EP2663289A2 - Cefpodoxime proxetil formulations comprising taste regulating agent - Google Patents

Cefpodoxime proxetil formulations comprising taste regulating agent

Info

Publication number
EP2663289A2
EP2663289A2 EP11767093.5A EP11767093A EP2663289A2 EP 2663289 A2 EP2663289 A2 EP 2663289A2 EP 11767093 A EP11767093 A EP 11767093A EP 2663289 A2 EP2663289 A2 EP 2663289A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
agent
range
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.)
Withdrawn
Application number
EP11767093.5A
Other languages
German (de)
French (fr)
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
Publication of EP2663289A2 publication Critical patent/EP2663289A2/en
Withdrawn legal-status Critical Current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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to pharmaceutical formulations comprising cefpodoxime proxetil.
  • Cefpodoxime proxetil (figure I), chemical name of which is pivaloyloxymethyl 7-[2-(2- amino-thiazole-4-yl]-2-(syn)-methoxyimino-acetamido]-3-methoxymethyl-3-cefem-4- carboxylate, was first disclosed in the patent numbered EP0049118.
  • Cefpodoxime proxetil is a third generation cephalosporin. Due to this feature, it is indicated in the treatment of infections caused by gram positive and gram negative bacteria.
  • 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.
  • Clavulanic acid and derivatives thereof can optionally be formulated as combined with antibiotics in order to increase efficiency of beta-lactam derivative antibiotics.
  • Tablets which contain 100 mg and 200 mg of cefpodoxime are available on the market. When these tablets containing 100 or 200 mg of active agent are formulated with excipients, they become too large in size and this makes the use of this dosage form inconvenient for patients who have swallowing difficulties, especially for pediatric and geriatric patients.
  • the molecule cefpodoxime proxetil has quite low water solubility; therefore bioavailability of tablet forms is rather low.
  • the subject matter of the present invention relates to water dispersible formulations comprising cefpodoxime and optionally clavulanic acid or derivatives thereof which comprises a sweetener combination composed of an artificial sweetener, a disaccharide and a salt.
  • a sweetener combination composed of an artificial sweetener, a disaccharide and a salt.
  • pharmaceutical dosage forms in the form of water dispersible powder, tablet and/or granule can be taken by the patients more comfortably as they disperse in water homogeneously prior to use and their bioavailability is superior to said solid dosage forms; b) in addition, it has been observed that bitter taste of cefpodoxime is not perceived in the formulations formulated according to the present invention and therefore they can be used more comfortably by patients.
  • Cefpodoxime that can be used in the water dispersible powder, tablet and/or granule formulations of the present invention can be in the form of its esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.
  • cefpodoxime proxetil is preferably used.
  • water dispersible powder, tablet and/or granule used in the text comprises single dose effervescent powder, tablets and/or granules; single dose water dispersible powders, tablets and granules; multiple dose powder, tablet and granules which are dispersed in water to form suspension; single dose water soluble powder, tablet and granules; multiple dose water soluble powder, tablet and granules. It is preferably in the form of multiple dose powder, tablet and granules which are dispersed in water to form suspension or single dose water dispersible powder, tablet or granules.
  • one aspect of the present invention is water dispersible powder, tablet and/or granule formulations comprising cefpodoxime as the active agent and a sweetener combination comprised of an artificial sweetener, a disaccharide and a salt.
  • another aspect of the present invention is water dispersible powder, tablet and/or granule formulations comprising cefpodoxime as the active agent and a sweetener combination comprised of an artificial sweetener, a disaccharide and a salt form, and additionally other pharmaceutically acceptable excipients.
  • the water dispersible powder, tablet and/or granule formulation can comprise various excipients such as, but not limited to, binders, glidants, diluents, lubricants, humectants, disintegrants, basic agents, acidic agents, taste regulating agents, viscosity agents, flavoring agent, preservative agents and optionally effervescent couple.
  • excipients such as, but not limited to, binders, glidants, diluents, lubricants, humectants, disintegrants, basic agents, acidic agents, taste regulating agents, viscosity agents, flavoring agent, preservative agents and optionally effervescent couple.
  • the binder that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone or combinations thereof.
  • the lubricant that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate.
  • talc is preferably used as lubricant.
  • the glidant that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof.
  • silicon dioxide is used as glidant in the formulation of the present invention.
  • the humectant that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate or a combination thereof.
  • the disintegrant that can be used in water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.
  • the diluent that can be used in water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
  • the basic agent that can be used in the water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate or combinations thereof.
  • the acidic agent that can be used in the water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.
  • citric acid is used in the formulation of the present invention as acidic agent.
  • the taste regulating agent that can be used in water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising artificial sweeteners such as acesulfame, aspartame, saccharine, saccharine sodium, lactitol, maltitol, sorbitol, sodium cyclamate, sucralose; a group comprising disaccharides such as sucrose, maltose, lactose; and a group comprising salts such as sodium chloride, potassium iodide, sodium iodide, sodium fluoride, potassium fluoride, potassium chloride.
  • artificial sweeteners such as acesulfame, aspartame, saccharine, saccharine sodium, lactitol, maltitol, sorbitol, sodium cyclamate, sucralose
  • disaccharides such as sucrose, maltose, lactose
  • salts such as sodium chloride, potassium iodide,
  • the ratio of disaccharide: artificial sugar: salt used in the formulation of the present invention is in the range of 15:5:1 to 5:1 :1, preferably in the range of 14:4:1 to 6:1:1, more preferably in the range of 13:3:1 to 7:1 :1.
  • another aspect of the present invention is water dispersible formulations of cefpodoxime in which the ratio of disaccharide: artificial sugar: salt is in the range of 15:5:1 to 5:1:1.
  • the sweetener combination for use in the formulation of the present invention preferably comprises aspartame as artificial sugar; sucrose as disaccharide; and sodium chloride as salt.
  • the viscosity agent that can be used in water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising carboxy methyl cellulose sodium, carboxy methyl cellulose calcium, colloidal silicone dioxide, ethyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose, hydroxyl methyl cellulose, hypromellose or a combination thereof.
  • the preservative agent that can be used in water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising methylparaben, ethylparaben, butylparaben, sorbic acid, tertiary ammonium salts, potassium sorbate, benzoic acid and/or salts thereof (sodium benzoate) and benzyl alcohol or a combination thereof.
  • the effervescent couple that can optionally be used in water dispersible powder, tablet and granule formulation of 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.
  • the water dispersible powder, tablet and granule formulation of the present invention can comprise cefpodoxime in the range of 20-800 mg or its pharmaceutically acceptable esters, salts, hydrates, solvates or a combination thereof in an equal amount.
  • the water dispersible powder, tablet and granule formulation of the present invention can comprise 5-60% of cefpodoxime or its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms in proportion to total weight of unit dose.
  • the water dispersible powder, tablet and granule formulation of the present invention can comprise 5-60 % of cefpodoxime and at least one; binder in the range of 0-40%; glidant in the range of 0.5-5%; lubricant in the range of 1-10%; humectant in the range of 0-40%; disintegrant and/or disintegrants in the range of 0-20%; diluent in the range of 0.5-60%; basic agent in the range of 0-40%; acidic agent in the range of 0.1-40%; taste regulating agent in the range of 1-25%; viscosity agent in the range of 2-15%; flavoring agent in the range of 0.1-5%; preservative agent in the range of 0-5% and optionally effervescent couple in the range of 0- 85% in proportion to the total weight of unit dose amount.
  • the formulation of the present invention can be used for pharmaceutical compositions comprising clavulanic acid or derivatives thereof along with cefpodoxime.
  • the present invention relates to pharmaceutical compositions comprising cefpodoxime and clavulanic acid or derivatives thereof; the sweetener combination comprised of an artificial sweetener, a disaccharide and a salt; and optionally pharmaceutically acceptable excipients in addition to these.
  • Clavulanic acid that can optionally be used in the pharmaceutical composition of the present invention can be in the form of solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or a combination thereof.
  • potassium clavulanate is used in the present invention.
  • the pharmaceutical composition of the present invention can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equal amount.
  • Clavulanic acid and its derivatives are extremely susceptible to moisture.
  • potassium clavulanate in the pharmaceutical composition of the present invention is preferably used with a humectant in the ratio of 1 : 1.
  • 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 syloid in the ratio of 1 : 1.
  • the pharmaceutical composition of the present invention can comprise 5-50% of clavulanic acid in proportion to total weight of unit dose amount or pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an equal amount.
  • the present invention relates to processes that can be used for preparation of water dispersible powder, tablet and/or granule formulations comprising pharmaceutically acceptable excipients in addition to cefpodoxime as active agent.
  • the process of the present invention comprises granulation of the active agent cefpodoxime proxetil by conventional wet and/or dry granulation methods; or powdering cefpodoxime proxetil and other excipients by mixing them by dry blending method and optionally compressing the mixture in tablet form.
  • the powder, tablet and/or granules obtained are dispersed in water before use by patients and taken in liquid form.
  • Another aspect of the present invention is that the formulation prepared according to said invention is used in the treatment of diseases related with infections caused by gram negative and gram positive bacteria.
  • Water dispersible tablets of the present invention can be prepared as specified below, yet the invention is not restricted to these examples.
  • EXAMPLE 1 Formulation and process for preparation of water dispersible granule
  • a method for preparation of water dispersible granule given in this example comprises, but not limited to, dissolving cefpodoxime proxetil in a suitable solvent; and granulating the diluent with this solution; and drying and then mixing the granules obtained with the other excipients.
  • a method for preparation of water dispersible granule given in this example comprises, but not limited to, dissolving cefpodoxime proxetil in a suitable solvent; and granulating the diluent with this solution; and drying and then mixing the granules obtained with the potassium clavylanate-syloid (1 :1) and the other excipients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to pharmaceutical formulations comprising cefpodoxime proxetil.

Description

CEFPODOXIME PROXETIL FORMULATIONS COMPRISING TASTE
REGULATING AGENT
The present invention relates to pharmaceutical formulations comprising cefpodoxime proxetil.
Background of the Invention:
Cefpodoxime proxetil (figure I), chemical name of which is pivaloyloxymethyl 7-[2-(2- amino-thiazole-4-yl]-2-(syn)-methoxyimino-acetamido]-3-methoxymethyl-3-cefem-4- carboxylate, was first disclosed in the patent numbered EP0049118.
Figure 1
Cefpodoxime proxetil is a third generation cephalosporin. Due to this feature, it is indicated in the treatment of infections caused by gram positive and gram negative bacteria.
Clavulanic acid and derivatives thereof (for instance its salts such as potassium clavulanate) are known as the beta-lactamase inhibitors which withstand the beta-lactamase-originated resistance mechanism by suppressing the activity of beta-lactamase enzymes. Clavulanic acid and derivatives thereof can optionally be formulated as combined with antibiotics in order to increase efficiency of beta-lactam derivative antibiotics.
Tablets which contain 100 mg and 200 mg of cefpodoxime are available on the market. When these tablets containing 100 or 200 mg of active agent are formulated with excipients, they become too large in size and this makes the use of this dosage form inconvenient for patients who have swallowing difficulties, especially for pediatric and geriatric patients. The molecule cefpodoxime proxetil has quite low water solubility; therefore bioavailability of tablet forms is rather low.
Water dispersible dosage forms have been developed in order to overcome problems that solid dosage forms pose. However, the fact that cefpodoxime has a quite bitter taste poses difficulties in developing formulations having pleasant taste which can be taken by patient without feeling uncomfortable.
In the current situation, there is need for water dispersible formulations which comprise cefpodoxime, bitter taste of which is masked, and optionally clavulanic acid or its derivatives; have higher bioavailability than solid dosage forms in order to meet the needs of patients requiring special consideration for instance pediatric and geriatric patients.
Description of the invention:
The subject matter of the present invention relates to water dispersible formulations comprising cefpodoxime and optionally clavulanic acid or derivatives thereof which comprises a sweetener combination composed of an artificial sweetener, a disaccharide and a salt. Surprisingly, it has been found that water dispersible powder, tablet and/or granules comprising cefpodoxime as the active agent and a sweetener combination comprised of an artificial sweetener, a disaccharide and a salt constitute a formulation in which the bitter taste of cefpodoxime is not perceived.
According to this, pharmaceutical dosage forms in the form of water dispersible powder, tablet and/or granule; a) can be taken by the patients more comfortably as they disperse in water homogeneously prior to use and their bioavailability is superior to said solid dosage forms; b) in addition, it has been observed that bitter taste of cefpodoxime is not perceived in the formulations formulated according to the present invention and therefore they can be used more comfortably by patients.
Cefpodoxime that can be used in the water dispersible powder, tablet and/or granule formulations of the present invention can be in the form of its esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. In the present invention, cefpodoxime proxetil is preferably used.
The term "water dispersible powder, tablet and/or granule" used in the text comprises single dose effervescent powder, tablets and/or granules; single dose water dispersible powders, tablets and granules; multiple dose powder, tablet and granules which are dispersed in water to form suspension; single dose water soluble powder, tablet and granules; multiple dose water soluble powder, tablet and granules. It is preferably in the form of multiple dose powder, tablet and granules which are dispersed in water to form suspension or single dose water dispersible powder, tablet or granules.
According to this, one aspect of the present invention is water dispersible powder, tablet and/or granule formulations comprising cefpodoxime as the active agent and a sweetener combination comprised of an artificial sweetener, a disaccharide and a salt.
According to this, another aspect of the present invention is water dispersible powder, tablet and/or granule formulations comprising cefpodoxime as the active agent and a sweetener combination comprised of an artificial sweetener, a disaccharide and a salt form, and additionally other pharmaceutically acceptable excipients.
In addition to cefpodoxime and the sweetener combination; the water dispersible powder, tablet and/or granule formulation can comprise various excipients such as, but not limited to, binders, glidants, diluents, lubricants, humectants, disintegrants, basic agents, acidic agents, taste regulating agents, viscosity agents, flavoring agent, preservative agents and optionally effervescent couple.
The binder that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone or combinations thereof.
The lubricant that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate. In the formulation of the present invention, talc is preferably used as lubricant. The glidant that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof. Preferably, silicon dioxide is used as glidant in the formulation of the present invention.
The humectant that can be used in the water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate or a combination thereof.
The disintegrant that can be used in water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.
The diluent that can be used in water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
The basic agent that can be used in the water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate or combinations thereof.
The acidic agent that can be used in the water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof. Preferably, citric acid is used in the formulation of the present invention as acidic agent.
The taste regulating agent that can be used in water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising artificial sweeteners such as acesulfame, aspartame, saccharine, saccharine sodium, lactitol, maltitol, sorbitol, sodium cyclamate, sucralose; a group comprising disaccharides such as sucrose, maltose, lactose; and a group comprising salts such as sodium chloride, potassium iodide, sodium iodide, sodium fluoride, potassium fluoride, potassium chloride.
The ratio of disaccharide: artificial sugar: salt used in the formulation of the present invention is in the range of 15:5:1 to 5:1 :1, preferably in the range of 14:4:1 to 6:1:1, more preferably in the range of 13:3:1 to 7:1 :1.
According to this, another aspect of the present invention is water dispersible formulations of cefpodoxime in which the ratio of disaccharide: artificial sugar: salt is in the range of 15:5:1 to 5:1:1.
The sweetener combination for use in the formulation of the present invention preferably comprises aspartame as artificial sugar; sucrose as disaccharide; and sodium chloride as salt.
The viscosity agent that can be used in water dispersible powder, tablet and/or granule formulation of the present invention can be selected from a group comprising carboxy methyl cellulose sodium, carboxy methyl cellulose calcium, colloidal silicone dioxide, ethyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose, hydroxyl methyl cellulose, hypromellose or a combination thereof.
The preservative agent that can be used in water dispersible powder, tablet and granule formulation of the present invention can be selected from a group comprising methylparaben, ethylparaben, butylparaben, sorbic acid, tertiary ammonium salts, potassium sorbate, benzoic acid and/or salts thereof (sodium benzoate) and benzyl alcohol or a combination thereof.
The effervescent couple that can optionally be used in water dispersible powder, tablet and granule formulation of 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.
The water dispersible powder, tablet and granule formulation of the present invention can comprise cefpodoxime in the range of 20-800 mg or its pharmaceutically acceptable esters, salts, hydrates, solvates or a combination thereof in an equal amount.
The water dispersible powder, tablet and granule formulation of the present invention can comprise 5-60% of cefpodoxime or its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms in proportion to total weight of unit dose. The water dispersible powder, tablet and granule formulation of the present invention can comprise 5-60 % of cefpodoxime and at least one; binder in the range of 0-40%; glidant in the range of 0.5-5%; lubricant in the range of 1-10%; humectant in the range of 0-40%; disintegrant and/or disintegrants in the range of 0-20%; diluent in the range of 0.5-60%; basic agent in the range of 0-40%; acidic agent in the range of 0.1-40%; taste regulating agent in the range of 1-25%; viscosity agent in the range of 2-15%; flavoring agent in the range of 0.1-5%; preservative agent in the range of 0-5% and optionally effervescent couple in the range of 0- 85% in proportion to the total weight of unit dose amount.
If required, the formulation of the present invention can be used for pharmaceutical compositions comprising clavulanic acid or derivatives thereof along with cefpodoxime.
According to this, the present invention relates to pharmaceutical compositions comprising cefpodoxime and clavulanic acid or derivatives thereof; the sweetener combination comprised of an artificial sweetener, a disaccharide and a salt; and optionally pharmaceutically acceptable excipients in addition to these.
Clavulanic acid that can optionally be used in the pharmaceutical composition of the present invention can be in the form of solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or a combination thereof. Preferably, potassium clavulanate is used in the present invention.
The pharmaceutical composition of the present invention can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equal amount.
Clavulanic acid and its derivatives (e.g. potassium clavulanate) are extremely susceptible to moisture. To this respect, potassium clavulanate in the pharmaceutical composition of the present invention is preferably used with a humectant in the ratio of 1 : 1.
One or more of the substances comprising silica; 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.
In the pharmaceutical composition of the present invention, potassium clavulanate is preferably used with syloid in the ratio of 1 : 1. The pharmaceutical composition of the present invention can comprise 5-50% of clavulanic acid in proportion to total weight of unit dose amount or pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an equal amount.
In another aspect, the present invention relates to processes that can be used for preparation of water dispersible powder, tablet and/or granule formulations comprising pharmaceutically acceptable excipients in addition to cefpodoxime as active agent.
According to this, the process of the present invention comprises granulation of the active agent cefpodoxime proxetil by conventional wet and/or dry granulation methods; or powdering cefpodoxime proxetil and other excipients by mixing them by dry blending method and optionally compressing the mixture in tablet form.
The powder, tablet and/or granules obtained are dispersed in water before use by patients and taken in liquid form.
Another aspect of the present invention is that the formulation prepared according to said invention is used in the treatment of diseases related with infections caused by gram negative and gram positive bacteria.
Water dispersible tablets of the present invention can be prepared as specified below, yet the invention is not restricted to these examples.
EXAMPLE 1: Formulation and process for preparation of water dispersible granule
A method for preparation of water dispersible granule given in this example comprises, but not limited to, dissolving cefpodoxime proxetil in a suitable solvent; and granulating the diluent with this solution; and drying and then mixing the granules obtained with the other excipients.
EXAMPLE 2: Formulation and process for preparation of water dispersible granule
A method for preparation of water dispersible granule given in this example comprises, but not limited to, dissolving cefpodoxime proxetil in a suitable solvent; and granulating the diluent with this solution; and drying and then mixing the granules obtained with the potassium clavylanate-syloid (1 :1) and the other excipients.

Claims

CLAIMS:
1. A pharmaceutical composition comprising cefpodoxime characterized in that said composition is water dispersible cefpodoxime formulation comprising a sweetener combination composed of an artificial sweetener, a disaccharide and a salt.
2. The pharmaceutical composition according to claim 1, wherein cefpodoxime that is used as active agent can be in the form of its esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or a combination thereof.
3. The pharmaceutical composition according to claim 2, wherein cefpodoxime proxetil is used as the active agent.
4. The pharmaceutical composition according to claim 1 , wherein said composition can be in the form of water dispersible powder, tablet and/or granules; single dose effervescent powder, tablets and/or granules; single dose water dispersible powders, tablets and/or granules; multiple dose powder, tablet and/or granules which are dispersed in water to form suspension; single dose water soluble powder, tablet and/or granules; multiple dose water soluble powder, tablet and/or granules.
5. The pharmaceutical composition according to claim 1, wherein said composition comprises pharmaceutically acceptable excipients in addition to cefpodoxime used as the active agent and a sweetener combination composed of an artificial sweetener, a disaccharide and a salt.
6. The pharmaceutical composition according to claim 5, wherein said composition can comprise binder, glidant, lubricant, humectant, disintegrant, diluent, basic agent, acidic agent, sweetener, viscosity agent, flavoring agent, preservative agent and/or effervescent couple in addition to cefpodoxime as the active agent and a sweetener combination composed of an artificial sweetener, a disaccharide and a salt.
7. The pharmaceutical composition according to claim 6, wherein the binder can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone or a combination thereof.
8. The pharmaceutical composition according to claim 6, wherein the lubricant can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate or a combination thereof.
9. The pharmaceutical composition according to claim 8, wherein talc is preferably used as lubricant.
10. The pharmaceutical composition according to claim 6, wherein the glidant can be selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof.
11. The pharmaceutical composition according to claim 10, wherein silicon dioxide is preferably used as glidant.
12. The pharmaceutical composition according to claim 6, wherein the humectant can be selected from a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate or a combination thereof.
13. The pharmaceutical composition according to claim 6, wherein the disintegrant can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate, starch or combinations thereof.
14. The pharmaceutical composition according to claim 6, wherein the diluent can be 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.
15. The pharmaceutical composition according to claim 6, wherein the basic agent can be selected from a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate or combinations thereof.
16. The pharmaceutical composition according to claim 6, wherein the acidic agent can be selected from a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof.
17. The pharmaceutical composition according to claim 16, wherein citric acid is preferably used as acidic agent.
18. The pharmaceutical composition according to claim 6, wherein the taste regulating agent can be selected from a group comprising artificial sweeteners such as acesulfame, aspartame, saccharine, saccharine sodium, lactitol, maltitol, sorbitol, sodium cyclamate, sucralose; a group comprising disaccharides such as sucrose, maltose, lactose; and a group comprising salts such as sodium chloride, potassium iodide, sodium iodide, sodium fluoride, potassium fluoride, potassium chloride.
19. The pharmaceutical composition according to claim 18, wherein the ratio of disaccharide: artificial sugar: salt in the taste regulating agent combination is in the range of 15:5:1 to 5:1:1.
20. The pharmaceutical composition according to claim 19, wherein the ratio of disaccharide: artificial sugar: salt in the taste regulating agent combination is in the range of 14:4:1 to 6:1:1.
21. The pharmaceutical composition according to claim 20, wherein the ratio of disaccharide: artificial sugar: salt in the taste regulating agent combination is in the range of 13:3:1 to7:l:l.
22. The pharmaceutical composition according to claim 18, wherein the taste regulating agent comprises aspartame as artificial sugar; sucrose as disaccharide; and sodium chloride as salt.
23. The pharmaceutical composition according to claim 6, wherein the viscosity agent can be selected from a group comprising carboxy methyl cellulose sodium, carboxy methyl cellulose calcium, colloidal silicone dioxide, ethyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose, hydroxyl methyl cellulose, hypromellose or a combination thereof.
24. The pharmaceutical composition according to claim 6, wherein the preservative agent can be selected from a group comprising methylparaben, ethylparaben, butylparaben, sorbic acid, tertiary ammonium salts, potassium sorbate, benzoic acid and/or salts thereof (sodium benzoate) and benzyl alcohol or a combination thereof.
25. The pharmaceutical composition according to claim 6, wherein the effervescent couple 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.
26. The pharmaceutical composition according to claim 1, wherein said composition can comprise cefpodoxime in the range of 20-800 mg or its pharmaceutically acceptable esters, salts, hydrates, solvates or a combination thereof in an equal amount.
27. The pharmaceutical composition according to claim 1, wherein said composition can comprise 5-60% of cefpodoxime or its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms in proportion to total amount of unit dose.
28. The pharmaceutical composition according to claim 1, wherein said composition can comprise 5-60 % of cefpodoxime; binder in the range of 0-40%; glidant in the range of 0.5-5%; lubricant in the range of 1-10%; humectant in the range of 0-40%; disintegrant and/or disintegrants in the range of 0-20%; diluent in the range of 0.5- 60%; basic agent in the range of 0-40%; acidic agent in the range of 0.1-40%; taste regulating agent in the range of 1-25%; viscosity agent in the range of 2-15%; flavoring agent in the range of 0.1-5%; preservative agent in the range of 0-5% and optionally effervescent couple in the range of 0-85% in proportion to the total weight of unit dose amount.
29. The pharmaceutical composition according to any preceding claims, wherein said composition comprises clavulanic acid or derivatives thereof in addition to cefpodoxime it comprises as active agent.
30. The pharmaceutical composition according to claim 29, wherein clavulanic acid can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or a combination thereof.
31. The pharmaceutical composition according to claim 30, wherein potassium clavulanate is used in said composition.
32. A method for preparation of the pharmaceutical composition as claimed in any of the claims above, wherein said method comprises granulation of the active agent cefpodoxime proxetil by conventional wet and/or dry granulation methods; or powdering cefpodoxime proxetil and other excipients after mixing them by dry blending method and optionally compressing tablets.
33. The pharmaceutical composition according to claim 1, wherein said composition is used in production of a drug prepared so as to be used in the treatment of diseases related with infections caused by gram negative and gram positive bacteria.
EP11767093.5A 2010-08-25 2011-08-24 Cefpodoxime proxetil formulations comprising taste regulating agent Withdrawn EP2663289A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/07107A TR201007107A1 (en) 2010-08-25 2010-08-25 Formulations of cefpodoxime proxetil containing taste regulating agent.
PCT/TR2011/000201 WO2012026908A2 (en) 2010-08-25 2011-08-24 Cefpodoxime proxetil formulations comprising taste regulating agent

Publications (1)

Publication Number Publication Date
EP2663289A2 true EP2663289A2 (en) 2013-11-20

Family

ID=44764206

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11767093.5A Withdrawn EP2663289A2 (en) 2010-08-25 2011-08-24 Cefpodoxime proxetil formulations comprising taste regulating agent

Country Status (3)

Country Link
EP (1) EP2663289A2 (en)
TR (1) TR201007107A1 (en)
WO (1) WO2012026908A2 (en)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4486425A (en) 1980-09-30 1984-12-04 Sankyo Company Limited 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylates
MXPA03007678A (en) * 2001-02-27 2004-03-16 Ranbaxy Lab Ltd Oral pharmaceutical composition of cefpodoxime proxetil.
TW200404550A (en) * 2002-07-08 2004-04-01 Sankyo Co Cepharospolin formulation for oral use
EP1539146A1 (en) * 2002-07-16 2005-06-15 Ranbaxy Laboratories, Ltd. Dispersible tablets for oral administration
WO2007017895A2 (en) * 2005-05-05 2007-02-15 Lupin Limited Stabilized oral pharmaceutical compositions of cephalosporins
TR201002878A2 (en) * 2010-04-13 2011-10-21 Bi̇lgi̇ç Mahmut Pharmaceutical compositions comprising cefpodoxime proxetil.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2012026908A2 *

Also Published As

Publication number Publication date
WO2012026908A2 (en) 2012-03-01
WO2012026908A3 (en) 2012-09-07
TR201007107A1 (en) 2012-03-21

Similar Documents

Publication Publication Date Title
EP2528589B1 (en) Stable efervescent formulations comprising cefaclor
US20130017156A1 (en) Cefdinir and cefixime formulations and uses thereof
WO2011142731A2 (en) Formulations comprising a third generation cephalosporin and clavulanic acid
WO2012060788A1 (en) Formulations of cephalosporins with controlled moisture content
EP2608776A2 (en) Cefpodoxime proxetil formulations
WO2012060790A2 (en) Water dispersible cefpodoxime proxetil formulations
EP2568957A1 (en) Pharmaceutical composition comprising cefixime and clavulanic acid derivative compound
WO2011139249A2 (en) Pharmaceutical composition comprising cefdinir
EP2515850B1 (en) Pharmaceutical compositions comprising cefdinir as an active agent
WO2011129792A1 (en) Water dispersible formulations comprising cefpodoxime proxetil
US20130129791A1 (en) Preparations of effervescent formulations comprising second and third generation cephalosporin and uses thereof
EP2566449B1 (en) Pharmaceutical compositions comprising ceftibuten
WO2011093828A2 (en) Solid dosage forms comprising cefprozil
EP2566451B1 (en) Pharmaceutical compositions comprising cefditoren pivoxil
WO2012060787A1 (en) Oral dosage forms comprising cefdinir and carboxymethyl cellulose calcium
EP2515859A1 (en) Rapidly dispersing effervescent formulation
EP2663289A2 (en) Cefpodoxime proxetil formulations comprising taste regulating agent
WO2012060791A2 (en) Production method for pharmaceutical compositions comprising cefdinir
EP2566450A2 (en) Pharmaceutical compositions comprising cefetamet
EP2575812A2 (en) Pharmaceutical composition comprising cefpodoxime proxetil and clavulanic acid
WO2012060792A1 (en) Pharmaceutical compositions comprising minimum 6 % of disintegrants by weight
WO2012060789A2 (en) Production method for cefdinir formulations
WO2012078121A2 (en) Solid oral dosage form comprising cefdinir
WO2013109201A1 (en) Pharmaceutical compositions comprising cefprozil and clavulanic acid
WO2013151517A1 (en) Tablet formulations comprising cefpodoxime proxetil and clavulanic acid

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130325

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20150303