Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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

Definitions

• Present invention relates to pharmaceutical formulations formulated in effervescent form comprising cefprozil active agent and the process for their preparation.
• Cefprozil which is a second generation cephalosporin, was first disclosed in the patent numbered US4520022 and its chemical name is 8-[2-amino-2-(4-hydroxyphenyl)-acetyl] amino-7-oxo-4-prop-l-enyl-2-thia-6- azabicyclo [4.2.0]oct-4-ene-5-carboxylic acid.
• Cefprozil shown with Formula 1 is indicated for use in treatment of bronchitis, ear infections, skin infections and for treatment of other infections.
• the formulations comprising cefprozil as active agent are present in tablet, capsule or oral suspension forms.
• the pharmaceutical formulations sold in the market under the tradename CEFZIL ® are present in tablet form comprising 250 and 500 mg cefprozil and in oral suspension form comprising 125 mg/5 ml and 250 mg/5 ml of cefprozil.
• Tablet forms comprising 250 and 500 mg active agent in one dose become bigger in size when formulated with excipients. Accordingly, oral tablet and capsule dosage forms cause difficulty in swallowing especially for old people and children since they are difficult to swallow even though they are aclministered with water and have an unpleasant taste. This case impedes the drug intake and affects the efficacy of the treatment negatively. Moreover, bioavailability of oral dosage forms is far less than that of suspension forms.
• suspension forms cause some problems such as; possibility to intake high and/or uncontrolled dose, the problems related to their physical and chemical stabilities after they are diluted with water and the difficulties in their usage and transferring.
• new approaches are needed for obtaining formulations which are stable, which provides an efficient dosing and ease of use for especially pediatric and geriatric patients, which can disperse quickly and form a homogeneous suspension and have a high bioavailability.
• the inventors have surprisingly found that the problems in the prior art can be solved by the effervescent formulations that are prepared in accordance with the present invention.
• the present invention is related to effervescent formulations comprising cefprozil and process for the preparation of these formulations.
• effervescent forms formulated with the formulation comprising 10-50% of cefprozil, 50-90 % of effervescent couple, 1-10% of binder and 1-15% of at least one pharmaceutically acceptable excipient with respect to the total weight of unit dose, homogeneously and quickly disperse in water, provide effective dosing and ease of use, appeal to a wider patient profile and are stable and highly bioavailable.
• the first aspect of the present invention is effervescent formulations comprising 10-50% of cefprozil, 50-90% of effervescent couple, 1-10% of binder and 1-15% of at least one pharmaceutically acceptable excipient with respect to the total weight of unit dose.
• effervescent formulations term used in the text comprises effervescent tablets, effervescent granules and effervescent powders.
• effervescent formulations in accordance with the present invention are in the tablet form.
• Effervescent powder, granule or tablet forms are more advantageous compared to the conventional forms due to the fact that they disperse quickly.
• Effervescent formulations disperse quickly and simultaneously and they disperse the active agents into the aqueous medium. Therefore, drug provides a homogeneous suspension by quickly dispersing in water and the bioavailability of the active agent increases considerably.
• the effervescent forms are more stable due to the fact that they are in solid form, they have a longer shelf-life compared to suspension forms. Effervescent dosage forms that are suitable for single dose usage provides a controlled dose intake.
• Cefprozil that is used in the formulations formulated in effervescent form in accordance with the present invention can be present in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or as a combination thereof.
• Cefprozil that is used in the present invention can be present in one of the forms of monohydrate, dihydrate, trihydrate and/or anhydrous. Preferably, it is present in the form of monohydrate.
• Effervescent formulations according to present invention may comprise effective amount of cefprozil, an effective effervescent couple and additionally at least one excipient which is selected from a group comprising pharmaceutically acceptable amounts of binder, lubricant and sweetener.
• effervescent formulation according to present invention comprises a mixture of components which gives off carbon dioxide gas upon contact with water.
• This type of effervescent components are generally an acid or an acidic salt which may give off carbon dioxide gas upon contact with an alkali or alkali earth metal carbonate or hydrogen carbonate and aqueous solution.
• Effervescent acid that is used in the effervescent formulation according to the present invention is selected from a group comprising pharmaceutically acceptable acids; especially organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, acetic acid, adipic acid, succinic acid, acetylsalicylic acid and/or acidic salts such as sodium citrate, sodium acetate, sodium dihydrogen phosphate, sodium acid pyrophosphate and sodium acid sulphite.
• citric acid is used.
• Alkali component that is used as effervescent base in the effervescent formulation according to the present invention can be selected from, but not limited with, sodium hydrogen carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate.
• sodium hydrogen carbonate is used.
• Effervescent formulations in accordance with the present invention comprises cefprozil, effervescent couple and additionally at least one excipient which is selected from a group comprising pharmaceutically acceptable amounts of binder, lubricant, sweetener and/or taste regulator, diluents, disintegrant, flavoring agent, coloring agent, surfactant, anti-foaming agent, humectants, acidic agent, basic agent.
• Binder used in the effervescent formulation in accordance with the present invention can be selected from, but not limited with, a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, polyvinylpyrrolidone and povidone.
• a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, polyvinylpyrrolidone and povidone.
• polyvinylpyrrolidone is used.
• Sweetener and/or taste regulator that can be used in effervescent formulations of the present invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharin, saccharin sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose and xylitol or a combination thereof.
• sodium chloride and/or sucralose is used.
• Lubricant used in the effervescent formulation in accordance with the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.
• PEG 6000 is used.
• Flavoring agents used in the present invention can be selected from a group comprising blackberry flavor, banana flavor, strawberry flavor, lemon flavor, orange flavor, peach flavor, vanilla flavor or similar natural fruits or might have the flavor of a natural herb.
• cefprozil in the range of 50-5000 mg or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an amount equivalent to that can be used.
• effervescent formulations in which cefprozil: binder ratio is in the range of 30:1 to 5:1, preferably 25:1 to 10:1, more preferably 20:1 to 12:1, are more stable and suitable for usage and transferring and can disperse more quickly.
• the present invention is related to effervescent formulations wherein cefprozil: binder ratio is in the range of 30:1 to 5:1, preferably 25:1 to 10:1, more preferably 20:1 to 12:1.
• the present invention is related to the effervescent formulations comprising cefprozil in an amount of 10-50%, effervescent couple in an amount of 50-90%, binder in an amount of 1-10 %, lubricant in an amount of 0.1-3 %, sweetener in an amount of 0.1-5 % by weight and at least one pharmaceutically acceptable excipient.
• the present invention is related to the process for the preparation of pharmaceutical combinations comprising cefprozil as active agent and pharmaceutically acceptable excipients.
• the present invention is related to the process comprising the steps of blending effervescent couple, binder and taste regulator and granulating them, obtaining the final mixture by adding cefprozil, lubricant and at least one pharmaceutically acceptable excipient into the obtained granules and preferably compressing the final mixture in the form of tablets.
• the present invention is related to the use of effervescent formulations comprising cefprozil as active agent and pharmaceutically acceptable excipients for treatment of the infections caused by gram positive and gram negative bacteria.
• EXAMPLE 1 Formulation and process for the preparation of effervescent tablet.
• Formulation that can be used in the present invention is obtained by blending effervescent couple, taste regulator and binder and granulating them, adding cefprozil and sweetener to the obtained granules and adding flavoring agent and lubricant to the mixture and blending them.
• the obtained mixture is compressed into tablets in the tablet pressing machine.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth 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)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
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• Oncology (AREA)
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• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2010
  • 2010-01-29 TR TR2010/00689A patent/TR201000689A1/tr unknown
• 2011
  • 2011-01-28 WO PCT/TR2011/000032 patent/WO2011093828A2/en active Application Filing
  • 2011-01-31 WO PCT/TR2011/000036 patent/WO2011093831A2/en active Application Filing
  • 2011-01-31 EP EP11708946A patent/EP2528593A2/en not_active Withdrawn

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