WO2011142731A2 - Formulations comprising a third generation cephalosporin and clavulanic acid - Google Patents

Formulations comprising a third generation cephalosporin and clavulanic acid Download PDF

Info

Publication number
WO2011142731A2
WO2011142731A2 PCT/TR2011/000124 TR2011000124W WO2011142731A2 WO 2011142731 A2 WO2011142731 A2 WO 2011142731A2 TR 2011000124 W TR2011000124 W TR 2011000124W WO 2011142731 A2 WO2011142731 A2 WO 2011142731A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
formulation according
agent
generation cephalosporin
sodium
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/TR2011/000124
Other languages
French (fr)
Other versions
WO2011142731A3 (en
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to EP11743665A priority Critical patent/EP2568959A2/en
Publication of WO2011142731A2 publication Critical patent/WO2011142731A2/en
Publication of WO2011142731A3 publication Critical patent/WO2011142731A3/en
Priority to US13/668,922 priority patent/US20130129791A1/en
Anticipated expiration legal-status Critical
Priority to US14/309,273 priority patent/US20150140111A1/en
Ceased legal-status Critical Current

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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical formulations comprising a third generation cephalosporin together with clavulanic acid and/or derivatives thereof as the active agents.
  • cefdaloxim cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefovecin, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefetamet belong to the group of the third generation cephalosporins.
  • Clavulanic acid is a beta-lactamase inhibitor.
  • Clavulanic acid and derivatives thereof e.g. its salts such as potassium clavulanate
  • beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta- lactamase enzymes.
  • EP0593573 discloses a formulation relating to suspension forms comprising beta-lactam antibiotics, especially amoxicillin and ampicillin, with beta lactamase inhibitors.
  • suspension forms are not preferable since they have the potential of high and/or uncontrolled dose intake; they have problems in their physical and chemical stability, they have high manufacture costs and they cause problems in use and carrying.
  • water dispersible tablets have been developed in order to improve the bioavailability of the antibiotic and to have them disintegrate faster.
  • the patent application numbered in EP 0282200 discloses dispersible formulations comprising an amphoteric beta- lactam antibiotic and as disintegrants, a cellulose product and low-substituted hydroxypropylcellulose.
  • clavulanic acid and its pharmaceutically acceptable derivatives are highly sensitive to conditions such as humidity and pH, for this reason it is very difficult to prepare stable and water soluble formulations wherein clavulanic acid or its pharmaceutically acceptable derivatives and third generation cephalosporins are used in combined form.
  • the inventors have surprisingly found that the water soluble dosage forms comprising third generation cephalosporin antibiotics and clavulanic acid derivatives pertaining to the present invention overcome the problems encountered in the prior art.
  • Subject of the present invention relates to water soluble pharmaceutical formulations comprising the third generation cephalosporins and clavulanic acid and/or derivatives thereof.
  • formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof entirely dissolve in water when a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer system and the ratio of the first pH agent having pKa value of 1-5, preferably 2-4 to the second pH agent having the pKa value of 5.1-15, preferably 5.5-12 is in the range of 3:l to 1 :1.
  • the inventors have found that the formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof according to the present invention have solved both the solubility problem of cefdinir and the stability problem of clavulanic acid and thereby a stable water soluble formulations comprising a combination of a third generation cephalosporin and clavulanic acid have been obtained.
  • the first aspect of the present invention is the water soluble formulations comprising a third generation cephalosporin and clavulanic acid and/or derivatives thereof in which a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer solution and the ratio of the first pH agent having pKa value of 1 -5 to the second pH agent having the pKa value of 5.1-15 is in the range of 3:1 to 1 :1.
  • the water soluble formulations according to present invention can be in the form of powder, granule or tablet.
  • the third generation cephalosporin that can be used in water soluble formulations of the present invention is used in 2%-15%, preferably 2%-12%, more preferably 3%-10% of the unit dose.
  • the third generation cephalosporin that can be used in water soluble formulations of the present invention can be selected from the group comprising cefpodoxime, cefditoren, ceftibuten, cefdinir, cefixime, cefetamet.
  • ceftibuten or cefdinir is used in scope of the present invention.
  • the third generation cephalosporin that can be used in water soluble formulations of the present invention can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
  • cefpodoxime is used in the present invention it is preferably used in its ester form, more preferably in cefpodoxime proxetil form.
  • cefditoren is used in the present invention it is preferably used in its ester form, more preferably in cefditoren pivoxil form.
  • cefixime is used in the present invention it is preferably used in its hydrate form, more preferably in trihydrate form.
  • ceftibuten is used in the present invention it is preferably used in its hydrate form, more preferably in dihydrate and/or trihydrate form.
  • cefdinir is used in the present invention it is preferably used in free form.
  • Clavulanic acid that can be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, alkaline metal salts, alkaline earth metal salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
  • potassium clavulanate is used in the present invention.
  • the first pH agent which has pKa in the range of 1-5, preferably 2-4, to be used in the formulation of the present invention can be selected from, but not limited to, citric acid and malic acid or a combination thereof.
  • citric acid is used.
  • the second pH agent which has pKa in the range of 5.1-15, preferably 5.5-12, to be used in the formulation of the present invention can be selected from, tribasic calcium phosphate, monosodium glutamate, potassium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof.
  • trisodium citrate is used.
  • the water soluble formulations comprising cefdinir or ceftibuten and clavulanate in which cefdinir or ceftibuten is used in 2%-15% of the unit dose; citric acid and trisodium citrate are used to form a buffer system and the ratio of citric acid to trisodium citrate is in the range of 3 : 1 to 1 : 1.
  • Another aspect of the present invention is water soluble formulations comprising pharmaceutically acceptable excipients in addition to the combination of the third generation cephalosporins and clavulanic acid and/or derivatives thereof as the active agents and the pH agents.
  • various excipients selected from, but not limited to, the group comprising sweeteners, preservative agents, viscosity agents, glidants, lubricants, disintegrants, diluents and flavoring agents can be used in addition to the third generation cephalosporin, clavulanic acid and pH agents.
  • the sweetener to be used in the formulation of the present invention can be selected from, but not limited to, a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, sugar, maltose, sorbitol, saccharine, saccharine sodium, saccharose, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
  • saccharose is used as the sweetener in the present invention.
  • the preservative agent to be used in the formulation of the present invention can be selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
  • sodium benzoate is used as the preservative agent.
  • the viscosity agent to be used in the formulation of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrin, polyvinyl alcohol or combinations thereof.
  • xanthan gum is used in the present invention.
  • the ratio of the third generation cephalosporin to xanthan gum is an important parameter influencing the dispersion time of the water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof. They have found that the dispersion time of the granules and powders comprising the formulations according to present invention in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1, preferably 8:1 to 13:1, more preferably 9:1 to 12:1 is shorter compared to the formulations comprising xanthan gum less or more than this amount.
  • another aspect of the present invention is water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1.
  • the glidant that can be used in the pharmaceutical combination of 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.
  • silicon dioxide is used as the glidant.
  • the lubricant that can be used in the pharmaceutical formulation of 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 or a combination thereof.
  • magnesium stearate is used as the lubricant in the pharmaceutical formulation pertaining to the present invention.
  • the disintegrant that can be used in the pharmaceutical formulation pertaining to the present invention can be selected from, but not limited to, 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.
  • the diluent that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
  • clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this can be used.
  • Clavulanic acid and its derivatives are extremely sensitive to moisture. Therefore, potassium clavulanate is used together with a humectant in the ratio of 1 : 1 in the pharmaceutical formulation of the present invention.
  • the humectant that can be used in the pharmaceutical formulation of the present invention can be selected from silica, colloidal silica, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, starch, syloid, microcrystalline cellulose and talc.
  • syloid or microcrystalline cellulose is used as humectants.
  • potassium clavulanate is used with syloid or microcrystalline cellulose preferably in the ratio of 1 : 1.
  • the amount of the third generation cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline or amorphous forms that the pharmaceutical formulation of the present invention can comprise is in the range of 2% to 15% with respect to the total weight of the unit dose.
  • the pharmaceutical formulation of the present invention can comprise clavulanic acid in the range of 5% to 30% with respect to the total weight of the unit dose or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this.
  • the pharmaceutical formulation of the present invention can comprise 2-15% a third generation cephalosporin, 5-30% potassium clavulanate, 0.1-4% glidant, 0.2-3% lubricant, 0- 20% disintegrant and/or disintegrants, 0-15% diluent, 30-90% sweetener, 0.5-4% pH agent, 0.1-2% preservative agent, 0.2-4% viscosity agent and 0.1-5% flavoring agent by weight with respect to the total weight of the unit dose.
  • the present invention relates to processes that can be used for preparation of the pharmaceutical formulations comprising pharmaceutically acceptable excipients in addition to the third generation cephalosporin and clavulanic acid or derivatives thereof as the active agent.
  • the process in scope of the present invention comprises granulation of the active agents, in other words third generation cephalosporin and clavulanic acid or derivatives thereof by conventional wet and/or dry granulation methods; or mixing the third generation cephalosporin, clavulanic acid derivatives and the other excipients by dry blending method and then pulverizing them, optionally compressing the obtained mixture in tablet form.
  • Another aspect of the present invention is the use of the pharmaceutical formulation prepared according to the present invention in the treatment of diseases related to infection caused by gram positive and gram negative bacteria.
  • Another aspect of the present invention is the use of the pharmaceutical formulation prepared according to the present invention in the production 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 production of a medicament so as to
  • EXAMPLE 1 Formulation and process for preparation of water soluble granule comprising ceftibuten and potassium clavulanate
  • trisodium citrate is in the range of 3:1 to 1 :1, specifically 1.3:1.
  • Ceftibuten, potassium clavulanate :syloid, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, then mixed.
  • the lubricant is added into the obtained mixture and the powder mixture is filled into sachets.
  • EXAMPLE 2 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
  • Cefdinir, potassium clavulanate microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed.
  • the lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
  • COMPARATIVE EXAMPLE 1 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
  • Cefdinir, potassium clavulanate microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed.
  • the lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
  • COMPARATIVE EXAMPLE 2 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
  • Cefdinir, potassium clavulanate microcrystalline cellulose, sweetener, viscosity agent, citric acid, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
  • COMPARATIVE EXAMPLE 3 Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
  • Cefdinir, potassium clavulanatermicrocrystalline cellulose, sweetener, viscosity agent, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed.
  • the lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
  • Table 1 indicates the comparative data of dissolution of the formulations for each example.
  • Table 1 Comparative Data of Dissolution of Cefdinir/ Ceftibuten Formulations in Water Soluble Form

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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The present invention relates to pharmaceutical formulations comprising a third generation cephalosporin and clavulanic acid and/or derivatives thereof as the active agent.

Description

FORMULATIONS COMPRISING A THIRD GENERATION CEPHALOSPORIN
AND CLAVULANIC ACID
The present invention relates to pharmaceutical formulations comprising a third generation cephalosporin together with clavulanic acid and/or derivatives thereof as the active agents.
Background of the Invention:
Third generation cephalosporins which are broad spectrum antibiotics are known to have antibacterial effect both on gram positive and gram negative bacteria.
The compounds known as cefdaloxim, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefovecin, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefetamet belong to the group of the third generation cephalosporins.
Clavulanic acid is a beta-lactamase inhibitor. Clavulanic acid and derivatives thereof (e.g. its salts such as potassium clavulanate) are known as beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta- lactamase enzymes.
The patent numbered EP0593573 discloses a formulation relating to suspension forms comprising beta-lactam antibiotics, especially amoxicillin and ampicillin, with beta lactamase inhibitors.
However, suspension forms are not preferable since they have the potential of high and/or uncontrolled dose intake; they have problems in their physical and chemical stability, they have high manufacture costs and they cause problems in use and carrying.
Alternatively, water dispersible tablets have been developed in order to improve the bioavailability of the antibiotic and to have them disintegrate faster. The patent application numbered in EP 0282200 discloses dispersible formulations comprising an amphoteric beta- lactam antibiotic and as disintegrants, a cellulose product and low-substituted hydroxypropylcellulose.
However, some problems have been observed in water dispersible formulations comprising third generation cephalosporin antibiotics due to low solubility of them. Although the third generation cephalosporins have broad spectrum, their water solubility is low, which leads to low dissolution and absorption of the third generation cephalosporin antibiotic and slow dispersion of their water dispersible formulations.
Furthermore, clavulanic acid and its pharmaceutically acceptable derivatives are highly sensitive to conditions such as humidity and pH, for this reason it is very difficult to prepare stable and water soluble formulations wherein clavulanic acid or its pharmaceutically acceptable derivatives and third generation cephalosporins are used in combined form.
As is seen, new formulations comprising third generation cephalosporin antibiotics and clavulanic acid derivatives are required to be developed in order to provide new dosage forms which disperse quickly by providing the entire dissolution of the antibiotic in water.
The inventors have surprisingly found that the water soluble dosage forms comprising third generation cephalosporin antibiotics and clavulanic acid derivatives pertaining to the present invention overcome the problems encountered in the prior art.
Description of the Invention
Subject of the present invention relates to water soluble pharmaceutical formulations comprising the third generation cephalosporins and clavulanic acid and/or derivatives thereof. Surprisingly, it was found that formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof entirely dissolve in water when a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer system and the ratio of the first pH agent having pKa value of 1-5, preferably 2-4 to the second pH agent having the pKa value of 5.1-15, preferably 5.5-12 is in the range of 3:l to 1 :1.
The inventors have found that the formulations comprising the combination of a third generation cephalosporin and clavulanic acid and/or derivatives thereof according to the present invention have solved both the solubility problem of cefdinir and the stability problem of clavulanic acid and thereby a stable water soluble formulations comprising a combination of a third generation cephalosporin and clavulanic acid have been obtained.
The first aspect of the present invention is the water soluble formulations comprising a third generation cephalosporin and clavulanic acid and/or derivatives thereof in which a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5, preferably 2-4 and the other has pKa in the range of 5.1-15, preferably 5.5-12 are used to form a buffer solution and the ratio of the first pH agent having pKa value of 1 -5 to the second pH agent having the pKa value of 5.1-15 is in the range of 3:1 to 1 :1.
The water soluble formulations according to present invention can be in the form of powder, granule or tablet.
The third generation cephalosporin that can be used in water soluble formulations of the present invention is used in 2%-15%, preferably 2%-12%, more preferably 3%-10% of the unit dose.
The third generation cephalosporin that can be used in water soluble formulations of the present invention can be selected from the group comprising cefpodoxime, cefditoren, ceftibuten, cefdinir, cefixime, cefetamet.
Preferably, ceftibuten or cefdinir is used in scope of the present invention.
The third generation cephalosporin that can be used in water soluble formulations of the present invention can be in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
In the case that cefpodoxime is used in the present invention it is preferably used in its ester form, more preferably in cefpodoxime proxetil form.
In the case that cefditoren is used in the present invention it is preferably used in its ester form, more preferably in cefditoren pivoxil form.
In the case that cefixime is used in the present invention it is preferably used in its hydrate form, more preferably in trihydrate form.
In the case that ceftibuten is used in the present invention it is preferably used in its hydrate form, more preferably in dihydrate and/or trihydrate form.
In the case that cefdinir is used in the present invention it is preferably used in free form.
Clavulanic acid that can be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, alkaline metal salts, alkaline earth metal salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or combinations thereof.
Preferably, potassium clavulanate is used in the present invention.
The first pH agent, which has pKa in the range of 1-5, preferably 2-4, to be used in the formulation of the present invention can be selected from, but not limited to, citric acid and malic acid or a combination thereof. Preferably, citric acid is used.
The second pH agent, which has pKa in the range of 5.1-15, preferably 5.5-12, to be used in the formulation of the present invention can be selected from, tribasic calcium phosphate, monosodium glutamate, potassium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof. Preferably, trisodium citrate is used.
Another aspect of the present invention, the water soluble formulations comprising cefdinir or ceftibuten and clavulanate in which cefdinir or ceftibuten is used in 2%-15% of the unit dose; citric acid and trisodium citrate are used to form a buffer system and the ratio of citric acid to trisodium citrate is in the range of 3 : 1 to 1 : 1.
Another aspect of the present invention is water soluble formulations comprising pharmaceutically acceptable excipients in addition to the combination of the third generation cephalosporins and clavulanic acid and/or derivatives thereof as the active agents and the pH agents.
In the formulation of the present invention, various excipients selected from, but not limited to, the group comprising sweeteners, preservative agents, viscosity agents, glidants, lubricants, disintegrants, diluents and flavoring agents can be used in addition to the third generation cephalosporin, clavulanic acid and pH agents.
The sweetener to be used in the formulation of the present invention can be selected from, but not limited to, a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, sugar, maltose, sorbitol, saccharine, saccharine sodium, saccharose, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof. Preferably, saccharose is used as the sweetener in the present invention.
The preservative agent to be used in the formulation of the present invention can be selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof. Preferably, sodium benzoate is used as the preservative agent.
The viscosity agent to be used in the formulation of the present invention can be selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrin, polyvinyl alcohol or combinations thereof. Preferably, xanthan gum is used in the present invention.
Based on the studies of the inventors, it has been observed that the ratio of the third generation cephalosporin to xanthan gum is an important parameter influencing the dispersion time of the water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof. They have found that the dispersion time of the granules and powders comprising the formulations according to present invention in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1, preferably 8:1 to 13:1, more preferably 9:1 to 12:1 is shorter compared to the formulations comprising xanthan gum less or more than this amount.
According to this, another aspect of the present invention is water soluble formulations comprising a third generation cephalosporin and clavulanic acid or derivatives thereof in which the ratio of the third generation cephalosporin to xanthan gum is in the range of 7:1 to 15:1.
The glidant that can be used in the pharmaceutical combination of 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. Preferably, silicon dioxide is used as the glidant.
The lubricant that can be used in the pharmaceutical formulation of 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 or a combination thereof. Preferably, magnesium stearate is used as the lubricant in the pharmaceutical formulation pertaining to the present invention.
The disintegrant that can be used in the pharmaceutical formulation pertaining to the present invention can be selected from, but not limited to, 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.
The diluent that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
In the pharmaceutical formulation of the present invention, 20-700 mg of a third generation cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this can be used.
In the pharmaceutical formulation of the present invention, 50-450 mg of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this can be used.
Clavulanic acid and its derivatives (e.g. potassium clavulanate) are extremely sensitive to moisture. Therefore, potassium clavulanate is used together with a humectant in the ratio of 1 : 1 in the pharmaceutical formulation of the present invention.
The humectant that can be used in the pharmaceutical formulation of the present invention can be selected from silica, colloidal silica, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, starch, syloid, microcrystalline cellulose and talc. Preferably, syloid or microcrystalline cellulose is used as humectants.
In the pharmaceutical formulation of the present invention, potassium clavulanate is used with syloid or microcrystalline cellulose preferably in the ratio of 1 : 1.
The amount of the third generation cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline or amorphous forms that the pharmaceutical formulation of the present invention can comprise is in the range of 2% to 15% with respect to the total weight of the unit dose.
The pharmaceutical formulation of the present invention can comprise clavulanic acid in the range of 5% to 30% with respect to the total weight of the unit dose or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in quantities equal to this. The pharmaceutical formulation of the present invention can comprise 2-15% a third generation cephalosporin, 5-30% potassium clavulanate, 0.1-4% glidant, 0.2-3% lubricant, 0- 20% disintegrant and/or disintegrants, 0-15% diluent, 30-90% sweetener, 0.5-4% pH agent, 0.1-2% preservative agent, 0.2-4% viscosity agent and 0.1-5% flavoring agent by weight with respect to the total weight of the unit dose.
In another aspect, the present invention relates to processes that can be used for preparation of the pharmaceutical formulations comprising pharmaceutically acceptable excipients in addition to the third generation cephalosporin and clavulanic acid or derivatives thereof as the active agent.
According to this, the process in scope of the present invention comprises granulation of the active agents, in other words third generation cephalosporin and clavulanic acid or derivatives thereof by conventional wet and/or dry granulation methods; or mixing the third generation cephalosporin, clavulanic acid derivatives and the other excipients by dry blending method and then pulverizing them, optionally compressing the obtained mixture in tablet form.
Another aspect of the present invention is the use of the pharmaceutical formulation prepared according to the present invention in the treatment of diseases related to infection caused by gram positive and gram negative bacteria.
Another aspect of the present invention, on the other hand, is the use of the pharmaceutical formulation prepared according to the present invention in the production 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.
The pharmaceutical formulation pertaining to the present invention can be prepared as described below, but not limited to the examples given. EXAMPLE 1 : Formulation and process for preparation of water soluble granule comprising ceftibuten and potassium clavulanate
Figure imgf000009_0001
*Citric acid: trisodium citrate is in the range of 3:1 to 1 :1, specifically 1.3:1.
Ceftibuten, potassium clavulanate :syloid, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, then mixed. The lubricant is added into the obtained mixture and the powder mixture is filled into sachets.
EXAMPLE 2: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
Figure imgf000010_0001
Cefdinir, potassium clavulanate: microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
COMPARATIVE EXAMPLE 1: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
Figure imgf000011_0001
*Citric acid: trisodium citrate is 5:1
Cefdinir, potassium clavulanate: microcrystalline cellulose, sweetener, viscosity agent, citric acid, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
4
COMPARATIVE EXAMPLE 2: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
Figure imgf000012_0001
*Only citric acid is used
Cefdinir, potassium clavulanate: microcrystalline cellulose, sweetener, viscosity agent, citric acid, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
COMPARATIVE EXAMPLE 3: Formulation and process for preparation of water soluble granule comprising cefdinir and potassium clavulanate
Figure imgf000013_0001
*Only trisodium citrate is used
Cefdinir, potassium clavulanatermicrocrystalline cellulose, sweetener, viscosity agent, trisodium citrate, glidant, flavoring agent and the preservative agent are sieved, and then mixed. The lubricant is added into the mixture obtained and the powder mixture is filled into sachets.
Results:
The inventors have studied on the dissolution data of the formulations illustrated in each example given above. According to the studies based on the comparison of their dissolution data, the results represented in Table 1 are observed. Table 1 indicates the comparative data of dissolution of the formulations for each example. Table 1: Comparative Data of Dissolution of Cefdinir/ Ceftibuten Formulations in Water Soluble Form
The results of the dissolution data of formulations of Example 1, Example 2, Comparative example 1, Comparative example 2, Comparative example 3 clearly indicate that the formulations comprising cefdinir or ceftibuten and potassium clavulanate of the present invention in which citric acid and trisodium citrate are used and citric acid: trisodium citrate ratio by weight is in the range of 3:1 to 1 :1, as shown in example 1 and example 2, have higher dissolution rate values compared to the others.

Claims

CLAIMS:
1. A water soluble pharmaceutical formulation comprising a third generation cephalosporin and clavulanic 'acid and/or derivatives thereof in which a third generation cephalosporin antibiotic is used in 2%-15% of the unit dose; two different pH agents wherein one pH agent has pKa in the range of 1-5 and the other has pKa in the range of 5.1-15 are used to form a buffer system and the ratio of the first pH agent having pKa value of 1-5 to the second pH agent having the pKa value of 5.1-15 is in the range of 3:1 to 1:1.
2. The pharmaceutical formulation according to claim 1, wherein said pharmaceutical formulation is in the formof water soluble powder, granule or tablet.
3. The pharmaceutical formulation according to claim 1, wherein the third generation cephalosporin used in said formulation is selected from a group comprising cefpodoxime, cefditoren, ceftibuten, cefdinir, cefixime, cefetamet.
4. The pharmaceutical formulation according to claim 3, wherein ceftibuten or cefdinir is used.
5. The pharmaceutical formulation according to claim 3, wherein the third generation cephalosporin is in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous form or in free form and/or a combination thereof.
6. The pharmaceutical formulation according to claim 5, wherein cefpodoxime is used in ester form, preferably as cefpodoxime proxetil.
7. The pharmaceutical formulation according to claim 5, wherein cefditoren is used in ester form, preferably as cefditoren pivoxil.
8. The pharmaceutical formulation according to claim 5, wherein ceftibuten is used in dihydrate and/or trihydrate form.
9. The pharmaceutical formulation according to claim 5, wherein cefdinir is used in free form.
10. The pharmaceutical formulation according to claim 5, wherein cefixime is used in trihydrate form.
11. The pharmaceutical formulation according to claim 1, wherein clavulanic acid is in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, in crystalline and amorphous forms or in free form and/or a combination thereof.
12. The pharmaceutical formulation according to claim 11, wherein potassium clavulanate salt is used.
13. The pharmaceutical formulation according to claim 1, wherein the first pH agent having pKa value in the range of 1 -5 is selected from citric acid and malic acid.
14. The pharmaceutical formulation according to claim 13, wherein citric acid is used as the first pH agent.
15. The pharmaceutical formulation according to claim 1, wherein the second pH agent having pKa value in the range of 5.1-15 is selected from tribasic calcium phosphate, monosodium glutamate, potassium citrate, trisodium citrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate or combinations thereof.
16. The pharmaceutical formulation according to claim 15, wherein trisodium citrate is used as the second pH agent.
17. The pharmaceutical formulation according to claim 1, wherein said formulation comprises pharmaceutically acceptable excipients in addition to the combination of the third generation cephalosporin, clavulanic acid and/or derivatives thereof and pH agents.
18. The pharmaceutical formulation according to claim 17, wherein sweeteners, preservative agents, viscosity agents, glidants, lubricants, disintegrants, diluents and flavoring agents can be used in said formulation apart from the third generation cephalosporin, potassium clavulanate and pH agents.
19. The pharmaceutical formulation according to claim 18, wherein the sweetener is selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, sugar, maltose, sorbitol, saccharine, saccharine sodium, saccharose, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof.
20. The pharmaceutical formulation according to claim 19, wherein saccharose is used as the sweetener.
21. The pharmaceutical formulation according to claim 18, wherein the preservative agent is selected from a group comprising ascorbic acid, citric acid, malic acid, propionic acid, sodium ascorbate, sodium benzoate or combinations thereof.
22. The pharmaceutical formulation according to claim 21, wherein sodium benzoate is used as the preservative agent.
23. The pharmaceutical formulation according to claim 18, wherein the viscosity agent is selected from a group comprising carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, chitosan, colloidal silicon dioxide, gelatin, guar gum, xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, maltodextrin, polyvinyl alcohol or combinations thereof.
24. The pharmaceutical formulation according to claim 23, wherein xanthan gum is used as the viscosity agent.
25. The pharmaceutical formulation according to claim 24, wherein the ratio of the third generation cephalosporin to xanthan gum is in the range of 7: 1 to 15:1.
26. The pharmaceutical formulation according to claim 18, wherein the glidant is selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or a combination thereof.
27. The pharmaceutical formulation according to claim 26, wherein silicon dioxide is used as the glidant.
28. The pharmaceutical formulation according to claim 18, wherein the lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate or a combination thereof.
29. The pharmaceutical formulation according to claim 28, wherein magnesium stearate is used as the lubricant.
30. The pharmaceutical formulation according to claim 18, wherein the disintegrant is selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropylcellulose, methylcellulose, povidone, magnesium aluminium silicate, starch or combinations thereof.
31. The pharmaceutical formulation according to claim 18, wherein the diluent is selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
32. The pharmaceutical formulation according to claim 1, wherein said formulation comprises 20-700 mg of a third generation cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in quantities equal to this.
33. The pharmaceutical formulation according to claim 1, wherein said formulation comprises 50-450 mg of clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in quantities equal to this.
34. The pharmaceutical formulation according to claim 1, wherein clavulanic acid and/or derivatives thereof are used with a humectant in the ratio of 1 : 1.
35. The pharmaceutical formulation according to claim 34, wherein the humectant is selected from a group comprising silica, colloidal silica, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, starch, syloid, microcrystalline cellulose and talc.
36. The pharmaceutical formulation according to claim 35, wherein syloid or microcrystalline cellulose is used as humectant.
37. The pharmaceutical formulation according to claim 1, wherein said formulation comprises clavulanic acid in the range of 5% to 30% or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an amount equal to this.
38. The pharmaceutical formulation according to claim 1, wherein said formulation comprises 2-15% a third generation cephalosporin, 5-30% potassium clavulanate, 0.1- 4% glidant, 0.2-3% lubricant, 0-20% disintegrant and/or disintegrants, 0-15% diluent, 30-90% sweetener, 0.5-4% pH agent, 0.1-2% preservative agent, 0.2-4% viscosity agent and 0.1-5% flavoring agent with respect to the total weight of the unit dose.
39. A process for preparation of the pharmaceutical formulation according to claim 1, wherein said process is composed of the steps of granulation of the active agents third generation cephalosporin and clavulanic acid or derivatives by conventional wet and/or dry granulation methods; or mixing the third generation cephalosporin, clavulanic acid derivatives and the other excipients by dry blending method and then pulverizing them and optionally compressing the obtained mixture in tablet form, or the combined use thereof.
PCT/TR2011/000124 2010-05-04 2011-05-13 Formulations comprising a third generation cephalosporin and clavulanic acid Ceased WO2011142731A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP11743665A EP2568959A2 (en) 2010-05-14 2011-05-13 Formulations comprising a third generation cephalosporin and clavulanic acid
US13/668,922 US20130129791A1 (en) 2010-05-04 2012-11-05 Preparations of effervescent formulations comprising second and third generation cephalosporin and uses thereof
US14/309,273 US20150140111A1 (en) 2010-05-04 2014-06-19 Preparations of effervescent formulations comprising second and third generation cephalosporin and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201003854 2010-05-14
TR2010/03854 2010-05-14

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000127 Continuation-In-Part WO2011139252A2 (en) 2010-05-04 2011-05-02 Efervescent formulations comprising cefdinir

Related Child Applications (2)

Application Number Title Priority Date Filing Date
PCT/TR2011/000131 Continuation-In-Part WO2011139254A2 (en) 2010-05-04 2011-05-02 Pharmaceutical formulations compising cefuroxime axetil
US13/668,922 Continuation-In-Part US20130129791A1 (en) 2010-05-04 2012-11-05 Preparations of effervescent formulations comprising second and third generation cephalosporin and uses thereof

Publications (2)

Publication Number Publication Date
WO2011142731A2 true WO2011142731A2 (en) 2011-11-17
WO2011142731A3 WO2011142731A3 (en) 2012-03-08

Family

ID=44487006

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000124 Ceased WO2011142731A2 (en) 2010-05-04 2011-05-13 Formulations comprising a third generation cephalosporin and clavulanic acid

Country Status (2)

Country Link
EP (1) EP2568959A2 (en)
WO (1) WO2011142731A2 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103142506A (en) * 2013-04-03 2013-06-12 天津医药集团津康制药有限公司 Cefpodoxime proxetil granules and preparation method thereof
WO2013103531A1 (en) * 2012-01-03 2013-07-11 Zoetis Llc A method for treating lyme disease
WO2016116892A1 (en) * 2015-01-24 2016-07-28 Wockhardt Limited Antibacterial compositions
CN106456534A (en) * 2014-03-19 2017-02-22 法姆拜欧韩国株式会社 Liquid pharmaceutical composition
US10624899B2 (en) 2016-07-14 2020-04-21 Achaogen, Inc. Combination products for the treatment of bacterial infections and methods of producing or dosing of same
CN113194943A (en) * 2021-03-22 2021-07-30 广州新创忆药物临床研究有限公司 Stable-quality beta lactamase inhibitor composition, and application and method thereof
US11612592B2 (en) 2015-08-17 2023-03-28 Ferring B.V. Liquid formulations containing picosulfate and magnesium citrate
US12458634B2 (en) 2016-07-08 2025-11-04 Ferring B.V. Stabilized liquid formations containing picosulfate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282200A2 (en) 1987-03-10 1988-09-14 Cardiff Laboratories for Energy & Resources Limited Whey processing
EP0593573A1 (en) 1991-07-11 1994-04-27 Smithkline Beecham Plc Pharmaceutical formulation of a beta-lactam antibiotic and clavulanic acid or a water-soluble salt thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW473393B (en) * 1996-02-29 2002-01-21 Fujisawa Pharmaceutical Co Beta-lactam antibiotic-containing tablet and production thereof
US20080139528A1 (en) * 2003-12-10 2008-06-12 Pujara Chetan P Cefdinir oral suspension
CN1706389A (en) * 2005-05-26 2005-12-14 济南平志医药科技有限公司 Effervescent cefdinir prepn and its prepn process
US20070128268A1 (en) * 2005-12-07 2007-06-07 Herwig Jennewein Pharmaceutical compositions comprising an antibiotic
CN101129381B (en) * 2006-08-25 2012-02-01 天津和美生物技术有限公司 Combination of Antibiotics Containing β-Lactam Antibiotics and Ion Chelating Agents
CN101352424A (en) * 2008-09-16 2009-01-28 天津市中央药业有限公司 Cefdinir dispersible tablet and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0282200A2 (en) 1987-03-10 1988-09-14 Cardiff Laboratories for Energy & Resources Limited Whey processing
EP0593573A1 (en) 1991-07-11 1994-04-27 Smithkline Beecham Plc Pharmaceutical formulation of a beta-lactam antibiotic and clavulanic acid or a water-soluble salt thereof

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013103531A1 (en) * 2012-01-03 2013-07-11 Zoetis Llc A method for treating lyme disease
US9265771B2 (en) 2012-01-03 2016-02-23 Zoetis Services Llc Method for treating Lyme disease
CN103142506A (en) * 2013-04-03 2013-06-12 天津医药集团津康制药有限公司 Cefpodoxime proxetil granules and preparation method thereof
AU2014386903B2 (en) * 2014-03-19 2020-01-30 Pharmbio Korea Co., Ltd. Liquid pharmaceutical composition
EP3120835A4 (en) * 2014-03-19 2017-10-18 Pharmbio Korea Co. Ltd. Liquid pharmaceutical composition
CN106456534B (en) * 2014-03-19 2019-05-14 辉凌国际制药（瑞士）有限公司 liquid pharmaceutical composition
US10624879B2 (en) 2014-03-19 2020-04-21 Ferring International Center S.A. Liquid pharmaceutical composition
CN106456534A (en) * 2014-03-19 2017-02-22 法姆拜欧韩国株式会社 Liquid pharmaceutical composition
US12576072B2 (en) 2014-03-19 2026-03-17 Ferring International Center S.A. Liquid pharmaceutical composition
US11191753B2 (en) 2014-03-19 2021-12-07 Ferring International Center Sa. Liquid pharmaceutical composition
US20180256592A1 (en) * 2015-01-24 2018-09-13 Wockhardt Limited Antibacterial compositions
WO2016116892A1 (en) * 2015-01-24 2016-07-28 Wockhardt Limited Antibacterial compositions
US11612592B2 (en) 2015-08-17 2023-03-28 Ferring B.V. Liquid formulations containing picosulfate and magnesium citrate
US12458634B2 (en) 2016-07-08 2025-11-04 Ferring B.V. Stabilized liquid formations containing picosulfate
US10624899B2 (en) 2016-07-14 2020-04-21 Achaogen, Inc. Combination products for the treatment of bacterial infections and methods of producing or dosing of same
CN115581700A (en) * 2021-03-22 2023-01-10 湘北威尔曼制药股份有限公司 Pharmaceutical composition containing cefotaxime-sulbactam or cefotaxime-tazobactam with stable quality and high antibacterial activity
CN113194943A (en) * 2021-03-22 2021-07-30 广州新创忆药物临床研究有限公司 Stable-quality beta lactamase inhibitor composition, and application and method thereof

Also Published As

Publication number Publication date
WO2011142731A3 (en) 2012-03-08
EP2568959A2 (en) 2013-03-20

Similar Documents

Publication Publication Date Title
EP2528594B1 (en) Effervescent formulations comprising second generation cephalosporin
EP2568959A2 (en) Formulations comprising a third generation cephalosporin and clavulanic acid
US20190083385A1 (en) Production method and effervescent formulations comprising cephalosporin and clavulanic acid
WO2012060788A1 (en) Formulations of cephalosporins with controlled moisture content
US20130129791A1 (en) Preparations of effervescent formulations comprising second and third generation cephalosporin and uses thereof
WO2011142730A1 (en) Pharmaceutical composition comprising cefixime and clavulanic acid derivative compound
EP2566449B1 (en) Pharmaceutical compositions comprising ceftibuten
EP2566451B1 (en) Pharmaceutical compositions comprising cefditoren pivoxil
EP2515862A1 (en) Rapidly dispersing pharmaceutical formulation with cefdinir
WO2012060790A2 (en) Water dispersible cefpodoxime proxetil formulations
WO2012026907A2 (en) Cefpodoxime proxetil formulations
WO2011093822A1 (en) Effervescent formulations comprising cefixime and clavulanic acid as active agents
WO2011078828A1 (en) Pharmaceutical composition with high purity
WO2011093821A1 (en) Effervescent formulations comprising cefdinir and clavulanic acid
WO2012060787A1 (en) Oral dosage forms comprising cefdinir and carboxymethyl cellulose calcium
WO2011152808A1 (en) Formulation comprising cefpodoxime proxetil and clavulanic acid
WO2012060791A2 (en) Production method for pharmaceutical compositions comprising cefdinir
WO2011152805A2 (en) Pharmaceutical composition comprising cefpodoxime proxetil and clavulanic acid
EP2566450A2 (en) Pharmaceutical compositions comprising cefetamet
WO2012060792A1 (en) Pharmaceutical compositions comprising minimum 6 % of disintegrants by weight
WO2012078121A2 (en) Solid oral dosage form comprising cefdinir
WO2012060793A2 (en) Process for the preparation of cefdinir formulations
EP2663289A2 (en) Cefpodoxime proxetil formulations comprising taste regulating agent
WO2013109201A1 (en) Pharmaceutical compositions comprising cefprozil and clavulanic acid
EP1681050A1 (en) Dispersible sustained release pharmaceutical compositions

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: 11743665

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2011743665

Country of ref document: EP