WO2014123500A1 - Formulations pharmaceutiques contenant du cefpodoxime proxétil et de l'acide clavulanique - Google Patents

Formulations pharmaceutiques contenant du cefpodoxime proxétil et de l'acide clavulanique Download PDF

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Publication number
WO2014123500A1
WO2014123500A1 PCT/TR2014/000031 TR2014000031W WO2014123500A1 WO 2014123500 A1 WO2014123500 A1 WO 2014123500A1 TR 2014000031 W TR2014000031 W TR 2014000031W WO 2014123500 A1 WO2014123500 A1 WO 2014123500A1
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WO
WIPO (PCT)
Prior art keywords
formulation
formulation according
disintegrant
lubricant
weight
Prior art date
Application number
PCT/TR2014/000031
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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 WO2014123500A1 publication Critical patent/WO2014123500A1/fr

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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
    • A61K9/2004—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 cefpodoxime and clavulanic acid containing pharmaceutical formulations used for the treatment of susceptible microorganisms. Said formulations are characterized by their tablet form.
  • Cefpodoxime proxetil was first described in patent application no. EP0049118. In said document, cefpodoxime proxetil was described as effective in treatment of infections caused by gram positive and gram negative bacteria.
  • Cefpodoxime proxetil is a third generation cephalosporin ester and used in treatment of upper respiratory tract and urinary tract infections. Like other beta-lactam antibiotics, cefpodoxime proxetil is a bactericidal antibiotic. It inhibits the synthesis of bacterial cell wall by binding to specific penicillin-binding proteins located in the inner surface of the wall. The specificity of cefpodoxime depends on the identification of and binding capacity for these proteins.
  • Cefpodoxime proxetil is orally administered as tablet and suspension. Following oral administration, approximately 50% of the dose is absorbed by body. Proxetil form with its non-crystalline structure is absorbed via gastrointestinal route, hydrolyzed by non-specific esterases located at intestinal wall or plasma and converted into parent molecule cefpodoxime acid. Low oral bioavailability of cefpodoxime proxetil mostly results from its low solubility in water and gelation in acidic media.
  • cefpodoxime proxetil In addition to low solubility, other properties of cefpodoxime proxetil are its powder form and its structure with poor viscosity properties. These properties of the antibiotic both reduce the solubility of formulation containing it and prevent achievement of weight uniformity. As the proper flow is not achieved in the formulation due to the poor flow properties, uniformity of weight could not be obtained while also the amount of active substance per unit dosage form differs. This results in loss in the treatment efficacy of dosage form taken.
  • Beta-lactam antibiotics can be used in combination with beta-lactamase inhibitors to improve their treatment efficacy.
  • Co-administration of cefpodoxime proxetil and clavulanic acid, a beta-lactamase inhibitor causes stability problems due to the moisture-sensitive nature of clavulanic acid and also negatively affects the stability of formulations comprising this combination with low solubility.
  • cefpodoxime-clavulanic acid formulations are needed which improve the solubility and thus, the bioavailability of cefpodoxime and which show good flow properties.
  • the inventors in their studies addressing this need, have determined that the ratio of amount of lubricant to amount of anti-adherent in the formulation has significant effects on flow pattern. .
  • the present invention relates to pharmaceutical tablet formulations comprising the combination of cefpodoxime proxetil and clavulanic acid.
  • the inventors in their studies, have discovered that if ratio of lubricant to anti-adherent in said formulations is in the range of 5: 1 to 1 :5 and preferably 3:1 to 1 :3 by weight, a satisfactory flow pattern and thus, desired uniformity of weight and solubility properties are achieved for the formulations.
  • the ratio of lubricant to anti- adherent is 5:1 to 1 :5 and preferably 3:1 to 1 :3 by weight.
  • Lubricant to be used in formulation of the present invention may be selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, calcium phosphate tribasic or combinations thereof.
  • Lubricant in formulation of the present invention is preferably colloidal silicon dioxide.
  • Anti-adherent to be used in formulation of the present invention may be selected from a group comprising talc, stearates, colloidal silicon dioxide, sodium sulfate, starch, leucine or combinations thereof.
  • Anti-adherent in formulation of the present invention is preferably talc.
  • the ratio of colloidal silicon dioxide to talc in the formulation is 5:1 to 1 :5 and preferably 3:1 to 1 :3 by weight.
  • specific surface area of the lubricant used in the tablet formulations of the present invention is between 125 and 300 m 2 /g and preferably between 150 and 250 m 2 /g.
  • Cefpodoxime proxetil-clavulanic acid formulations of the present invention may contain at least one pharmaceutically acceptable excipient in addition to lubricant and anti-adherent.
  • At least one excipient to be used in formulations of the present invention may be selected from a group comprising disintegrants, diluents, surfactants, glidants and film-coating agents.
  • Disintegrant to be used in formulation of the present invention may be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate.
  • Diluent to be used in formulations of the present invention may be selected from a group comprising microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, modified cellulose and/or combinations thereof.
  • Surfactant to be used in formulations of the present invention may be selected from a group comprising cetrimide, docusate sodium, glyceryl monooleate, sorbitan esters and sodium lauryl sulfate and/or combinations thereof.
  • Glidant to be used in formulations of the present invention may be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate and sodium benzoate.
  • Formulations of the present invention may be prepared in any of the oral tablet forms such as film-coated tablets, extended-release tablets, modified-release tablets, effervescent tablets, orodispersible tablets and chewable tablets.
  • Formulations of the present invention are preferably prepared in film-coated tablet form.
  • Film-coating agent 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.
  • bulk density of diluent used in the formulation is between 0.1 and 0.70 g/ml, preferably between 0.20 and 0.55 g/ml and most preferably between 0.20-0.40 g/ml.
  • microcrystalline cellulose is used as diluent in formulations of the present invention.
  • Solubility problem experienced with cefpodoxime proxetil due to its nature also negatively affects the disintegration time of formulation in tablet form.
  • the inventors After determining that tablet disintegration times are insufficient, the inventors have performed studies and discovered that the desired values of disintegration time could be obtained when formulation contains a disintegrant combination composed of a first and a second disintegrant and when the ratio of first disintegrant to second disintegrant is 5:1 to 1 :5 and preferably 3: 1 to 1 :2 by weight.
  • the ratio of first disintegrant to second disintegrant, which compose the disintegrant combination is 5:1 to 1 :5 and preferably 3: 1 to 1 :2 by weight.
  • Carboxymethyl cellulose calcium or croscarmellose sodium are preferably used as the first disintegrant in formulations of the present invention.
  • Starch is preferably used as the second disintegrant in formulations of the present invention.
  • the ratio of carboxymethyl cellulose calcium or croscarmellose sodium to starch, which compose the disintegrant combination is 5:1 to 1 :5 and preferably 3:1 to 1 :2 by weight.
  • Formulations of the present invention comprising cefpodoxime proxetil with poor viscosity properties and clavulanic acid that is moisture-sensitive are susceptible to aggregate formation during manufacture.
  • amount of disintegrant in the formulation should be adjusted to resolve this issue during manufacture and ensure a sufficient disintegration time for obtained tablet after manufacture.
  • the inventors have surprisingly obtained tablets with mentioned properties when the ratio of amount of cefpodoxime proxetil to total amount of disintegrant is 10:1 to 1 :1 and preferably 6:1 to 1 :1 by weight.
  • the ratio of amount of cefpodoxime proxetil to total amount of disintegrant is 10:1 to 1 : 1 and preferably 6:1 to 1 : 1 by weight.
  • the first active ingredient, cefpodoxime proxetil may be used at a rate of 10-70%, preferably of 15-65% and most preferably of 20-60% of the tablet 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.
  • Cefpodoxime - clavulanic acid formulations of the present invention may contain cefpodoxime proxetil, potassium clavulanate, diluent, disintegrant, surfactant, anti-adherent, lubricant, glidant and film-coating agent, respectively, at a rate of 10-70%, 1 -60%, 5-25%, 5-30%, 0.5-3%, 0.1-2%), 0.1-2%, 0.1-2.5% and 1-10% of the total weight of unit dose.
  • the present invention relates to processes used for preparation of formulations comprising cefpodoxime proxetil and clavulanic acid as active ingredients as well as pharmaceutically acceptable excipients.
  • the process in scope of the present invention covers the steps of granulation of active ingredients, cefpodoxime and/or clavulanic acid by conventional wet and/or dry granulation methods or pulverization of cefpodoxime, clavulanic acid and other excipients by mixing with dry blending method and compression of the same in tablet form.
  • cefpodoxime - clavulanic acid formulations of the present invention may comprise the following steps:
  • cefpodoxime - clavulanic acid formulations of the present invention may comprise . the following steps:
  • Formulations of the present invention may be used in treatment of infections including upper respiratory tract infections (tonsillitis, pharyngitis, acute sinusitis, acute otitis media (only in children), lower respiratory tract infections (acute bronchitis, pneumonia, superinfections of chronic obstructive pulmonary disease), uncomplicated lower and upper urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.
  • upper respiratory tract infections pharyngitis, acute sinusitis, acute otitis media (only in children)
  • lower respiratory tract infections acute bronchitis, pneumonia, superinfections of chronic obstructive pulmonary disease
  • uncomplicated lower and upper urinary tract infections uncomplicated gonococcal urethritis
  • skin and soft tissue infections uncomplicated gonococcal urethritis

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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)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques contenant du cefpodoxime et de l'acide clavulanique, utilisées pour le traitement de microorganismes sensibles. Lesdites formulations sont caractérisées par leur forme de comprimé.
PCT/TR2014/000031 2013-02-11 2014-02-11 Formulations pharmaceutiques contenant du cefpodoxime proxétil et de l'acide clavulanique WO2014123500A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201301597 2013-02-11
TR2013/01597 2013-02-11

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WO2014123500A1 true WO2014123500A1 (fr) 2014-08-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108815130A (zh) * 2018-08-27 2018-11-16 邓倩 一种头孢泊肟酯药片及其生产工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049118A2 (fr) 1980-09-30 1982-04-07 Sankyo Company Limited Dérivés de céphalosporines, leur préparation et compositions les contenant
WO2011152807A1 (fr) * 2010-06-03 2011-12-08 Bilgic Mahmut Préparations pharmaceutiques comprenant du cefpodoxime proxetil et de l'acide clavulanique
WO2011152808A1 (fr) * 2010-06-03 2011-12-08 Mahmut Bilgic Formulation comprenant du cefpodoxime proxétil et de l'acide clavulanique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049118A2 (fr) 1980-09-30 1982-04-07 Sankyo Company Limited Dérivés de céphalosporines, leur préparation et compositions les contenant
WO2011152807A1 (fr) * 2010-06-03 2011-12-08 Bilgic Mahmut Préparations pharmaceutiques comprenant du cefpodoxime proxetil et de l'acide clavulanique
WO2011152808A1 (fr) * 2010-06-03 2011-12-08 Mahmut Bilgic Formulation comprenant du cefpodoxime proxétil et de l'acide clavulanique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108815130A (zh) * 2018-08-27 2018-11-16 邓倩 一种头孢泊肟酯药片及其生产工艺

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