WO2011078832A1 - Effervescent formulations comprising cefixime - Google Patents

Effervescent formulations comprising cefixime Download PDF

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Publication number
WO2011078832A1
WO2011078832A1 PCT/TR2010/000262 TR2010000262W WO2011078832A1 WO 2011078832 A1 WO2011078832 A1 WO 2011078832A1 TR 2010000262 W TR2010000262 W TR 2010000262W WO 2011078832 A1 WO2011078832 A1 WO 2011078832A1
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Prior art keywords
pharmaceutical composition
composition according
sodium
acid
effervescent
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PCT/TR2010/000262
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French (fr)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2011078832A1 publication Critical patent/WO2011078832A1/en
Priority to US13/532,120 priority Critical patent/US8614315B2/en
Priority to US14/089,355 priority patent/US20140079647A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent

Definitions

  • Cefixime was first described in European patent no EP0030630 (Bl) and it is known with the chemical name of 6R,1R)-1- ⁇ [2-(2-amino-l,3-thiazol-4-yl)-2-
  • Cefixime physically appears as white or light yellow crystal powder. It is freely soluble in methanol and propylene glycol, partially soluble in ethanol and acetone however it does not dissolve in ether, ethyl acetate, hexane and water. Its solubility in aqueous solutions changes with respect to the pH of the solution. Accordingly its solubility in a solution with a pH value of 3.2 is 0.5 mg/mL at room temperature; however when the pH of the solution is increased to 4.2 solubility increases to 18 mg/mL.
  • the product named as SUPRAX that is sold by Fujisawa/Astellas comprises cefixime as active agent and is present in oral tablet or oral suspension forms and in dosages comprising high amounts like 200 mg and 400 mg cefixime.
  • Suprax is indicated for use in the treatment of upper and lower respiratory tract infections, urinary tract infections and infections arising from microorganisms, especially beta-lactamase.
  • Formulations comprising cefixime are generally present in oral tablet or oral suspension forms. In these dosage forms where large amounts of cefixime. that is used as active agent, become bigger in size when formulated with the excipients and this affects the usage negatively. Alternatively, the use of reliable and user-friendly effervescent forms is suggested. In addition to the active agent, some excipients are incorporated into the efervesan formulations comprising cefixime in order to obtain a final product having the desired physical properties. For instance, it. is aimed to bring .hardness of the final product to a desired point and make the product disperse in water effectively by adding at least one binder into the granulation solution during granulation.
  • binder used in the effervescent formulations comprising an antibiotic of cephalosporin group like cefixime affects the physical properties of effervescent forms negatively.
  • binder causes increase the dispersion time of the obtained tablet in water, also some problems are confronted during handling or the hardness of tablets are not become sufficient for effective dispersion. These problems causes ineffective dispersion of the drug in the effervescent form during the use of the final product and thus the absorption and depending on that bioavailability of the product decrease.
  • effervescent formulations which are desirably hard, suitable for carrying and handling and which can disperse in water rapidly. Therefore, it is also seen that these effervescent formulations provide high absorption and bioavailability without confronting the problems observed in the prior art.
  • the present invention is related to the effervescent formulations comprising cefixime used as active agent and the methods for the preparation of these formulations.
  • the ratio of cefixime: binder used in the formulation is in the range of 20: 1 and 8: 1, preferably 17: 1 and 10:1 and more preferably 15: 1 and 11 :1, it was surprisingly seen that effervescent tablets which have the desirable hardness, suitable for carrying and handling and can also disperse in water rapidly were obtained.
  • the first aspect of the present invention is effervescent formulations comprising cefixime and binder in an amount such that cefixime :povidone ratio is in the range of 20: 1 and 8:1, preferably 17: 1 and 10: 1 and more preferably 15:1 and 11 : 1.
  • "Effervescent formulations" term mentioned in the text includes effervescent tablets, effervescent granules and effervescent powders.
  • Binder used in the effervescent formulation in accordance with the present invention can be selected from a group comprising; alginic acid, chitosan, carbomer, carboxymethyl cellulose sodium, dextrin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose ethyl cellulose, gelatine, hypromellose, magnesium aluminium silicate, maltodextrin, polyethylene oxide and povidone or a combination thereof.
  • povidone is used.
  • the present invention is the effervescent formulations comprising cefixime and povidone in an amount such that cefixime :povidone ratio is in the range of 20:1 and 8:1, preferably 17:1 and 10:1 and more preferably 15:1 and 11 : 1.
  • Second aspect of the present invention is use of cefixime in an amount 1-55%, preferably in an amount 5-45% and more preferably in an amount 10-35% in said effervescent formulation.
  • cefixime or its pharmaceutically acceptable salts, hydrates, solvates and/or a combination thereof can be used.
  • cefixime used in the present invention can be present in monohydrate, dihydrate, trihydrate and/or anhydrous form.
  • Another aspect of the invention is pharmaceutical composition comprising cefixime, at least one binder and in addition to that pharmaceutically acceptable excipients.
  • composition formulated in effervescent form in accordance with the present invention comprises cefixime as active agent and at least one binder, preferably povidone and can also include one or more of pharmaceutically acceptable excipients such as effervescent acid and base comprising effervescent couple, sweetener and/or taste regulator, water soluable lubricant, flavoring agent, glidant, diluents, disintegrant, coloring agent, surfactant, anti-foaming agent, humectants, acidic agent, basic agent and stabilizing agent.
  • Effervescent acid used in the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, adipic acid and succinic acid. Preferably citric acid is used.
  • Effervescent base used in the present invention can be selected from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate.
  • basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate.
  • sodium hydrogen carbonate is used.
  • Sweetener and/or taste regulator that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group of acesulfame, aspartame, dextrose, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose, saccharin, saccharin sodium, lactitol, maltitol, maltose, sorbitol, sodium cyclamate, sucrose and xylitol or a combination thereof.
  • Lubricant that can be used in effervescent formulations of the present invention can be selected from a group comprising PEG6000 and sodium benzoate.
  • Flavoring agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, natural aroma oils (peppermint oil, oil of wintergreen, oil of cloves, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptole, cinnamon, 1 -methyl acetate, sage, eugenol, oxanon, alpha-irison, marjoram, lemon, orange, blackberry, propenyl guaethol acethyl, cinnamon, vanilla, thymol, linalol, cinnamalaldehyde glycerol acethal, N-quadric p-menthan-3-carboxamide, 3,1-methoxy propane 1,
  • Glidant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof.
  • Disintegrant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminium silicate and starch or a combination thereof.
  • Diluent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group comprising calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof.
  • Coloring agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, caratenoids and chlorophyl and a combination thereof.
  • Surfactant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, sodium lauryl sulfate and magnesium lauryl sulfate and a combination thereof.
  • Anti-foaming agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, simethicone and dimethyl siloxane, silicone oil or a combination thereof.
  • Humectant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, anhydrous sodium sulphate, silica gel and potassium carbonate or combinations thereof.
  • Acidic agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group of acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.
  • Basic agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group of potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, or combinations thereof.
  • Stabilizing agent that can be used in effervescent formulations of the present invention can be selected from agents such as antioxidants, chelating agents, alkalinizing agents and photo- protectors.
  • Antioxidants can be selected from some substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, gallates (like propil gallates), tocoferole, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate.
  • Chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or their combinations.
  • Alkalinizing agents can be selected from the organic compounds such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, alkali metal salts like sodium aluminate; calcium carbonate, calcium hydroxide, dibasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, the alkaline earth metal salts like magnesium aluminate, primary, secondary and tertiary amines, cyclic amines, ⁇ , ⁇ '-dibenzylethylenediamin, dietanolamine, ethylenediamin, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate.
  • Photo-protecting agents can be selected from metal oxides such as titanium oxide, iron oxide or zinc oxide.
  • “Final product” means the final state of drug, which is ready for use and is obtained by the process wherein the formulations comprise at least one antibiotic in effervescent dosage form.
  • cefixime in an amount of 1-55%
  • effervescent couple in an amount of 10-85%
  • sweetener in an amount of 0.2-6%
  • binder in an amount of 0.2-15%
  • water soluble lubricant in an amount of 0.2- 5%
  • flavoring agent in an amount of 0.2-6%
  • Another aspect of the present invention is the use of the pharmaceutical composition prepared in accordance with said invention in the treatment of the diseases of upper respiratory tract infections such as pharyngitis, tonsillitis and otitis media, lower respiratory tract infections such as acute pneumonia, acute and chronic bronchitis and urinary tract infections such as acute cystitis, cystourethritis.
  • upper respiratory tract infections such as pharyngitis, tonsillitis and otitis media
  • lower respiratory tract infections such as acute pneumonia, acute and chronic bronchitis
  • urinary tract infections such as acute cystitis, cystourethritis.
  • Another aspect of the invention is related to processes for use in the preparation of effervescent tablet and granules comprising cefixime. Said process comprises use of wet and/or dry granulation techniques present in the state of the art.
  • a process for the preparation of the effervescent formulation in accordance with the present invention 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 the formed mixture in tablet pressing machine.
  • efervescent formulations in accordance with the present invention can be prepared according to the following examples.
  • a granulation solution comprising water and/or optionally another solvent is prepared.
  • the mixture comprising cefixime, effervescent base, effervescent acid, sweetener and binder is added to the fluid bed dryer and granulated with the granulation solution. Dried granules are mixed with flavoring agent and water soluble lubricant. Finally, obtained mixture is optionally compressed in the tablet pressing machine.

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Abstract

Present invention relates to effervescent formulations and preparation of these formulations.

Description

EFFERVESCENT FORMULATIONS COMPRISING CEFIXIME
Present invention relates to effervescent formulations and preparation of these formulations. Background of the invention
Cefixime was first described in European patent no EP0030630 (Bl) and it is known with the chemical name of 6R,1R)-1- {[2-(2-amino-l,3-thiazol-4-yl)-2-
(carboxymethyloxyimino)acetyl]amino}-3-ethenyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2- carboxylic acid (Formula 1). It is defined as a third generation cephalosporin and indicated for use in the treatment of infections caused by gram positive and gram negative bacteria.
Figure imgf000002_0001
Formula 1
Cefixime physically appears as white or light yellow crystal powder. It is freely soluble in methanol and propylene glycol, partially soluble in ethanol and acetone however it does not dissolve in ether, ethyl acetate, hexane and water. Its solubility in aqueous solutions changes with respect to the pH of the solution. Accordingly its solubility in a solution with a pH value of 3.2 is 0.5 mg/mL at room temperature; however when the pH of the solution is increased to 4.2 solubility increases to 18 mg/mL.
The product named as SUPRAX that is sold by Fujisawa/Astellas comprises cefixime as active agent and is present in oral tablet or oral suspension forms and in dosages comprising high amounts like 200 mg and 400 mg cefixime. Suprax is indicated for use in the treatment of upper and lower respiratory tract infections, urinary tract infections and infections arising from microorganisms, especially beta-lactamase.
Formulations comprising cefixime are generally present in oral tablet or oral suspension forms. In these dosage forms where large amounts of cefixime. that is used as active agent, become bigger in size when formulated with the excipients and this affects the usage negatively. Alternatively, the use of reliable and user-friendly effervescent forms is suggested. In addition to the active agent, some excipients are incorporated into the efervesan formulations comprising cefixime in order to obtain a final product having the desired physical properties. For instance, it. is aimed to bring .hardness of the final product to a desired point and make the product disperse in water effectively by adding at least one binder into the granulation solution during granulation.
However in the prior art, it is observed that binder used in the effervescent formulations comprising an antibiotic of cephalosporin group like cefixime affects the physical properties of effervescent forms negatively. In cases where said effervescent forms are produced in tablet forms, binder causes increase the dispersion time of the obtained tablet in water, also some problems are confronted during handling or the hardness of tablets are not become sufficient for effective dispersion. These problems causes ineffective dispersion of the drug in the effervescent form during the use of the final product and thus the absorption and depending on that bioavailability of the product decrease.
As it is seen, development of new formulations are required for obtaining the drugs in the effervescent form having desired physical properties for the purpose of providing sufficient absorption and bioavailability of cefixime that is used as active agent.
The inventors have surprisingly found effervescent formulations which are desirably hard, suitable for carrying and handling and which can disperse in water rapidly. Therefore, it is also seen that these effervescent formulations provide high absorption and bioavailability without confronting the problems observed in the prior art.
Detailed Description of the Invention
The present invention is related to the effervescent formulations comprising cefixime used as active agent and the methods for the preparation of these formulations. In cases where the ratio of cefixime: binder used in the formulation is in the range of 20: 1 and 8: 1, preferably 17: 1 and 10:1 and more preferably 15: 1 and 11 :1, it was surprisingly seen that effervescent tablets which have the desirable hardness, suitable for carrying and handling and can also disperse in water rapidly were obtained.
Accordingly, the first aspect of the present invention is effervescent formulations comprising cefixime and binder in an amount such that cefixime :povidone ratio is in the range of 20: 1 and 8:1, preferably 17: 1 and 10: 1 and more preferably 15:1 and 11 : 1. "Effervescent formulations" term mentioned in the text includes effervescent tablets, effervescent granules and effervescent powders.
Binder used in the effervescent formulation in accordance with the present invention can be selected from a group comprising; alginic acid, chitosan, carbomer, carboxymethyl cellulose sodium, dextrin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose ethyl cellulose, gelatine, hypromellose, magnesium aluminium silicate, maltodextrin, polyethylene oxide and povidone or a combination thereof. Preferably povidone is used.
In another aspect, the present invention is the effervescent formulations comprising cefixime and povidone in an amount such that cefixime :povidone ratio is in the range of 20:1 and 8:1, preferably 17:1 and 10:1 and more preferably 15:1 and 11 : 1.
Second aspect of the present invention is use of cefixime in an amount 1-55%, preferably in an amount 5-45% and more preferably in an amount 10-35% in said effervescent formulation.
In the effervescent formulation of the present invention, cefixime or its pharmaceutically acceptable salts, hydrates, solvates and/or a combination thereof can be used. Another aspect of the present invention is that cefixime used in the present invention can be present in monohydrate, dihydrate, trihydrate and/or anhydrous form.
Another aspect of the invention is pharmaceutical composition comprising cefixime, at least one binder and in addition to that pharmaceutically acceptable excipients.
Pharmaceutical composition formulated in effervescent form in accordance with the present invention comprises cefixime as active agent and at least one binder, preferably povidone and can also include one or more of pharmaceutically acceptable excipients such as effervescent acid and base comprising effervescent couple, sweetener and/or taste regulator, water soluable lubricant, flavoring agent, glidant, diluents, disintegrant, coloring agent, surfactant, anti-foaming agent, humectants, acidic agent, basic agent and stabilizing agent. Effervescent acid used in the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, adipic acid and succinic acid. Preferably citric acid is used.
Effervescent base used in the present invention can be selected from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate. Preferably sodium hydrogen carbonate is used.
Sweetener and/or taste regulator that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group of acesulfame, aspartame, dextrose, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose, saccharin, saccharin sodium, lactitol, maltitol, maltose, sorbitol, sodium cyclamate, sucrose and xylitol or a combination thereof.
Lubricant that can be used in effervescent formulations of the present invention can be selected from a group comprising PEG6000 and sodium benzoate. Flavoring agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, natural aroma oils (peppermint oil, oil of wintergreen, oil of cloves, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptole, cinnamon, 1 -methyl acetate, sage, eugenol, oxanon, alpha-irison, marjoram, lemon, orange, blackberry, propenyl guaethol acethyl, cinnamon, vanilla, thymol, linalol, cinnamalaldehyde glycerol acethal, N-quadric p-menthan-3-carboxamide, 3,1-methoxy propane 1,2-diol or a combination thereof.
Glidant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof.
Disintegrant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminium silicate and starch or a combination thereof.
Diluent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group comprising calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof. Coloring agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, caratenoids and chlorophyl and a combination thereof.
Surfactant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, sodium lauryl sulfate and magnesium lauryl sulfate and a combination thereof.
Anti-foaming agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, simethicone and dimethyl siloxane, silicone oil or a combination thereof.
Humectant that can be used in effervescent formulations of the present invention can be selected from, but not limited with, anhydrous sodium sulphate, silica gel and potassium carbonate or combinations thereof.
Acidic agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group of acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof. Basic agent that can be used in effervescent formulations of the present invention can be selected from, but not limited with, a group of potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, or combinations thereof.
Stabilizing agent that can be used in effervescent formulations of the present invention can be selected from agents such as antioxidants, chelating agents, alkalinizing agents and photo- protectors.
Antioxidants can be selected from some substances such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, gallates (like propil gallates), tocoferole, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbil palmitate, ethylenediamine tetraacetate. Chelating agents can be selected from disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or their combinations.
Alkalinizing agents can be selected from the organic compounds such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, alkali metal salts like sodium aluminate; calcium carbonate, calcium hydroxide, dibasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, the alkaline earth metal salts like magnesium aluminate, primary, secondary and tertiary amines, cyclic amines, Ν,Ν'-dibenzylethylenediamin, dietanolamine, ethylenediamin, meglumine, monosodium glutamate, polacrilin sodium, sodium alginate. Photo-protecting agents can be selected from metal oxides such as titanium oxide, iron oxide or zinc oxide.
"Effervescent couple" term means the use of acidic agent and basic agent together.
"Final product" means the final state of drug, which is ready for use and is obtained by the process wherein the formulations comprise at least one antibiotic in effervescent dosage form. In pharmaceutical composition in effervescent form in accordance with the present invention, cefixime in an amount of 1-55%, effervescent couple in an amount of 10-85%, sweetener in an amount of 0.2-6%, binder in an amount of 0.2-15%, water soluble lubricant in an amount of 0.2- 5%, flavoring agent in an amount of 0.2-6% are used.
Another aspect of the present invention is the use of the pharmaceutical composition prepared in accordance with said invention in the treatment of the diseases of upper respiratory tract infections such as pharyngitis, tonsillitis and otitis media, lower respiratory tract infections such as acute pneumonia, acute and chronic bronchitis and urinary tract infections such as acute cystitis, cystourethritis.
Another aspect of the invention is related to processes for use in the preparation of effervescent tablet and granules comprising cefixime. Said process comprises use of wet and/or dry granulation techniques present in the state of the art.
Although not limited with the following example, a process for the preparation of the effervescent formulation in accordance with the present invention 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 the formed mixture in tablet pressing machine.
Provided that it is not limited by these examples, efervescent formulations in accordance with the present invention can be prepared according to the following examples. Example: The effervescent formulation according to present invention and process for preparation
A granulation solution comprising water and/or optionally another solvent is prepared. The mixture comprising cefixime, effervescent base, effervescent acid, sweetener and binder is added to the fluid bed dryer and granulated with the granulation solution. Dried granules are mixed with flavoring agent and water soluble lubricant. Finally, obtained mixture is optionally compressed in the tablet pressing machine.
Figure imgf000008_0001

Claims

1. A pharmaceutical composition comprising cefixime formulated in effervescent form characterized in that the ratio of cefixime: binder is in the range of 20: 1 and 8: 1, preferably 17:1 and 10: 1 and more preferably 15: 1 and 11 :1.
2. A pharmaceutical composition according to claim 1, wherein binder can be selected from a group comprising; alginic acid, chitosan, carbomer, carboxymethyl cellulose sodium, dextrin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose ethyl cellulose, gelatine, hypromellose, magnesium aluminium silicate, maltodextrin, polyethylene oxide and povidone or a combination thereof.
3. A pharmaceutical composition according to claim 2, wherein preferably povidone is used.
4. A pharmaceutical composition according to claim 1, wherein cefixime that is used as active agent can be in the form of its pharmaceutically acceptable salts, hydrates, solvates and/or a combination thereof.
5. A pharmaceutical composition according to claim 4, wherein cefixime that is used as active agent can be in monohydrate, dihydrate, trihydrate or anhydrous form.
6. A pharmaceutical composition according to claim 1, wherein said composition comprises cefixime in an amount in the range of 1-55%, preferably in an amount in the range of 5-45% and more preferably in an amount in the range of 10-35%.
7. A pharmaceutical composition according to claim 1, wherein said composition comprises other pharmaceutically acceptable excipients in addition to cefixime and binder.
8. A pharmaceutical composition according to claim 7, wherein said composition comprises cefixime as active agent and at least one binder, preferably povidone and can also include one or a few of pharmaceutically acceptable excipients such as effervescent acid and base comprising effervescent couple, sweetener and/or taste regulator, water soluble lubricant, flavoring agent, glidant, diluents, disintegrant, coloring agent, surfactant, anti-foaming agent, humectants, acidic agent, basic agent and stabilizing agent.
9. A pharmaceutical composition according to claim 8, wherein effervescent acid is selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, adipic acid and succinic acid.
10. A pharmaceutical composition according to claim 8, wherein effervescent base is selected from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate.
11. A pharmaceutical composition according to claim 9 and 10, wherein preferable effervescent acid is citric acid and preferable effervescent base is sodium hydrogen carbonate.
12. A pharmaceutical composition according to claim 8, wherein sweetener and/or taste regulator is selected from a group of acesulfame, aspartame, dextrose, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose, saccharin, saccharin sodium, lactitol, maltitol, maltose, sorbitol, sodium cyclamate, sucrose and xylitol or a combination thereof.
13. A pharmaceutical composition according to claim 8, wherein lubricant is selected from a group comprising PEG6000 and sodium benzoate.
14. A pharmaceutical composition according to claim 8, wherein flavoring is selected from natural aroma oils (peppermint oil, oil of wintergreen, oil of cloves, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptole, cinnamon, 1 -methyl acetate, sage, eugenol, oksanon, alpha-irison, marjoram, lemon, orange, blackberry, propenyl guaethol acethyl, cinnamon, vanilla, thymol, linalol, cinnamalaldehyde glycerol acethal, N-quadric p-menthan-3-carboxamide, 3,1-methoxy prophanel,2-diol or a combination thereof.
15. A pharmaceutical composition according to claim 8, wherein glidant is selected from sodium lauryl sulfate, sodium benzoate, sodium chloride, sodium acetate, sodium acetate, sodium fumarate, carbowax 4000, L-leucine(17), PEG or a combination thereof.
16. A pharmaceutical composition according to claim 8, wherein diluent is selected from a group comprising calcium carbonate, calcium sulfate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof.
17. A pharmaceutical composition according to claim 8, wherein disintegrant is selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminium silicate and starch or a combination thereof.
18. A pharmaceutical composition according to claim 8, wherein coloring agent is selected from caratenoids and chlorophyl and a combination thereof.
19. A pharmaceutical composition according to claim 8, wherein surfactant is selected from sodium lauryl sulfate and magnesium lauryl sulfate and a combination thereof.
20. A pharmaceutical composition according to claim 8, wherein anti-foaming agent is selected from simethicone and dimethyl siloxane, silicone oil or a combination thereof.
21. A pharmaceutical composition according to claim 8, wherein humectant is selected from anhydrous sodium sulphate, silica gel and potassium carbonate or combinations thereof.
22. A pharmaceutical composition according to claim 8, wherein acidic agent is selected from a group of acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.
23. A pharmaceutical composition according to claim 8, wherein basic is selected from a group of potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate, or combinations thereof.
24. A pharmaceutical composition according to claim 8, wherein stabilizing agent is selected from agents such as antioxidants, chelating agents, alkalinizing agents and photo-protectors.
25. A pharmaceutical composition described in any of the previous claims, wherein cefixime in an amount of 1-55%, effervescent couple in an amount of 10-85%, sweetener in an amount of 0.2-6%, binder in an amount of 0.2-15%, water soluble lubricant in an amount of 0.2-5%, flavoring agent in an amount of 0.2-6% are used in said composition.
26. A method for the preparation of the pharmaceutical composition described in any of the previous claims, wherein said method includes the steps such as 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 the formed mixture in tablet pressing machine.
27. A pharmaceutical composition according to claim 1, wherein said composition is used in the treatment of the diseases of upper respiratory tract infections such as pharyngitis, tonsillitis and otitis media, lower respiratory tract infections such as acute pneumonia, acute and chronic bronchitis and urinary tract infections such as acute cystitis, cystourethritis.
PCT/TR2010/000262 2009-12-25 2010-12-24 Effervescent formulations comprising cefixime WO2011078832A1 (en)

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