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
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • 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

Definitions

• the present invention relates to pharmaceutical compositions comprising cefetamet or any pharmaceutically acceptable derivative thereof, and the use of said compositions in the treatment of bacterial infections.
• Cefetamet which has the chemical name (6R,7R)-7-[[(2Z)-2-(2-amino-4- thiazolyl)(methoxyimino)acetyl] amino] -3 -methyl- 8-oxo-5 -thia- 1 -azabicyclo [4.2.0]
• oct-2-ene- 2-carboxylic acid is a third generation cephalosporin antibiotic that has a perfect effect particularly on the species streptococcus, enterobacter, neisseria, hemophilus. It was first disclosed in the patent numbered US4396681 and its strong effect on gram positive and gram negative bacteria was indicated in that patent document.
• Cefetamet is more durable against the enzyme beta-lactamase compared to penicillin, first and second generation cephalosporins.
• the formulation comprising the active agent cefetamet is marketed in 250 mg and 500 mg oral tablet forms.
• the tablet forms comprising 250 and 500 mg active agent in a single dose are formulated with excipients, they become quite large in size and this made the use of this dosage form inconvenient in patients with dysphagia, particularly in pediatric and geriatric patients.
• suspension forms have been developed to overcome said problems in the prior art.
• the patent application numbered in CN 1650868 discloses a medicine in the form of oral liquid or suspension for treating pulmonary infectious diseases which is prepared from ambroxol hydrochloride and one of cefixime, cefetamet sodium and cefetamet hydrochloride.
• suspension forms comprising cefetamet are not preferred since they have the potential of high and/or uncontrolled dose intake and are not physically and chemically stable.
• Cefetamet has a low solubility in water. For that reason, it is generally observed that water dispersible formulations comprising cefetamet cannot quickly disperse since cefetamet cannot dissolve in water entirely. Accordingly, the desirable amount of cefetamet cannot be absorbed and this leads to low bioavailability of it.
• the inventors have surprisingly found that the water dispersible dosage forms comprising cefetamet and its any pharmaceutically acceptable derivative pertaining to the present invention overcome the problems encountered in the prior art.
• the present invention relates to the water dispersible powder, tablet and granules comprising cefetamet and/or pharmaceutically acceptable salts, hydrates, solvates, esters, amorphous and crystal forms of cefetamet and/or combination thereof; their formulations and the procedures for their preparation.
• cefetamet in which d 50 value of the molecule cefetamet is in the range of 10-50 ⁇ solubility problem of cefetamet can be overcome and the formulation comprising it can disperse entirely and quickly.
• the inventors have found that the water dispersible formulations comprising cefetamet in which d 0 value of the cefetamet is in the range of 10-50 ⁇ , has increased solubility of cefetamet and thus the rapid and entire dispersion of said formulations. This provides the increase of the absorption of cefetamet as the active agent and hence the increase of its bioavailability.
• the first aspect of the present invention is the water dispersible formulations comprising cefetamet wherein d 50 value of the molecule cefetamet is in the range of 10-50 ⁇ .
• water dispersible formulations present in the text comprises effervescent tablets, effervescent granules, effervescent powders, water dispersible tablets, water dispersible powders, water dispersible granules, water soluble tablets, water soluble powders and water soluble granules.
• the formulation pertaining to the present invention comprises 5-60%, preferably 5-50%, more preferably 10-40% of cefetamet as the active agent or a pharmaceutically acceptable derivative thereof in an amount equivalent to that.
• Cefetamet which is comprised in the water dispersible formulation pertaining to the present invention, can be in the form of its pharmaceutically acceptable hydrates, solvates, esters, enantiomers, polymorphs, crystal forms, amorphous forms, salts or in free base form and/or a combination thereof.
• Cefetamet comprised in the water dispersible formulation pertaining to the present invention is in ester form. It is preferably cefetamet pivoxil.
• Cefetamet pivoxil comprised in the water dispersible formulation pertaining to the present invention is preferably in salt form. It is preferably cefetamet pivoxil hydrochloride.
• another aspect of the present invention is the water dispersible formulations comprising cefetamet pivoxil hydrochloride wherein d 50 value of the molecule cefetamet pivoxil hydrochloride is in the range of 10-50 ⁇ .
• the water dispersible formulation pertaining to the present invention can comprise one or more of the excipients including binders, lubricants, disintegrants, diluents, flavoring agents, sweeteners, coloring agents, surfactants, anti-foam agent, stabilizing agents, viscosity agents in addition to the cefetamet.
• excipients including binders, lubricants, disintegrants, diluents, flavoring agents, sweeteners, coloring agents, surfactants, anti-foam agent, stabilizing agents, viscosity agents in addition to the cefetamet.
• the lubricant that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising talc, magnesium stearate, stearic acid, sodium stearil fumarate, polyoxyethylene glycol, leucine, alanine, glycine, sodium benzoate, sodium acetate, fumaric acid or a combination thereof.
• the present invention relates to water dispersible dosage formulations comprising cefetamet wherein the amount of lubricant used is in the range of 1 - 8% by weight.
• the ratio of cefetamet to lubricant is an important parameter on both dissolution and flowability of the formulations. It is observed that the desired flowability and solubility can be provided in the case that the ratio of cefetamet to lubricant is in the range of 20:1 to 1 :1, preferably 15:1 to 2:1, more preferably 10:1 to 5: 1 by weight.
• the present invention relates to water dispersible dosage formulations comprising cefetamet wherein the ratio of cefetamet to lubricant is in the range of 20:1 to 1 : 1 by weight.
• the effervescent acid that is optionally used in the water dispersible formulations pertaining to the present invention can be selected from, but not limited to, a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or a combination thereof.
• the effervescent base that is optionally used in the water dispersible formulations pertaining to the present invention can be selected from, but not limited to, a group comprising potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen citrate or a combination thereof.
• the binder that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone), polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol, and water or a combination thereof.
• starches such as potato starch, corn starch, wheat starch
• sugars such as sucrose, glucose, dextrose, lactose, maltodextrin
• natural and synthetic gums such as cellulose derivatives such as microcrystalline cellulose, HPC, H
• the disintegrant that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate; cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose; polyvinylpyrrolidone; crospovidone; alginic acid and its salts; clays such as xanthan gum or Veegum; ion exchange resins or a combination thereof.
• starches such as potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate
• cellulose derivatives such as croscarmellose sodium or microcrystalline cellulose
• polyvinylpyrrolidone such as crospovidone
• alginic acid and its salts such as xanthan gum or Veegum
• ion exchange resins or a combination thereof such as xanthan gum or Veegum
• the diluent that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group lactose, maltose, dextrin, maltodextrin, mannitol, sorbitol, starch or a combination thereof.
• the flavoring agent that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising natural aroma oils (peppermint oil, wintergreen oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, lemon, orange, blackberry, propenyl guaetol acetyl, cinnamon, vanilla, thymol, linalool or a combination thereof.
• natural aroma oils peppermint oil, wintergreen oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil
• menthol eucalyptol
• cinnamon 1 -methyl acetate
• sage eugenol
• oxanone lemon, orange
• blackberry propenyl guaetol acetyl
• cinnamon vanilla
• the sweetener that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, laevulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulfame potassium, aspartame, D-tryptophane, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotame, alitame, stevioside and cyclamates or a combination thereof.
• the viscosity agent that is used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising carboxymethyl cellulose, methyl cellulose, xanthan gum, gummi tragacanthae, gum arabic, aerosil 200, collidone, agar-agar, bentonite, hydroxyethyl cellulose or a combination thereof.
• the formulation in water dispersible form pertaining to the present invention comprises; cefetamet in the range of 5-60% by weight
• disintegrant in the range of 0- 10% by weight
• binder in the range of 0-20% by weight.
• the pharmaceutical composition of the present invention can be prepared through a process which is comprised of dry blending or dry granulation or wet granulation of the components or a combination thereof and generally known standard techniques and manufacture procedures in technology.
• the present invention relates to the use of water dispersible dosage forms comprising cefetamet or its any pharmaceutically acceptable derivative in the treatment of the infections caused by gram negative and gram positive bacteria.
• the present invention relates to the use of the pharmaceutical compositions in water dispersible dosage forms comprising cefetamet or any pharmaceutically acceptable derivative thereof in the manufacture 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
• Example 1 Formulation and process for the preparation of effervescent powder, granules or tablets
• the process in scope of the present invention comprises granulating a mixture comprising effervescent couple and sweetener with the granulation solution comprising binder and a solvent through conventional wet and/or dry granulation methods, then sieving the mixture; adding cefetamet pivoxil hydrochloride, lubricant and other excipients into the obtained granules, and optionally compressing the obtained mixture in tablet compressing machine.
• Example 2 Formulation and process for the preparation of water dispersible powder, granules or tablets
• the process in scope of the present invention comprises granulating a mixture comprising cefetamet and binder and the other excipients with the granulation solution comprising the diluent through conventional wet and/or dry granulation methods, then sieving the mixture; adding sweetener and the lubricant into the obtained granules, and optionally compressing the obtained mixture in tablet compressing machine.

Landscapes

• Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Medicinal Preparation (AREA)
• Cephalosporin Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=44201076

Family Applications (1)

Country Status (2)

Families Citing this family (2)

Family Cites Families (4)

• 2011
  • 2011-05-02 WO PCT/TR2011/000133 patent/WO2011139255A2/en active Application Filing
  • 2011-05-02 EP EP11724475A patent/EP2566450A2/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events