WO2013151516A1 - Film tablet formulations comprising cefuroxime axetil and clavulanic acid - Google Patents

Film tablet formulations comprising cefuroxime axetil and clavulanic acid Download PDF

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Publication number
WO2013151516A1
WO2013151516A1 PCT/TR2013/000107 TR2013000107W WO2013151516A1 WO 2013151516 A1 WO2013151516 A1 WO 2013151516A1 TR 2013000107 W TR2013000107 W TR 2013000107W WO 2013151516 A1 WO2013151516 A1 WO 2013151516A1
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formulation
formulation according
cellulose
comprised
weight
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PCT/TR2013/000107
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French (fr)
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Priority to EP13724645.0A priority Critical patent/EP2833873A1/en
Publication of WO2013151516A1 publication Critical patent/WO2013151516A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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

Definitions

  • the present invention relates to pharmaceutical formulations comprising cefuroxime axetil and clavulanic acid for use in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
  • Said formulations are characterized in being in film coated tablet form.
  • Cefuroxime was first disclosed in the application numbered US3974153.
  • cefuroxime is effective in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
  • upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis
  • lower respiratory tract infections such as pyelonephritis, cystitis and urethritis
  • skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
  • Cefuroxime is found in form of 125, 250 and 500 mg tablet and suspension on the market.
  • cefuroxime axetil which is ester form of cefuroxime
  • cefuroxime axetil is a pretty effective beta- lactam antibiotic against a broad spectrum of microorganisms
  • bioavailability of cefuroxime required to enable its absorption through the blood circulation by the gastrointestinal tract is low.
  • the reasons for this are low solubility of cefuroxime in aqueous solutions and its stability problems.
  • difficulties of providing high bioavailability for orally administrable cefuroxime axetil formulations are mentioned.
  • cefuroxime axetil provide good bioavailability when cefuroxime axetil is used in pure amorphous form or high amounts of disintegrant are used to enable quick dissolution in gastrointestinal liquid.
  • tablet forms are developed comprising combinations of a beta-lactam group cephalosporin antibiotic such as cefuroxime axetil and a beta-lactam inhibitor such as clavulanic acid in order to prevent bacterial resistance and provide an even higher antibacterial resistance.
  • a beta-lactam group cephalosporin antibiotic such as cefuroxime axetil
  • a beta-lactam inhibitor such as clavulanic acid
  • problems of solubility and stability seen in cefuroxime axetil formulations are more prominent in tablet formulations comprising cefuroxime axetil and clavulanic acid in the prior art since clavulanic acid has a high potential to absorb moisture due to its hygroscopic nature. This results in observation of instability in oral tablet forms comprising cefuroxime axetil and clavulanic acid, therefore low solubility and low bioavailability during use.
  • the formulations comprising cefuroxime axetil and clavulanic acid and formulated in film coated tablet form are stabile and have high solubility in gastrointestinal liquid, therefore their absorption through blood circulation increases in the case that they comprise at least one cellulose based diluent and the ratio of cefuroxime axetil: diluent is in the range of 1 :5 to 5:1 by weight.
  • the present invention relates to formulations comprising cefuroxime axetil and clavulanic acid formulated in film coated tablet form and is characterized in that said formulations comprise at least one cellulose based diluent and the ratio of cefuroxime axetihdiluent is in the range of 1 :5 to 5: 1 by weight.
  • Characteristic features of the film coated tablet formulations of the present invention are that they are stabile, present high solubility and fast dispersion during use and therefore have high bioavailability as their absorption through the blood circulation increases as a result of comprising at least one cellulose based diluent and having the ratio of cefuroxime axetil .-diluent in the range of 1 :5 to 5:1 by weight.
  • the present invention relates to formulations formulated in film coated tablet form comprising cefuroxime axetil and clavulanic acid, and it is characterized in comprising at least one cellulose based diluent and having the ratio of cefuroxime axetihdiluent preferably in the range of 1 :2 to 4: 1 by weight.
  • the diluent used in the formulations of the present invention can be selected from a group comprising microcrystalline cellulose, silicified microcrystalline, cellulose acetate, modified cellulose and/or combinations thereof.
  • microcrystalline cellulose can be used as diluent in the tablet formulations prepared according to the present invention.
  • the tablet formulations of the present invention comprise at least one pharmaceutically acceptable excipient in addition to cefuroxime axetil, clavulanic acid and the diluent.
  • the pharmaceutically acceptable excipients that can be used in the formulations of the present invention can be selected from a group comprising disintegrant, glidant, lubricant, binder, humectant and film coating agent.
  • the disintegrant that can be used in the tablet formulations of the present invention comprising cefuroxime axetil and clavulanic acid can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminium silicate, starch.
  • carboxymethyl cellulose sodium or carboxymethyl cellulose calcium or a disintegrant composition comprising the combination thereof can be used as disintegrant in the formulations of the present invention. More preferably, carboxymethyl cellulose calcium can be used.
  • the film tablet formulations comprising cefuroxime axetil and clavulanic acid to disperse fast and homogeneously in body and provide an effective treatment during use.
  • the inventors have seen that optimum hardness and brittleness values are attained and thus the formulations can disperse fast and homogeneously as desired in the case that the film tablet formulations comprising cefuroxime axetil and clavulanic acid comprise a diluent and a disintegrant such that the ratio of diluen disintegrant is in the range of 1 : 1 to 6: 1 , preferably in the range of 2: 1 to 5 : 1 by weight.
  • Another characteristic of the tablet formulations of the present invention comprising cefuroxime axetil and clavulanic acid is that the ratio of diluent:disintegrant is in the range of 1 :1 to 6: 1, preferably in the range of 2: 1 to 5:1 by weight.
  • the glidant that can be used in the formulations of the present invention can be selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof.
  • silicon dioxide can be used as the glidant in the formulations of the present invention.
  • the lubricant that can be used in the formulations prepared according to the present invention can be selected form a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
  • sodium stearyl fumarate can be used as the lubricant in the formulations of the present invention.
  • the binder that can be used in the formulations of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyl ethyl cellulose, hydroxyl methyl cellulose, hydroxyl propyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, povidone.
  • the humectant that can be used in the tablet formulations of the present invention comprising cefuroxime axetil and clavulanic acid can be selected from a group comprising silica, colloidal silica, magnesium trisilicate, powder cellulose, microcrystalline cellulose, magnesium oxide, calcium silicate, starch, microcrystalline cellulose and talc.
  • Clavulanic acid can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and free base, polymorphous forms, crystalline forms, amorphous forms and esters.
  • Clavulanic acid used as the second active agent in addition to cefuroxime in the tablet formulations of the present invention comprising cefuroxime is preferably in potassium clavulanate form. Another characteristic of the formulations of the present invention is that the ratio of potassium clavulanate :humectant is 1 : 1.
  • the film coating agent that can be used in the film coated tablet formulations prepared according to the present invention can be selected from a group comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, lecithin or a combination thereof.
  • the film coating agent marketed under the name of Opadry Yellow® can be used.
  • formulations of the present invention comprise cefuroxime axetil in the range of 5-80%, preferably in the range of 20-70%, more preferably in the range of 30-60% by weight in proportion to total weight of the unit dose amount.
  • formulations comprise potassium clavulanate-humectant mixture in the range of 10-50%, preferably in the range of 10-40%, more preferably in the range of 15-35% by weight in proportion to total weight of the unit dose amount.
  • the formulations prepared according to the present invention can comprise 5-30% diluent, 1- 10% disintegrant, 0.1-2% binder, 0.1-2% glidant, 0.1-2% lubricant, 0.5-2.5% coating agent by weight in proportion to total weight of the unit dose amount.
  • wet granulation method is used for preparation of the formulation of the present invention.
  • the granulation solution prepared using binder and purified water is used to granulate the mixture comprising sieved cefuroxime axetil, diluent and disintegrant.
  • potassium clavulanate, diluent, disintegrant and glidant are added to the mixture and they are mixed again.
  • lubrication is applied with the lubricant and the final mixture obtained is compressed in tablet form.
  • the tablets compressed are coated with film.
  • the film coated tablets are blistered and put into cartons.
  • the formulations of the present invention can be used in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
  • upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis
  • lower respiratory tract infections such as pyelonephritis, cystitis and urethritis
  • skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
  • Example I Tablet formulation comprising cefuroxime axetil and clavulanic acid
  • the formulation given above is prepared by wet granulation method. After cefuroxime axetil and potassium clavulanate are granulated with the granulation solution comprising binder; the granules are mixed with the mixture comprising diluent, disintegrant, binder and glidant in the container. The mixture lubricated with the lubricant is sent to tablet compression. The tablets are coated with film, blistered and put into cartons.

Abstract

The present invention relates to pharmaceutical formulations comprising cefuroxime axetil and clavulanic acid for use in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases. Said formulations are characterized in being in film coated tablet form.

Description

FILM TABLET FORMULATIONS COMPRISING CEFUROXIME AXETIL AND
CLAVULANIC ACID
The present invention relates to pharmaceutical formulations comprising cefuroxime axetil and clavulanic acid for use in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases. Said formulations are characterized in being in film coated tablet form. Cefuroxime was first disclosed in the application numbered US3974153. It has been disclosed in said document that use of cefuroxime is effective in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
Figure imgf000002_0001
Cefuroxime is found in form of 125, 250 and 500 mg tablet and suspension on the market.
Although cefuroxime axetil, which is ester form of cefuroxime, is a pretty effective beta- lactam antibiotic against a broad spectrum of microorganisms, it is known that bioavailability of cefuroxime required to enable its absorption through the blood circulation by the gastrointestinal tract is low. The reasons for this are low solubility of cefuroxime in aqueous solutions and its stability problems. In the prior art, difficulties of providing high bioavailability for orally administrable cefuroxime axetil formulations are mentioned.
In the patent numbered US4820833, it was disclosed that solubility of pure amorphous form of cefuroxime in oral dosage forms is higher compared to its crystalline forms and has a better bioavailability.
In the patent numbered US4897270, it was seen that absorption of film coated cefuroxime axetil formulations through blood circulation remains low unless coating is formulated to disperse quickly when the film-coated tablet reaches the stomach.
According to the prior art, it is seen that oral forms of cefuroxime axetil provide good bioavailability when cefuroxime axetil is used in pure amorphous form or high amounts of disintegrant are used to enable quick dissolution in gastrointestinal liquid.
Furthermore, tablet forms are developed comprising combinations of a beta-lactam group cephalosporin antibiotic such as cefuroxime axetil and a beta-lactam inhibitor such as clavulanic acid in order to prevent bacterial resistance and provide an even higher antibacterial resistance. However, problems of solubility and stability seen in cefuroxime axetil formulations are more prominent in tablet formulations comprising cefuroxime axetil and clavulanic acid in the prior art since clavulanic acid has a high potential to absorb moisture due to its hygroscopic nature. This results in observation of instability in oral tablet forms comprising cefuroxime axetil and clavulanic acid, therefore low solubility and low bioavailability during use.
According to the problems mentioned in the prior art, there is need for development of stabile oral tablet formulations comprising cefuroxime axetil and clavulanic acid combination which have high solubility in gastrointestinal liquid, high absorption through the blood circulation by the gastrointestinal tract and therefore high bioavailability. The inventors have seen that film coated tablet forms comprising cefuroxime axetil and clavulanic acid they developed are highly stabile and they present high solubility and fast dispersion during use and thus they have high bioavailability.
The inventors have surprisingly seen that the formulations comprising cefuroxime axetil and clavulanic acid and formulated in film coated tablet form are stabile and have high solubility in gastrointestinal liquid, therefore their absorption through blood circulation increases in the case that they comprise at least one cellulose based diluent and the ratio of cefuroxime axetil: diluent is in the range of 1 :5 to 5:1 by weight.
Description of the Invention
According to this, the present invention relates to formulations comprising cefuroxime axetil and clavulanic acid formulated in film coated tablet form and is characterized in that said formulations comprise at least one cellulose based diluent and the ratio of cefuroxime axetihdiluent is in the range of 1 :5 to 5: 1 by weight.
Characteristic features of the film coated tablet formulations of the present invention are that they are stabile, present high solubility and fast dispersion during use and therefore have high bioavailability as their absorption through the blood circulation increases as a result of comprising at least one cellulose based diluent and having the ratio of cefuroxime axetil .-diluent in the range of 1 :5 to 5:1 by weight.
According to this in another aspect, the present invention relates to formulations formulated in film coated tablet form comprising cefuroxime axetil and clavulanic acid, and it is characterized in comprising at least one cellulose based diluent and having the ratio of cefuroxime axetihdiluent preferably in the range of 1 :2 to 4: 1 by weight.
The diluent used in the formulations of the present invention can be selected from a group comprising microcrystalline cellulose, silicified microcrystalline, cellulose acetate, modified cellulose and/or combinations thereof. Preferably, microcrystalline cellulose can be used as diluent in the tablet formulations prepared according to the present invention.
Another characteristic feature of the tablet formulations of the present invention is that said formulations comprise at least one pharmaceutically acceptable excipient in addition to cefuroxime axetil, clavulanic acid and the diluent. According to this, the pharmaceutically acceptable excipients that can be used in the formulations of the present invention can be selected from a group comprising disintegrant, glidant, lubricant, binder, humectant and film coating agent.
The disintegrant that can be used in the tablet formulations of the present invention comprising cefuroxime axetil and clavulanic acid can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminium silicate, starch.
Preferably, carboxymethyl cellulose sodium or carboxymethyl cellulose calcium or a disintegrant composition comprising the combination thereof can be used as disintegrant in the formulations of the present invention. More preferably, carboxymethyl cellulose calcium can be used.
Physical characteristics of the tablets such as hardness and brittleness are required to be at optimum values in order for the film tablet formulations comprising cefuroxime axetil and clavulanic acid to disperse fast and homogeneously in body and provide an effective treatment during use. The inventors have seen that optimum hardness and brittleness values are attained and thus the formulations can disperse fast and homogeneously as desired in the case that the film tablet formulations comprising cefuroxime axetil and clavulanic acid comprise a diluent and a disintegrant such that the ratio of diluen disintegrant is in the range of 1 : 1 to 6: 1 , preferably in the range of 2: 1 to 5 : 1 by weight.
Another characteristic of the tablet formulations of the present invention comprising cefuroxime axetil and clavulanic acid is that the ratio of diluent:disintegrant is in the range of 1 :1 to 6: 1, preferably in the range of 2: 1 to 5:1 by weight.
The glidant that can be used in the formulations of the present invention can be selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof.
Preferably, silicon dioxide can be used as the glidant in the formulations of the present invention.
The lubricant that can be used in the formulations prepared according to the present invention can be selected form a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
Preferably, sodium stearyl fumarate can be used as the lubricant in the formulations of the present invention. The binder that can be used in the formulations of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyl ethyl cellulose, hydroxyl methyl cellulose, hydroxyl propyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, povidone. The humectant that can be used in the tablet formulations of the present invention comprising cefuroxime axetil and clavulanic acid can be selected from a group comprising silica, colloidal silica, magnesium trisilicate, powder cellulose, microcrystalline cellulose, magnesium oxide, calcium silicate, starch, microcrystalline cellulose and talc.
Clavulanic acid can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and free base, polymorphous forms, crystalline forms, amorphous forms and esters.
Clavulanic acid used as the second active agent in addition to cefuroxime in the tablet formulations of the present invention comprising cefuroxime is preferably in potassium clavulanate form. Another characteristic of the formulations of the present invention is that the ratio of potassium clavulanate :humectant is 1 : 1.
The film coating agent that can be used in the film coated tablet formulations prepared according to the present invention can be selected from a group comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, lecithin or a combination thereof. For instance, the film coating agent marketed under the name of Opadry Yellow® can be used.
Another characteristic of the formulations of the present invention is that said formulations comprise cefuroxime axetil in the range of 5-80%, preferably in the range of 20-70%, more preferably in the range of 30-60% by weight in proportion to total weight of the unit dose amount. Another characteristic of the formulations of the present invention is that said formulations comprise potassium clavulanate-humectant mixture in the range of 10-50%, preferably in the range of 10-40%, more preferably in the range of 15-35% by weight in proportion to total weight of the unit dose amount. The formulations prepared according to the present invention can comprise 5-30% diluent, 1- 10% disintegrant, 0.1-2% binder, 0.1-2% glidant, 0.1-2% lubricant, 0.5-2.5% coating agent by weight in proportion to total weight of the unit dose amount.
Preferably, wet granulation method is used for preparation of the formulation of the present invention. According to this method, the granulation solution prepared using binder and purified water is used to granulate the mixture comprising sieved cefuroxime axetil, diluent and disintegrant. After the obtained granules are dried and sieved; potassium clavulanate, diluent, disintegrant and glidant are added to the mixture and they are mixed again. At the last phase, lubrication is applied with the lubricant and the final mixture obtained is compressed in tablet form. The tablets compressed are coated with film. The film coated tablets are blistered and put into cartons.
The formulations of the present invention can be used in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.
The examples below are given in order to explain the pharmaceutical compositions of the present invention and their preparation methods, yet the invention cannot be limited to these.
Example I. Tablet formulation comprising cefuroxime axetil and clavulanic acid
Figure imgf000008_0001
The formulation given above is prepared by wet granulation method. After cefuroxime axetil and potassium clavulanate are granulated with the granulation solution comprising binder; the granules are mixed with the mixture comprising diluent, disintegrant, binder and glidant in the container. The mixture lubricated with the lubricant is sent to tablet compression. The tablets are coated with film, blistered and put into cartons.

Claims

1. A formulation comprising cefuroxime axetil and clavulanic acid and formulated in film coated tablet form, characterized in that said formulation comprises at least one cellulose based diluent,
• the ratio of cefuroxime axetil: diluent is in the range of 1 :5 to 5 : 1 and
• the ratio of diluen disintegrant is in the range of 1 : 1 to 6: 1 by weight.
2. The formulation according to claim 1, characterized in that said formulation comprises at least one cellulose based diluent and the ratio of cefuroxime axeti diluent is in the range of 1 :2 to 4:1 by weight.
3. The formulation according to claims 1-2, characterized in that the diluent comprised in said formulation is selected from a group comprising microcrystalline cellulose, silicified microcrystalline, cellulose acetate, modified cellulose and/or a combination thereof.
4. The formulation according to claim 3, characterized in that the diluent comprised in said formulation is microcrystalline cellulose.
5. The formulation according to claims 1-4, characterized in that said formulation comprises at least one pharmaceutically acceptable excipient in addition to cefuroxime axetil, clavulanic acid and the diluent.
6. The formulation according to claim 5, characterized in that the excipients that can be comprised in said formulation are selected from a group comprising disintegrant, glidant, lubricant, binder, humectant and film coating agent.
7. The formulation according to claim 6, characterized in that the disintegrant that can be comprised in said formulation is selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
8. The formulation according to claim 7, characterized in that the disintegrant that can be comprised in said formulation is selected from carboxymethyl cellulose sodium or carboxymethyl cellulose calcium or a disintegrant composition comprising a combination thereof.
9. The formulation according to claim 8, characterized in that the disintegrant that can be comprised in said formulation is carboxymethyl cellulose calcium.
10. The formulation according to claims 5-9, characterized in that the glidant that can be comprised in said formulation is selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or a combination thereof.
1 1. The formulation according to claim 10, characterized in that the glidant that can be used in said formulations is silicon dioxide.
12. The formulation according to claims 5-1 1 , characterized in that the lubricant that can be comprised in said formulation is selected form a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
13. The formulation according to claim 12, characterized in that the lubricant that can be used in said formulations is sodium stearyl fumarate.
14. The formulation according to claim 5-13, characterized in that the binder that can be comprised in said formulation is selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, povidone.
15. The formulation according to claims 5-14, characterized in that the humectant that can be comprised in said formulation is selected from a group comprising silica, colloidal silica, magnesium trisilicate, powder cellulose, microcrystalline cellulose, magnesium oxide, calcium silicate, starch, microcrystalline cellulose and talc.
16. The formulation according to claims 5-15, characterized in that the coating agent that can be comprised in said formulation is selected from a group comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, lecithin or a combination thereof.
17. The formulation according to claims 1 -16, characterized in that the ratio of diluent:disintegrant comprised in said formulation is in the range of 2: 1 to 5: 1 by weight.
18. The formulation according to any preceding claims, characterized in that clavulanic acid comprised in said formulation is selected from a group comprising its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts and free base form, polymorphs, crystalline forms, amorphous forms and esters.
19. The formulation according to any preceding claims, characterized in that clavulanic acid comprised in said formulation is in potassium clavulanate form.
20. The formulation according to any preceding claims, characterized in that the ratio of potassium clavulanate:humectant in said formulation is 1 : 1.
21. The formulation according to any preceding claims, characterized in that said formulation comprises 5-80% cefuroxime axetil by weight.
22. The formulation according to claim 21 , characterized in that said formulation comprises 20-70% cefuroxime axetil by weight.
23. The formulation according to claim 22, characterized in that said formulation comprises 30-60%) cefuroxime axetil by weight.
24. The formulation according to any preceding claims, characterized in that said formulation comprises potassium clavulanate-humectant mixture in the range of 10- 50% by weight.
25. The formulation according to claim 24, characterized in that said formulation comprises potassium clavulanate-humectant mixture in the range of 10-40% by weight.
26. The formulation according to claim 25, characterized in that said formulation comprises potassium clavulanate-humectant mixture in the range of 10-40% by weight.
27. The formulation according to any preceding claims, characterized in that said formulation comprises 5-30% of diluent, 1-10%> of disintegrant, 0.1-2% of binder, 0.1- 2% of glidant, 0.1-2% of lubricant, 0.5-2.5% of coating agent by weight in proportion to total weight of the unit dose amount.
28. A method for production of the formulation according to any preceding claims, characterized in that said method comprises the steps of wet granulation, drying, sieving, lubrication, tablet compression and film coating.
PCT/TR2013/000107 2012-04-04 2013-04-03 Film tablet formulations comprising cefuroxime axetil and clavulanic acid WO2013151516A1 (en)

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