CA2250395C - Eprosartan dihydrate and a process for its production and formulation - Google Patents
Eprosartan dihydrate and a process for its production and formulation Download PDFInfo
- Publication number
- CA2250395C CA2250395C CA002250395A CA2250395A CA2250395C CA 2250395 C CA2250395 C CA 2250395C CA 002250395 A CA002250395 A CA 002250395A CA 2250395 A CA2250395 A CA 2250395A CA 2250395 C CA2250395 C CA 2250395C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- treatment
- compound according
- hypertension
- diuretic
- 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.)
- Expired - Lifetime
Links
- -1 Eprosartan dihydrate Chemical class 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 18
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 239000002080 C09CA02 - Eprosartan Substances 0.000 title description 15
- 229960004563 eprosartan Drugs 0.000 title description 15
- 238000009472 formulation Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 36
- 206010020772 Hypertension Diseases 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 9
- 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 7
- 201000006370 kidney failure Diseases 0.000 claims abstract description 7
- 102000008873 Angiotensin II receptor Human genes 0.000 claims abstract description 6
- 108050000824 Angiotensin II receptor Proteins 0.000 claims abstract description 6
- UAAKJEVCDBPTQS-UHFFFAOYSA-N methanesulfonic acid;dihydrate Chemical compound O.O.CS(O)(=O)=O UAAKJEVCDBPTQS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 239000008187 granular material Substances 0.000 claims description 15
- 239000002934 diuretic Substances 0.000 claims description 13
- 239000005541 ACE inhibitor Substances 0.000 claims description 12
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 12
- 230000001882 diuretic effect Effects 0.000 claims description 12
- 238000005469 granulation Methods 0.000 claims description 12
- 230000003179 granulation Effects 0.000 claims description 12
- 239000002461 renin inhibitor Substances 0.000 claims description 12
- 229940086526 renin-inhibitors Drugs 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims description 11
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000007909 solid dosage form Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 8
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical group C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 8
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 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 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 5
- 239000002171 loop diuretic Substances 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 5
- 108010061435 Enalapril Proteins 0.000 claims description 4
- 229960000830 captopril Drugs 0.000 claims description 4
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical group SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 4
- 229960000873 enalapril Drugs 0.000 claims description 4
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 4
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 4
- 229960003883 furosemide Drugs 0.000 claims description 4
- 229960001597 nifedipine Drugs 0.000 claims description 4
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical group COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 4
- 229960003712 propranolol Drugs 0.000 claims description 4
- 108090000312 Calcium Channels Proteins 0.000 claims description 3
- 102000003922 Calcium Channels Human genes 0.000 claims description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 claims 9
- 239000000480 calcium channel blocker Substances 0.000 claims 9
- 239000000314 lubricant Substances 0.000 claims 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 14
- 229920002472 Starch Polymers 0.000 description 12
- 239000008107 starch Substances 0.000 description 12
- 229940032147 starch Drugs 0.000 description 12
- 235000019698 starch Nutrition 0.000 description 11
- 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 description 10
- 239000008101 lactose Substances 0.000 description 10
- 229960001375 lactose Drugs 0.000 description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 9
- 238000002411 thermogravimetry Methods 0.000 description 8
- 238000005550 wet granulation Methods 0.000 description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 7
- 229940088679 drug related substance Drugs 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 229910052925 anhydrite Inorganic materials 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229940014259 gelatin Drugs 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 239000003929 acidic solution Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- 229920003084 Avicel® PH-102 Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical class CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 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 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 229940049654 glyceryl behenate Drugs 0.000 description 2
- 238000009478 high shear granulation Methods 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 229940097420 Diuretic Drugs 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 206010061216 Infarction Diseases 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229940121792 Thiazide diuretic Drugs 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- UKMSUNONTOPOIO-UHFFFAOYSA-M behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC([O-])=O UKMSUNONTOPOIO-UHFFFAOYSA-M 0.000 description 1
- 229940116224 behenate Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229950008138 carmellose Drugs 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- 229910052920 inorganic sulfate Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- IQSHMXAZFHORGY-UHFFFAOYSA-N methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O IQSHMXAZFHORGY-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
This invention relates to (E)-.alpha.[2-n-butyl-1-[(4-carboxyphenyl)methyl]- 1H- imidazol-5-yl]methylene-2-thiopheneproprionic acid monomethanesulfonate dihydrate, a process for its production, compositions containing the compound and methods of using the compound to block angiotensin II receptors and to treat hypertension, congestive hear t failure and renal failure.
Description
Enrosartan Dihydate and a Process for its Production and Formulation Field of the Invention This invention relates to a pharmaceutically active compound, a process for its production, compositions containing the compound and methods of using the compound in the treatment of certain disease states in mammals, in particular man.
More specifically, the present invention relates to (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate, a wet granulation process for preparing said compound, compositions containing this compound, and methods of using (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate to block angiotensin II
(AII) receptors and to treat hypertension, congestive heart failure and renal failure.
Background of the Invention The compound (E)-a-(2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate is known by the name "eprosartan" and is the subject of U.S. Patent No. 5,185,351 (the '351 patent), issued February 9, 1993. This patent discloses in Example 41 a process for making the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate. Additionally, the '351 patent discloses conventional techniques for formulating (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-S-yl)methylene-2-thiophenepropionic acid monomethanesulfonate and Examples 108-111 specifically detail the preparation of certain formulations. This compound is claimed to have utility in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
Surprisingly, it has been found that the dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophe~epropionic acid monomethanesulfonate is formed in situ during the wet granulation process for preparing solid dosage forms of the anhydrous form of said compound.
Additionally, it has been found that the dehydrate of eprosartan is obtained by recrysallizing the anhydrouus form from an aqueous acidic solution. The dehydrate has the improved property of being more compactible in the solid dosage form when compared to the corresponding anhydrous form of the compound. This is particularly important when formulating (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethane-sulfonate for therapeutic use.
Summary of the Invention The present invention provides a novel dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate, in particular, in pharmaceutical compositions for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure.
The present invention also provides a process for preparing (E)-a-[2-n-butyl-I -[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate during wet granulation of the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
Another aspect of this invention provides a process for preparing (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate by recrystallizing the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous acidic solution, in particular, an aqueous solution of methanesulfonic acid.
Brief Descr~tion of the Fi ures Figures l, 3 and 5 show, respectively, the differential scanning calorimetric (DSC) thermogram, the thermogravimetric analysis (TGA) and the powder X-ray diffraction (XRD) pattern of the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
The anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate exhibits a single thermal event, a melting endotherm at about 250°C associated with a weight loss, suggesting that melting is followed by decomposition of the drug substance (Figure 1). No significant weight loss prior to melting is observed in its TGA
(thermogravimetric analysis) [Figure 3], suggesting that this compound does not contain significant quantities of surface adsorbed water and/or residual solvents.
The powder X-ray diffraction pattern [Figure 5] exhibits characteristic diffraction lines corresponding to 28 values of 7, 14, 18.9, 22.2 and 29 degrees.
Figures 2, 4 and 6 show, respectively, the differential scanning calorimetric (DSC) thermogram, the thermogravimetric analysis (TGA) and the powder X-ray diffraction (XRD) pattern of the dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
The DSC of the dehydrate [Figure 2] exhibits 3 characteristic endothermic peaks at about 71 °C, 99°C and 250°C. The exotherm in Figure 2 at 124°C
corresponds to the recrystallization of eprosartan dehydrate to the anhydrite upon dehydration. A typical TGA for the dehydrate obtained by granulating the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate with an excipient, such as lactose, xanthan gum, starch and gelatin, which act as a facilitator or stabilizer (i.e., stabilizing the dehydrate) exhibits a two-step moisture loss in the temperature range of 25-125°C [Figure 4J. The loss of water associated with the first-step moisture loss begins at 25°C and is essentially complete by 70°C. This weight loss amounts to about 3%, corresponding stoichiometrically to one mole of water per mole of eprosartan anhydrite. The water associated with the second-step moisture loss is lost in the temperature range of 75°-125°C. The dehydrate also exhibits a characteristic powder X-ray diffraction (XRD). The XRD [Figure 6) exhibits characteristic diffraction lines corresponding to 28 values of 8, 10.8, 16.8, 21.9, 26.6 and 30.4 degrees.
Detailed Description of the Invention (E)-a-[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate is known to exist in an anhydrous form and is characterized by the data shown in Figures 1, 3 and 5. This compound has the following structure:
COOH
~ CH3S03H
N COOH
N S
More specifically, the present invention relates to (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate, a wet granulation process for preparing said compound, compositions containing this compound, and methods of using (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate to block angiotensin II
(AII) receptors and to treat hypertension, congestive heart failure and renal failure.
Background of the Invention The compound (E)-a-(2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate is known by the name "eprosartan" and is the subject of U.S. Patent No. 5,185,351 (the '351 patent), issued February 9, 1993. This patent discloses in Example 41 a process for making the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate. Additionally, the '351 patent discloses conventional techniques for formulating (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-S-yl)methylene-2-thiophenepropionic acid monomethanesulfonate and Examples 108-111 specifically detail the preparation of certain formulations. This compound is claimed to have utility in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
Surprisingly, it has been found that the dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophe~epropionic acid monomethanesulfonate is formed in situ during the wet granulation process for preparing solid dosage forms of the anhydrous form of said compound.
Additionally, it has been found that the dehydrate of eprosartan is obtained by recrysallizing the anhydrouus form from an aqueous acidic solution. The dehydrate has the improved property of being more compactible in the solid dosage form when compared to the corresponding anhydrous form of the compound. This is particularly important when formulating (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethane-sulfonate for therapeutic use.
Summary of the Invention The present invention provides a novel dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate, in particular, in pharmaceutical compositions for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure.
The present invention also provides a process for preparing (E)-a-[2-n-butyl-I -[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate during wet granulation of the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
Another aspect of this invention provides a process for preparing (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate by recrystallizing the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous acidic solution, in particular, an aqueous solution of methanesulfonic acid.
Brief Descr~tion of the Fi ures Figures l, 3 and 5 show, respectively, the differential scanning calorimetric (DSC) thermogram, the thermogravimetric analysis (TGA) and the powder X-ray diffraction (XRD) pattern of the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
The anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate exhibits a single thermal event, a melting endotherm at about 250°C associated with a weight loss, suggesting that melting is followed by decomposition of the drug substance (Figure 1). No significant weight loss prior to melting is observed in its TGA
(thermogravimetric analysis) [Figure 3], suggesting that this compound does not contain significant quantities of surface adsorbed water and/or residual solvents.
The powder X-ray diffraction pattern [Figure 5] exhibits characteristic diffraction lines corresponding to 28 values of 7, 14, 18.9, 22.2 and 29 degrees.
Figures 2, 4 and 6 show, respectively, the differential scanning calorimetric (DSC) thermogram, the thermogravimetric analysis (TGA) and the powder X-ray diffraction (XRD) pattern of the dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
The DSC of the dehydrate [Figure 2] exhibits 3 characteristic endothermic peaks at about 71 °C, 99°C and 250°C. The exotherm in Figure 2 at 124°C
corresponds to the recrystallization of eprosartan dehydrate to the anhydrite upon dehydration. A typical TGA for the dehydrate obtained by granulating the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate with an excipient, such as lactose, xanthan gum, starch and gelatin, which act as a facilitator or stabilizer (i.e., stabilizing the dehydrate) exhibits a two-step moisture loss in the temperature range of 25-125°C [Figure 4J. The loss of water associated with the first-step moisture loss begins at 25°C and is essentially complete by 70°C. This weight loss amounts to about 3%, corresponding stoichiometrically to one mole of water per mole of eprosartan anhydrite. The water associated with the second-step moisture loss is lost in the temperature range of 75°-125°C. The dehydrate also exhibits a characteristic powder X-ray diffraction (XRD). The XRD [Figure 6) exhibits characteristic diffraction lines corresponding to 28 values of 8, 10.8, 16.8, 21.9, 26.6 and 30.4 degrees.
Detailed Description of the Invention (E)-a-[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1 H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate is known to exist in an anhydrous form and is characterized by the data shown in Figures 1, 3 and 5. This compound has the following structure:
COOH
~ CH3S03H
N COOH
N S
(E)-ac-[2-n-B utyi-1-[(4-carboxyphenye)methyl]-1 H-inudazol-S-yl] methy iene-2-thiophenepropionic acid imonomethanesulfonate, eprosartan, is claimed in U.S.
Patent No. 5,185,351. Reference should be made to said patent for its full disclosure, including the methods of preparing and using this compound.
Eprosartan is anhydrous, and, by itself, is stable at ambient temperature and humidity, as well as at accelerated conditions (30°CJ79~oRH ar 40°C/7S%RH for up to 6 months). This drug substance does not pick up moisture at higher humidities (typically up to 95°loRH). However, the anhydrous form of the compound converts to the hydrated form, if it is moistened prior to storage in a closed container at ambient or higher temperatures, or if the dry powder is stored at a relative humidity of 98% or higher at ambient or higher temperatures for 8 days or longer. In the former case where the hydrate is obtained by moistening the drug substance, the hydrated form is not stable, and is generally converted back into the anhydrous form during drying.
In accordance with the present invention, it has been unexpectedly found that a stable dehydrated form of (E)-a [2-n-butyl-1-[(4-carboxyphenyl)methyl].1H-imidazol-S-yl]methyiene-2-thivpheneprogionic acid monomethanesulfonate is produced in situ during the wet granulation processing of the anhydrous form of said .
24 compound into solid dosage forms (e.g., capsules and tablets). The granules containing (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yi]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate are produced by mixing the anhydrous form of the compound with one or more pharmaceutically acceptable excipients, followed by granulation with water.
The dehydrated form of eprosartan can also be prepared by recrystallizing the anydrous form of eprosartan from an aqueous acidic solution, for example, an aqueous solution of methanesulfonic acid.
The dehydrate of the instant invention is characterized by the data shown in Figures 2, 4 and 6. The anhydrous form of {E)-a [2-n-butyl-1-[(4-carbvxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid mvnomethane-sulfonate and its dehydrate have been characterized further. The crystal structure of both eprosartan anhydrate and eprosartan dehydrate have been determined from three-demensional X-ray diffraction data collected on single crystals at ambient temperatures. The anhydrate crystallizes in the triclinic system, while the dehydrate crystallizes in the monoclinic system, with the following cell dimensions:
Patent No. 5,185,351. Reference should be made to said patent for its full disclosure, including the methods of preparing and using this compound.
Eprosartan is anhydrous, and, by itself, is stable at ambient temperature and humidity, as well as at accelerated conditions (30°CJ79~oRH ar 40°C/7S%RH for up to 6 months). This drug substance does not pick up moisture at higher humidities (typically up to 95°loRH). However, the anhydrous form of the compound converts to the hydrated form, if it is moistened prior to storage in a closed container at ambient or higher temperatures, or if the dry powder is stored at a relative humidity of 98% or higher at ambient or higher temperatures for 8 days or longer. In the former case where the hydrate is obtained by moistening the drug substance, the hydrated form is not stable, and is generally converted back into the anhydrous form during drying.
In accordance with the present invention, it has been unexpectedly found that a stable dehydrated form of (E)-a [2-n-butyl-1-[(4-carboxyphenyl)methyl].1H-imidazol-S-yl]methyiene-2-thivpheneprogionic acid monomethanesulfonate is produced in situ during the wet granulation processing of the anhydrous form of said .
24 compound into solid dosage forms (e.g., capsules and tablets). The granules containing (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yi]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate are produced by mixing the anhydrous form of the compound with one or more pharmaceutically acceptable excipients, followed by granulation with water.
The dehydrated form of eprosartan can also be prepared by recrystallizing the anydrous form of eprosartan from an aqueous acidic solution, for example, an aqueous solution of methanesulfonic acid.
The dehydrate of the instant invention is characterized by the data shown in Figures 2, 4 and 6. The anhydrous form of {E)-a [2-n-butyl-1-[(4-carbvxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid mvnomethane-sulfonate and its dehydrate have been characterized further. The crystal structure of both eprosartan anhydrate and eprosartan dehydrate have been determined from three-demensional X-ray diffraction data collected on single crystals at ambient temperatures. The anhydrate crystallizes in the triclinic system, while the dehydrate crystallizes in the monoclinic system, with the following cell dimensions:
Space Group and Unit cell Dimensions of Eprosartan Parameter Anhydrate Dih, dy_ rate Space group P1 P2 /C
a 8.65 A 18'35 A
b 12.68 A 17.10 A
c 13.66 A 17.35 A
a 112.7 90 (3 101.4 90.8 y 96.7 90 According to the instant invention, excipients, such as lactose, starch, polyvinyl pyrrolidone) (Povidone, PVP), xanthan gum, sodium alginate and gelatin, in the granulation, added as a dry powder or in solution, facilitate the conversion of the anhydrate into the dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethane-sulfonate and they stabilize the dehydrate thus formed. Dehydrate formation is usually complete in about 2-10 minutes using a high shear wet granulation process in the preparation of solid dosage forms of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethane-sulfonate anhydrate. The granulation thus prepared, which contains the drug substance in the dehydrate form, can be dried, while keeping the drug substance in the hydrated form.
The process for preparing the solid dosage form containing the compound comprises: (i) producing granules containing (E)-a-[2-n-butyl-1-[(4-carboxy-phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate in its dehydrated form in the presence of water and one or more pharmaceutically acceptable excipients and (ii) blending said granules with other pharmaceutically acceptable excipients to be filled into capsules or compressed into tablets exhibiting immediate release ( 100% release in a short period of time in a suitable dissolution medium) or modified release (sustained release or delayed release) profiles. This process for the preparation of solid dosage forms containing of {E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl)-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate comprises the in situ formation of a stable dehydrate of the compound during wet granulation, said formation being facilitated and stabilized by an excipient. Complete hydration takes place in about 2 minutes to 24 hours, preferably in about 2-10 minutes in the presence of preferred excipients.
In order to produce granules containing (E)-a-[2-n-butyl-I-[(4-carboxy-phenyl)methyl]-1H-imidazol-5-yl)methylene-2-thiophenepropionic acid in its dehydrated form, the anhydrous form of the compound is well mixed with pharmaceutically acceptable excipients, such as fillers, diluents, disintegrants ~ lu»ricants and binders, granulated with water and dried to a predetermined water content (loss on drying). Any combination of pharmaceutically acceptable excipients, e.g.
diluents, fillers, binders and disintegrants, in desired proportions may be utilized in accordance with the wet granulation process of the present invention. The excipienEs commonly used in pharmaceutical industry are well described in the literature [refer to the Handbook of Pharmaceutical Excipients, A. Wade and P. J. Weller (Editors), American Pharmaceutical Association (1994}]. Pharmaceutically acceptable fillers and diluents include, but are not limited to, the following: lactose {hydrous as well as anhydrous), starch [unmodified (corn starch) or modified (for example, Starch 1500 available from Colorcon)], mannitol, sarbitol, cellulose, inorganic sulfates and phosphates. Disintegrants include, but are not limited to, the following:
sodium starch glyeolate, sodium carmellose and crosslinked polyvinyl pyrrolidone, and binders include, but are not limited to, the following: gelatin, corn starch, modified starch (Starch 1551, pregelatinized starch), hydmxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC}. Examples of excipients suitable for modified release applications include, but are not limted to, the following: high molecular . weight HPMCs, polymethacrylate polymers known as Eudragits, polyethylene oxide, Polyox~ (Union Carbide Corporation), modified ethyl cellulose, Surelease~
(Colorcon), crosslinked acrylic acid polymers, Carbopol~ (BF Goodrich Speciality Chemicals) and waxy materials, such as glyceryl behenate (Compritol~, glyceryI
palmitostearate (Precirol~), and Gelucires~ [all from Gattefosse S.a., France]
and carnauba wax.
Preferably, the pharmaceutically acceptable excipients used as binders, diluents and fillers during the wet granulation process of this invention are lactose, starch (corn starch, soluble starch, or Starch 1551), gelatin, xanthan gum, sodium alginate, Povidone (PVP}, and microerystalline. or powdered cellulose, each one of which acts as a facilitator in the formation of a stable dehydrate of eprosartan. More preferably, the excipients are lactose, Starch 1551, cellulose, and Povidone (PVP).
Most preferably, the excipients are lactose, cellulose and Starch 1551, Preferably, the excipients used in the wet granulation process are present in i-70% on a weight for weight basis depending on the unit dose strength of WO 97/36874 PCT/US97l04877 eprosartan required. Most preferably, the excipients may be present at as low as 1-7% on a weight for weight basis in order to produce granulations with a high drug load.
The process for preparing the solid dosage forms in accordance with the present invention may be carried out using a planetary mixture, a V-blender, a high shear granulator, a fluid bed granulator or a tableting machine. Optionally, the anhydrous form of (E)-a-[2-n-butyl-I-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl)methylene-2-thiophenepropionic acid monomethanesulfonate may be granulated first with a suitable excipient using a conventional granulating equipment, said excipient stabilizing the dehydrate which is formed in about 2-10 minutes (time duration for a high shear granulation). Optionally, drying of the granulation may be avoided by using less water at the granulation stage, and the granulation thus produced is suitable for the preparation of direct compression immediate or modified release dosage forms. Optionally, the immediate release tablet cores may be coated with a membrane of a polymer imparting delayed or sustained release properties.
Thus, the present invention provides a pharmaceutical composition which comprises (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate and a pharmaceutically acceptable carrier. The pharmaceutical composition is adapted for oral administration. The composition is presented as a unit dose pharmaceutical composition containing from about 50 mg to about 1.0 g of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-IH-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate, preferably from about 200 to about 400 mg.
Such a composition is normally taken from 1 to 4 times daily, preferably from 1 to 2 times daily. The preferred unit dosage forms include tablets or capsules. The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable pharmaceutically acceptable carriers for use in this invention include diluents, fillers, binders and disintegrants. , (E)-a-[2-n-Butyl-1-[(4-carboxyphenyl)methylJ-IH-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate may be co-administered with ether pharmaceutically active compounds, for example, in physical combination or by sequential administration. Conveniently, the compound of this invention and the other active compound are formulated in a pharmaceutical composition. Thus, this invention also relates to pharmaceutical compositions comprising (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate, a pharmaceutically acceptable carrier, and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel Mocker, a 13-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor. Examples of compounds which may be included in pharmaceutical compositions in combination with (E)-a-[2-n-butyl-I-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate are diuretics, particularly a thiazide diuretic, such as hydrochlorothiazide, or a loop diuretic, such as furosemide, calcium channel Mockers, particularly dihydropyridine antagonists, such as nifedipine,13-adrenoceptor blockers, such as propranolol, renin inhibitors, such as enalkinen, and angiotensin converting enzyme inhibitors, such as captopril or enalapril.
Preferably, the pharmaceutical composition contains 200-400 mg of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate in combination with 6.25-25 mg of hydrochlorothiazide.
No unacceptable toxicological effects are expected when (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate is administered in accordance with the present envention.
(E)-a-[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate is useful for treating diseases in which blockade of the angiotensin II receptor would be beneficial.
Preferably, this compound is used alone or in combination with said second pharmaceutically active compounds in the treatment of hypertension, congestive heart failure and renal failure. Additionally, (E)-a-[2-n-butyl-1-[(4-carboxy-phenyi)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate is of value in the treatment of left ventricular hypertrophy regression, diabetic nephropathy, diabetic retinopathy, mascular degeneration, haemorrhagic stroke, primary and secondary prevention of infarction, prevention of atheroma progression and the regression of atheroma, prevention of restinosis after angioplasty or bypass surgery, improving cognitive function, angina, glaucoma, and CNS disorders, such as anxiety.
The following examples are illustrative of the instant invention. These examples are not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelow.
_g_ In Examples 1-5, below, the term "internals" means the ingredients which are granulated and the term "externals" means the ingredients which are blended with the granulation, Exarnnles Exarnnles 1-5 Pre aration and F mulatio of E -a- 2-n-Bu 1-1- 4-car x hen meth 1 -11-I
imid z I- - 1 me h ~ lene- -th'o he a ro ion'c Acid Mono thanesulfonate Dihl dt rate AB E
Formulation Summary Example Example Example Example Example (% (% % % (%) Internals Com ound A* 30-50 60-80 50-70 50-70 50-70 Lactose, h 15-30 7-20 1-5 2-'7. 1-4 drous .
.* *
Cellulose Avicel~2-15 ?-20 - 2-8 -Starch 1551 2-7 - - - 2-9 -Povidone (PVP)~- 2-8 - - -Purified water** ** ** ** **
~ternals Polyethylene - - 5-25 -oxide G1 ce 1 behenate 5-25 Avicel PH 102 10-20 5-25 5-25 10-25 5-25 Corn starch 3-7 - - - -Ac-Di-Sol - 2-8 - 2-8 -Ma . stearate 0.5-1.5 0.5-i.5 0.2-1.0 0.5-1.5 0.2-1.0 * (E)-a-[2-n-butyl-I-((4-carboxyphenyl)methyl]-1H-imidazol-5-yt]methylene-2 thiophenepropionic acid monomethanesulfonate, anhydrous form ** Composition does not take into account the formation of the dihydrate during granulation.
*** Trade-mark - 9 -Table I, above, summarizes the amounts of Compound A and excipients on a weight for weight basis used in the formulations detailed in Examples I-5 below.
Exam lp a 1 A fluid bed granulator, UniGlait, is charged with the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate and Impalpable Lactose, homogenized with an aqueous suspension of Starch 1551 and granulated by spraying at a desirable flow rate and dry wet mass to an LOD (loss on drying) of 5.5-6.5°k determined using a Sartorius'moisture meter tested at 110°C. The hydrate formation is checked by TGA and powder X-ray diffraction. The dry granulation is processed through a #30 mesh screen and then a compression mix is prepared by blending with the externals and the tablets are manufactured:
Example 2 The intenaals are premixed in the Collette bowl for. l min at a low chopper setting and granulated for 4 ruin by adding. water (added in parts) at a high chopper setting. The granulate is then milled through an appropriate screen and dried to an LOD of.' S.5-6.5%. The dried granulate.is milled, mixed with the externals and compressed into tablets. The tablets have been shown to contain the drug substance in the dehydrate form.
Exam 1 The internals are premixed in a high shear granulator and granulated at a high chopper setting with hydrous lactose added in solution. The granulate, containing the active in the dehydrated form, is mixed with the externals [polyethylene oxide of high molecular weight (Polyox~, Union Carbide Corporation), microcrystaliine cellulose (Avicel PH102~, and.magnesium stearate] and compressed into tablets which exhibit sustained release profiles.
Example 4 A scaled up batch is manufactured using a 700 liter high shear Fie~der granulator, Quadro Cotrul fitted with ll4" screen for wet milling and a #20 mesh screen for diy milling, a fluid bed dryer for a total moisture content (I,OD) of about 69'o and a Manesty Unipress for compressing tablets of hardness in the range of 8-20 * Trade-mark kP. The tablets thus manufactured have been shown to contain the active ingredient in the dihydrated form.
Example 5 A granulation (batchsize : 8 kgs} of (E)-oc-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-ylJmethylene-2-thiophenepropionic acid monomethanesulfonate dihydrate is manufactured in a 25 liter Fielder bowl using a solution of lactose at a high chopper setting. The granulation mixed with glyceryl behenate [Compritol~, Gattefosse S.a.] is roller compacted, milled and sifted.
#18-40 mesh cut granules are subjected to a thermal treatment using a bed granulator at about 65°C for 15 min. The cooled granulate, containing the active in the dihydrated form, is mixed with the externals and compressed into tablets exhibiting sustained release profiles.
Example 6 Preparation of lE)-a-f2-n-Butt-f(4-carboxyphen llmethy~-1H-imidazol-5-vllmethvlene-2-thionhenepropionic Acid Monomethanesulfonate Dih dv rate Eprosartan anhydrite was suspended in an aqueous solution of 3.0 M
methanesulfonic acid. The suspension was continuously stirred and heated to 65-70°C. The filtrate obtained by suction was maintained at 75°C
for several minutes to ensure the absence of the anhydrite in solution. The solution was slowly cooled to ambient temperature and clear colorless crystalline drug substance was harvested by filtration and air dried.
It is to be understood that the invention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims.
a 8.65 A 18'35 A
b 12.68 A 17.10 A
c 13.66 A 17.35 A
a 112.7 90 (3 101.4 90.8 y 96.7 90 According to the instant invention, excipients, such as lactose, starch, polyvinyl pyrrolidone) (Povidone, PVP), xanthan gum, sodium alginate and gelatin, in the granulation, added as a dry powder or in solution, facilitate the conversion of the anhydrate into the dehydrated form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethane-sulfonate and they stabilize the dehydrate thus formed. Dehydrate formation is usually complete in about 2-10 minutes using a high shear wet granulation process in the preparation of solid dosage forms of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethane-sulfonate anhydrate. The granulation thus prepared, which contains the drug substance in the dehydrate form, can be dried, while keeping the drug substance in the hydrated form.
The process for preparing the solid dosage form containing the compound comprises: (i) producing granules containing (E)-a-[2-n-butyl-1-[(4-carboxy-phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate in its dehydrated form in the presence of water and one or more pharmaceutically acceptable excipients and (ii) blending said granules with other pharmaceutically acceptable excipients to be filled into capsules or compressed into tablets exhibiting immediate release ( 100% release in a short period of time in a suitable dissolution medium) or modified release (sustained release or delayed release) profiles. This process for the preparation of solid dosage forms containing of {E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl)-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate comprises the in situ formation of a stable dehydrate of the compound during wet granulation, said formation being facilitated and stabilized by an excipient. Complete hydration takes place in about 2 minutes to 24 hours, preferably in about 2-10 minutes in the presence of preferred excipients.
In order to produce granules containing (E)-a-[2-n-butyl-I-[(4-carboxy-phenyl)methyl]-1H-imidazol-5-yl)methylene-2-thiophenepropionic acid in its dehydrated form, the anhydrous form of the compound is well mixed with pharmaceutically acceptable excipients, such as fillers, diluents, disintegrants ~ lu»ricants and binders, granulated with water and dried to a predetermined water content (loss on drying). Any combination of pharmaceutically acceptable excipients, e.g.
diluents, fillers, binders and disintegrants, in desired proportions may be utilized in accordance with the wet granulation process of the present invention. The excipienEs commonly used in pharmaceutical industry are well described in the literature [refer to the Handbook of Pharmaceutical Excipients, A. Wade and P. J. Weller (Editors), American Pharmaceutical Association (1994}]. Pharmaceutically acceptable fillers and diluents include, but are not limited to, the following: lactose {hydrous as well as anhydrous), starch [unmodified (corn starch) or modified (for example, Starch 1500 available from Colorcon)], mannitol, sarbitol, cellulose, inorganic sulfates and phosphates. Disintegrants include, but are not limited to, the following:
sodium starch glyeolate, sodium carmellose and crosslinked polyvinyl pyrrolidone, and binders include, but are not limited to, the following: gelatin, corn starch, modified starch (Starch 1551, pregelatinized starch), hydmxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC}. Examples of excipients suitable for modified release applications include, but are not limted to, the following: high molecular . weight HPMCs, polymethacrylate polymers known as Eudragits, polyethylene oxide, Polyox~ (Union Carbide Corporation), modified ethyl cellulose, Surelease~
(Colorcon), crosslinked acrylic acid polymers, Carbopol~ (BF Goodrich Speciality Chemicals) and waxy materials, such as glyceryl behenate (Compritol~, glyceryI
palmitostearate (Precirol~), and Gelucires~ [all from Gattefosse S.a., France]
and carnauba wax.
Preferably, the pharmaceutically acceptable excipients used as binders, diluents and fillers during the wet granulation process of this invention are lactose, starch (corn starch, soluble starch, or Starch 1551), gelatin, xanthan gum, sodium alginate, Povidone (PVP}, and microerystalline. or powdered cellulose, each one of which acts as a facilitator in the formation of a stable dehydrate of eprosartan. More preferably, the excipients are lactose, Starch 1551, cellulose, and Povidone (PVP).
Most preferably, the excipients are lactose, cellulose and Starch 1551, Preferably, the excipients used in the wet granulation process are present in i-70% on a weight for weight basis depending on the unit dose strength of WO 97/36874 PCT/US97l04877 eprosartan required. Most preferably, the excipients may be present at as low as 1-7% on a weight for weight basis in order to produce granulations with a high drug load.
The process for preparing the solid dosage forms in accordance with the present invention may be carried out using a planetary mixture, a V-blender, a high shear granulator, a fluid bed granulator or a tableting machine. Optionally, the anhydrous form of (E)-a-[2-n-butyl-I-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl)methylene-2-thiophenepropionic acid monomethanesulfonate may be granulated first with a suitable excipient using a conventional granulating equipment, said excipient stabilizing the dehydrate which is formed in about 2-10 minutes (time duration for a high shear granulation). Optionally, drying of the granulation may be avoided by using less water at the granulation stage, and the granulation thus produced is suitable for the preparation of direct compression immediate or modified release dosage forms. Optionally, the immediate release tablet cores may be coated with a membrane of a polymer imparting delayed or sustained release properties.
Thus, the present invention provides a pharmaceutical composition which comprises (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate and a pharmaceutically acceptable carrier. The pharmaceutical composition is adapted for oral administration. The composition is presented as a unit dose pharmaceutical composition containing from about 50 mg to about 1.0 g of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-IH-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate, preferably from about 200 to about 400 mg.
Such a composition is normally taken from 1 to 4 times daily, preferably from 1 to 2 times daily. The preferred unit dosage forms include tablets or capsules. The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing. Suitable pharmaceutically acceptable carriers for use in this invention include diluents, fillers, binders and disintegrants. , (E)-a-[2-n-Butyl-1-[(4-carboxyphenyl)methylJ-IH-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate may be co-administered with ether pharmaceutically active compounds, for example, in physical combination or by sequential administration. Conveniently, the compound of this invention and the other active compound are formulated in a pharmaceutical composition. Thus, this invention also relates to pharmaceutical compositions comprising (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate, a pharmaceutically acceptable carrier, and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel Mocker, a 13-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor. Examples of compounds which may be included in pharmaceutical compositions in combination with (E)-a-[2-n-butyl-I-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate are diuretics, particularly a thiazide diuretic, such as hydrochlorothiazide, or a loop diuretic, such as furosemide, calcium channel Mockers, particularly dihydropyridine antagonists, such as nifedipine,13-adrenoceptor blockers, such as propranolol, renin inhibitors, such as enalkinen, and angiotensin converting enzyme inhibitors, such as captopril or enalapril.
Preferably, the pharmaceutical composition contains 200-400 mg of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate dehydrate in combination with 6.25-25 mg of hydrochlorothiazide.
No unacceptable toxicological effects are expected when (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate is administered in accordance with the present envention.
(E)-a-[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate is useful for treating diseases in which blockade of the angiotensin II receptor would be beneficial.
Preferably, this compound is used alone or in combination with said second pharmaceutically active compounds in the treatment of hypertension, congestive heart failure and renal failure. Additionally, (E)-a-[2-n-butyl-1-[(4-carboxy-phenyi)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dehydrate is of value in the treatment of left ventricular hypertrophy regression, diabetic nephropathy, diabetic retinopathy, mascular degeneration, haemorrhagic stroke, primary and secondary prevention of infarction, prevention of atheroma progression and the regression of atheroma, prevention of restinosis after angioplasty or bypass surgery, improving cognitive function, angina, glaucoma, and CNS disorders, such as anxiety.
The following examples are illustrative of the instant invention. These examples are not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelow.
_g_ In Examples 1-5, below, the term "internals" means the ingredients which are granulated and the term "externals" means the ingredients which are blended with the granulation, Exarnnles Exarnnles 1-5 Pre aration and F mulatio of E -a- 2-n-Bu 1-1- 4-car x hen meth 1 -11-I
imid z I- - 1 me h ~ lene- -th'o he a ro ion'c Acid Mono thanesulfonate Dihl dt rate AB E
Formulation Summary Example Example Example Example Example (% (% % % (%) Internals Com ound A* 30-50 60-80 50-70 50-70 50-70 Lactose, h 15-30 7-20 1-5 2-'7. 1-4 drous .
.* *
Cellulose Avicel~2-15 ?-20 - 2-8 -Starch 1551 2-7 - - - 2-9 -Povidone (PVP)~- 2-8 - - -Purified water** ** ** ** **
~ternals Polyethylene - - 5-25 -oxide G1 ce 1 behenate 5-25 Avicel PH 102 10-20 5-25 5-25 10-25 5-25 Corn starch 3-7 - - - -Ac-Di-Sol - 2-8 - 2-8 -Ma . stearate 0.5-1.5 0.5-i.5 0.2-1.0 0.5-1.5 0.2-1.0 * (E)-a-[2-n-butyl-I-((4-carboxyphenyl)methyl]-1H-imidazol-5-yt]methylene-2 thiophenepropionic acid monomethanesulfonate, anhydrous form ** Composition does not take into account the formation of the dihydrate during granulation.
*** Trade-mark - 9 -Table I, above, summarizes the amounts of Compound A and excipients on a weight for weight basis used in the formulations detailed in Examples I-5 below.
Exam lp a 1 A fluid bed granulator, UniGlait, is charged with the anhydrous form of (E)-a-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate and Impalpable Lactose, homogenized with an aqueous suspension of Starch 1551 and granulated by spraying at a desirable flow rate and dry wet mass to an LOD (loss on drying) of 5.5-6.5°k determined using a Sartorius'moisture meter tested at 110°C. The hydrate formation is checked by TGA and powder X-ray diffraction. The dry granulation is processed through a #30 mesh screen and then a compression mix is prepared by blending with the externals and the tablets are manufactured:
Example 2 The intenaals are premixed in the Collette bowl for. l min at a low chopper setting and granulated for 4 ruin by adding. water (added in parts) at a high chopper setting. The granulate is then milled through an appropriate screen and dried to an LOD of.' S.5-6.5%. The dried granulate.is milled, mixed with the externals and compressed into tablets. The tablets have been shown to contain the drug substance in the dehydrate form.
Exam 1 The internals are premixed in a high shear granulator and granulated at a high chopper setting with hydrous lactose added in solution. The granulate, containing the active in the dehydrated form, is mixed with the externals [polyethylene oxide of high molecular weight (Polyox~, Union Carbide Corporation), microcrystaliine cellulose (Avicel PH102~, and.magnesium stearate] and compressed into tablets which exhibit sustained release profiles.
Example 4 A scaled up batch is manufactured using a 700 liter high shear Fie~der granulator, Quadro Cotrul fitted with ll4" screen for wet milling and a #20 mesh screen for diy milling, a fluid bed dryer for a total moisture content (I,OD) of about 69'o and a Manesty Unipress for compressing tablets of hardness in the range of 8-20 * Trade-mark kP. The tablets thus manufactured have been shown to contain the active ingredient in the dihydrated form.
Example 5 A granulation (batchsize : 8 kgs} of (E)-oc-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-ylJmethylene-2-thiophenepropionic acid monomethanesulfonate dihydrate is manufactured in a 25 liter Fielder bowl using a solution of lactose at a high chopper setting. The granulation mixed with glyceryl behenate [Compritol~, Gattefosse S.a.] is roller compacted, milled and sifted.
#18-40 mesh cut granules are subjected to a thermal treatment using a bed granulator at about 65°C for 15 min. The cooled granulate, containing the active in the dihydrated form, is mixed with the externals and compressed into tablets exhibiting sustained release profiles.
Example 6 Preparation of lE)-a-f2-n-Butt-f(4-carboxyphen llmethy~-1H-imidazol-5-vllmethvlene-2-thionhenepropionic Acid Monomethanesulfonate Dih dv rate Eprosartan anhydrite was suspended in an aqueous solution of 3.0 M
methanesulfonic acid. The suspension was continuously stirred and heated to 65-70°C. The filtrate obtained by suction was maintained at 75°C
for several minutes to ensure the absence of the anhydrite in solution. The solution was slowly cooled to ambient temperature and clear colorless crystalline drug substance was harvested by filtration and air dried.
It is to be understood that the invention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims.
Claims (61)
1. A compound which is (E)-.alpha.-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate.
2. A process for the preparation of the compound according to claim 1 which comprises recrystallizing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[(4-carboxyphenyl)methyl)-1H-imidazol-5-yl)methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous solution containing an acid.
3. The process according to claim 2 wherein the acid is methanesulfonic acid.
4. A process for the preparation of the compound according to claim 1 which comprises:
(i) mixing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[(4-carboxy-phenyl)methyl)-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate with one or more pharmaceutically acceptable excipients;
(ii) granulating the mixture with water; and (iii) drying the granulation to a predetermined water content.
(i) mixing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[(4-carboxy-phenyl)methyl)-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate with one or more pharmaceutically acceptable excipients;
(ii) granulating the mixture with water; and (iii) drying the granulation to a predetermined water content.
5. The process according to claim 4 wherein the pharmaceutically acceptable excipient is selected from the group consisting of diluents, fillers, binders, disintegrants and lubricants.
6. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
7. A process for the preparation of a solid dosage form containing the compound according to claim 1 which comprises:
(i) producing granules containing (E)-.alpha.-[2-n-butyl-1-[(4-carboxy-phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate; and (ii) blending said granules with other pharmaceutically acceptable excipients to be filled into a capsule or compressed into a tablet.
(i) producing granules containing (E)-.alpha.-[2-n-butyl-1-[(4-carboxy-phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate dihydrate; and (ii) blending said granules with other pharmaceutically acceptable excipients to be filled into a capsule or compressed into a tablet.
8. A process for the preparation of a solid dosage form containing the compound according to claim 1 which comprises:
(i) storing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate at a relative humidity of 98% or higher at ambient or high temperatures for 8 days or longer;
(ii) producing granules containing the dehydrate and (iii) blending said granules with other pharmaceutically acceptable excipients to be filled into a capsule or compressed into a tablet.
(i) storing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate at a relative humidity of 98% or higher at ambient or high temperatures for 8 days or longer;
(ii) producing granules containing the dehydrate and (iii) blending said granules with other pharmaceutically acceptable excipients to be filled into a capsule or compressed into a tablet.
9. A process for the preparation of a solid dosage form containing the compound according to claim 1 which comprises:
(i) recrystallizing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[{4-carboxy-phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous solution containing an acid;
(ii) producing granules containing the dehydrate and (iii) blending said granules with other pharmaceutically acceptable excipients to be filled into a capsule or compressed into a tablet.
(i) recrystallizing the anhydrous form of (E)-.alpha.-[2-n-butyl-1-[{4-carboxy-phenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate from an aqueous solution containing an acid;
(ii) producing granules containing the dehydrate and (iii) blending said granules with other pharmaceutically acceptable excipients to be filled into a capsule or compressed into a tablet.
10. The process according to claim 9 wherein the acid is methanesulfonic acid.
11. A pharmaceutical composition comprising the compound according to claim 1, a pharmaceutically acceptable carrier and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a .beta.-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor.
12. The pharmaceutical composition according to claim 11 wherein the second pharmaceutically active compound is a diuretic.
13. The pharmaceutical composition according to claim 12 wherein the diuretic is hydrochlorothiazide.
14. The pharmaceutical composition according to claim 11 wherein the second pharmaceutically active compound is a loop diuretic.
15. The pharmaceutical composition according to claim 14 wherein the loop diuretic is furosemide.
16. The pharmaceutical composition according to claim 11 wherein the second pharmaceutically active compound is a calcium channel blocker.
17. The pharmaceutical composition according to claim 16 wherein the calcium channel blocker is nifedipine.
18. The pharmaceutical composition according to claim 11 wherein the second pharmaceutically active compound is a .beta.-adrenoceptor blocker.
19. The pharmaceutical composition according to claim 18 wherein the .beta.-adrenoceptor blocker is propranolol.
20. The pharmaceutical composition according to claim 11 wherein the second pharmaceutically active compound is an angiotensin converting enzyme inhibitor.
21. The pharmaceutical composition according to claim 20 wherein the angiotensin converting enzyme inhibitor is captopril or enalapril.
22. The pharmaceutical composition according to claim 11 wherein the second pharmaceutically active compound is a renin inhibitor.
23. The pharmaceutical composition according to claim 22 wherein the renin inhibitor is enalkinen.
24. Use of the compound according to claim 1 to block angiotensin II
receptors.
receptors.
25. Use of the compound according to claim 1 in the manufacture of a medicament to block angiotensin II receptors.
26. Use of the compound according to claim 1 for the treatment of hypertension.
27. Use of the compound according to claim 1 in the manufacture of a medicament for the treatment of hypertension.
28. Use of the compound according to claim 1 and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel Mocker, a .beta.-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor for the treatment of hypertension.
29. Use of the compound according to claim 1 and a second pharmaceutically active compound selected from the group consisting of a diuretic, a calcium channel blocker, a .beta.-adrenoceptor blocker, a renin inhibitor, and an angiotensin converting enzyme inhibitor in the manufacture of a medicament for the treatment of hypertension.
30. The use according to claim 28 or 29 wherein the second pharmaceutically active compound is a diuretic.
31. The use according to claim 30 wherein the diuretic is hydrochlorothiazide.
32. The use according to claim 28 or 29 wherein the second pharmaceutically active compound is a loop diuretic.
33. The use of claim 32 wherein the loop diuretic is furosemide.
34. The use according to claim 28 or 29 wherein the second pharmaceutically active compound is a calcium channel blocker.
35. The use according to claim 34 wherein the calcium channel blocker is nifedipine.
36. The use according to claim 28 or 29 wherein the second pharmaceutically active compound is a .beta.-adrenoceptor blocker.
37. The use according to claim 36 wherein the .beta.-adrenoceptor blocker is propranolol.
38. The use according to claim 28 or 29 wherein the second pharmaceutically active compound is an angiotensin converting enzyme inhibitor.
39. The use according to claim 38 wherein the angiotensin converting enzyme inhibitor is captopril or enalapril.
40. The use according to claim 28 or 29 wherein the second pharmaceutically active compound is a renin inhibitor.
41. The use according to claim 40 wherein the renin inhibitor is enalkinen.
42. Use of the compound according to claim 1 for the treatment of congestive heart failure.
43. Use of the compound according to claim 1 in the manufacture of a medicament for the treatment of congestive heart failure.
44. Use of the compound according to claim 1 for the treatment of renal failure.
45. Use of the compound according to claim 1 in the manufacture of a medicament for the treatment of renal failure.
46. The use of a compound according to claim 1 and a diuretic in the manufacture of a medicament for the treatment of hypertension.
47. The use of a compound according to claim 1 and a diuretic for the treatment of hypertension.
48. The use according to claim 46 or 47 wherein the diuretic is hydrochlorothiazide.
49. The use according to claim 46 wherein the diuretic is furosemide.
50. The use of a compound according to claim 1 and a calcium channel blocker in the manufacture of a medicament for the treatment of hypertension.
51. The use of a compound according to claim 1 and a calcium channel blocker for the treatment of hypertension.
52. The use according to claim 50 or 51 wherein the calcium channel blocker is nifedipine.
53. The use of a compound according to claim 1 and a .beta.-adrenoceptor blocker in the manufacture of a medicament for the treatment of hypertension.
54. The use of a compound according to claim 1 and a .beta.-adrenoceptor blocker for the treatment of hypertension.
55. The use according to claim 53 or 54 wherein the .beta.-adrenoceptor blocker is propranolol.
56. The use of a compound according to claim 1 and a renin inhibitor in the manufacture of a medicament for the treatment of hypertension.
57. The use of a compound according to claim 1 and a renin inhibitor for the treatment of hypertension.
58. The use according to claim 56 or 57 wherein the renin inhibitor is enalkinen.
59. The use of a compound according to claim 1 and an angiotensin converting enzyme inhibitor in the manufacture of a medicament for the treatment of hypertension.
60. The use of a compound according to claim 1 and an angiotensin converting enzyme inhibitor for the treatment of hypertension.
61. The use according to claim 59 or 60 wherein the angiotensin converting enzyme inhibitor is captopril or enalapril.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1441496P | 1996-03-29 | 1996-03-29 | |
| US60/014,414 | 1996-03-29 | ||
| PCT/US1997/004877 WO1997036874A1 (en) | 1996-03-29 | 1997-03-26 | Eprosartan dihydrate and a process for its production and formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2250395A1 CA2250395A1 (en) | 1997-10-09 |
| CA2250395C true CA2250395C (en) | 2005-09-06 |
Family
ID=21765344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002250395A Expired - Lifetime CA2250395C (en) | 1996-03-29 | 1997-03-26 | Eprosartan dihydrate and a process for its production and formulation |
Country Status (35)
| Country | Link |
|---|---|
| EP (1) | EP0889880B1 (en) |
| JP (1) | JP4316013B2 (en) |
| CN (2) | CN1214682A (en) |
| AP (1) | AP901A (en) |
| AR (1) | AR006439A1 (en) |
| AT (1) | ATE239723T1 (en) |
| AU (1) | AU726694B2 (en) |
| BG (1) | BG64095B1 (en) |
| BR (1) | BR9708336A (en) |
| CA (1) | CA2250395C (en) |
| CZ (1) | CZ293345B6 (en) |
| DE (1) | DE69721749T2 (en) |
| DK (1) | DK0889880T3 (en) |
| DZ (1) | DZ2199A1 (en) |
| EA (1) | EA001958B1 (en) |
| EG (1) | EG23889A (en) |
| ES (1) | ES2198564T3 (en) |
| HU (1) | HU228263B1 (en) |
| ID (1) | ID16507A (en) |
| IL (1) | IL126319A0 (en) |
| MA (1) | MA24437A1 (en) |
| MY (1) | MY117682A (en) |
| NO (2) | NO311760B1 (en) |
| NZ (1) | NZ332008A (en) |
| OA (1) | OA11176A (en) |
| PL (1) | PL188816B1 (en) |
| PT (1) | PT889880E (en) |
| RO (1) | RO118870B1 (en) |
| SK (1) | SK282346B6 (en) |
| TR (1) | TR199801954T2 (en) |
| TW (1) | TW434239B (en) |
| UA (1) | UA49880C2 (en) |
| UY (1) | UY24504A1 (en) |
| WO (1) | WO1997036874A1 (en) |
| ZA (1) | ZA972686B (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4475685B2 (en) * | 1997-06-27 | 2010-06-09 | スミスクライン・ビーチャム・コーポレイション | Eprosartan monohydrate |
| CN1285739A (en) * | 1997-11-17 | 2001-02-28 | 史密丝克莱恩比彻姆公司 | High drug load immediate and modified release oral dosage formulations and process for their production |
| US6558699B2 (en) * | 1997-11-17 | 2003-05-06 | Smithkline Beecham Corporation | High drug load immediate and modified release oral dosage formulations and processes for their manufacture |
| SK11902000A3 (en) | 1998-03-04 | 2001-02-12 | Takeda Chemical Industries, Ltd. | Sustained-release preparation for angiotensin ii antagonist, production and use thereof |
| ZA991922B (en) * | 1998-03-11 | 1999-09-13 | Smithkline Beecham Corp | Novel compositions of eprosartan. |
| AU763309B2 (en) * | 1998-07-20 | 2003-07-17 | Smithkline Beecham Corporation | Bioenhanced formulations comprising eprosartan in oral solid dosage form |
| GB9820405D0 (en) * | 1998-09-18 | 1998-11-11 | Smithkline Beecham Plc | Process |
| AU1157500A (en) * | 1998-11-06 | 2000-05-29 | Boehringer Ingelheim International Gmbh | Medicaments based on combinations of lacidipine and telmisartan or of physiological derivatives thereof |
| WO2000027397A1 (en) * | 1998-11-06 | 2000-05-18 | Glaxo Group Limited | Antihypertensive medicaments containing lacidipine and telmisartan |
| AU774799B2 (en) * | 1999-04-28 | 2004-07-08 | Takeda Pharmaceutical Company Limited | Preventives / remedies / progression inhibitors for simplex retinopathy or preproliferating retinopathy |
| GB9920919D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel compound |
| GB9920917D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel process |
| RU2298418C2 (en) * | 2000-04-12 | 2007-05-10 | Новартис Аг | Combination of at least two compounds chosen from groups at1-receptor antagonists or inhibitors of ace (angiotensin-converting enzyme) or inhibitors of hmg-coa-reductase (beta-hydroxy-beta-methylglutaryl-coenzyme-a-reductase) |
| BR0214383A (en) * | 2001-11-23 | 2004-11-03 | Solvay Pharm Gmbh | Treatment of hypertonia during the acute phase of stroke |
| KR100517638B1 (en) | 2002-04-08 | 2005-09-28 | 주식회사 엘지생명과학 | New process for preparing acid salts of Gemifloxacin |
| US20060014839A1 (en) * | 2002-05-17 | 2006-01-19 | Califf Robert M | Combination of angiotensin II receptor blocker and beta-blocker for secondary prevention of myocardial infarction |
| EG24716A (en) | 2002-05-17 | 2010-06-07 | Novartis Ag | Combination of organic compounds |
| DE10230272A1 (en) * | 2002-07-05 | 2004-01-22 | Solvay Pharmaceuticals Gmbh | 1 receptor antagonist for the prevention of secondary stroke |
| KR101194453B1 (en) | 2003-01-31 | 2012-10-24 | 다이이찌 산쿄 가부시키가이샤 | Medicine for prevention of and treatment for arteriosclerosis and hypertension |
| WO2009013760A2 (en) | 2007-07-25 | 2009-01-29 | Hetero Drugs Limited | Eprosartan mesylate crystalline particles and a process for preparing pure eprosartan |
| WO2009084028A2 (en) * | 2007-12-03 | 2009-07-09 | Neuland Laboratories Ltd | Improved process for manufacturing anhydrous (e)-3-[2-butyl-1- {(4-carboxyphenyl) methyl}-1h-imidazole-5-yl]-(thiophen-2- ylmethyl)prop-2-enoic acid methane sulfonate |
| CN101333216A (en) * | 2008-08-03 | 2008-12-31 | 浙江华海药业股份有限公司 | Novel saltforming process of eprosartan mesylate |
| CN113354553B (en) * | 2021-06-03 | 2023-09-15 | 北京宝诺康医药科技有限公司 | Preparation method of metoclopramide monohydrochloride monohydrate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5185351A (en) * | 1989-06-14 | 1993-02-09 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids useful as angiotensin II receptor antagonists |
| US5312828A (en) * | 1989-06-14 | 1994-05-17 | Finkelstein Joseph A | Substituted imidazoles having angiotensin II receptor blocking activity |
| AU9137791A (en) * | 1990-12-14 | 1992-07-08 | Smithkline Beecham Corporation | Imidazolyl-alkenoic acids |
-
1997
- 1997-03-26 NZ NZ332008A patent/NZ332008A/en not_active IP Right Cessation
- 1997-03-26 AT AT97917004T patent/ATE239723T1/en active
- 1997-03-26 ES ES97917004T patent/ES2198564T3/en not_active Expired - Lifetime
- 1997-03-26 UA UA98095006A patent/UA49880C2/en unknown
- 1997-03-26 CN CN97193471A patent/CN1214682A/en active Pending
- 1997-03-26 TR TR1998/01954T patent/TR199801954T2/en unknown
- 1997-03-26 SK SK1322-98A patent/SK282346B6/en not_active IP Right Cessation
- 1997-03-26 UY UY24504A patent/UY24504A1/en not_active IP Right Cessation
- 1997-03-26 DK DK97917004T patent/DK0889880T3/en active
- 1997-03-26 PT PT97917004T patent/PT889880E/en unknown
- 1997-03-26 WO PCT/US1997/004877 patent/WO1997036874A1/en not_active Ceased
- 1997-03-26 MA MA24539A patent/MA24437A1/en unknown
- 1997-03-26 AR ARP970101257A patent/AR006439A1/en active IP Right Grant
- 1997-03-26 BR BR9708336A patent/BR9708336A/en not_active IP Right Cessation
- 1997-03-26 CA CA002250395A patent/CA2250395C/en not_active Expired - Lifetime
- 1997-03-26 AU AU25470/97A patent/AU726694B2/en not_active Expired
- 1997-03-26 DE DE69721749T patent/DE69721749T2/en not_active Expired - Lifetime
- 1997-03-26 JP JP53538497A patent/JP4316013B2/en not_active Expired - Lifetime
- 1997-03-26 EA EA199800873A patent/EA001958B1/en not_active IP Right Cessation
- 1997-03-26 CZ CZ19983101A patent/CZ293345B6/en not_active IP Right Cessation
- 1997-03-26 HU HU9902769A patent/HU228263B1/en unknown
- 1997-03-26 IL IL12631997A patent/IL126319A0/en active IP Right Grant
- 1997-03-26 EP EP97917004A patent/EP0889880B1/en not_active Expired - Lifetime
- 1997-03-26 PL PL97329046A patent/PL188816B1/en unknown
- 1997-03-26 RO RO98-01406A patent/RO118870B1/en unknown
- 1997-03-27 MY MYPI97001335A patent/MY117682A/en unknown
- 1997-03-27 ZA ZA9702686A patent/ZA972686B/en unknown
- 1997-03-27 AP APAP/P/1997/000956A patent/AP901A/en active
- 1997-03-27 EG EG24497A patent/EG23889A/en active
- 1997-03-29 DZ DZ970046A patent/DZ2199A1/en active
- 1997-03-31 ID IDP971059A patent/ID16507A/en unknown
- 1997-06-17 TW TW086108370A patent/TW434239B/en not_active IP Right Cessation
-
1998
- 1998-09-28 NO NO19984503A patent/NO311760B1/en not_active IP Right Cessation
- 1998-09-29 OA OA9800184A patent/OA11176A/en unknown
- 1998-10-07 BG BG102822A patent/BG64095B1/en unknown
-
2001
- 2001-06-09 CN CN01121133A patent/CN1332167A/en active Pending
-
2002
- 2002-07-19 NO NO2002005C patent/NO2002005I1/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2250395C (en) | Eprosartan dihydrate and a process for its production and formulation | |
| US6558699B2 (en) | High drug load immediate and modified release oral dosage formulations and processes for their manufacture | |
| CA2338256C (en) | Bioenhanced formulations comprising eprosartan in oral solid dosage form | |
| US6420412B2 (en) | Eprosartan dihydate and a process for its production and formulation | |
| CA2310028C (en) | High drug load immediate and modified release oral dosage formulations and processes for their manufacture | |
| CA2294515C (en) | Eprosartan monohydrate | |
| CA2299470C (en) | Eprosartan arginyl charge-neutralization-complex and a process for its production and formulation | |
| HK1016594B (en) | Eprosartan dihydrate and a process for its production and formulation | |
| KR100477295B1 (en) | Eprosartan Dihydrate and a Process for its Production and Formulation | |
| CZ2001227A3 (en) | Biologically enhanced preparations containing eprosartan in solid oral dosage form |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20170327 |