in isopropyl alcohol;
3) mixing the solution of step (1) with the solution of step (2);
4) dry mixing the following pharmaceutical excipients: silicified MCC 90 (Prosolv ), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide;
14 5) screening the content obtained from step (4) and then blending;
6) adding to the blend of step (5) to the granulation solution of step (3);
7) drying the wet granules in a fluid bed drier;
8) screening the dried granules obtained from step (7);
9) mixing the granules of step (8) with magnesium oxide heavy and the colloidal silicon dioxide (Aerosil ) and screening the obtained mixture;
10) screening HCTZ, microcrystalline cellulose PH102 (Avicel(g) and croscarmellose sodium, and blending with the granules of step (9);
11) dispersing a portion of blend with magnesium stearate and screening;
12) blending the content of step (11) together with the granules of step (9);
13) separately screening the xnicrocrystalline cellulose, yellow iron oxide, colloidal silicon dioxide and croscarmellose sodium, through 440 sieve (400pm) and blending the content;
14) screening magnesium stearate and blending with the blend of step (12);
6) adding to the blend of step (5) to the granulation solution of step (3);
7) drying the wet granules in a fluid bed drier;
8) screening the dried granules obtained from step (7);
9) mixing the granules of step (8) with magnesium oxide heavy and the colloidal silicon dioxide (Aerosil ) and screening the obtained mixture;
10) screening HCTZ, microcrystalline cellulose PH102 (Avicel(g) and croscarmellose sodium, and blending with the granules of step (9);
11) dispersing a portion of blend with magnesium stearate and screening;
12) blending the content of step (11) together with the granules of step (9);
13) separately screening the xnicrocrystalline cellulose, yellow iron oxide, colloidal silicon dioxide and croscarmellose sodium, through 440 sieve (400pm) and blending the content;
14) screening magnesium stearate and blending with the blend of step (12);
15) compressing the lubricated blend of step (14) and the blend of step (12), using a bilayer compression machine.
Preferably, the granulation solution is prepared by dissolving the telimisartan gradually by stirring in purified water with sodium hydroxide. The isopropyl alcohol and povidone (K-30) is dissolved in a separate vessel. Then, the content of solution of step (1) is mixed with the content of the solution of step (2).
Preferably, the obtained content is dry mixed and then screened with the following pharmaceutical excipients: silicified MCC 90 (Prosoly 0), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide.
Preferably, the content of step (3) is added to the blend of step (5) and the granulation is carried out in a ribbon blender.
Preferably, the wet granules are dried in a fluid bed drier at inlet temperature of 50 C*5 C until a loss on drying value of 3.8%f 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes (step (7)).
Preferably, the dried granules obtained from step (7) are screened through a comill equipped with 0.039R screen (1000 gm) (step (8)).
Preferably, the granules of step (8) are mixed with magnesium oxide heavy and colloidal silicon dioxide (Aeresil ) and screened through #30 sieve (600 m) (step (9)).
Preferably, HCTZ, microcrystalline cellulose PHI 02 (Avicel ) and croscarmellose sodium are screened through #40 sieve (400 m), added to the granules of step (9) and blended for 20 minutes (step (10)).
Preferably, a portion of the blend obtained from step (10) is dispersed with magnesium stearate, and then screened manually through #40 sieve (400 m) and blended for minutes (step (11)).
Preferably, mierocrystalline cellulose PHI 02, yellow iron oxide, colloidal silicon dioxide and croscarmellose sodium are screened through #40 sieve (400 m.) and blended for 15 minutes (step (13)).
Preferably, magnesium stearate is passed through a 40 (400 m) mesh screen, is introduced into the bin blender and blended for 3 minutes with mixture obtained from step (12), prior to compression (step (14)).
Preferably, the lubricated blend is compressed using capsule shaped tooling at average weight of 700 mg on a stokes bilayer compression machine (step (15)).
While several embodiments of the invention have been described it will be understood that the present invention is capable of further modifications and this application is intended to cover any variations uses or adaptations of the invention following in general the principles of the invention and including such departures from the present disclosure as to come within knowledge customary practices in the art to which the invention pertains, as may be applied to the essential features herein before set forth and falling within the scope of the invention.
Preferably, the granulation solution is prepared by dissolving the telimisartan gradually by stirring in purified water with sodium hydroxide. The isopropyl alcohol and povidone (K-30) is dissolved in a separate vessel. Then, the content of solution of step (1) is mixed with the content of the solution of step (2).
Preferably, the obtained content is dry mixed and then screened with the following pharmaceutical excipients: silicified MCC 90 (Prosoly 0), dibasic calcium phosphate hydrous, croscarmellose sodium and colloidal silicon dioxide.
Preferably, the content of step (3) is added to the blend of step (5) and the granulation is carried out in a ribbon blender.
Preferably, the wet granules are dried in a fluid bed drier at inlet temperature of 50 C*5 C until a loss on drying value of 3.8%f 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes (step (7)).
Preferably, the dried granules obtained from step (7) are screened through a comill equipped with 0.039R screen (1000 gm) (step (8)).
Preferably, the granules of step (8) are mixed with magnesium oxide heavy and colloidal silicon dioxide (Aeresil ) and screened through #30 sieve (600 m) (step (9)).
Preferably, HCTZ, microcrystalline cellulose PHI 02 (Avicel ) and croscarmellose sodium are screened through #40 sieve (400 m), added to the granules of step (9) and blended for 20 minutes (step (10)).
Preferably, a portion of the blend obtained from step (10) is dispersed with magnesium stearate, and then screened manually through #40 sieve (400 m) and blended for minutes (step (11)).
Preferably, mierocrystalline cellulose PHI 02, yellow iron oxide, colloidal silicon dioxide and croscarmellose sodium are screened through #40 sieve (400 m.) and blended for 15 minutes (step (13)).
Preferably, magnesium stearate is passed through a 40 (400 m) mesh screen, is introduced into the bin blender and blended for 3 minutes with mixture obtained from step (12), prior to compression (step (14)).
Preferably, the lubricated blend is compressed using capsule shaped tooling at average weight of 700 mg on a stokes bilayer compression machine (step (15)).
While several embodiments of the invention have been described it will be understood that the present invention is capable of further modifications and this application is intended to cover any variations uses or adaptations of the invention following in general the principles of the invention and including such departures from the present disclosure as to come within knowledge customary practices in the art to which the invention pertains, as may be applied to the essential features herein before set forth and falling within the scope of the invention.
16 Examples The following examples illustrate the preferred embodiment and various aspects of the present invention.
Example 1 IMMEDIATE RELEASE DOSAGE FORM OF TELMISARTAN / HCTZ ACCORDING
TO A PREFERRED EMBODIMENT OF THE PRESENT INVENTION
1. Pre aration Of Granulating Solution:
1) In a vessel of purified water was added sodium hydroxide and dissolved under stirring. The required quantity of telmisartan was added gradually and dissolved under stirring.
2) In another vessel to isopropyl alcohol was added povidone (K-30) and dissolved under stirring.
3) The granulation solution is prepared by adding to the content of telmisartan solution (1) the Povidone K-30 solution (2) and mixing for 15 minutes.
Dry Mixing 4) Silicified MCC 90 (Prosolv ), dibasic calcium phosphate hydrous, Croscarmellose sodium and Colloidal Silicon Dioxide (Aerosil ) was introduced into a ribbon blender and blended for 5 minutes. The blend was screened through a comill screen 0,045R (1190 gm). This blend was reintroduced into the ribbon blender and blended for 5 minutes.
Granulation 5) The blend of step 4 was granulated with solution of step 3 in a ribbon blender.
6) The wet granules were dried in a fluid bed drier at an inlet temperature of 50 C 5 C till a Loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes.
7) The dried granules were screened through a co mill screen 0.039R screen (1000 m) for further processing.
Example 1 IMMEDIATE RELEASE DOSAGE FORM OF TELMISARTAN / HCTZ ACCORDING
TO A PREFERRED EMBODIMENT OF THE PRESENT INVENTION
1. Pre aration Of Granulating Solution:
1) In a vessel of purified water was added sodium hydroxide and dissolved under stirring. The required quantity of telmisartan was added gradually and dissolved under stirring.
2) In another vessel to isopropyl alcohol was added povidone (K-30) and dissolved under stirring.
3) The granulation solution is prepared by adding to the content of telmisartan solution (1) the Povidone K-30 solution (2) and mixing for 15 minutes.
Dry Mixing 4) Silicified MCC 90 (Prosolv ), dibasic calcium phosphate hydrous, Croscarmellose sodium and Colloidal Silicon Dioxide (Aerosil ) was introduced into a ribbon blender and blended for 5 minutes. The blend was screened through a comill screen 0,045R (1190 gm). This blend was reintroduced into the ribbon blender and blended for 5 minutes.
Granulation 5) The blend of step 4 was granulated with solution of step 3 in a ribbon blender.
6) The wet granules were dried in a fluid bed drier at an inlet temperature of 50 C 5 C till a Loss on drying value of 3.8% 0.4% is obtained on a moisture analyzer set at 105 C for 10 minutes.
7) The dried granules were screened through a co mill screen 0.039R screen (1000 m) for further processing.
17 Lubrication 8) The dried screened granules of step 7 was added to a bin blender.
9) Magnesium oxide heavy and Colloidal Silicon Dioxide ( Aerosil ) were dispersed and screened through #30 sieve (600 m).This sieved dispersion was added to the bin blender of step 8.
10) HCTZ, Microcrystalline Cellulose PH102 (Avicel )and croscarmellose sodium was screened through #40 sieve (400 m).This sieved dispersion was introduced into the bin blender of step 8 and blended for 20 minutes.
11) Magnesium stearate was dispersed with a portion of the blend of step 10 in a polyethylene bag and screened manually through #40 sieve (400 m).This sieved dispersion was introduced into the bin blender of step 8 and blended for 3 minutes.
H. Manufacturing of Yellow Placebo Blend 12) Microcrystallfr a Cellulose PH 102 (Avicel(D), Yellow oxide iron, Colloidal Silicon Dioxide (Aerosil ) and croscarmellose sodium was screened through #40 sieve (400 m) and introduced into the bin blender and blended for 15 minutes.
13) Magnesium steaxate was screened through #40 sieve (400gm) and introduced into the bin blender of step 12 and blended for 3 minutes.
Compression 14) The lubricated blend of step 11 and step 13 was compressed using capsule shaped tooling at an average weight of 700 mg on a stokes bilayer compression machine.
9) Magnesium oxide heavy and Colloidal Silicon Dioxide ( Aerosil ) were dispersed and screened through #30 sieve (600 m).This sieved dispersion was added to the bin blender of step 8.
10) HCTZ, Microcrystalline Cellulose PH102 (Avicel )and croscarmellose sodium was screened through #40 sieve (400 m).This sieved dispersion was introduced into the bin blender of step 8 and blended for 20 minutes.
11) Magnesium stearate was dispersed with a portion of the blend of step 10 in a polyethylene bag and screened manually through #40 sieve (400 m).This sieved dispersion was introduced into the bin blender of step 8 and blended for 3 minutes.
H. Manufacturing of Yellow Placebo Blend 12) Microcrystallfr a Cellulose PH 102 (Avicel(D), Yellow oxide iron, Colloidal Silicon Dioxide (Aerosil ) and croscarmellose sodium was screened through #40 sieve (400 m) and introduced into the bin blender and blended for 15 minutes.
13) Magnesium steaxate was screened through #40 sieve (400gm) and introduced into the bin blender of step 12 and blended for 3 minutes.
Compression 14) The lubricated blend of step 11 and step 13 was compressed using capsule shaped tooling at an average weight of 700 mg on a stokes bilayer compression machine.
18 Table I - Formulation of Example 1 No Ingredient mg/Tablet (Telmisartan and HCTZ granules) 1 Telmisartan 80.0 2 Sodium Hydroxide 6.624 3 Povidione (k30) 4.80 4 Purified water 110.0*
Isopropyl Alcohol 12.7**
6 Silicified MCC 90 (Prosolv ) 168.0 7 Colloidal Silicon Dioxide ( Aerosil ) 4.8 Dibasic Calcium phosphate Hydrous 72.0 9 Croscarmellose Sodium 19.2 10 Magnesium Oxide Heavy 24.0 11 Colloidal Silicon Dioxide (Aerosil ) 2.4 12 HCTZ 25.0 13 Microcrystalline Cellulose PH 102 (Avicel(D) 70.23 14 Croscarmellose Sodium 19.2 15 Magnesium Stearate 3.75 Total 500.0 Yellow Placebo granules 16 Microcrystalline Cellulose PH 102 (Avicel ) 194.65 17 Yellow oxide iron 0.33 18 Colloidal Silicon Dioxide (Aerosil ) 0.5
Isopropyl Alcohol 12.7**
6 Silicified MCC 90 (Prosolv ) 168.0 7 Colloidal Silicon Dioxide ( Aerosil ) 4.8 Dibasic Calcium phosphate Hydrous 72.0 9 Croscarmellose Sodium 19.2 10 Magnesium Oxide Heavy 24.0 11 Colloidal Silicon Dioxide (Aerosil ) 2.4 12 HCTZ 25.0 13 Microcrystalline Cellulose PH 102 (Avicel(D) 70.23 14 Croscarmellose Sodium 19.2 15 Magnesium Stearate 3.75 Total 500.0 Yellow Placebo granules 16 Microcrystalline Cellulose PH 102 (Avicel ) 194.65 17 Yellow oxide iron 0.33 18 Colloidal Silicon Dioxide (Aerosil ) 0.5
19 Croscarmellose sodium 4.0
20 Magnesium Stearate 0.5 Total 200.0 Total of both layers 700.0 & **: Evaporates during processing. Does not appear in the final formulation, Dissolution The tablets obtained from Example 1 were subsequently tested for in vitro dissolution rate, measured by Apparatus II (US? Paddle Method), using the following parameters:
Speed: 75 rpm Media: 900 ml, pH 7.5 Phosphate buffer Temperature: 37 C.
The dissolution results are set out in Table 2 and 3 below, Tables II and III compare the dissolution of Micardis Plus 80/25 mg (telnisartan/HCTZ - telmisartan and HCTZ are dispersed in two separate layers) against the dissolution of Example 1 80/25 mg (telmisartan/HCTZ - telmisartan and hydrochlorothiazide are dispersed in a single layer) Table H
Media: 900 ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 Micardis Plus 80/25 mg Time Lot no :810094 Example 1 minutes % Telmisartan Dissolved % Telmisartan Dissolved Table III
Media: 900ml, 7.5 Phosphate buffer Apparatus: USP Type II
Micardis Plus 80/25 mg Time Lot No :810094 Example 1 % HCTZ % HCTZ
min Dissolved Dissolved TIT' 98 95 Staff The stability of the illustrated embodiment of the formulation of present invention 5 (Examplel) was evaluated in two types of packaging at 40 C /75% relative humidity conditions. The following parameters were evaluated, 1) Degradation of telmisartan and HCTZ in the formulation as per the present invention.
2) Dissolution of telmisartan and HCTZ in the formulation as per the present 10 invention.
3) Moisture content of the formulation as per the present invention, The results of degradation, dissolution and moisture content are set out in Tables N, V, VI, VU, VIII and DC below
Speed: 75 rpm Media: 900 ml, pH 7.5 Phosphate buffer Temperature: 37 C.
The dissolution results are set out in Table 2 and 3 below, Tables II and III compare the dissolution of Micardis Plus 80/25 mg (telnisartan/HCTZ - telmisartan and HCTZ are dispersed in two separate layers) against the dissolution of Example 1 80/25 mg (telmisartan/HCTZ - telmisartan and hydrochlorothiazide are dispersed in a single layer) Table H
Media: 900 ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 Micardis Plus 80/25 mg Time Lot no :810094 Example 1 minutes % Telmisartan Dissolved % Telmisartan Dissolved Table III
Media: 900ml, 7.5 Phosphate buffer Apparatus: USP Type II
Micardis Plus 80/25 mg Time Lot No :810094 Example 1 % HCTZ % HCTZ
min Dissolved Dissolved TIT' 98 95 Staff The stability of the illustrated embodiment of the formulation of present invention 5 (Examplel) was evaluated in two types of packaging at 40 C /75% relative humidity conditions. The following parameters were evaluated, 1) Degradation of telmisartan and HCTZ in the formulation as per the present invention.
2) Dissolution of telmisartan and HCTZ in the formulation as per the present 10 invention.
3) Moisture content of the formulation as per the present invention, The results of degradation, dissolution and moisture content are set out in Tables N, V, VI, VU, VIII and DC below
21 Table IV: Degradation of formulation of Example I in HDPE bottles at 40 C/75%
RH
Pack I : HDPE pack with desiccant (Trisorb ) Lot No: Formulation as per Example 1 Parameter Initial (T=0) 1 Month 2 Months Moisture content (9b) 3.71% 3.58% 3.34%
Degradation of Telmisartan Known Impurities Comp 3 - -Comp 4 -Comp 5 - -Comp 6 0-07% 0.07% 0.06%
Comp 7 -Unknown Impurities RRT % RRT % RRT 0/0 0.87 0.03 0.87 0.03 1.40 0.03 1.41 0.03 1.40 0.03 1.41 0.10 1.42 0.07 1.41 0.09 Degradation of Hydrochiorothiazide Known Impurities Comp 1* 0.07% 0.07% 0.06%
Comp 2 0.04% 0.04% 0.04%
Unknown Impurities RRT % RRT % RRT %
2.60 0.04 2.58 0.04 2.58 0.05 ' DSA Impurity
RH
Pack I : HDPE pack with desiccant (Trisorb ) Lot No: Formulation as per Example 1 Parameter Initial (T=0) 1 Month 2 Months Moisture content (9b) 3.71% 3.58% 3.34%
Degradation of Telmisartan Known Impurities Comp 3 - -Comp 4 -Comp 5 - -Comp 6 0-07% 0.07% 0.06%
Comp 7 -Unknown Impurities RRT % RRT % RRT 0/0 0.87 0.03 0.87 0.03 1.40 0.03 1.41 0.03 1.40 0.03 1.41 0.10 1.42 0.07 1.41 0.09 Degradation of Hydrochiorothiazide Known Impurities Comp 1* 0.07% 0.07% 0.06%
Comp 2 0.04% 0.04% 0.04%
Unknown Impurities RRT % RRT % RRT %
2.60 0.04 2.58 0.04 2.58 0.05 ' DSA Impurity
22 Table V: Dissolution of Telndsartan from formulation as per Example 1 in HDPE
pack at 40 Cf 75% RH
Media: 900 `-ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 TO 1 Month 2 Months Time % Telmisartan in minutes Dissolved % Telmisartan Dissolved % Telmisartan Dissolved Table VI: Dissolution of Hydrochioro i 'de from formulation as per example 1 in 5 HDPE pack at 40 C/75% RH
Media: 900m1, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 TO 1 Month 2 Months % Hydrochlorothiazide % Hydrochlorothiazide % Hydrochlorothiazide Time Dissolved Dissolved Dissolved
pack at 40 Cf 75% RH
Media: 900 `-ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 TO 1 Month 2 Months Time % Telmisartan in minutes Dissolved % Telmisartan Dissolved % Telmisartan Dissolved Table VI: Dissolution of Hydrochioro i 'de from formulation as per example 1 in 5 HDPE pack at 40 C/75% RH
Media: 900m1, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 TO 1 Month 2 Months % Hydrochlorothiazide % Hydrochlorothiazide % Hydrochlorothiazide Time Dissolved Dissolved Dissolved
23 Table VII: Comparative Degradation of Example I and Micardis plus in ALU/ALU
Blisters at 40 C/75% RH.
Park II ! ALU/ALU Blister pack Example 'l Micardis Plus 80/25 mg Lot No 810094 Parameter Initial (T=O) 1 Month 2 Months ]Initial (T=O) 1Month Moisture 3.71% 3.8% 3.5% 1.74% 1.71%
content (%) Degradation of Telmisartan Known Impurities Cam 3 - - -Camp 4 - - -Camp 5 - - -Camp 6 0.07% 0.07% 0.06% -Camp 7 - - -Unknown RRT % RAT % RRT % RRT % RRT 0/6 Impurities 0.87 0.03 0.87 0.03 0.87 0.03 1.46 0.03 1.46 0.03 1.41 0.03 1.41 0.09 1.40 0.04 1.47 0.04 1.47 0.03 1.42 0.07 1.41 0.10 Degradation of Hydrochlorothiazide Known Impurities Comp 1 0.07% 0.06% 0.07% 0.10% 0.12%
Comp 2 0.04% 0.04% 0.04% 0.03% 0.03%
Unknown RRT % RRT % RRT % RRT % RRT %
Impurities 2.60 0.04 2.58 0.04 2.60 j0.05 2.58 0.05 2.58 0.05
Blisters at 40 C/75% RH.
Park II ! ALU/ALU Blister pack Example 'l Micardis Plus 80/25 mg Lot No 810094 Parameter Initial (T=O) 1 Month 2 Months ]Initial (T=O) 1Month Moisture 3.71% 3.8% 3.5% 1.74% 1.71%
content (%) Degradation of Telmisartan Known Impurities Cam 3 - - -Camp 4 - - -Camp 5 - - -Camp 6 0.07% 0.07% 0.06% -Camp 7 - - -Unknown RRT % RAT % RRT % RRT % RRT 0/6 Impurities 0.87 0.03 0.87 0.03 0.87 0.03 1.46 0.03 1.46 0.03 1.41 0.03 1.41 0.09 1.40 0.04 1.47 0.04 1.47 0.03 1.42 0.07 1.41 0.10 Degradation of Hydrochlorothiazide Known Impurities Comp 1 0.07% 0.06% 0.07% 0.10% 0.12%
Comp 2 0.04% 0.04% 0.04% 0.03% 0.03%
Unknown RRT % RRT % RRT % RRT % RRT %
Impurities 2.60 0.04 2.58 0.04 2.60 j0.05 2.58 0.05 2.58 0.05
24 Table Vill: Dissolution of Telmiisartan from formulation as per example 1 in ALU/ALU Blister pack at 40"C/75% RYA
Media: 900m1, 7-5 Phosphate buffer Apparatus: USP Type 11 RPM : 75 T=0 I Month 2 Months Time in minutes % Telmisartan Dissolved % Telmisartan Dissolved % Telmisartan Dissolved ::f6O 91 93 95 5 Table IX: Dissolution of Hydrochlorothiazide from formulation as per example 1 in ALU/ALU Blister pack at 40 C/75% RH
Media 900ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 TO 1 Month 2 Months Hydrochlorothiazide % Hydrochlorothiazide % Hydrochlorothiazide Time Dissolved Dissolved Dissolved In light of the data presented in the tables set out above, the following can be concluded:
1) From Tables IV & VII the formulation according to present invention has comparable stability in both blister as well as M PE pack with that of Micardis Plus) (80/25 mg).
2) From Tables V, VI, VIII and IX the dissolution rate of HCTZ and telmisartan from formulations according to the present invention is not affected by the stability.
Media: 900m1, 7-5 Phosphate buffer Apparatus: USP Type 11 RPM : 75 T=0 I Month 2 Months Time in minutes % Telmisartan Dissolved % Telmisartan Dissolved % Telmisartan Dissolved ::f6O 91 93 95 5 Table IX: Dissolution of Hydrochlorothiazide from formulation as per example 1 in ALU/ALU Blister pack at 40 C/75% RH
Media 900ml, 7.5 Phosphate buffer Apparatus: USP Type II
RPM : 75 TO 1 Month 2 Months Hydrochlorothiazide % Hydrochlorothiazide % Hydrochlorothiazide Time Dissolved Dissolved Dissolved In light of the data presented in the tables set out above, the following can be concluded:
1) From Tables IV & VII the formulation according to present invention has comparable stability in both blister as well as M PE pack with that of Micardis Plus) (80/25 mg).
2) From Tables V, VI, VIII and IX the dissolution rate of HCTZ and telmisartan from formulations according to the present invention is not affected by the stability.
Claims (22)
1. A stable pharmaceutical formulation comprising telmisartan, or a pharmaceutically acceptable salt thereof, and a diuretic dispersed in a matrix, said matrix comprising:
- at least one disintegrant in an amount ranging from about 0.5 % to about 20%
by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from about 1:1 to about 10:1;
- a water-insoluble diluent in an amount ranging from about 15% to about 75%
by weight; and - at least one other pharmaceutically acceptable excipient / or adjuvant in an amount ranging from about 0 to about 25% by weight.
- at least one disintegrant in an amount ranging from about 0.5 % to about 20%
by weight;
- a dissolution enhancing agent present in a molar ratio of dissolution enhancing agent to telmisartan of from about 1:1 to about 10:1;
- a water-insoluble diluent in an amount ranging from about 15% to about 75%
by weight; and - at least one other pharmaceutically acceptable excipient / or adjuvant in an amount ranging from about 0 to about 25% by weight.
2. The stable pharmaceutical formulation according to claim 1 wherein the diuretic is hydrochlorothiazide.
3. A stable pharmaceutical formulation according to claim 1 or 2, further comprising a surfactant or emulsifier present in an amount ranging from about 0.5% to about 10% by weight.
4. A stable pharmaceutical formulation according to any one of claims 1 to 3 wherein the in vitro dissolution rate of said formulation is at least about 80 % by weight of telmisartan dissolved within 30 minutes and at least about 80% of the diuretic dissolved within 30 minutes as measured by using USP type II apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.
5. The formulation according to any one of claims 1 to 4, wherein the disintegrant is selected from the group consisting of: crospovidone, croscarmellose sodium, sodium starch glycolate, starch, modified starch, maize starch, microcrystalline cellulose, cross-linked polyvinylpolypyrrolidone (PVP), alginic acid, sodium alginate, pregelatinized starch, carboxymethyl cellulose (CMC), CMC-calcium CMC-sodium, low-substituted hydroxyl propyl cellulose, and combinations thereof.
6. The formulation according to claim 5 wherein the disintegrant is croscarmellose sodium.
7. The formulation according to any one of claims 1 to 6, wherein the dissolution enhancing agent is selected from the group consisting of: NaHCO5, KHCO3, NA2CO3, Na2HPO4, K2HPO4, tromethamine, triethanolamine, MgO, and MgCO3.
8. The formulation according to claim 7, wherein the dissolution enhancing agent is MgO.
9. The formulation according to any one of claims 1 to 8, further comprising a solubilizing agent selected from the group consisting of alkali metal hydroxides such as NaOH and KOH.
10. The formulation according to claim 9, where the solubilizing agent is NaOH.
11. The formulation according to any one of claims 1 to 10, wherein the water insoluble diluent is selected from the group consisting of: microcrystalline cellulose, di-or tri-basic calcium phosphate, crystalline cellulose, powdered cellulose, anhydrous silicic acid, calcium carbonate, calcium sulphate, magnesium silicate, magnesium trisilicate, magnesium aluminium metasilicate, kaolin, starch, starch derivatives, and co-processed excipients.
12. The formulation according to claim 11, wherein the co-processed excipients is selected from the group consisting of: Ludipress® (mixture of lactose and 3.2%
Povidone K30), Cellactose® (mixture of lactose and cellulose), and Silicified microcrystalline cellulose (Prosolv®), and combinations thereof.
Povidone K30), Cellactose® (mixture of lactose and cellulose), and Silicified microcrystalline cellulose (Prosolv®), and combinations thereof.
13. The formulation according to claim 12 wherein the co-processed excipient is silicified microcrystalline cellulose (Prosolv®).
14. The formulation according to any one of claims 1 to 13, wherein the composition further comprises at least one pharmaceutically acceptable excipient selected from the group consisting of: binders, lubricants, flow agents, adsorbants, crystallization retarders, anti-adherents, pH modifiers and coloring agents.
15. The formulation according to any one of claims 1 to 14, further comprising less than 0.5% wt of 4-amino-6-chloro-1,3 benzenedisulfonamide (DSA) impurity in comparison to the initial hydrochlorothiazide content.
16. The formulation according to any one of claims claim 1 to 15, wherein the in vitro dissolution rate for telmisartan and the diuretic remains similar to the initial value for telmisartan and for the diuretic as measured by using USP type II apparatus at 75 rpm in 900ml of pH 7.5 phosphate buffer.
17. A low shear granulation process for preparing a stable pharmaceutical composition as per claim 1.
18. A process for the preparation of a stable pharmaceutical formulation according to claim 1, wherein said process comprises the following steps:
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.
(1) - preparation of granulation solution;
(2) - dry mixing;
(3) - granulation;
(4) - lubrication; and (5) - compression.
19. A process for the preparation of a stable pharmaceutical formulation containing a pharmaceutically acceptable salt form of an angiotensin II receptor antagonist, a diuretic and a dissolution enhancing agent in a matrix, wherein said process comprises a step of dry blending and direct compression.
20. Use of a stable pharmaceutical formulation containing two active ingredients in a single layer, in an immediate release form, according to any one of claims 1 to 16 for the treatment or prevention of hypertension.
21. The formulation according to any one of claims 1 to 16, wherein the formulation is in the form of a monolithic tablet or a single layer tablet.
22. The formulation according to any one of claims 1 to 16, wherein the formulation is in the form of a bilayer tablet dosage form wherein a first layer is a placebo layer and the second layer comprises telmisartan, or a pharmaceutically acceptable salt thereof, and a diuretic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2801020A CA2801020A1 (en) | 2010-05-28 | 2011-05-27 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2706292A CA2706292A1 (en) | 2010-05-28 | 2010-05-28 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
| CA2,706,292 | 2010-05-28 | ||
| PCT/CA2011/000621 WO2011147026A2 (en) | 2010-05-28 | 2011-05-27 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
| CA2801020A CA2801020A1 (en) | 2010-05-28 | 2011-05-27 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2801020A1 true CA2801020A1 (en) | 2011-12-01 |
Family
ID=45004457
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2706292A Abandoned CA2706292A1 (en) | 2010-05-28 | 2010-05-28 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
| CA2801020A Abandoned CA2801020A1 (en) | 2010-05-28 | 2011-05-27 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2706292A Abandoned CA2706292A1 (en) | 2010-05-28 | 2010-05-28 | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide |
Country Status (2)
| Country | Link |
|---|---|
| CA (2) | CA2706292A1 (en) |
| WO (1) | WO2011147026A2 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885789A (en) * | 2012-04-05 | 2013-01-23 | 常州制药厂有限公司 | Preparation method of compound preparation for treating high blood pressure |
| WO2014068507A1 (en) * | 2012-11-02 | 2014-05-08 | Abbott Healthcare Pvt. Ltd. | Solid oral pharmaceutical compositions of telmisartan, essentially free of surfactants |
| US11357742B2 (en) | 2015-12-14 | 2022-06-14 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
| EP3389634B1 (en) | 2015-12-14 | 2021-10-06 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
| WO2017112894A1 (en) | 2015-12-22 | 2017-06-29 | X4 Pharmaceuticals, Inc. | Methods for treating immunodeficiency disease |
| CN108883132A (en) * | 2016-01-22 | 2018-11-23 | X4 制药有限公司 | Method for treating cancer |
| CA3019394A1 (en) | 2016-04-08 | 2017-10-12 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
| EP3808748A1 (en) | 2016-06-21 | 2021-04-21 | X4 Pharmaceuticals, Inc. | Substituted piperidines as cxcr4-inhibitors |
| CN109641838A (en) | 2016-06-21 | 2019-04-16 | X4 制药有限公司 | CXCR4 inhibitor and application thereof |
| WO2017223229A1 (en) | 2016-06-21 | 2017-12-28 | X4 Pharmaceuticals, Inc. | Cxcr4 inhibitors and uses thereof |
| CN107501192A (en) * | 2017-08-15 | 2017-12-22 | 中国科学院上海药物研究所 | The eutectic of Telmisartan and Hydrochioro |
| US10548889B1 (en) | 2018-08-31 | 2020-02-04 | X4 Pharmaceuticals, Inc. | Compositions of CXCR4 inhibitors and methods of preparation and use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10244681A1 (en) * | 2002-09-24 | 2004-04-08 | Boehringer Ingelheim International Gmbh | New solid telmisartan-containing pharmaceutical formulations and their preparation |
| DE10319450A1 (en) * | 2003-04-30 | 2004-11-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical formulation of telmisartan sodium salt |
| CA2644179C (en) * | 2007-11-21 | 2018-09-25 | Pharmascience Inc. | Novel pharmaceutical composition comprising a disintegration matrix |
| TR200906506A2 (en) * | 2009-08-24 | 2011-03-21 | Bi̇lgi̇ç Mahmut | Solid dosage forms containing telmisartan. |
-
2010
- 2010-05-28 CA CA2706292A patent/CA2706292A1/en not_active Abandoned
-
2011
- 2011-05-27 CA CA2801020A patent/CA2801020A1/en not_active Abandoned
- 2011-05-27 WO PCT/CA2011/000621 patent/WO2011147026A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011147026A3 (en) | 2012-01-26 |
| CA2706292A1 (en) | 2011-11-28 |
| WO2011147026A2 (en) | 2011-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2801020A1 (en) | A stable pharmaceutical formulation comprising telmisartan and hydrochlorothiazide | |
| CA2780428C (en) | Tablet formulations of neratinib maleate | |
| KR100876302B1 (en) | A method for the preparation of substantially amorphous telmisartan | |
| US20050186274A1 (en) | Multilayer tablet | |
| US20090104262A9 (en) | Chlorthalidone combinations | |
| KR20070085754A (en) | Stabilized ramipril compositions and methods of making | |
| EP1098634A2 (en) | Bioenhanced formulations comprising eprosartan in oral solid dosage form | |
| EP2252273B1 (en) | Solid pharmaceutical composition comprising a non-peptide angiotensin ii receptor antagonist and a diuretic | |
| CA2644179C (en) | Novel pharmaceutical composition comprising a disintegration matrix | |
| TWI586353B (en) | Pharmaceutical preparations containing calcium antagonists and angiotensin II receptor antagonists | |
| JP6302802B2 (en) | Method for producing pharmaceutical preparation containing calcium antagonist / angiotensin II receptor antagonist | |
| KR20110085307A (en) | Oral solid dosage form comprising poorly soluble drugs | |
| US11260055B2 (en) | Oral pharmaceutical composition of lurasidone and preparation thereof | |
| WO2006067601A1 (en) | Oral pharmaceutical compositions of irbesartan and hydrochlorothiazide and processes for their preparation | |
| KR20080100292A (en) | A method for the preparation of substantially amorphous telmisartan | |
| WO2008008057A1 (en) | Stable formulation comprising a combination of a moisture sensitive drug and a second drug and manufacturing procedure thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20160504 |
|
| FZDE | Discontinued |
Effective date: 20190617 |
|
| FZDE | Discontinued |
Effective date: 20190617 |