WO2012060785A1 - Production method for tablets comprising cephalosporin - Google Patents
Production method for tablets comprising cephalosporin Download PDFInfo
- Publication number
- WO2012060785A1 WO2012060785A1 PCT/TR2011/000250 TR2011000250W WO2012060785A1 WO 2012060785 A1 WO2012060785 A1 WO 2012060785A1 TR 2011000250 W TR2011000250 W TR 2011000250W WO 2012060785 A1 WO2012060785 A1 WO 2012060785A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diluent
- disintegrant
- formulation according
- tablet
- pharmaceutical formulation
- Prior art date
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- 229940124587 cephalosporin Drugs 0.000 title claims abstract description 29
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 239000003085 diluting agent Substances 0.000 claims abstract description 56
- 239000007884 disintegrant Substances 0.000 claims abstract description 56
- 239000008187 granular material Substances 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 38
- 239000013543 active substance Substances 0.000 claims abstract description 16
- 230000003115 biocidal effect Effects 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 11
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- 239000003826 tablet Substances 0.000 claims description 43
- 238000009472 formulation Methods 0.000 claims description 41
- 235000002639 sodium chloride Nutrition 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 31
- 150000004677 hydrates Chemical class 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 17
- 238000007906 compression Methods 0.000 claims description 14
- 230000006835 compression Effects 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
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- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 229960002160 maltose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 210000004086 maxillary sinus Anatomy 0.000 claims description 2
- 229960002900 methylcellulose Drugs 0.000 claims description 2
- 239000007912 modified release tablet Substances 0.000 claims description 2
- 150000007524 organic acids Chemical group 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000004300 potassium benzoate Substances 0.000 claims description 2
- 229940103091 potassium benzoate Drugs 0.000 claims description 2
- 235000010235 potassium benzoate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 230000002035 prolonged effect Effects 0.000 claims description 2
- 208000020029 respiratory tract infectious disease Diseases 0.000 claims description 2
- 206010040872 skin infection Diseases 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229960001462 sodium cyclamate Drugs 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 206010044008 tonsillitis Diseases 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 208000000143 urethritis Diseases 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001271 cephalosporin group Chemical group 0.000 claims 3
- 108090000204 Dipeptidase 1 Chemical group 0.000 claims 2
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 claims 1
- HOKIDJSKDBPKTQ-UHFFFAOYSA-N 3-(acetyloxymethyl)-7-[(5-amino-5-carboxypentanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(NC(=O)CCCC(N)C(O)=O)C12 HOKIDJSKDBPKTQ-UHFFFAOYSA-N 0.000 claims 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 claims 1
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren 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/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 claims 1
- 238000000576 coating method Methods 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
- 238000002156 mixing Methods 0.000 claims 1
- 238000007873 sieving Methods 0.000 claims 1
- 239000007916 tablet composition Substances 0.000 claims 1
- 239000000654 additive Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 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 description 5
- 239000002552 dosage form Substances 0.000 description 4
- 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 description 3
- 239000006185 dispersion Substances 0.000 description 3
- ALYUMNAHLSSTOU-CIRGZYLNSA-N (6r,7r)-7-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 ALYUMNAHLSSTOU-CIRGZYLNSA-N 0.000 description 2
- WKJGTOYAEQDNIA-IOOZKYRYSA-N (6r,7r)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 WKJGTOYAEQDNIA-IOOZKYRYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 150000004683 dihydrates Chemical class 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
- 239000003906 humectant Substances 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 150000004684 trihydrates Chemical group 0.000 description 2
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009798 acute exacerbation Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 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
- 229960002142 cefditoren pivoxil Drugs 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime 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=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 description 1
- 229960004797 cefpodoxime proxetil Drugs 0.000 description 1
- 229960002620 cefuroxime axetil Drugs 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940041006 first-generation cephalosporins Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to the process for the preparation of the pharmaceutical formulations comprising cephalosporin antibiotics.
- Cephalosporins were first isolated in 1948 and first generation cephalosporins were produced and released in 1960.
- Cephem derivative 7- amino-cephalosporinic acid constitutes the basic core of cephalosporins. Cephalosporins are classified into different generations according to a classification method which is chronological and practical in terms of reflecting the improvement in antibacterial spectrum.
- the physical properties of the final product in tablet form such as hardness and dissolution time can change according to the methods used in developing the formulations.
- Hardness of the tablets is important, if the tablet is too hard then it may be too brittle and as a result it may break into pieces while carrying them; dispersion time is important because as the dispersion time gets shorter, the onset time of the medication gets shorter as well so the medication shows its effect in a shorter time.
- the inventors have found that the relative proportion of the excipients used while preparing the cephalosporin containing granules and while preparing a pharmaceutical formulation with the prepared granules plays an important role in the hardness and the dissolution time of the dosage forms prepared with the obtained formulations. Additionally, the compression force that is used when preparing tablet forms from the formulations according to present invention also play an important role in the dissolution and hardness properties of the dosage forms obtained with these formulations.
- Inventors of the present invention use two portions of diluent and disintegrant compositions while preparing the formulations; one portion is used for preparing the granules comprising cephalosporin antibiotic and the other portion is used for preparing the formulation with the obtained granules.
- the granules are mixed with the diluent and disintegrant composition, and if need be with at least one other excipients to give the formulations according to present invention
- the first aspect of the present invention is the process for preparing the formulation comprising a cephalosporin antibiotic and other excipients wherein said formulation consists of (a) granules comprising cephalosporin antibiotic and diluent and disintegrant composition and (b) an other diluent and disintegrant composition and at least one other pharmaceutically acceptable excipient and the process is characterized in that the granules comprising cephalosporin antibiotic, diluent and disintegrant are mixed with the other diluent and disintegrant composition wherein the other diluent and disintegrant composition is in an amount of 96-100% by weight in proportion to the amount of diluent and disintegrant composition that was used for obtaining the granules and wherein a tablet compression force in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied.
- the formulation prepared according to present invention consists of a mixture of (a) and (b).
- the formulation consists of a mixture of granules comprising cephalosporin antibiotic, diluent and disintegrant composition with other diluent and disintegrant composition and at least one other excipient.
- friability value An important parameter relating to tablet hardness is friability value.
- the inventors have seen that when the tablet compression force having a value in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied, the friability value of the tablet forms is in the range of 0.01- 0.1, preferably 0.02- 0.05.
- another aspect of the present invention is the process for preparing the tablet forms comprising cefdinir with the friability value in the range of 0.01- 0.1, preferably 0.02- 0.05.
- cepholosporin group molecules stated in the text comprises cepholosporin group molecules such as cefpodoxime, cefditoren, cefdinir, cefixime, cefuroxime, cefaclor, ceftibuten, cefprozil, cefepime and cefetamet.
- Cefpodoxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
- cefpodoxime proxetil is used.
- Cefditoren can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
- cefditoren pivoxil is used.
- Cefdinir can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
- Cefixime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Cefixime can be in monohydrate, dihydrate or trihydrate form before granulation. Cefuroxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefuroxime axetil is used.
- Cefaclor can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
- Ceftibuten can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphousforms or free form and/or a combination thereof. Ceftibuten can be in monohydrate, dihydrate or trihydrate form before granulation.
- Cefprozil can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
- Cefetamet can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
- cefetamet pivoxil is used.
- formulations produced according to the process of the present invention comprise preferably cefdinir, cefixime, ceftibuten and cefetamet pivoxil.
- the disintegrant that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.
- Carboxymethyl cellulose calcium is preferably used as disintegrant.
- the diluent that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof. Microcrystalline cellulose is preferably used as diluent.
- the diluent and the disintegrant composition that is used for preparation of the granules (a) can be the same as or different from the other diluent and the disintegrant composition used in (b). Preferably the same disintegrant and diluent compositions are used in both steps.
- present invention relates to a process for preparing the formulation comprising a cephalosporin antibiotic and other excipients wherein said formulation consists of (a) granules comprising cephalosporin antibiotic and microcrystalline cellulose and carboxymethyl cellulose calcium composition and (b) an other microcrystalline cellulose and carboxymethyl cellulose calcium composition and at least one other pharmaceutically acceptable excipient and the process is characterized in that the granules comprising cephalosporin antibiotic, microcrystalline cellulose and carboxymethyl cellulose calcium are mixed with the other microcrystalline cellulose and carboxymethyl cellulose calcium composition wherein the other microcrystalline cellulose and carboxymethyl cellulose calcium composition is in an amount of 96-100% by weight in proportion to the amount of microcrystalline cellulose and carboxymethyl cellulose calcium composition that was used for obtaining the granules and wherein a tablet compression force in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied.
- the pharmaceutical formulation prepared by the process according to the present invention can further comprise various excipients such as binders, sweeteners, lubricants, effervescent couples, glidants along with the active agent, diluents and disintegrants.
- excipients such as binders, sweeteners, lubricants, effervescent couples, glidants along with the active agent, diluents and disintegrants.
- the binder that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone.
- the lubricant that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate and sodium benzoate.
- the glidant that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising magnesium silicate, silicone dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.
- the sweetener that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
- the effervescent couple that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
- the pharmaceutical formulation prepared by the process according to the present invention can be in various dosage forms, for instance; tablet, film-coated tablet, effervescent tablet, orodispersible tablet, prolonged-release tablet, modified-release tablet.
- these formulations comprising the granules of the present invention are in the form of tablet or film- coated tablet.
- the pharmaceutical formulation prepared by the process according to the present invention can comprise 1-4000 mg cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.
- the pharmaceutical formulation prepared by the process according to the present invention can further comprise an active agent along with the said granules and the excipients specified above.
- the second active substance can be selected from cephalosporins or beta-lactamases.
- clavulanic acid is used or derivatives thereof.
- the clavulanic acid that can be used optionally in the pharmaceutical formulation prepared by the process can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or the combination thereof.
- potassium clavulanate is used.
- said formulation prepared by the process can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.
- Clavulanic acid and its derivatives e.g. potassium clavulanate
- potassium clavulanate is preferably used with a humectant in the ratio of 1 :1 in the pharmaceutical formulation prepared by the process of the present invention.
- colloidal silica for instance colloidal silica anhydrous, for instance silicondioxide, magnesium trisilicate, cellulose powder, fumed silicamagnesium oxide, calcium silicate, amorphous silica, starch, microcrystalline cellulose, talc can be used as the humectant.
- potassium clavulanate is preferably used with amorphous silica in the ratio of 1 : 1.
- the pharmaceutical formulation prepared by the process according to the present invention comprises 50-75% of cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms, and 2-8% binder; 2-8% lubricant; 1-4% sweetener; 2-20% diluent; 8-14% disintegrant; 0-85% effervescent couple; 2-4% glidant; 0-90% clavulanic acid or an equivalent amount of its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in proportion to the total weight of unit dose amount.
- the process pertaining to the present invention is composed of the following steps;
- Granulation solution is prepared by dissolving the binder in water
- Cephalosporin, diluent and disintegrant are granulated with the granulation solution prepared
- step III Granules obtained in step III are sieved
- Granules are blended with diluent, disintegrant, glidant and optionally the second active agent and effervescent couple,
- the pharmaceutical composition obtained is stored in a required dosage form. It is compressed in tablet form and optionally packed with commercially available coating agents by using the techniques in the prior art.
- the granules are sieved with a sieve, mesh size of which is in the range of 0,5-5 mm, preferably in the range of 1-3 mm.
- the pharmaceutical composition prepared by the process according to the present invention can be used in treatment of upper respiratory infections, such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections, such as pneumonia, acute bronchitis and acute exacerbation of acute bronchitis; genitourinary infections, such as pyelonephritis, cystitis, urethritis; skin and soft tissue infections, such as furuncle, pyoderma, impetigo; and such diseases as community-acquired pneumonia, acute maxillary sinus infection.
- upper respiratory infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis
- lower respiratory tract infections such as pneumonia, acute bron
- Example 1 Formulation and process for preparation of film-coated tablet comprising cefdinir.
- Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed withglidant, and the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules,. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with an appropriate coating agent.
- Example 2 Formulation and process for preparation of tablet comprising cefdinir and potassium clavulanate.
- Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant, the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with the coating agent.
- Example 3 Formulation and process for preparation of tablet comprising cefixime.
- Cefixime is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant and the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and and pressed to form tablets.
- Example 4 Formulation and process for preparation of tablet comprising ceftibuten.
- Ceftibuten is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant, sweetenerand the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and and pressed to form tablets.
- Example 5 Formulation and process for preparation of tablet comprising cefetamet pivoxil.
- Cefetamet pivoxil is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant, sweetenerand the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and pressed to form tablets.
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Abstract
The present invention relates to process for the preparation of the pharmaceutical formulations comprising a cephalosporin antibiotic as an active agent, a diluent and a disintegrant. The amount of diluent and disintegrant in the granules is essentially equal to the amount of these additives in the extragranular space.
Description
PRODUCTION METHOD FOR FORMULATIONS COMPRISING
CEPHALOSPORIN
The present invention relates to the process for the preparation of the pharmaceutical formulations comprising cephalosporin antibiotics.
Background of the Invention
Cephalosporins were first isolated in 1948 and first generation cephalosporins were produced and released in 1960.
Cephem derivative 7- amino-cephalosporinic acid (formula 1) constitutes the basic core of cephalosporins. Cephalosporins are classified into different generations according to a classification method which is chronological and practical in terms of reflecting the improvement in antibacterial spectrum.
FORMULA 1
The physical properties of the final product in tablet form such as hardness and dissolution time can change according to the methods used in developing the formulations. Hardness of the tablets is important, if the tablet is too hard then it may be too brittle and as a result it may break into pieces while carrying them; dispersion time is important because as the dispersion time gets shorter, the onset time of the medication gets shorter as well so the medication shows its effect in a shorter time.
As the tablet becomes harder, the fragility lowers however on the other hand the dispersion becomes slower. This causes an increase in the time period it takes to get the drug ready for use and thus leads to an insufficient delivery of the drug.
Therefore, there is a requirement for development of new preparation methods for formulations comprising cephalosporin antibiotics with optimized hardness and dissolution time.
Granulation of the active agents is a commonly used technique used in the state of the art. Inventors have also used granulation of the active agent along with pharmaceutically acceptable excipients such as diluent and disintegrant. However, it was found that simply granulating the active agent is not sufficient to end up with formulations having optimized hardness and dissolution properties. The inventors have found that the relative proportion of the excipients used while preparing the cephalosporin containing granules and while preparing a pharmaceutical formulation with the prepared granules plays an important role in the hardness and the dissolution time of the dosage forms prepared with the obtained formulations. Additionally, the compression force that is used when preparing tablet forms from the formulations according to present invention also play an important role in the dissolution and hardness properties of the dosage forms obtained with these formulations.
Inventors of the present invention use two portions of diluent and disintegrant compositions while preparing the formulations; one portion is used for preparing the granules comprising cephalosporin antibiotic and the other portion is used for preparing the formulation with the obtained granules. In other words, the granules are mixed with the diluent and disintegrant composition, and if need be with at least one other excipients to give the formulations according to present invention
It has been surprisingly seen that when granules comprising cephalosporin antibiotic, diluent and disintegrant are mixed with the other portion of diluent and disintegrant composition wherein said diluent and disintegrant composition is in an amount of 96-100% by weight in proportion to the amount of diluent and disintegrant composition that was used for obtaining the granules and when a tablet compression force in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied to the formulation, the obtained tablet forms have a desired tablet hardness and dissolution time.
Accordingly, the first aspect of the present invention is the process for preparing the formulation comprising a cephalosporin antibiotic and other excipients wherein said formulation consists of (a) granules comprising cephalosporin antibiotic and diluent and disintegrant composition and (b) an other diluent and disintegrant composition and at least one other pharmaceutically acceptable excipient and the process is characterized in that the granules comprising cephalosporin antibiotic, diluent and disintegrant are mixed with the other diluent and disintegrant composition wherein the other diluent and disintegrant composition is in an amount of 96-100% by weight in proportion to the amount of diluent and
disintegrant composition that was used for obtaining the granules and wherein a tablet compression force in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied.
The formulation prepared according to present invention consists of a mixture of (a) and (b). In other words the formulation consists of a mixture of granules comprising cephalosporin antibiotic, diluent and disintegrant composition with other diluent and disintegrant composition and at least one other excipient.
An important parameter relating to tablet hardness is friability value. The inventors have seen that when the tablet compression force having a value in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied, the friability value of the tablet forms is in the range of 0.01- 0.1, preferably 0.02- 0.05.
According to this, another aspect of the present invention is the process for preparing the tablet forms comprising cefdinir with the friability value in the range of 0.01- 0.1, preferably 0.02- 0.05.
The term "cepholosporin group molecules" stated in the text comprises cepholosporin group molecules such as cefpodoxime, cefditoren, cefdinir, cefixime, cefuroxime, cefaclor, ceftibuten, cefprozil, cefepime and cefetamet.
Cefpodoxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefpodoxime proxetil is used.
Cefditoren can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefditoren pivoxil is used.
Cefdinir can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
Cefixime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Cefixime can be in monohydrate, dihydrate or trihydrate form before granulation.
Cefuroxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefuroxime axetil is used.
Cefaclor can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
Ceftibuten can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphousforms or free form and/or a combination thereof. Ceftibuten can be in monohydrate, dihydrate or trihydrate form before granulation.
Cefprozil can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
Cefetamet can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefetamet pivoxil is used.
The formulations produced according to the process of the present invention comprise preferably cefdinir, cefixime, ceftibuten and cefetamet pivoxil.
The disintegrant that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate and starch or combinations thereof. Carboxymethyl cellulose calcium is preferably used as disintegrant.
The diluent that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof. Microcrystalline cellulose is preferably used as diluent.
The diluent and the disintegrant composition that is used for preparation of the granules (a) can be the same as or different from the other diluent and the disintegrant composition used in (b). Preferably the same disintegrant and diluent compositions are used in both steps.
In another aspect present invention relates to a process for preparing the formulation comprising a cephalosporin antibiotic and other excipients wherein said formulation consists of (a) granules comprising cephalosporin antibiotic and microcrystalline cellulose and carboxymethyl cellulose calcium composition and (b) an other microcrystalline cellulose and carboxymethyl cellulose calcium composition and at least one other pharmaceutically acceptable excipient and the process is characterized in that the granules comprising cephalosporin antibiotic, microcrystalline cellulose and carboxymethyl cellulose calcium are mixed with the other microcrystalline cellulose and carboxymethyl cellulose calcium composition wherein the other microcrystalline cellulose and carboxymethyl cellulose calcium composition is in an amount of 96-100% by weight in proportion to the amount of microcrystalline cellulose and carboxymethyl cellulose calcium composition that was used for obtaining the granules and wherein a tablet compression force in the range of 5-200 kN, preferably 10-150 kN, more preferably 20-100 kN is applied.
The pharmaceutical formulation prepared by the process according to the present invention can further comprise various excipients such as binders, sweeteners, lubricants, effervescent couples, glidants along with the active agent, diluents and disintegrants.
The binder that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone.
The lubricant that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate and sodium benzoate.
The glidant that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising magnesium silicate, silicone dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.
The sweetener that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
The effervescent couple that can be used in the pharmaceutical formulation prepared by the process according to the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
The pharmaceutical formulation prepared by the process according to the present invention can be in various dosage forms, for instance; tablet, film-coated tablet, effervescent tablet, orodispersible tablet, prolonged-release tablet, modified-release tablet. Preferably, these formulations comprising the granules of the present invention are in the form of tablet or film- coated tablet.
The pharmaceutical formulation prepared by the process according to the present invention can comprise 1-4000 mg cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.
The pharmaceutical formulation prepared by the process according to the present invention can further comprise an active agent along with the said granules and the excipients specified above.
The second active substance can be selected from cephalosporins or beta-lactamases. Preferably, clavulanic acid is used or derivatives thereof.
The clavulanic acid that can be used optionally in the pharmaceutical formulation prepared by the process can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or the combination thereof. Preferably, potassium clavulanate is used.
According to this, said formulation prepared by the process can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.
Clavulanic acid and its derivatives (e.g. potassium clavulanate) are extremely susceptible to moisture. To this respect, potassium clavulanate is preferably used with a humectant in the ratio of 1 :1 in the pharmaceutical formulation prepared by the process of the present invention.
One or more of the substances comprising silica; colloidal silica, for instance colloidal silica anhydrous, for instance silicondioxide, magnesium trisilicate, cellulose powder, fumed silicamagnesium oxide, calcium silicate, amorphous silica, starch, microcrystalline cellulose, talc can be used as the humectant.
In the pharmaceutical formulation prepared by the process of the present invention, potassium clavulanate is preferably used with amorphous silica in the ratio of 1 : 1.
The pharmaceutical formulation prepared by the process according to the present invention comprises 50-75% of cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms, and 2-8% binder; 2-8% lubricant; 1-4% sweetener; 2-20% diluent; 8-14% disintegrant; 0-85% effervescent couple; 2-4% glidant; 0-90% clavulanic acid or an equivalent amount of its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in proportion to the total weight of unit dose amount.
The process pertaining to the present invention is composed of the following steps;
I. Granulation solution is prepared by dissolving the binder in water,
II. Cephalosporin, diluent and disintegrant are granulated with the granulation solution prepared,
III. Obtained granules are dried at 40 °C,
IV. Granules obtained in step III are sieved,
V. Granules are blended with diluent, disintegrant, glidant and optionally the second active agent and effervescent couple,
VI. Lubricant is added into the mixture obtained.
VII. The pharmaceutical composition obtained is stored in a required dosage form. It is compressed in tablet form and optionally packed with commercially available coating agents by using the techniques in the prior art.
According to this, the granules are sieved with a sieve, mesh size of which is in the range of 0,5-5 mm, preferably in the range of 1-3 mm.
The pharmaceutical composition prepared by the process according to the present invention can be used in treatment of upper respiratory infections, such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections, such as pneumonia, acute bronchitis and acute exacerbation of acute bronchitis; genitourinary infections, such as pyelonephritis, cystitis, urethritis; skin and soft tissue infections, such as furuncle, pyoderma, impetigo; and such diseases as community-acquired pneumonia, acute maxillary sinus infection.
The subject of the present invention can be prepared as specified below, yet the invention is not restricted to these examples;
Example 1: Formulation and process for preparation of film-coated tablet comprising cefdinir.
Process:
Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed withglidant, and the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules,. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with an appropriate coating agent.
Example 2: Formulation and process for preparation of tablet comprising cefdinir and potassium clavulanate.
Process:
Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant, the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with the coating agent.
Example 3: Formulation and process for preparation of tablet comprising cefixime.
Cefixime is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant and the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and and pressed to form tablets.
Example 4: Formulation and process for preparation of tablet comprising ceftibuten.
Process:
Ceftibuten is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant, sweetenerand the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and and pressed to form tablets.
Example 5: Formulation and process for preparation of tablet comprising cefetamet pivoxil.
Process:
Cefetamet pivoxil is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C and sieved with a 1-3 mm mesh sieve. Said granules are mixed with glidant, sweetenerand the diluent and disintegrant composition which is 96-100% by weight in proportion to the amount of diluent and disintegrant used for obtaining granules. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and pressed to form tablets.
Claims
1. The process for preparation of a tablet formulation comprising a cephalosporin antibiotic and other excipients such that said formulation consists of (a) granules comprising cephalosporin antibiotic and a diluent and disintegrant composition and (b) an other diluent and disintegrant composition and at least one other pharmaceutically acceptable excipient wherein the process is characterized in that;
• the granules comprising cephalosporin antibiotic, diluent and disintegrant are mixed with the other diluent and disintegrant composition wherein the other diluent and disintegrant composition is in an amount of 96-100% by weight in proportion to the amount of diluent and disintegrant composition that was used for obtaining the granules and
• when said formulation is compressed in tablet form, a tablet compression force in the range of 5-200 kN is applied
2. The formulation according to claim 1, wherein the tablet compression force is in the range of 10-150 kN.
3. The formulation according to claim 2, wherein the tablet compression force is in the range of 20- 100 kN.
4. The process for the preparation of the formulation comprising a cephalosporin antibiotic according to claims 1-3 characterized in that said method comprises the steps of;
I. Preparing the granulation solution by dissolving the binder in water,
II. Granulating cephalosporin, diluent and disintegrant with the granulation solution prepared in step I,
III. Drying the granules which are obtained in step II at 40 °C,
IV. Sieving the granules prepared in step III,
V. Mixing the granules obtained in step IV with the diluent and disintegrant composition, glidant and optionally the second active agent and effervescent couple,
VI. Adding lubricant to the mixture.
VII. Compression of the final mixture into tablet form and optionally coating with commercially available coating agents.
5. The process according to claims 1-4, wherein the granules obtained in step III are sieved with a 0.5-5 mm mesh sieve after they are dried.
6. The process according to claim 5, wherein the granules obtained in step III are sieved with a 1-3 mm mesh sieve after they are dried.
7. The pharmaceutical formulation prepared by the process according to claims 1-6, wherein said formulation comprises a cephalosporin antibiotic, disintegrant and diluent.
8. The pharmaceutical formulation according to claim 7 wherein friability value of the tablet forms is in the range of 0.01- 0.1.
9. The pharmaceutical formulation according to claim 7, wherem cephalosporin group molecules are selected from a group comprising cefpodoxime, cefditoren, cefdinir, cefixime, cefuroxime, cefaclor, ceftibuten, cefprozil and cefetamet.
10. The pharmaceutical formulation according to claim 9, wherein cephalosporin group molecules are selected from cefdinir, cefixime, ceftibuten and cefetamet pivoxil.
11. The pharmaceutical formulation according to claim 7, wherein cephalosporin group molecules are in the form of their pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
12. The pharmaceutical formulation according to claim 7, wherein disintegrant are selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.
13. The pharmaceutical formulation according to claim 12, wherein disintegrant is carboxymethyl cellulose calcium.
14. The pharmaceutical formulation according to claim 7, wherein diluent are 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 and xylitol or combinations thereof.
15. The pharmaceutical formulation according to claim 14, wherein diluent is microcrystalline cellulose.
16. The pharmaceutical formulation according to claim 7, wherein said formulation comprises various excipients along with active agent, disintegrant and diluent.
17. The pharmaceutical formulation according to claim 16, wherein said formulation comprises excipients such as binders, sweeteners, lubricants, glidants, optionally effervescent couple along with active agent disintegrant and diluents.
18. The pharmaceutical formulation according to claim 17, wherein the binder is selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone .
19. The pharmaceutical formulation according to claim 17, wherein the lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
20. The pharmaceutical formulation according to claim 17, wherein the glidant is selected from a group comprising magnesium silicate, silicone dioxide, starch, talc and tribasic calcium phosphate or combinations thereof.
21. The pharmaceutical formulation according to claim 17, wherein the sweetener is selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose and xylitol or combinations thereof.
22. The pharmaceutical formulation according to claim 17, wherein the effervescent couple is selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
23. The formulation according to claim 7-22, wherein said formulation is in the form of tablet, film-coated tablet, effervescent tablet, orodispersible tablet, prolonged-release tablet, modified-release tablet.
24. The formulation according to claim 23, wherein said formulation is in the form of tablet or film-coated tablet.
25. The formulation according to claim 7-24, wherein said formulation can further comprise at least one more active agent along with the active agent, disintegrant and diluent.
26. The formulation according to claim 25, wherein the other active agent is selected from cephalosporin or beta-lactamase group of substances.
27. The formulation according to claims 25-26, wherein the other active agent is a substance from beta-lactamase group.
28. The formulation according to claims 25-27, wherein the other active agent is clavulanic acid or a pharmaceutically acceptable salt thereof.
29. The pharmaceutical composition according to claim 7, wherein the said composition comprises 50-75% of cephalosporine or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms, and 2-8% binder; 2-8%, lubricant; 1-4% sweetener; 2-20% diluent; 8-14% disintegrant; 0-85% effervescent couple; 2-4% glidant; 0-90% clavulanic acid or an equivalent amount of its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in proportion to the total weight of unit dose amount.
30. The pharmaceutical composition prepared by the process according to claims 1-6, wherein said composition is used in the production of a drug to be used in treatment of upper respiratory infections such as, otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as, pneumonia, acute bronchitis and acute exacerbation of chronic bronchitis; genitourinary infections such as, pyelonephritis, cystitis, urethritis; skin and soft tissue infections such as, furuncle, pyoderma, impetigo; and such diseases as community-acquired pneumonia, acute maxillary sinus infection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2010/09167 | 2010-11-05 | ||
| TR2010/09167A TR201009167A2 (en) | 2010-11-05 | 2010-11-05 | Pharmaceutical granules containing cephalosporin. |
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| WO2012060785A1 true WO2012060785A1 (en) | 2012-05-10 |
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| PCT/TR2011/000250 WO2012060785A1 (en) | 2010-11-05 | 2011-11-03 | Production method for tablets comprising cephalosporin |
| PCT/TR2011/000253 WO2012060788A1 (en) | 2010-11-05 | 2011-11-03 | Formulations of cephalosporins with controlled moisture content |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| PCT/TR2011/000253 WO2012060788A1 (en) | 2010-11-05 | 2011-11-03 | Formulations of cephalosporins with controlled moisture content |
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| WO2013109203A1 (en) * | 2012-01-18 | 2013-07-25 | Mahmut Bilgic | Tablet formulations comprising cefditoren pivoxil |
| WO2013109225A1 (en) * | 2012-01-18 | 2013-07-25 | Mahmut Bilgic | Pharmaceutical tablet formulations comprising ceftibuten |
| CN105168147A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefetamet pivoxil hydrochloride composite granule for treating bacterial infection |
| WO2018071810A1 (en) * | 2016-10-13 | 2018-04-19 | RhinoNase, Inc. | Antibiotic compositions for nasal irrigation and methods |
| CN108743548A (en) * | 2018-06-28 | 2018-11-06 | 苏州中联化学制药有限公司 | A kind of Cefprozil granule and preparation method thereof |
| US10624899B2 (en) | 2016-07-14 | 2020-04-21 | Achaogen, Inc. | Combination products for the treatment of bacterial infections and methods of producing or dosing of same |
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| CN103405387B (en) * | 2013-08-13 | 2015-11-04 | 江苏正大清江制药有限公司 | A kind of new Cefixime suspension and preparation method thereof |
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| EP0281200A1 (en) * | 1987-03-02 | 1988-09-07 | Yamanouchi Europe B.V. | Pharmaceutical composition, pharmaceutical granulate and process for their preparation |
| CA2393614A1 (en) * | 2002-07-19 | 2002-10-28 | Abbott Laboratories | Antibacterial clarithromycin compositions and processes for making the same |
| WO2004006917A1 (en) * | 2002-07-16 | 2004-01-22 | Ranbaxy Laboratories Limited | Dispersible tablets for oral administration |
| WO2005115347A1 (en) * | 2004-05-31 | 2005-12-08 | Sam-A Pharmaceuticals Co., Ltd. | Dispersible tablet comprising beta lactam antibiotics and process for preparing the same |
| WO2007058397A1 (en) * | 2005-11-17 | 2007-05-24 | Gl Pharmtech Corp. | A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008540403A (en) * | 2005-05-05 | 2008-11-20 | ルピン・リミテッド | Stabilized oral pharmaceutical composition of cephalosporin |
| EP2575782A2 (en) * | 2010-06-03 | 2013-04-10 | Mahmut Bilgic | Effervescent formulations comprising cephalosporin and clavulanic acid |
-
2010
- 2010-11-05 TR TR2010/09167A patent/TR201009167A2/en unknown
-
2011
- 2011-11-03 WO PCT/TR2011/000250 patent/WO2012060785A1/en active Application Filing
- 2011-11-03 WO PCT/TR2011/000253 patent/WO2012060788A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0281200A1 (en) * | 1987-03-02 | 1988-09-07 | Yamanouchi Europe B.V. | Pharmaceutical composition, pharmaceutical granulate and process for their preparation |
| WO2004006917A1 (en) * | 2002-07-16 | 2004-01-22 | Ranbaxy Laboratories Limited | Dispersible tablets for oral administration |
| CA2393614A1 (en) * | 2002-07-19 | 2002-10-28 | Abbott Laboratories | Antibacterial clarithromycin compositions and processes for making the same |
| WO2005115347A1 (en) * | 2004-05-31 | 2005-12-08 | Sam-A Pharmaceuticals Co., Ltd. | Dispersible tablet comprising beta lactam antibiotics and process for preparing the same |
| WO2007058397A1 (en) * | 2005-11-17 | 2007-05-24 | Gl Pharmtech Corp. | A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013109203A1 (en) * | 2012-01-18 | 2013-07-25 | Mahmut Bilgic | Tablet formulations comprising cefditoren pivoxil |
| WO2013109225A1 (en) * | 2012-01-18 | 2013-07-25 | Mahmut Bilgic | Pharmaceutical tablet formulations comprising ceftibuten |
| WO2013109227A1 (en) * | 2012-01-18 | 2013-07-25 | Mahmut Bilgic | Pharmaceutical compositions comprising ceftibuten |
| CN105168147A (en) * | 2015-09-11 | 2015-12-23 | 青岛蓝盛洋医药生物科技有限责任公司 | Pharmaceutical cefetamet pivoxil hydrochloride composite granule for treating bacterial infection |
| US10624899B2 (en) | 2016-07-14 | 2020-04-21 | Achaogen, Inc. | Combination products for the treatment of bacterial infections and methods of producing or dosing of same |
| WO2018071810A1 (en) * | 2016-10-13 | 2018-04-19 | RhinoNase, Inc. | Antibiotic compositions for nasal irrigation and methods |
| US10420776B2 (en) | 2016-10-13 | 2019-09-24 | RhinoNase, Inc. | Antibiotic compositions for nasal irrigation and methods |
| US10849909B2 (en) | 2016-10-13 | 2020-12-01 | RhinoNase, Inc. | Antibiotic compositions for nasal irrigation and methods |
| CN108743548A (en) * | 2018-06-28 | 2018-11-06 | 苏州中联化学制药有限公司 | A kind of Cefprozil granule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012060788A1 (en) | 2012-05-10 |
| TR201009167A2 (en) | 2012-05-21 |
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