WO2012026908A2 - Préparations de cefpodoxime proxétil comprenant un agent régulateur de goût - Google Patents

Préparations de cefpodoxime proxétil comprenant un agent régulateur de goût Download PDF

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Publication number
WO2012026908A2
WO2012026908A2 PCT/TR2011/000201 TR2011000201W WO2012026908A2 WO 2012026908 A2 WO2012026908 A2 WO 2012026908A2 TR 2011000201 W TR2011000201 W TR 2011000201W WO 2012026908 A2 WO2012026908 A2 WO 2012026908A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
agent
range
sodium
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Application number
PCT/TR2011/000201
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English (en)
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WO2012026908A3 (fr
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Priority to EP11767093.5A priority Critical patent/EP2663289A2/fr
Publication of WO2012026908A2 publication Critical patent/WO2012026908A2/fr
Publication of WO2012026908A3 publication Critical patent/WO2012026908A3/fr

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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.

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  • 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)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des préparations pharmaceutiques comprenant du cefpodoxime proxétil.
PCT/TR2011/000201 2010-08-25 2011-08-24 Préparations de cefpodoxime proxétil comprenant un agent régulateur de goût WO2012026908A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11767093.5A EP2663289A2 (fr) 2010-08-25 2011-08-24 Préparations de cefpodoxime proxétil comprenant un agent régulateur de goût

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/07107A TR201007107A1 (tr) 2010-08-25 2010-08-25 Tat düzenleyici ajan içeren sefpodoksim proksetil formülasyonları.
TR2010/07107 2010-08-25

Publications (2)

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WO2012026908A2 true WO2012026908A2 (fr) 2012-03-01
WO2012026908A3 WO2012026908A3 (fr) 2012-09-07

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PCT/TR2011/000201 WO2012026908A2 (fr) 2010-08-25 2011-08-24 Préparations de cefpodoxime proxétil comprenant un agent régulateur de goût

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EP (1) EP2663289A2 (fr)
TR (1) TR201007107A1 (fr)
WO (1) WO2012026908A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049118A2 (fr) 1980-09-30 1982-04-07 Sankyo Company Limited Dérivés de céphalosporines, leur préparation et compositions les contenant

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067943A1 (fr) * 2001-02-27 2002-09-06 Ranbaxy Laboratories Limited Composition pharmaceutique orale de cefpodoxime-proxetil
TW200404550A (en) * 2002-07-08 2004-04-01 Sankyo Co Cepharospolin formulation for oral use
KR20050062514A (ko) * 2002-07-16 2005-06-23 랜박시 래보러터리스 리미티드 경구 투여용 분산성 정제
JP2008540403A (ja) * 2005-05-05 2008-11-20 ルピン・リミテッド セファロスポリンの安定化経口用医薬組成物
TR201002878A2 (tr) * 2010-04-13 2011-10-21 Bi̇lgi̇ç Mahmut Sefpodoksim proksetil içeren farmasötik bileşimler.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0049118A2 (fr) 1980-09-30 1982-04-07 Sankyo Company Limited Dérivés de céphalosporines, leur préparation et compositions les contenant

Also Published As

Publication number Publication date
EP2663289A2 (fr) 2013-11-20
WO2012026908A3 (fr) 2012-09-07
TR201007107A1 (tr) 2012-03-21

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