EP2521540A2 - Forme posologique orale solide contenant de l'olmésartan médoxomil - Google Patents
Forme posologique orale solide contenant de l'olmésartan médoxomilInfo
- Publication number
- EP2521540A2 EP2521540A2 EP11701630.3A EP11701630A EP2521540A2 EP 2521540 A2 EP2521540 A2 EP 2521540A2 EP 11701630 A EP11701630 A EP 11701630A EP 2521540 A2 EP2521540 A2 EP 2521540A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- dosage form
- oral dosage
- solid oral
- olmesartan medoxomil
- process according
- 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.)
- Withdrawn
Links
- 239000007787 solid Substances 0.000 title claims abstract description 49
- 239000006186 oral dosage form Substances 0.000 title claims abstract description 42
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 39
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 39
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 22
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 34
- 230000008569 process Effects 0.000 claims description 34
- 239000008187 granular material Substances 0.000 claims description 22
- 239000013543 active substance Substances 0.000 claims description 21
- 239000000314 lubricant Substances 0.000 claims description 16
- 239000003381 stabilizer Substances 0.000 claims description 16
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 15
- 238000005550 wet granulation Methods 0.000 claims description 13
- 229960000528 amlodipine Drugs 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 12
- 239000007884 disintegrant Substances 0.000 claims description 12
- 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 11
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 11
- 238000000576 coating method Methods 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 235000021355 Stearic acid Nutrition 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000008117 stearic acid Substances 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical class CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical class CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical class CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
- 238000007580 dry-mixing Methods 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical class CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000194 fatty acid Substances 0.000 claims description 3
- 229930195729 fatty acid Natural products 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 229960001375 lactose Drugs 0.000 claims description 3
- 229960001021 lactose monohydrate Drugs 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 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 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000001828 Gelatine Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical class [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 2
- 235000013681 dietary sucrose Nutrition 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 229960001031 glucose Drugs 0.000 claims description 2
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Chemical class CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims description 2
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Chemical class CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052816 inorganic phosphate Inorganic materials 0.000 claims description 2
- 239000000905 isomalt Substances 0.000 claims description 2
- 235000010439 isomalt Nutrition 0.000 claims description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Chemical class CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 239000010773 plant oil Substances 0.000 claims description 2
- 229960000540 polacrilin potassium Drugs 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 229920003124 powdered cellulose Polymers 0.000 claims description 2
- 235000019814 powdered cellulose Nutrition 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 239000007909 solid dosage form Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 150000008163 sugars Chemical class 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940057977 zinc stearate Drugs 0.000 claims description 2
- ONCLVQFEAFTXMN-UHFFFAOYSA-N (1-hexadecanoyloxy-3-hydroxypropan-2-yl) octadecanoate Chemical class CCCCCCCCCCCCCCCCCC(=O)OC(CO)COC(=O)CCCCCCCCCCCCCCC ONCLVQFEAFTXMN-UHFFFAOYSA-N 0.000 claims 1
- 239000005639 Lauric acid Chemical class 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 208000019622 heart disease Diseases 0.000 claims 1
- 208000017169 kidney disease Diseases 0.000 claims 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims 1
- 235000010234 sodium benzoate Nutrition 0.000 claims 1
- 239000004299 sodium benzoate Substances 0.000 claims 1
- 229940023144 sodium glycolate Drugs 0.000 claims 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 27
- 239000008194 pharmaceutical composition Substances 0.000 description 18
- 238000009472 formulation Methods 0.000 description 10
- 239000005480 Olmesartan Substances 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 229960005117 olmesartan Drugs 0.000 description 8
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 102000005862 Angiotensin II Human genes 0.000 description 5
- 101800000733 Angiotensin-2 Proteins 0.000 description 5
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 5
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 5
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 229950006323 angiotensin ii Drugs 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 4
- 230000036772 blood pressure Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 4
- -1 5-methyl-2-oxo-2H-1 ,3-dioxol-4-yl Chemical group 0.000 description 3
- 108090000783 Renin Proteins 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 2
- 101800000734 Angiotensin-1 Proteins 0.000 description 2
- 102400000344 Angiotensin-1 Human genes 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
- 206010047139 Vasoconstriction Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960002478 aldosterone Drugs 0.000 description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000036581 peripheral resistance Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000025033 vasoconstriction Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QHZLMUACJMDIAE-UHFFFAOYSA-N 1-monopalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 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
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940096898 glyceryl palmitate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 239000008202 granule composition Substances 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000008060 renal absorption Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
Definitions
- the present invention relates to a pharmaceutical solid oral dosage form comprising olmesartan medoxomil. More particularly, the present invention relates to formulations, processes for preparing these formulations, and to formulations for the treatment or prevention of hypertension, heart and circulatory diseases. Specifically, the present invention relates to the use of (5-methyl-2-oxo-2H-1 ,3-dioxol-4-yl)methyl-4-(2-hydroxypropan-2-yl)-2-propyl-1-( ⁇ 4-[2- (2H-1 ,2,3,4-tetrazol-5-yl)phenyl]phenyl ⁇ methyl)-1H-imidazole-5-carboxylate in the preparation of immediate release formulations.
- EP0503785B1 discloses generically a series of 1-(biphenylmethyl)imidazole derivatives having an activity as angiotensin II receptor antagonist including olmesartan medoxomil and a process for its preparation.
- Olmesartan medoxomil is a prodrug that is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
- Olmesartan works by blocking the binding of angiotensin II to the AT-i receptors in vascular muscle; it is therefore independent of angiotensin II synthesis pathways, unlike angiotensin converting enzyme (ACE) inhibitors.
- Angiotensin I is converted to angiotensin II through removal of two terminal residues by the enzyme ACE.
- the renin-angiotension system provides one of the important mechanisms for maintaining the homeostasis of blood pressure in living animals.
- this system is activated.
- the enzyme renin and ACE are activated and act on angiotensinogen, which is first decomposed by renin to produce angiotensin I (Al).
- This Al is then converted by ACE to angiotensin II (All). All is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.
- olmesartan By blocking the binding rather than blocking the synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. As a result of this blockage, olmesartan reduces vasoconstriction and the secretion of aldosterone. This lowers blood pressure by producing vasodilation, and decreasing peripheral resistance.
- the compound of formula (I) exists in different polymorphic forms like the crystalline form G as disclosed in US2006/0281800 A1 , olmesartan medoxomil hemihydrate as disclosed in EP1801111 A1; Form B as provided by WO2008/149160 A1 and an amorphous form as disclosed in WO2007/017135 A2.
- WO 2007/128478 A2 reports that olmesartan medoxomil is susceptible to degradation under basic conditions and also under highly acidic conditions while it is most stable at a pH in the range of 3-5. According to WO2007/128478 A2 stabilization of a pharmaceutical composition containing olmesartan medoxomil can be achieved with pharmaceutically acceptable constituents where each of the constituents being incorporated into a composition has a pH of less than 8 and wherein one of the constituents is stearic acid.
- One object of the present invention is therefore to provide a solid oral dosage form containing olmesartan medoxomil which is sufficiently stable without the incorporation into a composition including pH lowering agents i.e. stearic acid as disclosed in WO 2007/128478 A2.
- the neutral compound polyethylene glycol having a molecular weight of 1000 - 10000, without acid-base-buffer capacity has a stabilizing effect on olmesartan medoxomil.
- the present invention relates to a solid oral dosage form comprising olmesartan medoxomil and polyethylene glycol having an average molecular weight of about 1000 - 10000.
- Another aspect of the invention is a solid oral dosage form as described herein for the treatment and/or prevention of hypertension and disorders associated therewith.
- the invention further relates to a process for the manufacture of a solid oral dosage form containing olmesartan medoxomil as a pharmaceutically active agent and polyethylene glycol having a molecular weight of about 1 ,000 - 10,000 as a stabilizer, comprising wet granulation.
- Another aspect of this invention is a process for the manufacture of a solid oral dosage form containing olmesartan medoxomil as a pharmaceutically active agent comprising the steps of a) dry mixing the active agent(s) with a diluent,
- a disintegrant is preferably added either to the mixture of the active agent and the diluent, i.e. step (a) or to the blend of the granules and the lubricant, i.e. step (f).
- Another aspect of this invention is a solid oral dosage form obtainable by the process of the present invention.
- Yet another aspect of the invention is the use of polyethylene glycol as a stabilizer of olmesartan medoxomil in a solid dosage form.
- solid ingredient refers to any constituent of the composition of the solid oral dosage form according to the present invention that is in the solid state under standard conditions, i.e. at 25 ° C and at a pressure of 1 atm (101.325 kPa).
- the phrase "Immediate release formulation” refers to any solid oral formulation that after taking, by the time olmesartan medoxomil leaves the stomach, olmesartan medoxomil is either in solution or it is in the form of a suspension of fine particles, e.g., in a form in which olmesartan can be readily absorbed. More specifically, the in vitro dissolution profiles for the immediate release formulations were generated using the paddle method USP Apparatus II at a stirring speed of 50 rpm in 0.1 HCI or phosphate buffer with a pH 6.8 at 37°C.
- the solid oral dosage form of the present invention preferably contains a unit dose in the range of about 10 to 250 mg, more preferably in the range of about 10 to 40 mg, particularly of 10, 20 or 40 mg of the active agent olmesartan medoxomil.
- Another object of the present invention is to provide a solid oral dosage form containing olmesartan medoxomil in combination with hydrochlorothiazide (HCTZ), amlodipine or hydrochlorothiazide and amlodipine and a process of forming the same.
- Amlodipine may formulated in form of pharmaceutical acceptable salts thereof, e.g. the besylate, mesylate or maleate salt. With mentioning the term amlodipine the free base and all pharmaceutically acceptable salts are included.
- Hydrochlorothiazide is a known therapeutic agent which is useful in the treatment of hypertension. It acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is believed to lower peripheral vascular resistance.
- Amlodipine is known as a long-acting calcium channel blocker and used as an antihypertensive and in the treatment of angina. Like other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing peripheral resistance and hence reducing blood pressure; in angina it increases blood flow to the heart muscle.
- the present invention particularly relates to a solid oral dosage form, which contains a unit dose in the range of about 10 to 250 mg, preferably in the range of about 10 to 40 mg, particularly of 10, 20 or 40 mg of the active ingredient olmesartan medoxomil and a unit dose in the range of about 6 to 60 mg, preferably in the range of about 10 to 30 mg, particularly of 12.5 or 25 mg of the active ingredient hydrochlorothiazide.
- the present invention particularly relates to a solid oral dosage form, which contains a unit dose in the range of about 10 to 250 mg, preferably in the range of about 10 to 40 mg, particularly of 10, 20 or 40 mg of the active agent olmesartan medoxomil and a unit dose in the range of about 1 to 20 mg, particularly of 5 or 10 mg of the active agent amlodipine, calculated as amlodipine free base.
- the present invention particularly relates to a solid oral dosage form, which contains a unit dose in the range of about 10 to 250 mg, preferably in the range of about 10 and 40 mg, particularly of 10, 20 or 40 mg of the active agent olmesartan medoxomil, a unit dose in the range of about 6 to 60 mg, preferably in the range of about 10 to 30 mg, particularly of 12.5 or 25 mg of the active agent hydrochlorothiazide and a unit dose in the range of about 1 to 20 mg, particularly of 5 or 10 mg of the active agent amlodipine, calculated as amlodipine free base.
- the solid oral dosage forms containing olmesartan medoxomil in combination with HCTZ and/or amlodipine do also contain polyethylene glycol having a molecular weight of 1000 - 10000 and are also preferably produced by the preferred process of the present invention.
- the pharmaceutical dosage form of the invention comprises at least one stabilizer to prevent the acid or base catalyzed decompositions of olmesartan medoxomil.
- the preferred stabilizer used in pharmaceutical composition is polyethylene glycol (PEG).
- PEG polyethylene glycol
- the numbers that are often included in the names of PEGs indicate their average molecular weights. For example, PEG 400 has an average molecular weight of 400 Da.
- the stabilizer present in the pharmaceutical compositions of the present invention is preferably PEG having an average molecular weight from 1 ,000 to 10,000, more preferably from 4,000 to 9,000, most preferably from 6,000 to 8,000.
- the PEG is preferably present in an amount of 0.1 to 3 weight-%, more preferably from 0.5 to 2.5 weight-%, e.g., about 1 weight-%, based on the total weight of the composition. Further excipients
- the solid oral dosage form according to the present invention can be in the form of tablets, capsules, caplets, sachets and soft capsules.
- lubricants are preferably added at the steps of filling or tabletting in consideration of handling properties, precision for filling and the like. Olmesartan medoxomil has potent adhesive properties, and the use of lubricants is therefore preferred. However, the use of the lubricants causes delaying in a dissolution time.
- the pharmaceutical composition according to the present invention can further comprise any additional excipients and adjuvants, which are pharmaceutically acceptable, and general coating materials, which are preferably applied as a coating to the solid form of the pharmaceutical composition of the present invention.
- additional excipients and adjuvants are known to the person skilled in the art, and can be referred to the standard textbook by Fiedler ("Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre", 5 th ed., 2002) or to the "Handbook of Excipients", edited by the American Pharmaceutical Association and Dr. Arthur H. Kibbe, 3 rd ed., 2000.
- the pharmaceutical composition of the solid oral dosage form according to the present invention comprises one or more diluents, binders, lubricants, stabilizers and/or coating materials and optionally colourants and/or surfactants, and in particular 1 to 90 weight-% of a diluent, 0.5 to 10 weight-% of a binder, 0 to 3 weight-% of a lubricant, 0.1 to 3 weight-% of a stabilizer, 0 to 5 weight-% of a coating material, and optionally 0 to 6 weight-% of a surfactant and 0 to 3 weight-% colourants based on the total weight of the composition.
- the further excipients and adjuvants and optionally coating materials or colourants are present in the pharmaceutical composition of the present invention, such that the total amount of the pharmaceutical composition including the amount of the active agents results in 100 weight-%.
- the capsule shell is excluded from the total amount of the pharmaceutical composition.
- diluent one or more components can be used, which contribute a part of the tablet to reach the necessary total mass of the tablet.
- Preferred diluents are inorganic phosphates, like dibasic calcium phosphate, sugars or sugar analogues and derivatives thereof, in particular lactose, such as lactose monohydrate or water-free lactose, dextrose, sorbitol, mannitol, saccharose, maltodextrin, isomalt and Tablettose ® .
- lactose such as lactose monohydrate or water-free lactose
- dextrose sorbitol
- mannitol mannitol
- saccharose maltodextrin
- isomalt isomalt
- Tablettose ® Tablettose ® .
- Celluloses like microcrystalline cellulose or powdered cellulose are further preferred diluents according to the present invention.
- the pharmaceutical composition according to the present invention comprises 1 to 90 weight-%, more preferable 40 to 90 weight-%, in particular 60 to 85 weight-%, e.g. about 80 weigth-% of a diluent, based on the total weight of the composition.
- binders i.e. a compound enabling granulation of the active ingredient and the further excipients and adjuvants into granules
- gelatine povidone (N-vinylpropylidone polymer), copovidone (copolymer of N-vinyl-2-pyrrolidone and vinyl acetate) and in particular hydroxypropyl cellulose or polyvinyl pyrrolidone can be exemplified, the latter being particularly preferred.
- the binder is preferably present in an amount of 0.5 to 10 weight-%, more preferably 0.5 to 5 weight-%, in particular 1 to 3 weight-%, based on the total weight of the composition.
- lubricants to be used in the pharmaceutical compositions of the present invention fatty acids or fatty acid derivates, such as alkali and earth alkali salts of stearic, lauric and/or palmitic acid, in particular magnesium stearate, glycerol monostearate or glycerol tristearate, glyceryl palmitate/stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, hydrogenated plant oil (Lubritab ® ), natriumbenzoate, or polyethylen glycol are exemplified, sodium stearyl fumarate and magnesium stearate are especially preferred.
- the lubricant is preferably present in an amount of 0 to 3 weight-%, more preferably 0.5 to 2.5 weight-%, such as about 1 weight- %, based on the total weight of the composition.
- the pharmaceutical composition of the present invention preferably comprises at least 1 weight-%, more preferably 1-10 weight-% and even more preferably 1-5 weight-% of a disintegrant, based on the total weight of the composition.
- Some disintegrants are known in the art which may also be used as binders, diluents or as further excipients or adjuvants different to disintegrants.
- Preferably used disintegrants according to the present invention are croscarmellose sodium, low substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate and polacrilin potassium.
- Stabilizers used in pharmaceutical compositions to prevent the acid or base catalyzed decompositions of olmesartan medoxomil are, e.g.
- PEG polyethylene glycol
- the stabilizer is preferably present in an amount of 0.1-3 weight-%, more preferably 0.5-2.5 weight-%, such as about 1 weight-%, based on the total weight of the composition.
- the pharmaceutical formulation of the invention does not contain stearic acid. In another embodiment, the pharmaceutical formulation of the invention does not contain stearic acid or a salt thereof.
- a particular advantage of the tablets of this invention is their advantageous dissolution profile.
- the tablets release a substantial portion of the active ingredient, olmesartan medoxomil, within 20 or 30 minutes, using USP Apparatus II, in 900 ml 0.05 M Phosphate Buffer, pH 6.8 at 37°C and 50 rpm.
- the tablets exhibit the following release of olmesartan medoxomil: at least 15% within 5 minutes, at least 50% within 10 minutes, at least 60% within 15 minutes, and at least 80% within 30 minutes, using USP Apparatus II, in 900 ml 0.05 M Phosphate Buffer, pH 6.8 at 37°C and 50 rpm.
- the tablets exhibit the following release of olmesartan medoxomil: 20 to 40% within 5 minutes, 50 to 75% within 10 minutes, 60 to 90% within 15 minutes, and at least 80% within 30 minutes, determined according to USP Apparatus II, in 900 ml 0.05 M Phosphate Buffer, pH 6.8 at 37°C and 50 rpm.
- the tablets release a substantial portion of the active ingredient, olmesartan medoxomil, within 10 or 15 minutes, using USP Apparatus II, in 900 ml 0.1 N HCI, pH 1.1 at 37°C and 50 rpm.
- the tablets exhibit the following release of olmesartan medoxomil: at least 30% within 5 minutes, at least 70% within 10 minutes, at least 80% within 15 minutes, and at least 90% within 30 minutes, using USP Apparatus II, in 900 ml 0.1 N HCI, pH 1.1 at 37°C and 50 rpm.
- the tablets exhibit the following release of olmesartan medoxomil: 40 to 70% within 5 minutes, 75 to 95% within 10 minutes and at least 85 to 100% within 15 minutes, using Apparatus II, in 900 ml 0.1 N HCI, pH 1.1 at 37°C and 50 rpm.
- the solid oral dosage form of the present invention and all its embodiments are provided for the treatment or prevention of hypertension and diseases related thereto.
- Diseases related to hypertension are diseases caused by high blood pressure, like angina pectoris and diseases of the heart, the kidney and the cerebrovascular system.
- solid oral dosage forms comprising olmesartan medoxomil and polyethylene glycol having an average molecular weight of about 1000 - 10000 formed from sized granules obtained by wet mass sifting during a wet granulation process show stable and excellently reproduceable immediate release profiles with each batch. Therefore, the present invention further provides a preferred process for the manufacture of a solid oral dosage form containing olmesartan medoxomil and preferably polyethylene glycol having an average molecular weight of about 1000 - 10000.
- the preferred process of the invention is a wet granulation process and more preferably the wet granules obtained in the wet granulation are subjected to wet sifting subsequently by wet granulation.
- electrostatic charges are generated by physical irritations caused through processes such as pulverization, agitation, blending, granulation and the like, which in turn cause a decrease in fluidity of pulverized, blended or granulated materials, worsen handling properties, and decrease precision for content uniformity of an active ingredient.
- the process for the manufacture of the solid oral dosage form according to the present invention is therefore preferably carried out in the presence of water, i.e. it is preferably a wet granulation method.
- wet granules are subjected to wet mass sifting, in order to obtain sized wet granules.
- the pharmaceutical composition is in the form of a tablet which can be obtained by wet granulation followed by wet mass sifting.
- the granules obtained by the preferred process of wet sifting using a comill of the present invention have a particle size of 10 to 1 mm, preferably 7 to 3 mm, in particular 4 mm after wet sifting.
- the preferred sieves to be used during the wet mass sifting are mesh 7L156Q03746 with a square hole size of 3.96 mm x 3.96 mm .
- a disintegrant is preferably added either to the mixture of the active agent and the diluent, i.e. step (a) or to the blend of the granules and the lubricant, i.e. step (d). All solid ingredients are preferably sieved before being employed in the process. More preferably the disintegrant and lubricant are sieved before being employed in the process.
- the blend obtained in step (iv) is compressed to tablets.
- the compression of the granulates to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine.
- the tablet cores may vary in shape and be, for example, round, oval, oblong, cylindrical or any other suitable shape, and may also vary in size depending on the concentration of the therapeutic agents.
- the tablets are coated by suitable coating methods well-known in the art.
- a solid oral dosage form obtainable by the preferred processes of the present invention is provided.
- the tablets of example 1 were prepared using a wet granulation process:
- the active agent(s), the diluent, e.g. lactose monohydrate and microcrystalline cellulose and optionally the disintegrant, e.g. low substituted hydroxypropyl cellulose were weighted out as indicated in the table.
- the powder blend was then mixed, followed by granulation with the binder solution, e.g. aqueous solution of a binder e.g. PVP and/or hydroxypropyl cellulose and a stabilizer e.g. PEG 6000, in a mixer/granulator and sieved 7L156Q03746 to form the "intragranular material".
- the binder solution e.g. aqueous solution of a binder e.g. PVP and/or hydroxypropyl cellulose and a stabilizer e.g. PEG 6000
- the wet granules were dried (in a fluid bed dryer) until a LOD (loss of drying) of typically 2.5% or less was reached, followed by passing the dried granules through a round hole screen 7L055R03732 with a diameter of 1.40 mm using a comill.
- the lubricant magnesium stearate and optionally the disintegrant, e.g. croscarmellose sodium were weighted and mixed with the granule blend described above. This final blend was then compressed into tablets using the tablet press and then optionally coated with the coating material Opadry.
- the tablets were prepared using a process similar to the process described in example 1.
- the tablets were prepared using a process similar to the process described in example 1 .
- Tablets prepared according to example 1 were further analyzed.
- a dissolution profile of the active ingredient was obtained by dissolving a tablet in an USP-Apparatus II in 900 ml 0.05M phosphate buffer pH 6.8 or 0.1 N HCI at 37°C and stirring speed of 50 rpm.
- the dissolution tests were carried out using USP-Apparatus I I.
- the release profile is shown in Figure 1 and 2.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention porte sur une forme posologique orale solide comprenant de l'olmésartan médoxomil et du polyéthylèneglycol ayant une masse moléculaire d'environ 1 000-10 000.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN26DE2010 | 2010-01-05 | ||
PCT/EP2011/050061 WO2011083112A2 (fr) | 2010-01-05 | 2011-01-04 | Forme posologique orale solide contenant de l'olmésartan médoxomil |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2521540A2 true EP2521540A2 (fr) | 2012-11-14 |
Family
ID=43795169
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP11701630.3A Withdrawn EP2521540A2 (fr) | 2010-01-05 | 2011-01-04 | Forme posologique orale solide contenant de l'olmésartan médoxomil |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP2521540A2 (fr) |
CA (1) | CA2785920A1 (fr) |
WO (1) | WO2011083112A2 (fr) |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE920540A1 (en) | 1991-02-21 | 1992-08-26 | Sankyo Co | 1-biphenylmethylimidazole derivatives, their preparation and¹their therapetuic use |
US20040198789A1 (en) * | 2003-02-28 | 2004-10-07 | Recordati Ireland Limited | Lercanidipine/ARB/diuretic therapeutic combinations |
US20060281800A1 (en) | 2005-04-12 | 2006-12-14 | Glenmark Pharmaceuticals Limited | Polymorphic form of olmesartan and process for its preparation |
US7943779B2 (en) | 2005-07-29 | 2011-05-17 | Krka | Process for the preparation of olmesartan medoxomil |
EP1801111B1 (fr) | 2005-12-20 | 2014-07-16 | LEK Pharmaceuticals d.d. | Formes polymorphes du Olmesartan Medoxomil |
ATE526963T1 (de) | 2006-05-04 | 2011-10-15 | Lek Pharmaceuticals | Pharmazeutische zusammensetzung mit olmesartan- medoxomil |
EP2167047A2 (fr) * | 2007-06-06 | 2010-03-31 | Dexcel Ltd. | Procédé de formation de formes posologiques orales solides dans des antagonistes du récepteur de l'angiotensine ii |
GB0710905D0 (en) | 2007-06-07 | 2007-07-18 | Generics Uk Ltd | Amorphous olmesartan medoxomil |
CN101066264A (zh) * | 2007-06-12 | 2007-11-07 | 杨喜鸿 | 奥美沙坦酯的固体分散体及其制备方法和药物应用 |
CN101313907A (zh) * | 2008-07-07 | 2008-12-03 | 北京润德康医药技术有限公司 | 一种用于治疗高血压的药用组合物 |
-
2011
- 2011-01-04 CA CA2785920A patent/CA2785920A1/fr not_active Abandoned
- 2011-01-04 WO PCT/EP2011/050061 patent/WO2011083112A2/fr active Application Filing
- 2011-01-04 EP EP11701630.3A patent/EP2521540A2/fr not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO2011083112A2 * |
Also Published As
Publication number | Publication date |
---|---|
WO2011083112A2 (fr) | 2011-07-14 |
CA2785920A1 (fr) | 2011-07-14 |
WO2011083112A3 (fr) | 2011-12-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1275391B1 (fr) | Composition pharmaceutique contenant de l'irbesartan et un diurétique | |
CA2846387C (fr) | Procedes de traitement de troubles cardiovasculaires | |
AU2007297333B2 (en) | Solid dosage form of olmesartan medoxomil and amlodipine | |
US20020098241A1 (en) | High drug load immediate and modified release oral dosage formulations and processes for their manufacture | |
JP5295123B2 (ja) | 新規医薬組成物 | |
CA2644179C (fr) | Composition pharmaceutique inedite comprenant une matrice de desintegration | |
AU2012303683A1 (en) | Methods for treating cardiovascular disorders | |
AU2005338461A1 (en) | Pharmaceutical compositions of telmisartan | |
CA2706292A1 (fr) | Une formulation pharmaceutique stable renfermant du telmisartan et de l'hydrochlorothiazide | |
JP6302802B2 (ja) | カルシウム拮抗薬/アンジオテンシンii受容体拮抗薬含有医薬製剤の製造方法 | |
US20120107397A1 (en) | Pharmaceutical compositions of valsartan | |
JP5854371B2 (ja) | カルシウム拮抗薬/アンジオテンシンii受容体拮抗薬含有医薬製剤 | |
WO2009013237A2 (fr) | Composition pharmaceutique solide stable comprenant du candesartan ou ses formes pharmaceutiquement acceptables | |
AU750611B2 (en) | High drug load immediate and modified release oral dosage formulations and processes for their manufacture | |
WO2007080074A1 (fr) | Composition pharmaceutique solide comprenant de l’irbesartan | |
TWI414310B (zh) | 溶出性改善之醫藥品組成物 | |
CN109481437B (zh) | 一种氯沙坦钾药物制剂 | |
TW200835525A (en) | Method for improvement of elution | |
EP2521540A2 (fr) | Forme posologique orale solide contenant de l'olmésartan médoxomil | |
WO2010026470A1 (fr) | Formes posologiques stables d’agents antihypertenseurs | |
CN111557924A (zh) | 一种奥美沙坦酯氢氯噻嗪片的制备方法及奥美沙坦酯氢氯噻嗪片 | |
KR20090052944A (ko) | 이르베사르탄을 함유하는 제약 조성물 | |
JP2017008018A (ja) | 溶出改善されたオルメサルタンメドキソミル錠 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20120626 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20140211 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: RATIOPHARM GMBH |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20170425 |