WO2012060789A2 - Production method for cefdinir formulations - Google Patents
Production method for cefdinir formulations Download PDFInfo
- Publication number
- WO2012060789A2 WO2012060789A2 PCT/TR2011/000254 TR2011000254W WO2012060789A2 WO 2012060789 A2 WO2012060789 A2 WO 2012060789A2 TR 2011000254 W TR2011000254 W TR 2011000254W WO 2012060789 A2 WO2012060789 A2 WO 2012060789A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- cefdinir
- tablet
- cellulose
- disintegrant
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 71
- 238000009472 formulation Methods 0.000 title claims abstract description 60
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 title claims abstract description 53
- 229960003719 cefdinir Drugs 0.000 title claims abstract description 53
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 claims abstract description 52
- 239000013543 active substance Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000007884 disintegrant Substances 0.000 claims description 19
- 239000003085 diluting agent Substances 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 10
- 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 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000005469 granulation Methods 0.000 claims description 9
- 230000003179 granulation Effects 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 8
- 150000004677 hydrates Chemical class 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 6
- 229960003324 clavulanic acid Drugs 0.000 claims description 6
- 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 description 6
- 239000007941 film coated tablet Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229940069328 povidone Drugs 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
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 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 4
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 4
- 239000001175 calcium sulphate Substances 0.000 claims description 4
- 235000011132 calcium sulphate Nutrition 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 235000010981 methylcellulose Nutrition 0.000 claims description 4
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000000395 magnesium oxide Substances 0.000 claims description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000391 magnesium silicate Substances 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 235000012239 silicon dioxide Nutrition 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 235000012222 talc Nutrition 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-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
- 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 2
- 108020004256 Beta-lactamase Proteins 0.000 claims description 2
- 229930186147 Cephalosporin Natural products 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 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
- 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
- 206010017553 Furuncle Diseases 0.000 claims description 2
- 239000001828 Gelatine Substances 0.000 claims description 2
- 206010018612 Gonorrhoea Diseases 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 206010021531 Impetigo Diseases 0.000 claims description 2
- 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 2
- 206010024971 Lower respiratory tract infections Diseases 0.000 claims description 2
- 208000016604 Lyme disease Diseases 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 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
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 206010033078 Otitis media Diseases 0.000 claims description 2
- 239000008118 PEG 6000 Substances 0.000 claims description 2
- 201000007100 Pharyngitis Diseases 0.000 claims description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 206010037596 Pyelonephritis Diseases 0.000 claims description 2
- 208000006311 Pyoderma Diseases 0.000 claims description 2
- 206010057190 Respiratory tract infections Diseases 0.000 claims description 2
- 206010062255 Soft tissue infection Diseases 0.000 claims description 2
- 206010046306 Upper respiratory tract infection Diseases 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
- 102000006635 beta-lactamase Human genes 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
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 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
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 229940124587 cephalosporin Drugs 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 201000003146 cystitis Diseases 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 2
- 239000007938 effervescent tablet Substances 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 208000001786 gonorrhea Diseases 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 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
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 239000007912 modified release tablet Substances 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
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 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
- 230000002035 prolonged effect Effects 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 208000020029 respiratory tract infectious disease Diseases 0.000 claims description 2
- 229960001866 silicon dioxide Drugs 0.000 claims description 2
- 201000009890 sinusitis Diseases 0.000 claims description 2
- 206010040872 skin infection Diseases 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
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 206010044008 tonsillitis Diseases 0.000 claims description 2
- 208000000143 urethritis Diseases 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
- SPAGIJMPHSUYSE-UHFFFAOYSA-N Magnesium peroxide Chemical compound [Mg+2].[O-][O-] SPAGIJMPHSUYSE-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003906 humectant Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 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 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000004554 water soluble tablet Substances 0.000 description 2
- LBKZSKPWJDKWHL-GHXIOONMSA-N (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-hydroxyiminoacetyl]amino]-3-ethynyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound NC=1SC=C(N1)/C(/C(=O)N[C@H]1[C@H]2SCC(=C(N2C1=O)C(=O)O)C#C)=N/O LBKZSKPWJDKWHL-GHXIOONMSA-N 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- -1 Cabosil® Chemical compound 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004549 water soluble granule Substances 0.000 description 1
- 239000004552 water soluble powder Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Cefdinir the chemical name of which is (6R, 7R)-7-[[(2Z)-(2-amino-4- thiazolyl)(hydroxyimino) acetyl]amino]-3-ethynyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid, was first disclosed in the patent numbered BE897864.
- the chemical structure of cefdinir is seen in Formula 1. This third generation molecule is indicated for the treatment of infections caused by gram positive and gram negative bacteria.
- cefdinir Physically appearing as a white powder, cefdinir has quite low solubility in common organic solvents such as methanol, ethanol, acetonitrile and in water. Due to this property, some problems are seen while developing formulations comprising this molecule.
- the difficulties encountered during the production of the formulation pose problems for physical characteristics of the end production, for instance in providing dose uniformity and in parameters such as hardness and dispersion time. This is disadvantageous for patients' use of drugs and poses problems for bioavailability parameters due to the fact that finished production has not dose uniformity. Production methods in which the components are mixed by dry blending methods can be preferred in order to prevent problems that low solubility of cefnidir poses.
- disintegrant and diluent amount added in step II and step IV of the present invention is in the range of 30-80% in step II, in the range of 20-70% in step IV.
- step II use of disintegrant and diluent preferably in the range of 48-53 % in step II, and use of disintegrant and diluent in the range of 47-52% in step IV have positive effects on reducing tablet friability.
- cefdinir formulation specified above is prepared as follows by using the process of the present invention; cefdinir, 50% of total amount of the disintegrant, 50% of total amount of the diluent are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 50% of total amount of the disintegrant and 50% of total amount of the diluent and the glidant. Lubricant is added to the end mixture. Then the obtained composition is compressed in tablet form and coated with the film coating agent.
Landscapes
- 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)
- Cephalosporin Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to processes to be used for preparation of formulations comprising cefdinir as the active agent and pharmaceutical compositions to be obtained by this process.
Description
PRODUCTION METHOD FOR CEFDINIR FORMULATIONS
The present invention relates to processes that can be used for preparation of tablet forms comprising cefdinir as the active agent and pharmaceutical compositions to be obtained with this process. Background of the Invention
Cefdinir, the chemical name of which is (6R, 7R)-7-[[(2Z)-(2-amino-4- thiazolyl)(hydroxyimino) acetyl]amino]-3-ethynyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid, was first disclosed in the patent numbered BE897864. The chemical structure of cefdinir is seen in Formula 1. This third generation molecule is indicated for the treatment of infections caused by gram positive and gram negative bacteria.
Formula I
Physically appearing as a white powder, cefdinir has quite low solubility in common organic solvents such as methanol, ethanol, acetonitrile and in water. Due to this property, some problems are seen while developing formulations comprising this molecule. The difficulties encountered during the production of the formulation pose problems for physical characteristics of the end production, for instance in providing dose uniformity and in parameters such as hardness and dispersion time. This is disadvantageous for patients' use of drugs and poses problems for bioavailability parameters due to the fact that finished production has not dose uniformity. Production methods in which the components are mixed by dry blending methods can be preferred in order to prevent problems that low solubility of cefnidir poses. However, it has been seen that in the case of tabletting the formulations produced by this method, the pharmaceutical composition prepared with said process fails to provide desired tablet hardness and friability value of the said tablets are inappropriate.
One of the problems frequently encountered in development of formulations is agglomeration of the active agent when it comes into contact with water in the processes in which wet granulation is used due to its hydrophobic characteristic and correspondingly dose uniformity cannot be provided.
When the prior art is taken into consideration, there is need for new processes that can be used for preparation of formulations comprising cefdinir which are stable, have high bioavailability and long shelf life.
Surprisingly, the inventors have found that the present problems in the prior art can be solved by using the process of the present invention for preparation of the formulations comprising cefdinir. Description of the Invention
The subject matter of the present invention is use of a production method composed of the following steps for production of formulations comprising cefdinir. According to this, said process is composed of the steps that;
I. Granulation solution is prepared by dissolving the disintegrant in water.
II. 30-80% of the total diluent amount, 30-80% of the total disintegrant amount and cefdinir are sieved, mixed and granulated with prepared granulation solution in fluid bed.
III. Obtained granules are dried and sieved.
IV. Obtained granules are mixed with 20-70% of the total diluent amount, 20-70-% of the total disintegrant amount and the glidant.
V. Lubricant is added to the obtained mixture.
VI. Obtained composition is stored in an appropriate pharmaceutical dosage form. Thanks to the process of the present invention;
• Agglomeration of cefdinir is prevented when it comes into contact with water and thus dose uniformity is attained in the end product, and
• Very low friability value, for instance friability value in the range of 0,0 to 0,05, is provided in the case of tabletting the formulation prepared by this method.
According to this, another aspect of the invention is use of the process specified above for production of compositions comprising cefdinir.
The term "pharmaceutical dosage forms" specified in the text comprises solid oral dosage forms such as tablet, film-coated tablet, capsule, prolonged-release tablet, modified-release tablet, effervescent tablet, orodispersible tablet, sachet, dry powder to form suspension and liquid dosage forms such as suspension. Preferably, formulations of the present invention are in tablet form.
Cefdinir which can be used in water soluble powder, tablet and granule formulations of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or the combination thereof. The water used as granulation solution in the process of the present invention is in the form of deionized water.
The ratio of the water to cefdinir is in the range of 10:1 and 1 :1, preferably in the range of 6:1 and 2:1.
In another aspect, disintegrant and diluent amount added in step II and step IV of the present invention is in the range of 30-80% in step II, in the range of 20-70% in step IV.
As a result of the studies conducted, the inventors have found that use of disintegrant and diluent preferably in the range of 48-53 % in step II, and use of disintegrant and diluent in the range of 47-52% in step IV have positive effects on reducing tablet friability.
The binder that can be used in the formulation to be produced according to the process of the present invention can be selected from, but not limited to, a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone. Preferably, povidone is used.
The diluent that can be used in the formulation to be produced according to the process of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
The disintegrant that can be used in the formulation to be produced according to the process of the present invention can be selected from a group comprising carboxymethyl cellulose
calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.
The glidant that can be used in the formulation to be produced according to the process of the present invention can be selected from a group comprising magnesium silicate, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof. Preferably, colloidal silicon dioxide is used as glidant in the formulation of the present invention.
The lubricant that can be used in the formulation to be produced according to the process of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate. Preferably, magnesium stearate is used as lubricant in the formulation of the present invention.
The effervescent formulation to be produced with the process of the present invention can comprise 1-4000 mg cefdinir or its pharmaceutically acceptable salts, hydrates, solvates, or the combination thereof in an equivalent amount.
The effervescent formulation to be produced with the process of the present invention can comprise;
• 5-60% of cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,
• 1-10% of binder,
• 0,1-3% of lubricant,
• 0,1-5% of glidant,
• 0,1-20% of disintegrant,
• 1-30% of diluent in proportion to the total weight of unit dose amount.
The cefdinir formulation to be produced with the process of the present invention can optionally comprise a second active agent. The second active agent can be selected from cephalosporins, beta-lactamases. Preferably, clavulanic acid or its derivatives is used.
Clavulanic acid that can optionally be used in the cefdinir formulation to be prepared with the process of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or the combination thereof. Preferably, potassium clavulanate is used. The cefdinir formulation to be produced by the process of the present invention can optionally comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in an equivalent amount.
Clavulanic acid and its derivatives (e.g. potassium clavulanate) are extremely susceptible to moisture. To this respect, potassium clavulanate in the pharmaceutical composition of the present invention is preferably used with a humectant in the ratio of 1 : 1.
One or more of the substances comprising silica; 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 humectants. In the cefdinir formulation to be produced by the process of the present invention, potassium clavulanate is preferably used with microcrystalline cellulose in the ratio of 1 : 1.
The cefdinir formulation to be produced by the process of the present invention can comprise 5-90%, preferably 10-80%, more preferably 20-60% of clavulanic acid in proportion to total weight of unit dose amount or its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in an equivalent amount.
According to this, in the case of using potassium clavulanate as the second active agent in the formulation to be produced with the process of the present invention, said second active agent is included in the process with the humectant in step IV.
In another aspect, potassium clavulanate as combined with microcrystalline cellulose can be mixed with the granules comprising cefdinir along with disintegrant, glidant and diluent dryly.
Water soluble tablets of the present invention can be prepared as specified below, yet the invention is not restricted to these examples.
EXAMPLE 1: Formulation and process for preparation of film-coated tablet comprising cefdinir as the active agent.
The cefdinir formulation specified above is prepared as follows by using the process of the present invention; cefdinir, 50% of total amount of the disintegrant, 50% of total amount of the diluent are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 50% of total amount of the disintegrant and 50% of total amount of the diluent and the glidant. Lubricant is added to the end mixture. Then the obtained composition is compressed in tablet form and coated with the film coating agent.
EXAMPLE 2: The formulation and process for preparation of film-coated tablet comprising cefdinir and potassium clavulanate as the active agent.
The cefdinir formulation specified above is prepared as follows by using the process of the present invention; cefdinir, 48% of total amount of the disintegrant, 53% of total amount of
the diluent are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 52% of the total amount of the disintegrant, 47% of the total amount of the diluent, mixture of potassium clavulanate, and microcrystalline cellulose and the glidant. Lubricant is added to the end mixture. Then, the obtained composition is compressed in tablet form and coated with the film coating agent.
In another aspect, the present invention relates to use of effervescent formulations comprising pharmaceutically acceptable excipients in addition to cefdinir as the active agent in treatment of infections caused by gram positive and gram negative bacteria.
In another aspect, the pharmaceutical formulation prepared according to said invention is used for production of a drug to be used in treatment and prophylaxis of upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
Claims
1. The process so as to be used for preparation of the formulation comprising cefdinir characterised in that
I. Granulation solution is prepared by dissolving the binder in water.
II. 30-80% of total amount of the diluent, 30-80% of the total amount of the disintegrant and cefdinir are sieved, mixed and granulated with the prepared granulation solution in fluid bed.
III. Obtained granules are dried and sieved.
IV. Obtained granules are mixed with 20-70% of total amount of the diluent, 20-70% of total amount of the disintegrant and the glidant.
V. Lubricant is added to obtained mixture.
VI. Obtained composition is stored in an appropriate dosage form.
2. The process to be used for preparation of the formulation comprising cefdinir according to claim 1 , wherein the ratio of water used for granulation to cefdinir is in the range of 10:1 and 1 :1.
3. The process to be used for preparation of the formulation comprising cefdinir according to claim 2, wherein the ratio of water used for granulation to cefdinir is in the range of 6: 1 and 2:1.
4. The process to be used for preparation of the formulation comprising cefdinir according to claim 1 , wherein the amount of disintegrant and diluent added in step II and step IV of the process is in the range of 30-80% in step II, in the range of 20-70% in step IV.
5. The process to be used for preparation of the formulation comprising cefdinir according to claim 4, wherein the amount of disintegrant and diluent added in step II and step IV of the process is in the range of 48-53% in step II, 47-52% in step IV.
6. The cefdinir formulation produced with the process claimed in claim 1, wherein said formulation can be in the form of tablet, film-coated tablet, capsule, prolonged-release tablet, modified-release tablet, effervescent tablet, orodispersible tablet, sachet, dry powder to form suspension.
7. The cefdinir formulation according to claim 6, wherein said formulation is in the form of tablet or film-coated tablet.
8. The cefdinir formulation according to claim 7, wherein the friability value of the tablet or film-coated tablet is in the range of 0,0 to 0,05.
9. The cefdinir formulation produced with the process claimed in claim 1, wherein cefdinir is in the form of solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or the combination thereof.
10. The cefdinir formulation produced with the process claimed in claim 1, wherein the binder is selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone.
11. The cefdinir formulation according to claim 10, wherein povidone is used as binder.
12. The cefdinir formulation produced with the process claimed in claim 1, wherein the diluent is selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol.
13. The cefdinir formulation produced with the process claimed in claim 1, wherein the disintegrant to be used in said formulation is selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate and starch or the combinations thereof.
14. The cefdinir formulation produced with the process claimed in claim 1, wherein the glidant to be used in said formulation is selected from a group comprising magnesium silicate, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.
15. The cefdinir formulation according to claim 14, wherein silicon dioxide is preferably used as glidant.
16. The cefdinir formulation produced with the process claimed in claim 1, wherein the lubricant to be used in said formulation is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
17. The cefdinir process according to claim 16, wherein magnesium dioxide is preferably used as lubricant.
18. The formulation prepared according to process claimed in claim 1, wherein said formulation can comprise; • 5-60% of cefdinir or pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,
• 1-10% of binder,
• 0.1-3% of lubricant,
• 0.1-5% of glidant,
• 0.1 -20% of disintegrant,
• 1-30% of diluent. in proportion to the total weight of unit dose amount.
19. The formulation prepared according to the process claimed in claim 1, wherein the second active agent selected from cephalosporins, beta-lactamases can be used in addition to cefdinir.
20. The formulation according to claim 19, wherein clavulanic acid, preferably potassium clavulanate is used as the second active agent.
21. The formulation according to claim 20, wherein potassium clavulanate is included in step IV of the process claimed in claim 1.
22. The formulation prepared according to process claimed in claim 1, wherein said formulation is used for production of a drug to be used in treatment and prophylaxis of upper respiratory tract infections such as otorhinolaryngological diseases, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2010/09167 | 2010-11-05 | ||
| TR2010/09167A TR201009167A2 (en) | 2010-11-05 | 2010-11-05 | Pharmaceutical granules containing cephalosporin. |
| TR2010/10860A TR201010860A2 (en) | 2010-11-05 | 2010-12-24 | Production method for cefdinir formulations. |
| TR2010/10860 | 2010-12-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2012060789A2 true WO2012060789A2 (en) | 2012-05-10 |
| WO2012060789A3 WO2012060789A3 (en) | 2012-06-28 |
Family
ID=45607339
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2011/000258 WO2012060793A2 (en) | 2010-11-05 | 2011-11-03 | Process for the preparation of cefdinir formulations |
| PCT/TR2011/000254 WO2012060789A2 (en) | 2010-11-05 | 2011-11-03 | Production method for cefdinir formulations |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2011/000258 WO2012060793A2 (en) | 2010-11-05 | 2011-11-03 | Process for the preparation of cefdinir formulations |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR201010860A2 (en) |
| WO (2) | WO2012060793A2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE897864A (en) | 1982-09-30 | 1984-03-29 | Fujisawa Pharmaceutical Co | PROCESS FOR PRODUCING 7-SUBSTITUTED 3-VINYL-3-CEPHEM COMPOUNDS AND NOVEL PRODUCTS THUS OBTAINED |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0281200B1 (en) * | 1987-03-02 | 1994-01-19 | Yamanouchi Europe B.V. | Pharmaceutical composition, pharmaceutical granulate and process for their preparation |
| KR20050062514A (en) * | 2002-07-16 | 2005-06-23 | 랜박시 래보러터리스 리미티드 | Dispersible tablets for oral administration |
| CA2393614C (en) * | 2002-07-19 | 2003-09-30 | Abbott Laboratories | Antibacterial clarithromycin compositions and processes for making the same |
| WO2005115347A1 (en) * | 2004-05-31 | 2005-12-08 | Sam-A Pharmaceuticals Co., Ltd. | Dispersible tablet comprising beta lactam antibiotics and process for preparing the same |
| WO2007058397A1 (en) * | 2005-11-17 | 2007-05-24 | Gl Pharmtech Corp. | A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same |
-
2010
- 2010-12-24 TR TR2010/10860A patent/TR201010860A2/en unknown
-
2011
- 2011-11-03 WO PCT/TR2011/000258 patent/WO2012060793A2/en active Application Filing
- 2011-11-03 WO PCT/TR2011/000254 patent/WO2012060789A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE897864A (en) | 1982-09-30 | 1984-03-29 | Fujisawa Pharmaceutical Co | PROCESS FOR PRODUCING 7-SUBSTITUTED 3-VINYL-3-CEPHEM COMPOUNDS AND NOVEL PRODUCTS THUS OBTAINED |
Also Published As
| Publication number | Publication date |
|---|---|
| TR201010860A2 (en) | 2012-05-21 |
| WO2012060793A3 (en) | 2012-06-28 |
| WO2012060793A2 (en) | 2012-05-10 |
| WO2012060789A3 (en) | 2012-06-28 |
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