EP2515858A1 - Pharmaceutical composition with high purity - Google Patents
Pharmaceutical composition with high purityInfo
- Publication number
- EP2515858A1 EP2515858A1 EP10805547A EP10805547A EP2515858A1 EP 2515858 A1 EP2515858 A1 EP 2515858A1 EP 10805547 A EP10805547 A EP 10805547A EP 10805547 A EP10805547 A EP 10805547A EP 2515858 A1 EP2515858 A1 EP 2515858A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cefdinir
- formulation according
- sodium
- amount
- agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 21
- 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 abstract description 70
- 229960003719 cefdinir Drugs 0.000 claims abstract description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000013543 active substance Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 55
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- 238000009472 formulation Methods 0.000 claims description 32
- 239000012535 impurity Substances 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 235000003599 food sweetener Nutrition 0.000 claims description 12
- 230000001105 regulatory effect Effects 0.000 claims description 12
- 239000003765 sweetening agent Substances 0.000 claims description 12
- 235000015165 citric acid Nutrition 0.000 claims description 11
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical group OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 11
- 239000001509 sodium citrate Substances 0.000 claims description 11
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 235000002639 sodium chloride Nutrition 0.000 claims description 10
- -1 glidants Substances 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 9
- 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 9
- 229940038773 trisodium citrate Drugs 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 229960003324 clavulanic acid Drugs 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000796 flavoring agent Substances 0.000 claims description 5
- 235000013355 food flavoring agent Nutrition 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 230000002335 preservative effect Effects 0.000 claims description 5
- 239000012453 solvate Substances 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
- 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
- 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
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-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
- 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 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 235000010234 sodium benzoate Nutrition 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 235000010980 cellulose Nutrition 0.000 claims description 3
- 239000000391 magnesium silicate Substances 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 235000019263 trisodium citrate Nutrition 0.000 claims description 3
- 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
- 239000004135 Bone phosphate Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 2
- 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-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
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 206010018612 Gonorrhoea Diseases 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 206010021531 Impetigo Diseases 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-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
- 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
- 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
- 206010062255 Soft tissue infection Diseases 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960005164 acesulfame Drugs 0.000 claims description 2
- 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 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 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
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 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
- 229940045110 chitosan Drugs 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 2
- 201000003146 cystitis Diseases 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 229940061607 dibasic sodium phosphate Drugs 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 229940014259 gelatin Drugs 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- 208000001786 gonorrhea Diseases 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 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
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 2
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 claims description 2
- 239000004223 monosodium glutamate Substances 0.000 claims description 2
- 235000013923 monosodium glutamate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 238000012856 packing Methods 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol 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
- 235000010235 potassium benzoate Nutrition 0.000 claims description 2
- 239000004300 potassium benzoate Substances 0.000 claims description 2
- 229940103091 potassium benzoate Drugs 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 206010040872 skin infection Diseases 0.000 claims description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 2
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 2
- 229960005055 sodium ascorbate Drugs 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 229960001790 sodium citrate Drugs 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 229960001462 sodium cyclamate Drugs 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 229940083608 sodium hydroxide Drugs 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 2
- 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
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- 229960002129 cefixime Drugs 0.000 claims 1
- 238000001035 drying Methods 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
- 239000011591 potassium Substances 0.000 claims 1
- 229960003975 potassium Drugs 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 239000002552 dosage form Substances 0.000 abstract description 4
- 239000003826 tablet Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000003460 beta-lactamyl group Chemical group 0.000 description 3
- 229940090805 clavulanate Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000002274 desiccant 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000004562 water dispersible granule Substances 0.000 description 2
- 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 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- RTXOFQZKPXMALH-PRHODGIISA-N Cefzon Chemical compound S1C(N)=NC(C(=NO)C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-PRHODGIISA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000006227 byproduct Substances 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
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229940031908 omnicef Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 206010044008 tonsillitis Diseases 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
- 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
Definitions
- Present invention is related to water dispersible pharmaceutical dosage forms comprising cefdinir as active agent and methods for preparation of these.
- Cefdinir molecule which is shown with Formula I was first disclosed in the patent numbered BE897864 and its chemical name is (6R,7R)-7-[[(2Z)-(2-amino-4- thiazolil)(hydroxyimino)acetyl] amino]-3-ethenyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2- carboxylic acid.
- the molecule, which is a third generation cephalosporin, is indicated for the treatment of several illnesses caused by gram positive and gram negative bacteria.
- Cefdinir which physically appears as a white powder has very poor solubility in common organic solvents such as methanol, ethanol, and acetonitrile and in water. Due to this property there are some problems while developing formulations comprising this molecule and in the bioavailability of the finished product.
- Cefdinir is an antibiotic which has a beta lactam ring in its structure. Beta lactam ring has a structure which disintegrates easily. Therefore, after cefdinir is formulated it decomposes in the formulation and can be converted into undesirable byproducts. This situation decreases the ratio of the active agent in the formulation and causes a decrease in the bio-availibity of the obtained product.
- the product sold in the market under the tradename OMNICEF ® is present in capsule and suspension forms. Clinic studies show that the bioavailability of the suspension product is 120% more than the bioavailability of the product in capsule form.
- suspension forms have higher bioavailability, use of this dosage form especially for pediatric and geriatric patients brings about the possibility of taking high and/or uncontrolled dose. Additionally, the fact that the suspensions have physical and chemical stability problems, they have short shelf life and high production costs and the fact that they cause problems while transporting and use are disadvantageous for the manufacturers. Due to the reasons stated above it is necessary to provide new dosage forms in antibiotic theraphy in order to provide effective dosing, meet patient requirements and to offer different alternatives to patients having special conditions, such as pediatric and geriatric patients.
- the present invention is related to water dispersible pharmaceutical compositions wherein the amount of impurity originating from cefdinir is less than 1%.
- Said compositions are characterized in that their impurity content originating from cefdinir is in an amount less than 1%, preferably 0.8% and more preferably 0.6%.
- the first aspect of the present invention is the water dispersible cefdinir formulations comprising the amount of impurity content originating from cefdinir is at most 1%, preferably 0.8% and more preferably 0.6% with respect to the total weight of the formulation comprising unit dose.
- compositions having impurity content originating from cefdinir in an amount of at most 1%.
- Said compositions can also comprise some pharmaceutically acceptable excipients in addition to cefdinir.
- Said pharmaceutical excipients can be selected from a group of sweeteners, pH regulating agents, preservatives, viscosity agents, glidants, lubricants and flavoring agents.
- Sweeteners that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in an amount of at most 1%, can be selected from a group comprising acesulfame, aspartamate, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharide, sodium saccharide, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
- pH regulating agent that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising citric acid, malic acid, tribasic calcium phosphate, monosodium glutamate, potassium citrate, sodium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof.
- citric acid and/or trisodium citrate more preferably a mixture of the combination of citric acid and trisodium citrate is used.
- the inventors have found that the use of the combination of two agents in the range of 5.5% and 7% has an important effect on decreasing the amount of impurity that is formed.
- Preservative that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
- Viscosity agent that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, ksantan gum, hydroxyethyl cellulose, hydroprophyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrine, ployvinyl alcohol or combinations thereof.
- Glidant that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising magnesium silicate, silicon dioxide, starch, talk, tribasic calcium phosphateor combinations thereof.
- silicon dioxide is used as a glidant.
- Lubricant that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talk, sodium benzoate or combinations thereof.
- the present invention is related to water dispersible pharmaceutical composition
- water dispersible pharmaceutical composition comprising impurity content originating from cefdinir in a ratio of at most 1%, cefdinir as active agent and pH regulating agent, sweetener, viscosity agent, lubricant, preservative as excipient.
- Water dispersible cefdinir formulations of the present invention comprising impurity content originating from cefdinir in a ratio of at most 1% can optionally comprise a second active agent.
- Second active agent is clavulanic acid or pharmaceutically acceptable salts thereof.
- the pharmaceutical composition comprising impurity content originating from cefdinir in a ratio of at most 1%, optionally 50-500 mg of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an amount equivalent to that can be used.
- Clavulanic acid and/or derivatives thereof are very sensitive to moisture. Therefore, in the pharmaceutical composition according to the present invention, potasium clavulanate is preferably used together with a desiccant in a ratio of 1 : 1.
- One or more than one of the following substances can be used as a desiccant; silica; colloid silica, for instance colloidal silica anhydrous, Aerosil® 200, magnesium trisilicate, powder cellulose, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose and talc.
- silica for instance colloidal silica anhydrous, Aerosil® 200, magnesium trisilicate, powder cellulose, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose and talc.
- potasium clavulanate is preferably used with syloid or microcrystalline cellulose in a ratio of 1 : 1.
- cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms can be present in an amount in the range of 2- 20% with respect to the total weight of the unit dose.
- clavulanic acid in an amount in the range of 0-50% with respect to the total weight of the unit dose or its pharmaceutically acceptable salts, solvates, hydrates or a combination thereof in an amount equivalent to that can be used.
- said composition comprises impurity content originating from cefdinir in a ratio of at most 1%, with respect to the total weight of the unit dose; 2-20% of cefdinir, 0-50% potassium clavulanate, 0.1 -5% lubricant, 0.1-5 % glidant 10-90% sweetener, 0.5-5% pH regulating agent, 0.1-5% preservative, 0.1 -5% viscosity agent and 0.1-10% flavoring agent can be used.
- the water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention can be present in water dispersible powder, granule or tablet form.
- the present invention is related to the process that can be used for the preparation of water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1 %.
- the process of the present invention comprises; granulation of cefdinir used as active agent and clavulanic acid, that is optionally used, or derivatives thereof by wet or dry granulation methods or dry blending of cefdinir, clavulanic acid derivatives and other excipients, optionally compressing them in tablet forms or packing in sachet form, preferably preparing them in sachet form.
- Another aspect of the present invention is the use of the pharmaceutical composition that is prepared according to the present invention for the treatment of infections caused by gram positive and gram negative bacteria.
- Another aspect of the present invention is the use of pharmaceutical formulation prepared according to the invention in the production of the drug to be used in the treatment and prophylaxis of upper respiratory tract infections such that ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis, lower respiratory tract infections such as pyelonephritis, cystitis and urethritis, skin and soft tissue infections such as froncle, pyoderma, impetigo and also gonorrhea and lyme diseases.
- upper respiratory tract infections such that ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis, lower respiratory tract infections such as pyelonephritis, cystitis and urethritis, skin and soft tissue infections such as froncle, pyoderma, impetigo and also gonorrhea and lyme diseases.
- Water dispersible formulations in accordance with the present invention can be prepared according to the following examples provided that they are not limited by these examples.
- EXAMPLE 1 Formulation and process for preparation of water dispersible granules comprising cefdinir
- Water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, sweetener, pH regulating agent and other excipients in amounts given in the example after sieving them with 1.3 mm sieve. Said composition is optionally compressed in tablet or filled in sachets.
- EXAMPLE 2 Formulation and process for preparation of water dispersibie granules comprising cefdinir
- Water dispersibie cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, sweetener, citric acid, trisodium citrate and other excipients in amounts given in the example and sieving them with 1.3 mm sieve. Said composition is optionally compressed in tablet or filled in sachets.
- EXAMPLE 3 Formulation of the preparation of water dispersibie granules comprising cefdinir and process for preparation
- Water dispersibie cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, a combination of the mixture of potassium clavulanate : microcrystalline cellulose, sweetener, pH regulating agent and other excipients in amounts given in the example after sieving them with 1.3 mm sieve. Optionally, said composition is compressed in tablet form or filled in sachets.
- EXAMPLE 4 Formulation of the preparation of water dispersible granules comprising cefdinir
- Water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, a combination of the mixture of potassium clavulanate : microcrystalline cellulose, sweetener, citric acid, trisodium citrate and other excipients in amounts given in the example after sieving them with 1.3 mm sieve.
- said composition is compressed in tablet form or filled in sachets.
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Abstract
Present invention is related to water dispersible pharmaceutical dosage forms comprising cefdinir as active agent and methods for preparation of these.
Description
PHARMACEUTICAL COMPOSITION WITH HIGH PURITY
Present invention is related to water dispersible pharmaceutical dosage forms comprising cefdinir as active agent and methods for preparation of these.
Background of the invention
Cefdinir molecule which is shown with Formula I was first disclosed in the patent numbered BE897864 and its chemical name is (6R,7R)-7-[[(2Z)-(2-amino-4- thiazolil)(hydroxyimino)acetyl] amino]-3-ethenyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2- carboxylic acid. The molecule, which is a third generation cephalosporin, is indicated for the treatment of several illnesses caused by gram positive and gram negative bacteria.
Formula I
Cefdinir which physically appears as a white powder has very poor solubility in common organic solvents such as methanol, ethanol, and acetonitrile and in water. Due to this property there are some problems while developing formulations comprising this molecule and in the bioavailability of the finished product.
Cefdinir is an antibiotic which has a beta lactam ring in its structure. Beta lactam ring has a structure which disintegrates easily. Therefore, after cefdinir is formulated it decomposes in the formulation and can be converted into undesirable byproducts. This situation decreases the ratio of the active agent in the formulation and causes a decrease in the bio-availibity of the obtained product.
The product sold in the market under the tradename OMNICEF® is present in capsule and suspension forms. Clinic studies show that the bioavailability of the suspension product is 120% more than the bioavailability of the product in capsule form.
Although the suspension forms have higher bioavailability, use of this dosage form especially for pediatric and geriatric patients brings about the possibility of taking high and/or uncontrolled dose. Additionally, the fact that the suspensions have physical and chemical stability problems, they have short shelf life and high production costs and the fact that they cause problems while transporting and use are disadvantageous for the manufacturers.
Due to the reasons stated above it is necessary to provide new dosage forms in antibiotic theraphy in order to provide effective dosing, meet patient requirements and to offer different alternatives to patients having special conditions, such as pediatric and geriatric patients.
The present invention is related to water dispersible pharmaceutical compositions wherein the amount of impurity originating from cefdinir is less than 1%. Said compositions are characterized in that their impurity content originating from cefdinir is in an amount less than 1%, preferably 0.8% and more preferably 0.6%.
Accordingly, the first aspect of the present invention is the water dispersible cefdinir formulations comprising the amount of impurity content originating from cefdinir is at most 1%, preferably 0.8% and more preferably 0.6% with respect to the total weight of the formulation comprising unit dose.
Another aspect of the present invention is water dispersible pharmaceutical compositions having impurity content originating from cefdinir in an amount of at most 1%. Said compositions can also comprise some pharmaceutically acceptable excipients in addition to cefdinir.
Said pharmaceutical excipients can be selected from a group of sweeteners, pH regulating agents, preservatives, viscosity agents, glidants, lubricants and flavoring agents.
Sweeteners, that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in an amount of at most 1%, can be selected from a group comprising acesulfame, aspartamate, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharide, sodium saccharide, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof. pH regulating agent, that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising citric acid, malic acid, tribasic calcium phosphate, monosodium glutamate, potassium citrate, sodium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof. In said pharmaceutical composition, preferably citric acid and/or trisodium citrate, more preferably a mixture of the combination of citric acid and trisodium citrate is used. The inventors have found that the use of the combination of two agents in the range of 5.5% and 7% has an important effect on decreasing the amount of impurity that is formed. The pH agent combination having acidic character, which is used in this amount, plays an important role in the protection of the stability of beta lactam ring.
Preservative, that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
Viscosity agent, that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, ksantan gum, hydroxyethyl cellulose, hydroprophyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrine, ployvinyl alcohol or combinations thereof.
Glidant, that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising magnesium silicate, silicon dioxide, starch, talk, tribasic calcium phosphateor combinations thereof. In the pharmaceutical composition of the present invention, preferably silicon dioxide is used as a glidant.
Lubricant, that can be used in water dispersible pharmaceutical compositions having impurity content originating from cefdinir in a ratio of at most 1%, can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talk, sodium benzoate or combinations thereof.
In another aspect, the present invention is related to water dispersible pharmaceutical composition comprising impurity content originating from cefdinir in a ratio of at most 1%, cefdinir as active agent and pH regulating agent, sweetener, viscosity agent, lubricant, preservative as excipient.
In water dispersible composition, 20-800 mg of cefdinir or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an amount equivalent to that can be used.
Water dispersible cefdinir formulations of the present invention comprising impurity content originating from cefdinir in a ratio of at most 1% can optionally comprise a second active agent. Second active agent is clavulanic acid or pharmaceutically acceptable salts thereof.
Accordingly, in the pharmaceutical composition comprising impurity content originating from cefdinir in a ratio of at most 1%, optionally 50-500 mg of clavulanic acid or its pharmaceutically
acceptable salts, hydrates, solvates or a combination thereof in an amount equivalent to that can be used.
Clavulanic acid and/or derivatives thereof (for example potasium clavulanate) are very sensitive to moisture. Therefore, in the pharmaceutical composition according to the present invention, potasium clavulanate is preferably used together with a desiccant in a ratio of 1 : 1.
One or more than one of the following substances can be used as a desiccant; silica; colloid silica, for instance colloidal silica anhydrous, Aerosil® 200, magnesium trisilicate, powder cellulose, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose and talc.
In the water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention, potasium clavulanate is preferably used with syloid or microcrystalline cellulose in a ratio of 1 : 1.
In the water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention, cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms can be present in an amount in the range of 2- 20% with respect to the total weight of the unit dose.
In the pharmaceutical composition according to the present invention, clavulanic acid in an amount in the range of 0-50% with respect to the total weight of the unit dose or its pharmaceutically acceptable salts, solvates, hydrates or a combination thereof in an amount equivalent to that can be used.
In the water dispersible cefdinir composition, wherein said composition comprises impurity content originating from cefdinir in a ratio of at most 1%, with respect to the total weight of the unit dose; 2-20% of cefdinir, 0-50% potassium clavulanate, 0.1 -5% lubricant, 0.1-5 % glidant 10-90% sweetener, 0.5-5% pH regulating agent, 0.1-5% preservative, 0.1 -5% viscosity agent and 0.1-10% flavoring agent can be used.
The water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention can be present in water dispersible powder, granule or tablet form.
The present invention is related to the process that can be used for the preparation of water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1 %.
Accordingly, the process of the present invention comprises; granulation of cefdinir used as active agent and clavulanic acid, that is optionally used, or derivatives thereof by wet or dry granulation methods or dry blending of cefdinir, clavulanic acid derivatives and other excipients, optionally compressing them in tablet forms or packing in sachet form, preferably preparing them in sachet form.
Another aspect of the present invention is the use of the pharmaceutical composition that is prepared according to the present invention for the treatment of infections caused by gram positive and gram negative bacteria.
Another aspect of the present invention is the use of pharmaceutical formulation prepared according to the invention in the production of the drug to be used in the treatment and prophylaxis of upper respiratory tract infections such that ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis, lower respiratory tract infections such as pyelonephritis, cystitis and urethritis, skin and soft tissue infections such as froncle, pyoderma, impetigo and also gonorrhea and lyme diseases.
Water dispersible formulations in accordance with the present invention can be prepared according to the following examples provided that they are not limited by these examples.
EXAMPLE 1: Formulation and process for preparation of water dispersible granules comprising cefdinir
Water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, sweetener, pH regulating agent and other excipients in amounts given in the example after sieving them with 1.3 mm sieve. Said composition is optionally compressed in tablet or filled in sachets.
EXAMPLE 2: Formulation and process for preparation of water dispersibie granules comprising cefdinir
Water dispersibie cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, sweetener, citric acid, trisodium citrate and other excipients in amounts given in the example and sieving them with 1.3 mm sieve. Said composition is optionally compressed in tablet or filled in sachets.
EXAMPLE 3: Formulation of the preparation of water dispersibie granules comprising cefdinir and process for preparation
Water dispersibie cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, a combination of the mixture of potassium clavulanate : microcrystalline cellulose, sweetener, pH regulating agent and other excipients in amounts given in the example after sieving them with 1.3 mm sieve. Optionally, said composition is compressed in tablet form or filled in sachets.
EXAMPLE 4: Formulation of the preparation of water dispersible granules comprising cefdinir
Water dispersible cefdinir composition comprising impurity content originating from cefdinir in a ratio of at most 1% according to the present invention is produced by mixing cefdinir, a combination of the mixture of potassium clavulanate : microcrystalline cellulose, sweetener, citric acid, trisodium citrate and other excipients in amounts given in the example after sieving them with 1.3 mm sieve. Optionally, said composition is compressed in tablet form or filled in sachets.
Claims
1. A water dispersible pharmaceutical composition comprising cefdinir as an active agent, wherein impurity content originating from cefdinir is in an amount of at most 1%.
2. A water dispersible pharmaceutical composition comprising cefdinir according to claim 1, wherein impurity content originating from cefdinir is in an amount of 0.8 %.
3. A water dispersible pharmaceutical composition comprising cefdinir according to claim 2, wherein impurity content originating from cefdinir is in an amount of less than 0.6 %.
4. A water dispersible cefdinir formulation comprising impurity content originating from cefdinir in an amount of at most 1 % according to claim 1, wherein said composition comprises pharmaceutically acceptable excipients in addition to cefdinir that is used as active agent.
5. A formulation according to claim 4, wherein pharmaceutical excipients are selected from a group of sweeteners, pH regulating agents, preservatives, viscosity agents, glidants, lubricants and flavoring agents.
6. A formulation according to claim 5, wherein sweetener is selected from a group comprising acesulfame, aspartamate, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharide, sodium saccharide, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
7. A formulation according to claim 5, wherein pH regulating agent is selected from a group comprising citric acid, malic acid, tribasic calcium phosphate, monosodium glutamate, potassium citrate, sodium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof.
8. A formulation according claim 7, wherein as pH regulating agent citric acid and/or trisodium citrate is used.
9. A formulation according to claim 8, wherein as pH regulating agent a composition comprising a combination of citric acid and/or trisodium citrate is used.
10. A formulation according claim 7, wherein the amount pH of regulating agent is in an amount in the range of 5.5% and 7% with respect to the total weight of the unit dose.
1 1. A formulation according to claim 9, wherein a composition comprising citric acid and trisodium citrate is used in an amount in the range of 5.5% and 7% with respect to the total weight of the unit dose.
12. A formulation according to claim 5, wherein preservative is selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
13. A formulation according to claim 5, wherein viscosity agent is selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, ksantan gum, hydroxyethyl cellulose, hydroprophyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrine, ployvinyl alcohol or combinations thereof.
14. A formulation according to claim 5, wherein glidant is selected from a group comprising magnesium silicate, silicon dioxide, starch, talk, tribasic calcium phosphateor combinations thereof.
15. A formulation according to claim 14, wherein glidant is silicon dioxide.
16. A formulation according to claim 5, wherein lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talk, sodium benzoate or combinations thereof.
17. A formulation according to claim 16, wherein lubricant is magnesium stearate.
18. A formulation according to claim 1, wherein 20-800 mg of cefdinir or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an amount equivalent to that is used.
19. A formulation according to claim 1, wherein said formulation optionally comprises a second active agent in addition to cefdinir.
20. A formulation according to claim 19, wherein second active agent is clavulanic acid or pharmaceutically acceptable derivatives thereof.
21. A formulation according to claim 20, wherein clavulanic acid is in the form of its pharmaceutically acceptable salts, preferably in the form of potassium and/or sodium salt.
22. A water dispersible formulation comprising cefdinir as active agent, wherein the impurity content originating from cefdinir is in an amount in the ratio of at most 1% according to any of the previous claims, comprising with respect to the total weight of the unit dose; 2-20% of cefdinir, 0-50% potassium clavulanate, 0.1-5% lubricant, 0.1 -5% glidant, 10-90% sweetener, 0.5-5% pH regulating agent, 0.1-5% preservative, 0.1-5% viscosity agent and 0.1 -10% flavoring agent.
23. A process for the preparation of water dispersible formulation comprising cefdinir as active agent, wherein the impurity content originating from cefdinir is in a ratio of at most 1%, comprises granulation of cefixime, effervescent couple, sweetener and binder with water or an aqueous solution, drying of the formed granules, mixing dried granules with flavoring agent and water soluble lubricant and optionally compressing them in tablet form or packing in sachet form. pharyngitis, lower respiratory tract infections such as pyelonephritis, cystitis and urethritis, skin and soft tissue infections such as froncle, pyoderma, impetigo and also gonorrhea and lyme diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2009/09786A TR200909786A1 (en) | 2009-12-25 | 2009-12-25 | Effervescent tablet and granule formulation containing cefixime. |
| TR201003854 | 2010-05-14 | ||
| PCT/TR2010/000258 WO2011078828A1 (en) | 2009-12-25 | 2010-12-24 | Pharmaceutical composition with high purity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2515858A1 true EP2515858A1 (en) | 2012-10-31 |
Family
ID=43706441
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10805547A Withdrawn EP2515858A1 (en) | 2009-12-25 | 2010-12-24 | Pharmaceutical composition with high purity |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP2515858A1 (en) |
| WO (1) | WO2011078828A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101420315B1 (en) | 2014-03-19 | 2014-07-17 | 남봉길 | Pharmaceutical liquid composition |
| 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 |
| CN107129508B (en) * | 2017-04-19 | 2018-12-07 | 广州牌牌生物科技有限公司 | Cefdinir mixtures of impurities and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA836918B (en) | 1982-09-30 | 1984-05-30 | Fujisawa Pharmaceutical Co | 7-substituted-3-vinyl-3-cephem compounds and processes for the production of the same |
| US20050131079A1 (en) * | 2003-12-10 | 2005-06-16 | Pujara Chetan P. | Cefdinir oral suspension |
| 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 |
| US20070128268A1 (en) * | 2005-12-07 | 2007-06-07 | Herwig Jennewein | Pharmaceutical compositions comprising an antibiotic |
| 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 |
-
2010
- 2010-12-24 EP EP10805547A patent/EP2515858A1/en not_active Withdrawn
- 2010-12-24 WO PCT/TR2010/000258 patent/WO2011078828A1/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2011078828A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011078828A1 (en) | 2011-06-30 |
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