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
  • A61K9/20—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
  • 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

Definitions

• the present invention relates to pharmaceutical tablet formulations comprising cefditoren pivoxil to be used in the treatment of the infectious diseases caused by gram positive and gram negative bacteria.
• Cefditoren pivoxil was first disclosed in the patent application numbered EP0175610. In said document, cefditoren pivoxil was indicated to be effective in the treatment of infectious diseases caused by gram positive and gram negative bacteria.
• Cefditoren pivoxil is available in 200 and 400 mg oral dosage forms on the market.
• Tablet hardness is an important physical parameter in pharmaceutical tablet formulations and is related to resistance of tablets to storage, transport, coating and erosion and breakage before usage. Tablets with low hardness are more exposed to erosion, friability or breakage and this case leads;
• Attaining appropriate tablet hardness is influenced by many parameters such as the types of active agents and excipients used, particle sizes thereof, flowability of the powder or granules prepared for tablet compressing and tablet compression force. When all of these parameters are considered, hardness value of tablets are aimed to be low enough to disintegrate fast in the stomach but high enough to preserve tablet uniformity during packaging, carrying and storing phases from the time of production until used by patient. As a result of the development studies conducted on pharmaceutical tablet formulations comprising cefditoren pivoxil, the inventors have found that the most perfect mechanical tablet resistance, the most appropriate dissolution rate and accordingly the highest bioavailability are attained with the tablet formulations that have a tablet hardness value between 3 kP and 50 kP.
• tablet formulations of the present invention comprise cefditoren pivoxil as active agent and at least one pharmaceutically acceptable excipient, and the value of tablet hardness is between 3 kP and 50 kP.
• tablet formulations of the present invention comprise cefditoren pivoxil as active agent and at least one pharmaceutically acceptable excipient, and the value of tablet hardness is between 4 kP and 40 kP.
• tablette formulations of the present invention comprise cefditoren pivoxil as active agent and at least one pharmaceutically acceptable excipient, and the value of tablet hardness is between 5 kP and 30 kP.
• tablette used throughout the text refers to tablet forms such as tablet, effervescent tablet, film-coated tablet, enteric-coated tablet, orodispersible tablet, water-soluble tablet, extended-release tablet, modified-release tablet, delayed-release tablet.
• the tablet form to be used is film-coated tablet.
• Cefditoren pivoxil comprised in the pharmaceutical formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; and in crystalline, amorphous forms or combinations thereof in terms of polymorphic structure.
• the pharmaceutical formulations of the present invention comprise at least one pharmaceutically acceptable excipient, in addition to the active agent, selected from the group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple composed of at least one effervescent acid and at least one effervescent base, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent.
• the active agent selected from the group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple composed of at least one effervescent acid and at least one effervescent base, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent.
• the diluent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or combinations thereof.
• the lubricant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.
• the glidant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc or combinations thereof.
• the binder that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch or combinations thereof.
• the effervescent acids that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and said effervescent bases can selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or combinations thereof.
• the pH regulating agent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts or combinations thereof.
• the surfactant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol or combinations thereof.
• the sweetener and/or the taste regulating agent that can be used in the pharmaceutical formulations of the invention can- be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride or combinations thereof.
• the flavoring agent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like or combinations thereof.
• the solvents that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising ethyl alcohol, methyl alcohol, propyl alcohol, benzene, toluene, acetone, deionized water or combinations thereof.
• the pharmaceutical formulations of the invention comprising cefditoren pivoxil as active agent comprise cefditoren pivoxil in the range of 0.1-99.9%, preferably in the range of 1-99%, more preferably in the range of 5-95% by weight.
• the pharmaceutical formulations of the invention comprising cefditoren pivoxil as active agent can optionally comprise a second active agent in addition to cefditoren pivoxil.
• the second active agent can be selected from a group comprising antacid, anticolinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarithmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedione
• the pharmaceutical tablet formulations of the invention comprising cefditoren pivoxil as active agent preferably comprise clavulanic acid, more preferably potassium clavulanate as an optional second active agent in addition to cefditoren pivoxil.
• Said tablet formulations can optionally be treated with film coating agents, for instance sugar- based coating agents, water-soluble film-coating agents, enteric coating agents, coating agents prepared to provide various release properties (such as fast release, slow release, controlled release) or coating compositions comprising any combination thereof.
• saccharose can be used on its own or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof.
• agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof.
• the water-soluble film coating agents can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan; or combinations thereof.
• cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
• synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan; or combinations thereof.
• the enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac; or combinations thereof.
• cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
• acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S
• natural substances such as shellac; or combinations thereof.
• release rate determining polymers that can be comprised in coating composition or pharmaceutical tablet composition can be selected from a group comprising pH dependent polymers, pH independent polymers, swellable polymers, non-swellable polymers, hydrophilic polymers, hydrophobic polymers, and/or one or more hydrophobic substances, sodium alginate, polyactides, polyglycolides, polyactide-co-glycolides, polyactic acids, polyglycolic acids, polyactic acid-co-glycolic acids, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, polyamino acids, polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, polydioxanones, polyalkylene alkylates, polyethylene glycol and polyorthoester copolymers, biodegradable polyurethanes, hydrogels, mixture
• the preparation method of the formulations of the invention comprises formulating the active agent with an appropriate excipient composition and compressing said formulation in the form of tablets under an appropriate compression force.
• a characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefditoren pivoxil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 3 kN and 50 kN.
• a characteristic feature of the tablet formulations of the present invention is that said tablet formulations comprise cefditoren pivoxil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 4 kN and 45 kN.
• Another characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefditoren pivoxil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 5 kN and 40 kN.
• the tablet formulations of the invention can be produced in accordance with any of the production methods given below;
• cefditoren pivoxil as active agent with, if present, the second active agent homogenously and, when necessary, adding at least one of the excipients stated above; treating the mixture optionally with at least one pharmaceutically acceptable lubricant; compressing this mixture in the form of tablets under an appropriate compression force according to the invention, 2.
• the production can be made through a method composed of using any of said methods above separately for active agent compositions and combining the obtained formulations together.
• the pharmaceutical composition of the invention can be used in the prevention and treatment of the infectious diseases caused by gram positive and gram negative bacteria.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
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• 2013
  • 2013-01-16 WO PCT/TR2013/000015 patent/WO2013109203A1/fr not_active Ceased
  • 2013-01-16 WO PCT/TR2013/000016 patent/WO2013109204A1/fr not_active Ceased

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