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WO2014126541A1 - Compositions pharmaceutiques utilisées pour traiter des infections bactériennes - Google Patents

Compositions pharmaceutiques utilisées pour traiter des infections bactériennes Download PDF

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Publication number
WO2014126541A1
WO2014126541A1 PCT/TR2014/000041 TR2014000041W WO2014126541A1 WO 2014126541 A1 WO2014126541 A1 WO 2014126541A1 TR 2014000041 W TR2014000041 W TR 2014000041W WO 2014126541 A1 WO2014126541 A1 WO 2014126541A1
Authority
WO
WIPO (PCT)
Prior art keywords
cefixime
pharmaceutical tablet
formulation according
formulations
tablet formulation
Prior art date
Application number
PCT/TR2014/000041
Other languages
English (en)
Inventor
Mahmut BILGIÇ
Original Assignee
Bilgiç Mahmut
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bilgiç Mahmut filed Critical Bilgiç Mahmut
Publication of WO2014126541A1 publication Critical patent/WO2014126541A1/fr

Links

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
    • A61K9/2072—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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • 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

Definitions

  • the present invention relates to formulations containing the combination of cefixime which is a third generation cephalosporin antibiotic and clavulanic acid which is a beta-lactamase inhibitor. Said formulations are characterized by their tablet form.
  • Cefixime was first described in patent application no. EP0030630 (Formula-1). In said document, cefixime was first described as to be used in the treatment of infections caused by pathogenic microorganisms and that cefixime can be presented in solid forms such as tablet, granule, powder, and capsule or in liquid forms such as suspension, syrup, emulsion.
  • medicaments containing cefixime as an active ingredient can be found commercially in the form of a suspension and tablet.
  • a beta-lactam antibiotic can be used in combination with a beta-lactamase inhibitor in order to increase the efficacy of treatment.
  • cefixime is used in combination with clavulanic acid.
  • Clavulanic acid and its derivatives are known as beta- lactamase inhibitors which resists beta-lactamase enzyme activity through the suppression of beta-lactamase mediated resistance mechanism (Formula - 2).
  • clavulanic acid is usually in the form of a pharmaceutically acceptable salt, particularly used in the form of potassium clavulanate.
  • potassium clavulanate is a material very difficult to formulate due to its hygroscopic property and the moisture sensitivity. Therefore during its production and use, it should be kept away from water and aqueous media otherwise it can be degraded.
  • Cefixime is a member of the BCS class II drug having low solubility and high permeability.
  • the bioavailability of cefixime tablets is between 40-50%.
  • Cefixime suspensions provide about 25-50% greater bioavailability compared to the tablet form.
  • dosage forms comprising the combination of cefixime and clavulanic acid or a pharmaceutically acceptable salt thereof as an active ingredient which provide ease of use to the patients and do not require expensive manufacturing methods are required.
  • formulations prepared in this invention containing cefixime and clavulanic acid or a pharmaceutically acceptable salt thereof do not require a complex production method, provide ease of use and have desired level of bioavailability because they are in tablet form.
  • the present invention is directed to the formulation of pharmaceutical formulations cefixime and clavulanic acid or a pharmaceutically acceptable salt thereof in tablet form.
  • Said tablet formulations may be prepared in any of the oral tablet forms such as film coated tablets, modified-release, sustained-release tablets, prolonged-release tablets, controlled release tablets.
  • Formulations of the present invention may be preferably in the form of tablets, film-coated tablets or film-coated extended release tablet. Tablets having release properties may also optionally be film coated.
  • cefixime may be present in the form of cefixime and/or their pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and / or their combinations.
  • cefixime may be found preferably in the form of cefixime trihydrate.
  • the ratio of two active substances to each other is important in order to provide the desired therapeutic activity.
  • the ratio of the first active ingredient cefixime to second active ingredient clavulanic acid or a pharmaceutically acceptable salt is 8:1 to 1 :5, preferably 5:1 to 1 :3, more preferably 3:1 to 1 :2 by weight, the desired therapeutic activity is provided.
  • the ratio of cefixime in the formulation to clavulanic acid in the formulation or a pharmaceutically acceptable salt thereof is 8:1 to 1 :5, preferably 5:1 to 1 :3, more preferably 3:1 to 1 :2 by weight.
  • potassium clavulanate is used together with a desiccant in pharmaceutical composition of the present invention preferably in a ratio of 1 : 1.
  • silica colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil ® 200, magnesium trisilicate, pulverized cellulose, Cabosil ® , magnesium oxide, calcium silicate, Syloid ® , starch, microcrystalline cellulose and talc.
  • Potassium clavulanate is used together with Syloid ® or microcrystalline cellulose in pharmaceutical composition of the present invention preferably in a ratio of 1 : 1.
  • Tablet formulations of the present invention contain 50-1000 mg, preferably 50-800 mg and more preferably 50 to 500 mg of cefixime.
  • Tablet formulations of the present invention per unit dosage form 5-500 mg, preferably 20- 400 mg and more preferably 50 to 250 mg of clavulanic acid.
  • Formulations of the present invention may comprise at least one pharmaceutically acceptable excipient in addition to cefixime and clavulanic acid used as active ingredients.
  • At least one excipient to be used in formulations of the present invention may be selected from a group comprising diluents, disintegrants, lubricants, binders, antiadherants, glidants, sweeteners, flavoring agents, speed-controlling agent, the film coating agent, solvent and/or combinations thereof.
  • Binder to be used in formulation of the present invention can be selected from a group comprising carboxymethylcellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, polyvinyl pyrrolidone, starch.
  • Formulations of the present invention can be sensitive to the moisture since clavulanic acid or a pharmaceutically acceptable salt thereof is used as an active ingredient in addition to cefixime. Thus another problem encountered during the preparation of the formulation of the present invention is the sensitivity of the composition to moisture.
  • the ratio of clavulanic acid to diluent used is 5:1 to 1 :5, preferably 3:1 to 1 :3, more preferably 2: 1 to 1 :2 by weight.
  • At least one diluent is used in the formulations of the present invention.
  • the diluent(s) can be selected form the group consisting of starch and derivatives, cellulose and derivatives, microcrystalline cellulose, lactose, sorbitol, silicon dioxide, dicalcium phosphate, or combinations thereof.
  • the amount of diluent used in said formulations is at a rate of 5-50%, preferably 10-40%, more preferably 15-35%.
  • the diluent used in the formulations of the present invention is preferably dicalcium phosphate, microcrystalline cellulose or combination thereof.
  • Disintegrant to be used in the formulations of the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hidrokspropilsuloz, methylcellulose, povidone, magnesium aluminum silicate, starch, and pregelatinized starch or combinations thereof.
  • Lubricant to be used in the formulations of the present invention is can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
  • Cefixime - clavulanic acid formulations of the present invention may contain cefixime, potassium clavulanate, diluent, disintegrant and film-coating agent, respectively, at a rate of 20-60 %, 51-50 %, 5-50 %, 5-25 %, 0, 1 -5 % and 0, 1 - 10 %.
  • Formulations of the present invention are preferably prepared in film-coated tablet form.
  • Film coating agent to be used in said film-coating can be selected from a group comprising sugar- based coating agents, coating agents, water-soluble coating agents, enteric coating agents, and delayed- release coating agents or combinations thereof.
  • sugar-based coatings sucrose alone or with talc, calcium carbonate, calcium phosphate , calcium sulfate, gelatin, gum arabic, carnauba gum, polyvinylpyrrolidone and pullulan can be used with or combination thereof can be used.
  • Water-soluble coating agents can be selected from a group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, metal hydroxyethyl cellulose and sodium carboxymethyl cellulose, cellulose derivatives, polyvinyl acetate, diethyl amino acetate, aminoalkyl methacrylate copolymer and/or combinations thereof.
  • Enteric coating agents can be selected from a group comprising hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose derivatives such as cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD and acrylic acid derivatives such as methacrylic acid copolymer S.
  • film-coating agents used for the film-coating of tablet obtained in formulations of the present invention may be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin or combinations thereof.
  • film-coating agent marketed under the trademark of Opadry Yellow® can be used.
  • second active agent is preferably in the form of potassium clavulanate salt.
  • the method used to prepare formulations of the present invention can be to formulate cefixime and potassium clavulanate together or separately and to compress as single and/or double layered tablets.
  • Said formulation process may comprise one or more known methods such as dry and/or wet granulation, dry blending, mixing, and compacting.
  • solvents to be used in said formulations are water and/or ethyl alcohol.
  • formulations of the present invention can be prepared by mixing a mixture resulting from the formulation of cefixime alone with a mixture resulting from the formulation of cefixime together with potassium clavulanate and transferring these mixtures together to tablet compression to obtain single-layered tablet or separately to obtain a double-layered tablet.
  • the formulations of the present invention are used in the treatment of varying severity of acute and chronic bacterial infection caused by susceptible bacteria.
  • Example - 1 Film Coated Tablet Formulations Comprising Cefixime and Clavulanic Acid Combination
  • cefixime trihydrate potassium clavulanate, diluents and dispersing are mixed. Lubricant is added to the mixture and the whole mixture is stirred again. The resulting final mixture is sent to tablet compression. The resulting tablets are coated with the film coating solution containing film coating agent.
  • Example - 2 Double Layered Tablet Comprising Cefixime and Clavulanic Acid Combination
  • cefixime trihydrate and diluent 1 are granulated by compaction.
  • potassium clavulanate and diluent 2 are mixed. Resulting mixture and the granules obtained previously are transferred to tablet compression separately and compressed in the form of double-layered tablet. Tablets are coated with a film-coating solution containing film-coating agent.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations contenant une association de céfixime, qui est un antibiotique céphalosporine de troisième génération, et d'acide clavulanique, qui est un inhibiteur de bêta-lactamase. Lesdites formulations sont caractérisées par leur forme de comprimés.
PCT/TR2014/000041 2013-02-14 2014-02-14 Compositions pharmaceutiques utilisées pour traiter des infections bactériennes WO2014126541A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2013/01807 2013-02-14
TR201301807 2013-02-14

Publications (1)

Publication Number Publication Date
WO2014126541A1 true WO2014126541A1 (fr) 2014-08-21

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2014/000041 WO2014126541A1 (fr) 2013-02-14 2014-02-14 Compositions pharmaceutiques utilisées pour traiter des infections bactériennes

Country Status (1)

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WO (1) WO2014126541A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030630A2 (fr) 1979-11-19 1981-06-24 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 7-acylamino-3-vinyl céphalosporanique, procédé pour leur préparation, compositions pharmaceutiques les contenant; leurs produits de départ et leur préparation
WO2011093822A1 (fr) * 2010-01-29 2011-08-04 Mahmut Bilgic Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs
WO2011142730A1 (fr) * 2010-05-14 2011-11-17 Mahmut Bilgic Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique
WO2012131690A1 (fr) * 2011-03-30 2012-10-04 Aggarwal Kumar Vijay Forme d'administration de médicament en tant que comprimé à deux couches

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0030630A2 (fr) 1979-11-19 1981-06-24 Fujisawa Pharmaceutical Co., Ltd. Dérivés de l'acide 7-acylamino-3-vinyl céphalosporanique, procédé pour leur préparation, compositions pharmaceutiques les contenant; leurs produits de départ et leur préparation
WO2011093822A1 (fr) * 2010-01-29 2011-08-04 Mahmut Bilgic Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs
WO2011142730A1 (fr) * 2010-05-14 2011-11-17 Mahmut Bilgic Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique
WO2012131690A1 (fr) * 2011-03-30 2012-10-04 Aggarwal Kumar Vijay Forme d'administration de médicament en tant que comprimé à deux couches

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANDIP KUMER MANGAL BHAI PATEL ET AL: "Formulation, development and evaluation of film coated tablet containing Cefixime and Potassium clavulanate", JOURNAL OF PHARMACY RESEARCH, ASSOCIATION OF PHARMACEUTICAL INNOVATORS, INDIA, vol. 4, no. 6, 11 June 2011 (2011-06-11), pages 1861 - 1863, XP002698642, ISSN: 0974-6943 *

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