EP2568957A1 - Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique - Google Patents
Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulaniqueInfo
- Publication number
- EP2568957A1 EP2568957A1 EP11720905A EP11720905A EP2568957A1 EP 2568957 A1 EP2568957 A1 EP 2568957A1 EP 11720905 A EP11720905 A EP 11720905A EP 11720905 A EP11720905 A EP 11720905A EP 2568957 A1 EP2568957 A1 EP 2568957A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- composition according
- cefixime
- acid
- effervescent
- 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- Withdrawn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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 57
- 229960002129 cefixime Drugs 0.000 title claims abstract description 44
- -1 clavulanic acid derivative compound Chemical class 0.000 title claims description 4
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 title abstract 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims abstract description 29
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229960003324 clavulanic acid Drugs 0.000 claims abstract description 25
- 239000013543 active substance Substances 0.000 claims abstract description 9
- IPYWNMVPZOAFOQ-NABDTECSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;trihydrate Chemical compound O.O.O.S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 IPYWNMVPZOAFOQ-NABDTECSSA-N 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 239000011230 binding agent Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- 235000003599 food sweetener Nutrition 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 10
- 239000003765 sweetening agent Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000007938 effervescent tablet Substances 0.000 claims description 9
- 239000003826 tablet Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000003086 colorant Substances 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 6
- 239000000796 flavoring agent Substances 0.000 claims description 6
- 235000013355 food flavoring agent Nutrition 0.000 claims description 6
- 239000003906 humectant Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 235000012222 talc Nutrition 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 108010011485 Aspartame Proteins 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 239000008118 PEG 6000 Substances 0.000 claims description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000000605 aspartame Substances 0.000 claims description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 4
- 235000010357 aspartame Nutrition 0.000 claims description 4
- 229960003438 aspartame Drugs 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 239000008119 colloidal silica Substances 0.000 claims description 4
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 claims description 4
- 239000000391 magnesium silicate Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 241000894006 Bacteria Species 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 150000004684 trihydrates Chemical class 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910002016 Aerosil® 200 Inorganic materials 0.000 claims description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 239000004376 Sucralose Substances 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
- 229930006000 Sucrose Natural products 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960005164 acesulfame Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 239000000378 calcium silicate Substances 0.000 claims description 2
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 2
- 150000004683 dihydrates Chemical class 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229960002737 fructose Drugs 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 235000019793 magnesium trisilicate Nutrition 0.000 claims description 2
- 229910000386 magnesium trisilicate Inorganic materials 0.000 claims description 2
- 229940099273 magnesium trisilicate Drugs 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 229960002160 maltose Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000004300 potassium benzoate Substances 0.000 claims description 2
- 229940103091 potassium benzoate Drugs 0.000 claims description 2
- 235000010235 potassium benzoate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229960001462 sodium cyclamate Drugs 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims 1
- 239000008273 gelatin Substances 0.000 claims 1
- 235000011852 gelatine desserts Nutrition 0.000 claims 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OKBVVJOGVLARMR-VINNURBNSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1C(N)=NC(C(=N/OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-VINNURBNSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- 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
- A61K31/542—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- 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
- A61K31/542—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
Definitions
- the present invention relates to pharmaceutical compositions comprising clavulanic acid and/or its derivatives with cefixime as the active agents.
- Cefixime which is in the form of a white or light yellow crystal powder, easily dissolves in methanol and propylene glycol while it partially dissolves in ethanol and acetone, and barely dissolves in ether, ethyl acetate, hexane and water. Its solubility in aqueous solutions, on the other hand, varies according to the pH value.
- Clavulanic acid is a beta-lactamase inhibitor illustrated in Formula 2.
- Clavulanic acid and derivatives thereof are known as the beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta-lactamase enzymes.
- the patent numbered EP0593573 comprises a formulation relating to suspension forms of beta-lactam antibiotics and beta lactamase.
- suspension forms are not preferred much as they have the potential of high and/or uncontrolled dose intake; there appear problems in their physical and chemical stability and they cause problems in use and carrying.
- the inventors have aimed to develop stable oral pharmaceutical formulations which comprise cefixime and clavulanic acid derivatives together and eliminate the low solubility problem of cefixime.
- the subject of the present invention relates to effervescent tablets and granules comprising cefixime and clavulanic acid derivative combinations and the procedures for their preparation.
- the effervescent tablets and granules pertaining to the present invention are packed in single dose packs, and therefore uncontrolled dose intake by the patients is prevented.
- the effervescent tablet and granules comprising the active agent cefixime which are formulated according to the present invention entirely dissolve in water and form a homogeneous solution.
- Said pharmaceutical composition is characterized in comprising 5- 20% cefixime in proportion to the total weight of the unit dose. It was unexpectedly observed that the pharmaceutical compositions comprising 5-20% cefixime with respect to the total unit dose weight dissolve in water without the need of any other disintegrant.
- the present invention is characterized in that the amount of cefixime in the pharmaceutical composition comprising cefixime and cluvulanic acid in a combined form is in the range of 5-20%.
- Cefixime which can be used in effervescent tablet and granule formulations pertaining to the present invention, can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or a combination thereof.
- Cefixime to be used in scope of the present invention can be in any of the monohydrate, dihydrate, trihydrate and/or anhydrate forms.
- cefixime trihydrate is used in the formulations pertaining to the present invention.
- Cluvulanic acid which can be used in the formulations pertaining to the present invention, can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or a combination thereof.
- potassium clavulanate is used in scope of the present invention.
- compositions comprising pharmaceutically acceptable excipients along with the active agents cefixime and potassium clavulanate.
- excipients selected from, but not limited to, a group comprising glidants, lubricants, sweeteners, binders, flavoring agents, coloring agents and effervescent couple can be used in the formulation pertaining to the present invention apart from cefixime and potassium clavulanate.
- the glidant which can be used in the formulation pertaining to the present invention can be selected from, but not limited to, a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or a combination thereof.
- the lubricant pertaining to the present invention can be selected from, but not limited to, a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate.
- PEG 6000 is used as the lubricant in the pharmaceutical composition pertaining to the present invention.
- the sweetener that can be used in the pharmaceutical composition according to the present invention can be selected from a group comprising acesulfame, aspartame, fructose, maltitol, maltose, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
- aspartame is used as the sweetener in the present invention.
- the effervescent couple that can be used in the pharmaceutical composition pertaining to the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
- organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc.
- basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
- citric acid and sodium hydrogen carbonate are used in the present invention.
- cluvulanic acid and its derivatives used in the formulations pertaining to the present invention undergo degradation catalysed by acids and/or bases.
- the ratio of the effervescent couple to be used to each other plays an important role on the stability of clavulanic acid and its derivatives in the formulation.
- the inventors have - observed that clavulanic acid is stable in the pharmaceutical compositions in the case that the ratio of effervescent acid to effervescent base used in the present invention is in the range of 5:1 to 1 :1, preferably in the range of 2:1 to 1.1 :1, most preferably in the range of 1.5:1 to 1.1:1.
- another aspect of the present invention is effervescent tablet and granule formulations comprising cefixime and clavulanic acid or a combination of derivatives thereof wherein the ratio of the effervescent acid to the effervescent base is in the range of 5:1 to 1:1, preferably in the range of 2: 1 to 1.1 : 1 , most preferably in the range of 1.5 : 1 to 1.1 :1.
- the binder that can be used in the tablet and granule formulations pertaining to the present invention can be selected from a group comprising ethyl cellulose, gelatine, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide and povidone.
- povidone is used in the present invention.
- the amount of the binder used in the formulation is significant for the obtained granule to be able to turn into tablets when desired and for the product that is turned into tablets to disperse in water in shorter than 5 minutes during the formulation of effervescent tablets and granules pertaining to the present invention.
- the granules can easily be turned into tablets and the tablets can dissolve in water in shorter than 5 minutes in the case that the ratio of cefixime to the binder is in the range of 10:1 to 1:1, preferably in the range of 6:1 to 3:1 in the pharmaceutical formulations prepared in accordance with the present invention.
- another aspect of the present invention is effervescent tablet and granule formulations comprising cefixime and clavulanic acid or derivatives thereof wherein the ratio of cefixime to the binder is in the range of 10: 1 to 1:1, preferably in the range of 6: 1 to 3 : 1.
- clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof on an amount equal to this can be used.
- Clavulanic acid and its derivatives for instance, potassium clavulanate
- potassium clavulanate is preferably used with a humectant in the ratio of 1 : 1 in the present invention.
- colloidal silica for instance colloidal silica anhydrous, for example Aerosil® 200, magnesium trisilicate, cellulose powder, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose, talc can be used as the humectant.
- potassium clavulanate is preferably used with microcrystalline cellulose or syloid in the ratio of 1 : 1 , most preferably with syloid.
- the amount of cefixime or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal or amorphous forms that the pharmaceutical composition pertaining to the present invention can comprise is in the range of 5-20%, preferably in the range of 8-15% with respect to the total weight of the unit dose.
- the amount of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equal amount to it that can be used in the pharmaceutical composition pertaining to the present invention is in the range of 5-50% with respect to the total weight of the unit dose.
- the pharmaceutical composition pertaining to the present invention can comprise 5-20 % cefixime; 5-50% potassium clavulanate; 0-5% glidant; 0.1-5% lubricant; 0-5% binder; 20- 90% effervescent couple; 0,1-10% sweetener; 0.1-5% flavoring agent; 0.1-5% coloring agent with respect to the total amount of the unit dose.
- the pharmaceutical composition comprising cefixime and clavulanic acid or its derivatives which is prepared according to the present invention can be in effervescent tablet or granule form.
- the present invention relates to the processes which can be used for the preparation of pharmaceutical compositions comprising pharmaceutically acceptable excipients in addition to cefixime and clavulanic acid as the active agents.
- the process pertaining to the present invention comprises granulation of the active agents cefixime and/or clavulanic acid or its derivatives through conventional wet and/or dry granulation methods, or mixing cefixime, clavulanic acid derivatives and the other excipients -through dry blending method, then powderizing them; and optionally compressing the mixture in tablet form.
- Clavulanic acid undergoes degradation when it contacts with water, which leads to problems in the production of the products especially in granule form. Therefore, the inventors have developed a method which provides to formulate clavulanic acid without contacting water for producing the pharmaceutical compositions pertaining to the present invention.
- the said process comprises the granulation of cefixime, the binder, the effervescent couple and the sweetener with an aqueous solution; drying the granules; mixing the obtained granules with clavulanic acid and/or its derivative, the coloring agent, the flavoring agent and the lubricant, and optionally compressing tablets in the tablet compressing machine.
- the present invention relates to the use of the pharmaceutical composition in the production of a medicament so as to be used in the treatment of gram positive and gram negative bacteria.
- the pharmaceutical composition prepared according to the present invention is used in the manufacture of a medicament so as to be used in upper respiratory infections such as ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin or soft tissue infections such as froncle, pyoderma, impetigo; in the treatment and prophylaxis of gonorrhea and lyme diseases.
- upper respiratory infections such as ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis
- lower respiratory tract infections such as pyelonephritis, cystitis and urethritis
- skin or soft tissue infections such as froncle, pyoderma, impetigo
- in the treatment and prophylaxis of gonorrhea and lyme diseases in the manufacture of a medicament so as to be used in upper respiratory infections such as
- composition pertaining to the present invention can be prepared as described below, but not limited to the examples given.
- EXAMPLE 1 Formulation for the preparation of film-coated tablet comprising cefixime and potassium clavulanate
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention concerne des compositions pharmaceutiques comprenant l'acide clavulanique et/ou ses dérivés, et la céfixime qui sont utiles comme agents actifs.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201003855 | 2010-05-14 | ||
| PCT/TR2011/000119 WO2011142730A1 (fr) | 2010-05-14 | 2011-05-02 | Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2568957A1 true EP2568957A1 (fr) | 2013-03-20 |
Family
ID=44315068
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP11720905A Withdrawn EP2568957A1 (fr) | 2010-05-14 | 2011-05-02 | Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2568957A1 (fr) |
| WO (1) | WO2011142730A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2528586A1 (fr) * | 2010-01-29 | 2012-12-05 | Mahmut Bilgic | Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs |
| CN111544412A (zh) * | 2020-04-17 | 2020-08-18 | 广州白云山医药集团股份有限公司白云山制药总厂 | 头孢克肟组合物及其制备方法 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014126541A1 (fr) * | 2013-02-14 | 2014-08-21 | Bilgiç Mahmut | Compositions pharmaceutiques utilisées pour traiter des infections bactériennes |
| WO2016116892A1 (fr) * | 2015-01-24 | 2016-07-28 | Wockhardt Limited | Compositions antibactériennes |
| WO2022056401A1 (fr) * | 2020-09-11 | 2022-03-17 | Meharry Medical College | Méthodes d'identification de compositions d'inhibition d'infectivité virale |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4409214A (en) | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical, Co., Ltd. | 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof |
| GB9114950D0 (en) | 1991-07-11 | 1991-08-28 | Smithkline Beecham Plc | Pharmaceutical formulation |
| WO2007086012A1 (fr) * | 2006-01-25 | 2007-08-02 | Jegannathan Srinivas | Préparation de cefpodoxime, d'acide clavulanique et de linezolide |
| CN100417383C (zh) * | 2006-03-07 | 2008-09-10 | 中国药科大学 | 一种含有头孢克肟的泡腾片及制法 |
| TR201000687A1 (tr) * | 2010-01-29 | 2011-08-22 | Bi̇lgi̇ç Mahmut | Aktif madde olarak sefiksim ve klavulanik asit içeren efervesan formülasyonlar |
-
2011
- 2011-05-02 EP EP11720905A patent/EP2568957A1/fr not_active Withdrawn
- 2011-05-02 WO PCT/TR2011/000119 patent/WO2011142730A1/fr not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2011142730A1 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2528586A1 (fr) * | 2010-01-29 | 2012-12-05 | Mahmut Bilgic | Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs |
| CN111544412A (zh) * | 2020-04-17 | 2020-08-18 | 广州白云山医药集团股份有限公司白云山制药总厂 | 头孢克肟组合物及其制备方法 |
| CN111544412B (zh) * | 2020-04-17 | 2022-06-24 | 广州白云山医药集团股份有限公司白云山制药总厂 | 头孢克肟组合物及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011142730A1 (fr) | 2011-11-17 |
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