WO2011142730A1 - Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique - Google Patents

Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique Download PDF

Info

Publication number
WO2011142730A1
WO2011142730A1 PCT/TR2011/000119 TR2011000119W WO2011142730A1 WO 2011142730 A1 WO2011142730 A1 WO 2011142730A1 TR 2011000119 W TR2011000119 W TR 2011000119W WO 2011142730 A1 WO2011142730 A1 WO 2011142730A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
cefixime
acid
effervescent
Prior art date
Application number
PCT/TR2011/000119
Other languages
English (en)
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
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 Mahmut Bilgic filed Critical Mahmut Bilgic
Priority to EP11720905A priority Critical patent/EP2568957A1/fr
Publication of WO2011142730A1 publication Critical patent/WO2011142730A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • 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 compositions comprising clavulanic acid and/or its derivatives with cefixime as the active agents.
  • Cefixime which is in the form of a white or light yellow crystal powder, easily dissolves in methanol and propylene glycol while it partially dissolves in ethanol and acetone, and barely dissolves in ether, ethyl acetate, hexane and water. Its solubility in aqueous solutions, on the other hand, varies according to the pH value.
  • Clavulanic acid is a beta-lactamase inhibitor illustrated in Formula 2.
  • Clavulanic acid and derivatives thereof are known as the beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta-lactamase enzymes.
  • the patent numbered EP0593573 comprises a formulation relating to suspension forms of beta-lactam antibiotics and beta lactamase.
  • suspension forms are not preferred much as they have the potential of high and/or uncontrolled dose intake; there appear problems in their physical and chemical stability and they cause problems in use and carrying.
  • the inventors have aimed to develop stable oral pharmaceutical formulations which comprise cefixime and clavulanic acid derivatives together and eliminate the low solubility problem of cefixime.
  • the subject of the present invention relates to effervescent tablets and granules comprising cefixime and clavulanic acid derivative combinations and the procedures for their preparation.
  • the effervescent tablets and granules pertaining to the present invention are packed in single dose packs, and therefore uncontrolled dose intake by the patients is prevented.
  • the effervescent tablet and granules comprising the active agent cefixime which are formulated according to the present invention entirely dissolve in water and form a homogeneous solution.
  • Said pharmaceutical composition is characterized in comprising 5- 20% cefixime in proportion to the total weight of the unit dose. It was unexpectedly observed that the pharmaceutical compositions comprising 5-20% cefixime with respect to the total unit dose weight dissolve in water without the need of any other disintegrant.
  • the present invention is characterized in that the amount of cefixime in the pharmaceutical composition comprising cefixime and cluvulanic acid in a combined form is in the range of 5-20%.
  • Cefixime which can be used in effervescent tablet and granule formulations pertaining to the present invention, can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or a combination thereof.
  • Cefixime to be used in scope of the present invention can be in any of the monohydrate, dihydrate, trihydrate and/or anhydrate forms.
  • cefixime trihydrate is used in the formulations pertaining to the present invention.
  • Cluvulanic acid which can be used in the formulations pertaining to the present invention, can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or a combination thereof.
  • potassium clavulanate is used in scope of the present invention.
  • compositions comprising pharmaceutically acceptable excipients along with the active agents cefixime and potassium clavulanate.
  • excipients selected from, but not limited to, a group comprising glidants, lubricants, sweeteners, binders, flavoring agents, coloring agents and effervescent couple can be used in the formulation pertaining to the present invention apart from cefixime and potassium clavulanate.
  • the glidant which can be used in the formulation pertaining to the present invention can be selected from, but not limited to, a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or a combination thereof.
  • the lubricant pertaining to the present invention can be selected from, but not limited to, a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate.
  • PEG 6000 is used as the lubricant in the pharmaceutical composition pertaining to the present invention.
  • the sweetener that can be used in the pharmaceutical composition according to the present invention can be selected from a group comprising acesulfame, aspartame, fructose, maltitol, maltose, xylitol, saccharine, sodium cyclamate, sucralose, sucrose.
  • aspartame is used as the sweetener in the present invention.
  • the effervescent couple that can be used in the pharmaceutical composition pertaining to the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
  • organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc.
  • basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.
  • citric acid and sodium hydrogen carbonate are used in the present invention.
  • cluvulanic acid and its derivatives used in the formulations pertaining to the present invention undergo degradation catalysed by acids and/or bases.
  • the ratio of the effervescent couple to be used to each other plays an important role on the stability of clavulanic acid and its derivatives in the formulation.
  • the inventors have - observed that clavulanic acid is stable in the pharmaceutical compositions in the case that the ratio of effervescent acid to effervescent base used in the present invention is in the range of 5:1 to 1 :1, preferably in the range of 2:1 to 1.1 :1, most preferably in the range of 1.5:1 to 1.1:1.
  • another aspect of the present invention is effervescent tablet and granule formulations comprising cefixime and clavulanic acid or a combination of derivatives thereof wherein the ratio of the effervescent acid to the effervescent base is in the range of 5:1 to 1:1, preferably in the range of 2: 1 to 1.1 : 1 , most preferably in the range of 1.5 : 1 to 1.1 :1.
  • the binder that can be used in the tablet and granule formulations pertaining to the present invention can be selected from a group comprising ethyl cellulose, gelatine, hypromellose, magnesium aluminum silicate, maltodextrin, polyethylene oxide and povidone.
  • povidone is used in the present invention.
  • the amount of the binder used in the formulation is significant for the obtained granule to be able to turn into tablets when desired and for the product that is turned into tablets to disperse in water in shorter than 5 minutes during the formulation of effervescent tablets and granules pertaining to the present invention.
  • the granules can easily be turned into tablets and the tablets can dissolve in water in shorter than 5 minutes in the case that the ratio of cefixime to the binder is in the range of 10:1 to 1:1, preferably in the range of 6:1 to 3:1 in the pharmaceutical formulations prepared in accordance with the present invention.
  • another aspect of the present invention is effervescent tablet and granule formulations comprising cefixime and clavulanic acid or derivatives thereof wherein the ratio of cefixime to the binder is in the range of 10: 1 to 1:1, preferably in the range of 6: 1 to 3 : 1.
  • clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof on an amount equal to this can be used.
  • Clavulanic acid and its derivatives for instance, potassium clavulanate
  • potassium clavulanate is preferably used with a humectant in the ratio of 1 : 1 in the present invention.
  • colloidal silica for instance colloidal silica anhydrous, for example Aerosil® 200, magnesium trisilicate, cellulose powder, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose, talc can be used as the humectant.
  • potassium clavulanate is preferably used with microcrystalline cellulose or syloid in the ratio of 1 : 1 , most preferably with syloid.
  • the amount of cefixime or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal or amorphous forms that the pharmaceutical composition pertaining to the present invention can comprise is in the range of 5-20%, preferably in the range of 8-15% with respect to the total weight of the unit dose.
  • the amount of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equal amount to it that can be used in the pharmaceutical composition pertaining to the present invention is in the range of 5-50% with respect to the total weight of the unit dose.
  • the pharmaceutical composition pertaining to the present invention can comprise 5-20 % cefixime; 5-50% potassium clavulanate; 0-5% glidant; 0.1-5% lubricant; 0-5% binder; 20- 90% effervescent couple; 0,1-10% sweetener; 0.1-5% flavoring agent; 0.1-5% coloring agent with respect to the total amount of the unit dose.
  • the pharmaceutical composition comprising cefixime and clavulanic acid or its derivatives which is prepared according to the present invention can be in effervescent tablet or granule form.
  • the present invention relates to the processes which can be used for the preparation of pharmaceutical compositions comprising pharmaceutically acceptable excipients in addition to cefixime and clavulanic acid as the active agents.
  • the process pertaining to the present invention comprises granulation of the active agents cefixime and/or clavulanic acid or its derivatives through conventional wet and/or dry granulation methods, or mixing cefixime, clavulanic acid derivatives and the other excipients -through dry blending method, then powderizing them; and optionally compressing the mixture in tablet form.
  • Clavulanic acid undergoes degradation when it contacts with water, which leads to problems in the production of the products especially in granule form. Therefore, the inventors have developed a method which provides to formulate clavulanic acid without contacting water for producing the pharmaceutical compositions pertaining to the present invention.
  • the said process comprises the granulation of cefixime, the binder, the effervescent couple and the sweetener with an aqueous solution; drying the granules; mixing the obtained granules with clavulanic acid and/or its derivative, the coloring agent, the flavoring agent and the lubricant, and optionally compressing tablets in the tablet compressing machine.
  • the present invention relates to the use of the pharmaceutical composition in the production of a medicament so as to be used in the treatment of gram positive and gram negative bacteria.
  • the pharmaceutical composition prepared according to the present invention is used in the manufacture of a medicament so as to be used in upper respiratory infections such as ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin or soft tissue infections such as froncle, pyoderma, impetigo; in the treatment and prophylaxis of gonorrhea and lyme diseases.
  • upper respiratory infections such as ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis
  • lower respiratory tract infections such as pyelonephritis, cystitis and urethritis
  • skin or soft tissue infections such as froncle, pyoderma, impetigo
  • in the treatment and prophylaxis of gonorrhea and lyme diseases in the manufacture of a medicament so as to be used in upper respiratory infections such as
  • composition pertaining to the present invention can be prepared as described below, but not limited to the examples given.
  • EXAMPLE 1 Formulation for the preparation of film-coated tablet comprising cefixime and potassium clavulanate

Landscapes

  • 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)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques comprenant l'acide clavulanique et/ou ses dérivés, et la céfixime qui sont utiles comme agents actifs.
PCT/TR2011/000119 2010-05-14 2011-05-02 Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique WO2011142730A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11720905A EP2568957A1 (fr) 2010-05-14 2011-05-02 Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/03855 2010-05-14
TR201003855 2010-05-14

Publications (1)

Publication Number Publication Date
WO2011142730A1 true WO2011142730A1 (fr) 2011-11-17

Family

ID=44315068

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000119 WO2011142730A1 (fr) 2010-05-14 2011-05-02 Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique

Country Status (2)

Country Link
EP (1) EP2568957A1 (fr)
WO (1) WO2011142730A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014126541A1 (fr) * 2013-02-14 2014-08-21 Bilgiç Mahmut Compositions pharmaceutiques utilisées pour traiter des infections bactériennes
WO2016116892A1 (fr) * 2015-01-24 2016-07-28 Wockhardt Limited Compositions antibactériennes
WO2022056401A1 (fr) * 2020-09-11 2022-03-17 Meharry Medical College Méthodes d'identification de compositions d'inhibition d'infectivité virale

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR201000687A1 (tr) * 2010-01-29 2011-08-22 Bi̇lgi̇ç Mahmut Aktif madde olarak sefiksim ve klavulanik asit içeren efervesan formülasyonlar
CN111544412B (zh) * 2020-04-17 2022-06-24 广州白云山医药集团股份有限公司白云山制药总厂 头孢克肟组合物及其制备方法

Citations (5)

* 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
EP0593573A1 (fr) 1991-07-11 1994-04-27 Smithkline Beecham Plc Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau
WO2007086012A1 (fr) * 2006-01-25 2007-08-02 Jegannathan Srinivas Préparation de cefpodoxime, d'acide clavulanique et de linezolide
CN100417383C (zh) * 2006-03-07 2008-09-10 中国药科大学 一种含有头孢克肟的泡腾片及制法
WO2011093822A1 (fr) * 2010-01-29 2011-08-04 Mahmut Bilgic Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs

Patent Citations (5)

* 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
EP0593573A1 (fr) 1991-07-11 1994-04-27 Smithkline Beecham Plc Formulation pharmaceutique comprenant une beta-lactamine et de l'acide clavulanique ou un sel de celui-ci soluble dans l'eau
WO2007086012A1 (fr) * 2006-01-25 2007-08-02 Jegannathan Srinivas Préparation de cefpodoxime, d'acide clavulanique et de linezolide
CN100417383C (zh) * 2006-03-07 2008-09-10 中国药科大学 一种含有头孢克肟的泡腾片及制法
WO2011093822A1 (fr) * 2010-01-29 2011-08-04 Mahmut Bilgic Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RAWAT DEEPTI ET AL: "IN VITRO EVALUATION OF A NEW CEFIXIME-CLAVULANIC ACID COMBINATION FOR GRAM-NEGATIVE BACTERIA", SOUTHEAST ASIAN JOURNAL OF TROPICAL MEDICINE AND PUBLIC HEALTH, PROJECT OD SEAMEO, BANGKOK, vol. 40, no. 1, 1 January 2009 (2009-01-01), pages 131 - 139, XP002633201, ISSN: 0125-1562 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014126541A1 (fr) * 2013-02-14 2014-08-21 Bilgiç Mahmut Compositions pharmaceutiques utilisées pour traiter des infections bactériennes
WO2016116892A1 (fr) * 2015-01-24 2016-07-28 Wockhardt Limited Compositions antibactériennes
WO2022056401A1 (fr) * 2020-09-11 2022-03-17 Meharry Medical College Méthodes d'identification de compositions d'inhibition d'infectivité virale

Also Published As

Publication number Publication date
EP2568957A1 (fr) 2013-03-20

Similar Documents

Publication Publication Date Title
EP2528594B1 (fr) Formulations effervescentes contenant de la céphalosporine de deuxième génération
US8614315B2 (en) Cefdinir and cefixime formulations and uses thereof
WO2011142730A1 (fr) Composition pharmaceutique comprenant la céfixime et un composé dérivé de l'acide clavulanique
WO2012060788A1 (fr) Formulations de céphalosporines avec teneur en humidité contrôlée
EP2568959A2 (fr) Formulations comprenant une céphalosporine et un acide clavulanique de troisième génération
WO2011139249A2 (fr) Composition pharmaceutique renfermant du cefdinir
EP2515850B1 (fr) Compositions pharmaceutiques comprenant cefdinir comme principe
US20130129791A1 (en) Preparations of effervescent formulations comprising second and third generation cephalosporin and uses thereof
EP2608776A2 (fr) Préparations de cefpodoxime proxétil
WO2012060790A2 (fr) Formulations de cefpodoxime proxétil dispersibles dans l'eau
EP2566451B1 (fr) Composition pharmaceutique contentant de cefditoren pivoxil
WO2011093822A1 (fr) Formulations effervescentes comprenant de la céfixime et de l'acide clavulanique comme agents actifs
EP2515859A1 (fr) Formulation effervescente à dispersion rapide
EP2515858A1 (fr) Composition pharmaceutique très pure
WO2012060787A1 (fr) Comprimés contenant du cefdinir
WO2011093821A1 (fr) Formulations effervescentes comprenant du cefdinir et de l'acide clavulanique
EP2566450A2 (fr) Compositions pharmaceutiques comprenant du céfétamet
WO2012060792A1 (fr) Compositions pharmaceutiques comprenant au minimum 6% en poids de délitants
WO2012060789A2 (fr) Procédé de production de formulations de cefdinir
EP2663289A2 (fr) Préparations de cefpodoxime proxétil comprenant un agent régulateur de goût
WO2012078121A2 (fr) Forme posologique orale solide comprenant cefdinir

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11720905

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2011720905

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE