EP2568959A2 - Formulations comprising a third generation cephalosporin and clavulanic acid - Google Patents
Formulations comprising a third generation cephalosporin and clavulanic acidInfo
- Publication number
- EP2568959A2 EP2568959A2 EP11743665A EP11743665A EP2568959A2 EP 2568959 A2 EP2568959 A2 EP 2568959A2 EP 11743665 A EP11743665 A EP 11743665A EP 11743665 A EP11743665 A EP 11743665A EP 2568959 A2 EP2568959 A2 EP 2568959A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical formulation
- formulation according
- agent
- generation cephalosporin
- sodium
- 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- Withdrawn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
- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 40
- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 40
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 40
- 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 title claims abstract description 35
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960003324 clavulanic acid Drugs 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims description 57
- 238000009472 formulation Methods 0.000 title claims description 44
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 60
- 239000013543 active substance Substances 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 51
- 239000003795 chemical substances by application Substances 0.000 claims description 36
- 235000002639 sodium chloride Nutrition 0.000 claims description 23
- 229960003719 cefdinir Drugs 0.000 claims description 20
- 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 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical class [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 235000015165 citric acid Nutrition 0.000 claims description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 16
- 239000001509 sodium citrate Substances 0.000 claims description 15
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 15
- 229940038773 trisodium citrate Drugs 0.000 claims description 15
- 229960004086 ceftibuten Drugs 0.000 claims description 13
- SSWTVBYDDFPFAF-DKOGRLLHSA-N ceftibuten dihydrate Chemical compound O.O.S1C(N)=NC(C(=C\CC(O)=O)\C(=O)N[C@@H]2C(N3C(=CCS[C@@H]32)C(O)=O)=O)=C1 SSWTVBYDDFPFAF-DKOGRLLHSA-N 0.000 claims description 13
- 235000003599 food sweetener Nutrition 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000003755 preservative agent Substances 0.000 claims description 13
- 239000003765 sweetening agent Substances 0.000 claims description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- -1 glidants Substances 0.000 claims description 10
- 239000007884 disintegrant Substances 0.000 claims description 9
- 239000000796 flavoring agent Substances 0.000 claims description 9
- 235000013355 food flavoring agent Nutrition 0.000 claims description 9
- 239000000230 xanthan gum Substances 0.000 claims description 9
- 235000010493 xanthan gum Nutrition 0.000 claims description 9
- 229920001285 xanthan gum Polymers 0.000 claims description 9
- 229940082509 xanthan gum Drugs 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 229920002472 Starch Polymers 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
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
- 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 6
- 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 6
- 230000003115 biocidal effect Effects 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000003906 humectant Substances 0.000 claims description 6
- 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 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 6
- 235000010234 sodium benzoate Nutrition 0.000 claims description 6
- 239000004299 sodium benzoate Substances 0.000 claims description 6
- 229960004793 sucrose Drugs 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
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 6
- 239000004549 water soluble granule Substances 0.000 claims description 6
- 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 5
- 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
- 229960004069 cefditoren Drugs 0.000 claims description 5
- 229960002129 cefixime Drugs 0.000 claims description 5
- 229960005090 cefpodoxime Drugs 0.000 claims description 5
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- 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 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 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 4
- 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 4
- 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 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 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 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 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 4
- 239000007853 buffer solution Substances 0.000 claims description 4
- 239000001175 calcium sulphate Substances 0.000 claims description 4
- 235000011132 calcium sulphate Nutrition 0.000 claims description 4
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 4
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 4
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 4
- 229960004041 cefetamet Drugs 0.000 claims description 4
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 235000013681 dietary sucrose Nutrition 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 229960001031 glucose Drugs 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
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- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 4
- 239000000395 magnesium oxide Substances 0.000 claims description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 4
- 235000012245 magnesium oxide Nutrition 0.000 claims description 4
- 239000000391 magnesium silicate Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- 150000004684 trihydrates Chemical group 0.000 claims description 4
- 239000000811 xylitol Substances 0.000 claims description 4
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 239000003826 tablet Substances 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
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- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
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- XSPUSVIQHBDITA-KXDGEKGBSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(5-methyltetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-KXDGEKGBSA-N 0.000 description 1
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- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
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- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
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- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- ZJGQFXVQDVCVOK-MSUXKOGISA-N cefovecin Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1[C@@H]1CCCO1 ZJGQFXVQDVCVOK-MSUXKOGISA-N 0.000 description 1
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- LNZMRLHZGOBKAN-KAWPREARSA-N cefpimizole Chemical compound N1=CNC(C(=O)N[C@@H](C(=O)N[C@@H]2C(N3C(=C(C[N+]=4C=CC(CCS(O)(=O)=O)=CC=4)CS[C@@H]32)C([O-])=O)=O)C=2C=CC=CC=2)=C1C(=O)O LNZMRLHZGOBKAN-KAWPREARSA-N 0.000 description 1
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- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 description 1
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- WJXAHFZIHLTPFR-JLRJEBFFSA-N ceftiolene Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C\SC1=NNC(=O)C(=O)N1CC=O WJXAHFZIHLTPFR-JLRJEBFFSA-N 0.000 description 1
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- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
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- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
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- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
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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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- the present invention relates to pharmaceutical formulations comprising a third generation cephalosporin together with clavulanic acid and/or derivatives thereof as the active agents.
- cefdaloxim cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefovecin, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefetamet belong to the group of the third generation cephalosporins.
- Clavulanic acid is a beta-lactamase inhibitor.
- Clavulanic acid and derivatives thereof e.g. its salts such as potassium clavulanate
- beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta- lactamase enzymes.
- EP0593573 discloses a formulation relating to suspension forms comprising beta-lactam antibiotics, especially amoxicillin and ampicillin, with beta lactamase inhibitors.
- suspension forms are not preferable since they have the potential of high and/or uncontrolled dose intake; they have problems in their physical and chemical stability, they have high manufacture costs and they cause problems in use and carrying.
- water dispersible tablets have been developed in order to improve the bioavailability of the antibiotic and to have them disintegrate faster.
- the patent application numbered in EP 0282200 discloses dispersible formulations comprising an amphoteric beta- lactam antibiotic and as disintegrants, a cellulose product and low-substituted hydroxypropylcellulose.
- clavulanic acid and its pharmaceutically acceptable derivatives are highly sensitive to conditions such as humidity and pH, for this reason it is very difficult to prepare stable and water soluble formulations wherein clavulanic acid or its pharmaceutically acceptable derivatives and third generation cephalosporins are used in combined form.
- the inventors have surprisingly found that the water soluble dosage forms comprising third generation cephalosporin antibiotics and clavulanic acid derivatives pertaining to the present invention overcome the problems encountered in the prior art.
- Subject of the present invention relates to water soluble pharmaceutical formulations comprising the third generation cephalosporins and clavulanic acid and/or derivatives thereof.
- formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof entirely dissolve in water when a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer system and the ratio of the first pH agent having pKa value of 1-5, preferably 2-4 to the second pH agent having the pKa value of 5.1-15, preferably 5.5-12 is in the range of 3:l to 1 :1.
- the inventors have found that the formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof according to the present invention have solved both the solubility problem of cefdinir and the stability problem of clavulanic acid and thereby a stable water soluble formulations comprising a combination of a third generation cephalosporin and clavulanic acid have been obtained.
- the first aspect of the present invention is the water soluble formulations comprising a third generation cephalosporin and clavulanic acid and/or derivatives thereof in which a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer solution and the ratio of the first pH agent having pKa value of 1 -5 to the second pH agent having the pKa value of 5.1-15 is in the range of 3:1 to 1 :1.
- the water soluble formulations according to present invention can be in the form of powder, granule or tablet.
- the third generation cephalosporin that can be used in water soluble formulations of the present invention is used in 2%-15%, preferably 2%-12%, more preferably 3%-10% of the unit dose.
- the third generation cephalosporin that can be used in water soluble formulations of the present invention can be selected from the group comprising cefpodoxime, cefditoren, ceftibuten, cefdinir, cefixime, cefetamet.
- ceftibuten or cefdinir is used in scope of the present invention.
- the third generation cephalosporin that can be used in water soluble formulations of the present invention can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
- cefpodoxime is used in the present invention it is preferably used in its ester form, more preferably in cefpodoxime proxetil form.
- cefditoren is used in the present invention it is preferably used in its ester form, more preferably in cefditoren pivoxil form.
- cefixime is used in the present invention it is preferably used in its hydrate form, more preferably in trihydrate form.
- ceftibuten is used in the present invention it is preferably used in its hydrate form, more preferably in dihydrate and/or trihydrate form.
- cefdinir is used in the present invention it is preferably used in free form.
- Clavulanic acid that can be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, alkaline metal salts, alkaline earth metal salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
- potassium clavulanate is used in the present invention.
- the first pH agent which has pKa in the range of 1-5, preferably 2-4, to be used in the formulation of the present invention can be selected from, but not limited to, citric acid and malic acid or a combination thereof.
- citric acid is used.
- the second pH agent which has pKa in the range of 5.1-15, preferably 5.5-12, to be used in the formulation of the present invention can be selected from, tribasic calcium phosphate, monosodium glutamate, potassium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof.
- trisodium citrate is used.
- the water soluble formulations comprising cefdinir or ceftibuten and clavulanate in which cefdinir or ceftibuten is used in 2%-15% of the unit dose; citric acid and trisodium citrate are used to form a buffer system and the ratio of citric acid to trisodium citrate is in the range of 3 : 1 to 1 : 1.
- Another aspect of the present invention is water soluble formulations comprising pharmaceutically acceptable excipients in addition to the combination of the third generation cephalosporins and clavulanic acid and/or derivatives thereof as the active agents and the pH agents.
- various excipients selected from, but not limited to, the group comprising sweeteners, preservative agents, viscosity agents, glidants, lubricants, disintegrants, diluents and flavoring agents can be used in addition to the third generation cephalosporin, clavulanic acid and pH agents.
- the sweetener to be used in the formulation of the present invention can be selected from, but not limited to, a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, sugar, maltose, sorbitol, saccharine, saccharine sodium, saccharose, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
- saccharose is used as the sweetener in the present invention.
- the preservative agent to be used in the formulation of the present invention can be selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
- sodium benzoate is used as the preservative agent.
- the viscosity agent to be used in the formulation of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrin, polyvinyl alcohol or combinations thereof.
- xanthan gum is used in the present invention.
- the ratio of the third generation cephalosporin to xanthan gum is an important parameter influencing the dispersion time of the water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof. They have found that the dispersion time of the granules and powders comprising the formulations according to present invention in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1, preferably 8:1 to 13:1, more preferably 9:1 to 12:1 is shorter compared to the formulations comprising xanthan gum less or more than this amount.
- another aspect of the present invention is water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1.
- the glidant that can be used in the pharmaceutical combination of 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.
- silicon dioxide is used as the glidant.
- the lubricant that can be used in the pharmaceutical formulation of 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 or a combination thereof.
- magnesium stearate is used as the lubricant in the pharmaceutical formulation pertaining to the present invention.
- the disintegrant that can be used in the pharmaceutical formulation pertaining to the present invention can be selected from, but not limited to, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
- the diluent that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, 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.
- clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this can be used.
- Clavulanic acid and its derivatives are extremely sensitive to moisture. Therefore, potassium clavulanate is used together with a humectant in the ratio of 1 : 1 in the pharmaceutical formulation of the present invention.
- the humectant that can be used in the pharmaceutical formulation of the present invention can be selected from silica, colloidal silica, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, starch, syloid, microcrystalline cellulose and talc.
- syloid or microcrystalline cellulose is used as humectants.
- potassium clavulanate is used with syloid or microcrystalline cellulose preferably in the ratio of 1 : 1.
- the amount of the third generation cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline or amorphous forms that the pharmaceutical formulation of the present invention can comprise is in the range of 2% to 15% with respect to the total weight of the unit dose.
- the pharmaceutical formulation of the present invention can comprise clavulanic acid in the range of 5% to 30% with respect to the total weight of the unit dose or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this.
- the pharmaceutical formulation of the present invention can comprise 2-15% a third generation cephalosporin, 5-30% potassium clavulanate, 0.1-4% glidant, 0.2-3% lubricant, 0- 20% disintegrant and/or disintegrants, 0-15% diluent, 30-90% sweetener, 0.5-4% pH agent, 0.1-2% preservative agent, 0.2-4% viscosity agent and 0.1-5% flavoring agent by weight with respect to the total weight of the unit dose.
- the present invention relates to processes that can be used for preparation of the pharmaceutical formulations comprising pharmaceutically acceptable excipients in addition to the third generation cephalosporin and clavulanic acid or derivatives thereof as the active agent.
- the process in scope of the present invention comprises granulation of the active agents, in other words third generation cephalosporin and clavulanic acid or derivatives thereof by conventional wet and/or dry granulation methods; or mixing the third generation cephalosporin, clavulanic acid derivatives and the other excipients by dry blending method and then pulverizing them, optionally compressing the obtained mixture in tablet form.
- Another aspect of the present invention is the use of the pharmaceutical formulation prepared according to the present invention in the treatment of diseases related to infection caused by gram positive and gram negative bacteria.
- Another aspect of the present invention is the use of the pharmaceutical formulation prepared according to the present invention in the production 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 production of a medicament so as to
- EXAMPLE 1 Formulation and process for preparation of water soluble granule comprising ceftibuten and potassium clavulanate
- trisodium citrate is in the range of 3:1 to 1 :1, specifically 1.3:1.
- Ceftibuten, potassium clavulanate :syloid, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, then mixed.
- the lubricant is added into the obtained mixture and the powder mixture is filled into sachets.
- EXAMPLE 2 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
- Cefdinir, potassium clavulanate microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed.
- the lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
- COMPARATIVE EXAMPLE 1 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
- Cefdinir, potassium clavulanate microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed.
- the lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
- COMPARATIVE EXAMPLE 2 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
- Cefdinir, potassium clavulanate microcrystalline cellulose, sweetener, viscosity agent, citric acid, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
- COMPARATIVE EXAMPLE 3 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
- Cefdinir, potassium clavulanatermicrocrystalline cellulose, sweetener, viscosity agent, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed.
- the lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
- Table 1 indicates the comparative data of dissolution of the formulations for each example.
- Table 1 Comparative Data of Dissolution of Cefdinir/ Ceftibuten Formulations in Water Soluble Form
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Abstract
The present invention relates to pharmaceutical formulations comprising a third generation cephalosporin and clavulanic acid and/or derivatives thereof as the active agent.
Description
FORMULATIONS COMPRISING A THIRD GENERATION CEPHALOSPORIN
AND CLAVULANIC ACID
The present invention relates to pharmaceutical formulations comprising a third generation cephalosporin together with clavulanic acid and/or derivatives thereof as the active agents.
Background of the Invention:
Third generation cephalosporins which are broad spectrum antibiotics are known to have antibacterial effect both on gram positive and gram negative bacteria.
The compounds known as cefdaloxim, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefovecin, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefetamet belong to the group of the third generation cephalosporins.
Clavulanic acid is a beta-lactamase inhibitor. Clavulanic acid and derivatives thereof (e.g. its salts such as potassium clavulanate) are known as beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta- lactamase enzymes.
The patent numbered EP0593573 discloses a formulation relating to suspension forms comprising beta-lactam antibiotics, especially amoxicillin and ampicillin, with beta lactamase inhibitors.
However, suspension forms are not preferable since they have the potential of high and/or uncontrolled dose intake; they have problems in their physical and chemical stability, they have high manufacture costs and they cause problems in use and carrying.
Alternatively, water dispersible tablets have been developed in order to improve the bioavailability of the antibiotic and to have them disintegrate faster. The patent application numbered in EP 0282200 discloses dispersible formulations comprising an amphoteric beta- lactam antibiotic and as disintegrants, a cellulose product and low-substituted hydroxypropylcellulose.
However, some problems have been observed in water dispersible formulations comprising third generation cephalosporin antibiotics due to low solubility of them. Although the third generation cephalosporins have broad spectrum, their water solubility is low, which leads to
low dissolution and absorption of the third generation cephalosporin antibiotic and slow dispersion of their water dispersible formulations.
Furthermore, clavulanic acid and its pharmaceutically acceptable derivatives are highly sensitive to conditions such as humidity and pH, for this reason it is very difficult to prepare stable and water soluble formulations wherein clavulanic acid or its pharmaceutically acceptable derivatives and third generation cephalosporins are used in combined form.
As is seen, new formulations comprising third generation cephalosporin antibiotics and clavulanic acid derivatives are required to be developed in order to provide new dosage forms which disperse quickly by providing the entire dissolution of the antibiotic in water.
The inventors have surprisingly found that the water soluble dosage forms comprising third generation cephalosporin antibiotics and clavulanic acid derivatives pertaining to the present invention overcome the problems encountered in the prior art.
Description of the Invention
Subject of the present invention relates to water soluble pharmaceutical formulations comprising the third generation cephalosporins and clavulanic acid and/or derivatives thereof. Surprisingly, it was found that formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof entirely dissolve in water when a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer system and the ratio of the first pH agent having pKa value of 1-5, preferably 2-4 to the second pH agent having the pKa value of 5.1-15, preferably 5.5-12 is in the range of 3:l to 1 :1.
The inventors have found that the formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof according to the present invention have solved both the solubility problem of cefdinir and the stability problem of clavulanic acid and thereby a stable water soluble formulations comprising a combination of a third generation cephalosporin and clavulanic acid have been obtained.
The first aspect of the present invention is the water soluble formulations comprising a third generation cephalosporin and clavulanic acid and/or derivatives thereof in which a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH
agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer solution and the ratio of the first pH agent having pKa value of 1 -5 to the second pH agent having the pKa value of 5.1-15 is in the range of 3:1 to 1 :1.
The water soluble formulations according to present invention can be in the form of powder, granule or tablet.
The third generation cephalosporin that can be used in water soluble formulations of the present invention is used in 2%-15%, preferably 2%-12%, more preferably 3%-10% of the unit dose.
The third generation cephalosporin that can be used in water soluble formulations of the present invention can be selected from the group comprising cefpodoxime, cefditoren, ceftibuten, cefdinir, cefixime, cefetamet.
Preferably, ceftibuten or cefdinir is used in scope of the present invention.
The third generation cephalosporin that can be used in water soluble formulations of the present invention can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
In the case that cefpodoxime is used in the present invention it is preferably used in its ester form, more preferably in cefpodoxime proxetil form.
In the case that cefditoren is used in the present invention it is preferably used in its ester form, more preferably in cefditoren pivoxil form.
In the case that cefixime is used in the present invention it is preferably used in its hydrate form, more preferably in trihydrate form.
In the case that ceftibuten is used in the present invention it is preferably used in its hydrate form, more preferably in dihydrate and/or trihydrate form.
In the case that cefdinir is used in the present invention it is preferably used in free form.
Clavulanic acid that can be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, alkaline
metal salts, alkaline earth metal salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
Preferably, potassium clavulanate is used in the present invention.
The first pH agent, which has pKa in the range of 1-5, preferably 2-4, to be used in the formulation of the present invention can be selected from, but not limited to, citric acid and malic acid or a combination thereof. Preferably, citric acid is used.
The second pH agent, which has pKa in the range of 5.1-15, preferably 5.5-12, to be used in the formulation of the present invention can be selected from, tribasic calcium phosphate, monosodium glutamate, potassium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof. Preferably, trisodium citrate is used.
Another aspect of the present invention, the water soluble formulations comprising cefdinir or ceftibuten and clavulanate in which cefdinir or ceftibuten is used in 2%-15% of the unit dose; citric acid and trisodium citrate are used to form a buffer system and the ratio of citric acid to trisodium citrate is in the range of 3 : 1 to 1 : 1.
Another aspect of the present invention is water soluble formulations comprising pharmaceutically acceptable excipients in addition to the combination of the third generation cephalosporins and clavulanic acid and/or derivatives thereof as the active agents and the pH agents.
In the formulation of the present invention, various excipients selected from, but not limited to, the group comprising sweeteners, preservative agents, viscosity agents, glidants, lubricants, disintegrants, diluents and flavoring agents can be used in addition to the third generation cephalosporin, clavulanic acid and pH agents.
The sweetener to be used in the formulation of the present invention can be selected from, but not limited to, a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, sugar, maltose, sorbitol, saccharine, saccharine sodium, saccharose, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof. Preferably, saccharose is used as the sweetener in the present invention.
The preservative agent to be used in the formulation of the present invention can be selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium
ascorbate, sodium benzoate or combinations thereof. Preferably, sodium benzoate is used as the preservative agent.
The viscosity agent to be used in the formulation of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrin, polyvinyl alcohol or combinations thereof. Preferably, xanthan gum is used in the present invention.
Based on the studies of the inventors, it has been observed that the ratio of the third generation cephalosporin to xanthan gum is an important parameter influencing the dispersion time of the water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof. They have found that the dispersion time of the granules and powders comprising the formulations according to present invention in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1, preferably 8:1 to 13:1, more preferably 9:1 to 12:1 is shorter compared to the formulations comprising xanthan gum less or more than this amount.
According to this, another aspect of the present invention is water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1.
The glidant that can be used in the pharmaceutical combination of 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. Preferably, silicon dioxide is used as the glidant.
The lubricant that can be used in the pharmaceutical formulation of 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 or a combination thereof. Preferably, magnesium stearate is used as the lubricant in the pharmaceutical formulation pertaining to the present invention.
The disintegrant that can be used in the pharmaceutical formulation pertaining to the present invention can be selected from, but not limited to, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon
dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
The diluent that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, 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.
In the pharmaceutical formulation of the present invention, 20-700 mg of a third generation cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this can be used.
In the pharmaceutical formulation of the present invention, 50-450 mg of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this can be used.
Clavulanic acid and its derivatives (e.g. potassium clavulanate) are extremely sensitive to moisture. Therefore, potassium clavulanate is used together with a humectant in the ratio of 1 : 1 in the pharmaceutical formulation of the present invention.
The humectant that can be used in the pharmaceutical formulation of the present invention can be selected from silica, colloidal silica, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, starch, syloid, microcrystalline cellulose and talc. Preferably, syloid or microcrystalline cellulose is used as humectants.
In the pharmaceutical formulation of the present invention, potassium clavulanate is used with syloid or microcrystalline cellulose preferably in the ratio of 1 : 1.
The amount of the third generation cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline or amorphous forms that the pharmaceutical formulation of the present invention can comprise is in the range of 2% to 15% with respect to the total weight of the unit dose.
The pharmaceutical formulation of the present invention can comprise clavulanic acid in the range of 5% to 30% with respect to the total weight of the unit dose or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this.
The pharmaceutical formulation of the present invention can comprise 2-15% a third generation cephalosporin, 5-30% potassium clavulanate, 0.1-4% glidant, 0.2-3% lubricant, 0- 20% disintegrant and/or disintegrants, 0-15% diluent, 30-90% sweetener, 0.5-4% pH agent, 0.1-2% preservative agent, 0.2-4% viscosity agent and 0.1-5% flavoring agent by weight with respect to the total weight of the unit dose.
In another aspect, the present invention relates to processes that can be used for preparation of the pharmaceutical formulations comprising pharmaceutically acceptable excipients in addition to the third generation cephalosporin and clavulanic acid or derivatives thereof as the active agent.
According to this, the process in scope of the present invention comprises granulation of the active agents, in other words third generation cephalosporin and clavulanic acid or derivatives thereof by conventional wet and/or dry granulation methods; or mixing the third generation cephalosporin, clavulanic acid derivatives and the other excipients by dry blending method and then pulverizing them, optionally compressing the obtained mixture in tablet form.
Another aspect of the present invention is the use of the pharmaceutical formulation prepared according to the present invention in the treatment of diseases related to infection caused by gram positive and gram negative bacteria.
Another aspect of the present invention, on the other hand, is the use of the pharmaceutical formulation prepared according to the present invention in the production 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.
The pharmaceutical formulation pertaining to the present invention can be prepared as described below, but not limited to the examples given.
EXAMPLE 1 : Formulation and process for preparation of water soluble granule comprising ceftibuten and potassium clavulanate
*Citric acid: trisodium citrate is in the range of 3:1 to 1 :1, specifically 1.3:1.
Ceftibuten, potassium clavulanate :syloid, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, then mixed. The lubricant is added into the obtained mixture and the powder mixture is filled into sachets.
EXAMPLE 2: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
Cefdinir, potassium clavulanate: microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
COMPARATIVE EXAMPLE 1: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
*Citric acid: trisodium citrate is 5:1
Cefdinir, potassium clavulanate: microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
4
COMPARATIVE EXAMPLE 2: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
*Only citric acid is used
Cefdinir, potassium clavulanate: microcrystalline cellulose, sweetener, viscosity agent, citric acid, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
COMPARATIVE EXAMPLE 3: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
*Only trisodium citrate is used
Cefdinir, potassium clavulanatermicrocrystalline cellulose, sweetener, viscosity agent, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
Results:
The inventors have studied on the dissolution data of the formulations illustrated in each example given above. According to the studies based on the comparison of their dissolution data, the results represented in Table 1 are observed. Table 1 indicates the comparative data of dissolution of the formulations for each example.
Table 1: Comparative Data of Dissolution of Cefdinir/ Ceftibuten Formulations in Water Soluble Form
The results of the dissolution data of formulations of Example 1, Example 2, Comparative example 1, Comparative example 2, Comparative example 3 clearly indicate that the formulations comprising cefdinir or ceftibuten and potassium clavulanate of the present invention in which citric acid and trisodium citrate are used and citric acid: trisodium citrate ratio by weight is in the range of 3:1 to 1 :1, as shown in example 1 and example 2, have higher dissolution rate values compared to the others.
Claims
1. A water soluble pharmaceutical formulation comprising a third generation cephalosporin and clavulanic 'acid and/or derivatives thereof in which a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5 and the other has pKa in the range of 5.1-15 are used to form a buffer system and the ratio of the first pH agent having pKa value of 1-5 to the second pH agent having the pKa value of 5.1-15 is in the range of 3:1 to 1:1.
2. The pharmaceutical formulation according to claim 1, wherein said pharmaceutical formulation is in the formof water soluble powder, granule or tablet.
3. The pharmaceutical formulation according to claim 1, wherein the third generation cephalosporin used in said formulation is selected from a group comprising cefpodoxime, cefditoren, ceftibuten, cefdinir, cefixime, cefetamet.
4. The pharmaceutical formulation according to claim 3, wherein ceftibuten or cefdinir is used.
5. The pharmaceutical formulation according to claim 3, wherein the third generation cephalosporin is in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous form or in free form and/or a combination thereof.
6. The pharmaceutical formulation according to claim 5, wherein cefpodoxime is used in ester form, preferably as cefpodoxime proxetil.
7. The pharmaceutical formulation according to claim 5, wherein cefditoren is used in ester form, preferably as cefditoren pivoxil.
8. The pharmaceutical formulation according to claim 5, wherein ceftibuten is used in dihydrate and/or trihydrate form.
9. The pharmaceutical formulation according to claim 5, wherein cefdinir is used in free form.
10. The pharmaceutical formulation according to claim 5, wherein cefixime is used in trihydrate form.
11. The pharmaceutical formulation according to claim 1, wherein clavulanic acid is in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or a combination thereof.
12. The pharmaceutical formulation according to claim 11, wherein potassium clavulanate salt is used.
13. The pharmaceutical formulation according to claim 1, wherein the first pH agent having pKa value in the range of 1 -5 is selected from citric acid and malic acid.
14. The pharmaceutical formulation according to claim 13, wherein citric acid is used as the first pH agent.
15. The pharmaceutical formulation according to claim 1, wherein the second pH agent having pKa value in the range of 5.1-15 is selected from tribasic calcium phosphate, monosodium glutamate, potassium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof.
16. The pharmaceutical formulation according to claim 15, wherein trisodium citrate is used as the second pH agent.
17. The pharmaceutical formulation according to claim 1, wherein said formulation comprises pharmaceutically acceptable excipients in addition to the combination of the third generation cephalosporin, clavulanic acid and/or derivatives thereof and pH agents.
18. The pharmaceutical formulation according to claim 17, wherein sweeteners, preservative agents, viscosity agents, glidants, lubricants, disintegrants, diluents and flavoring agents can be used in said formulation apart from the third generation cephalosporin, potassium clavulanate and pH agents.
19. The pharmaceutical formulation according to claim 18, wherein the sweetener is selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, sugar, maltose, sorbitol, saccharine, saccharine sodium, saccharose, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
20. The pharmaceutical formulation according to claim 19, wherein saccharose is used as the sweetener.
21. The pharmaceutical formulation according to claim 18, wherein the preservative agent is selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
22. The pharmaceutical formulation according to claim 21, wherein sodium benzoate is used as the preservative agent.
23. The pharmaceutical formulation according to claim 18, wherein the viscosity agent is selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrin, polyvinyl alcohol or combinations thereof.
24. The pharmaceutical formulation according to claim 23, wherein xanthan gum is used as the viscosity agent.
25. The pharmaceutical formulation according to claim 24, wherein the ratio of the third generation cephalosporin to xanthan gum is in the range of 7: 1 to 15:1.
26. The pharmaceutical formulation according to claim 18, wherein the glidant is selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or a combination thereof.
27. The pharmaceutical formulation according to claim 26, wherein silicon dioxide is used as the glidant.
28. The pharmaceutical formulation according to claim 18, wherein the lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate or a combination thereof.
29. The pharmaceutical formulation according to claim 28, wherein magnesium stearate is used as the lubricant.
30. The pharmaceutical formulation according to claim 18, wherein the disintegrant is selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropylcellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
31. The pharmaceutical formulation according to claim 18, 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 or combinations thereof.
32. The pharmaceutical formulation according to claim 1, wherein said formulation comprises 20-700 mg of a third generation cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in quantities equal to this.
33. The pharmaceutical formulation according to claim 1, wherein said formulation comprises 50-450 mg of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in quantities equal to this.
34. The pharmaceutical formulation according to claim 1, wherein clavulanic acid and/or derivatives thereof are used with a humectant in the ratio of 1 : 1.
35. The pharmaceutical formulation according to claim 34, wherein the humectant is selected from a group comprising silica, colloidal silica, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, starch, syloid, microcrystalline cellulose and talc.
36. The pharmaceutical formulation according to claim 35, wherein syloid or microcrystalline cellulose is used as humectant.
37. The pharmaceutical formulation according to claim 1, wherein said formulation comprises clavulanic acid in the range of 5% to 30% or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an amount equal to this.
38. The pharmaceutical formulation according to claim 1, wherein said formulation comprises 2-15% a third generation cephalosporin, 5-30% potassium clavulanate, 0.1- 4% glidant, 0.2-3% lubricant, 0-20% disintegrant and/or disintegrants, 0-15% diluent, 30-90% sweetener, 0.5-4% pH agent, 0.1-2% preservative agent, 0.2-4% viscosity agent and 0.1-5% flavoring agent with respect to the total weight of the unit dose.
39. A process for preparation of the pharmaceutical formulation according to claim 1, wherein said process is composed of the steps of granulation of the active agents third generation cephalosporin and clavulanic acid or derivatives by conventional wet and/or dry granulation methods; or mixing the third generation cephalosporin, clavulanic acid derivatives and the other excipients by dry blending method and then pulverizing them and optionally compressing the obtained mixture in tablet form, or the combined use thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201003854 | 2010-05-14 | ||
| PCT/TR2011/000124 WO2011142731A2 (en) | 2010-05-14 | 2011-05-13 | Formulations comprising a third generation cephalosporin and clavulanic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2568959A2 true EP2568959A2 (en) | 2013-03-20 |
Family
ID=44487006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP11743665A Withdrawn EP2568959A2 (en) | 2010-05-14 | 2011-05-13 | Formulations comprising a third generation cephalosporin and clavulanic acid |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2568959A2 (en) |
| WO (1) | WO2011142731A2 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2014008194A (en) | 2012-01-03 | 2015-03-19 | Zoetis Llc | A method for treating lyme disease. |
| CN103142506B (en) * | 2013-04-03 | 2015-02-25 | 天津医药集团津康制药有限公司 | Cefpodoxime proxetil granules and preparation method thereof |
| KR101420315B1 (en) | 2014-03-19 | 2014-07-17 | 남봉길 | Pharmaceutical liquid composition |
| US20170252351A1 (en) * | 2015-01-24 | 2017-09-07 | Wockhardt Limited | Antibacterial Compositions |
| US11612592B2 (en) | 2015-08-17 | 2023-03-28 | Ferring B.V. | Liquid formulations containing picosulfate and magnesium citrate |
| AR108992A1 (en) | 2016-07-08 | 2018-10-17 | Ferring Bv | STABILIZED LIQUID FORMULATIONS CONTAINING PICOSULFATE |
| KR20190039137A (en) | 2016-07-14 | 2019-04-10 | 아카오젠, 인코포레이티드 | Combination of ceftibuten and clavulanic acid for use in the treatment of bacterial infections |
| CN113194943B (en) * | 2021-03-22 | 2022-11-25 | 广州新创忆药物临床研究有限公司 | Pharmaceutical composition containing cefotaxime sulbactam or cefotaxime tazobactam with stability and antibacterial activity |
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|---|---|---|---|---|
| US20070128268A1 (en) * | 2005-12-07 | 2007-06-07 | Herwig Jennewein | Pharmaceutical compositions comprising an antibiotic |
| US20080139528A1 (en) * | 2003-12-10 | 2008-06-12 | Pujara Chetan P | Cefdinir oral suspension |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8705562D0 (en) | 1987-03-10 | 1987-04-15 | Cardiff Energy & Resources | Whey processing |
| GB9114950D0 (en) | 1991-07-11 | 1991-08-28 | Smithkline Beecham Plc | Pharmaceutical formulation |
| ATE216887T1 (en) * | 1996-02-29 | 2002-05-15 | Fujisawa Pharmaceutical Co | TABLETS CONTAINING BETA-LACTAM ANTIBIOTIC AND METHOD FOR THE PRODUCTION THEREOF |
| CN1706389A (en) * | 2005-05-26 | 2005-12-14 | 济南平志医药科技有限公司 | Effervescent cefdinir prepn and its prepn process |
| CN101129381B (en) * | 2006-08-25 | 2012-02-01 | 天津和美生物技术有限公司 | Combination of Antibiotics Containing β-Lactam Antibiotics and Ion Chelating Agents |
| CN101352424A (en) * | 2008-09-16 | 2009-01-28 | 天津市中央药业有限公司 | Cefdinir dispersible tablet and preparation method thereof |
-
2011
- 2011-05-13 EP EP11743665A patent/EP2568959A2/en not_active Withdrawn
- 2011-05-13 WO PCT/TR2011/000124 patent/WO2011142731A2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080139528A1 (en) * | 2003-12-10 | 2008-06-12 | Pujara Chetan P | Cefdinir oral suspension |
| US20070128268A1 (en) * | 2005-12-07 | 2007-06-07 | Herwig Jennewein | Pharmaceutical compositions comprising an antibiotic |
Non-Patent Citations (1)
| Title |
|---|
| See also references of WO2011142731A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011142731A2 (en) | 2011-11-17 |
| WO2011142731A3 (en) | 2012-03-08 |
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