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
  • A61K9/2009—Inorganic compounds
• • 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
  • 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
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

• the present invention relates to pharmaceutical compositions comprising cefpodoxime proxetil and clavulanic acid and/or derivatives thereof as the active agents.
• Cefpodoxime proxetil (formula 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.
• Clavulanic acid is a beta-lactamase inhibitor illustrated in Formula 2.
• 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.
• EP0593573 comprises a formulation relating to suspension forms of beta-lactam antibiotics and beta lactamase inhibitors.
• suspension forms are not preferred much as they have the potential of high and/or uncontrolled dose intake; there appear problems in their physical and chemical stability; they have high manufacture costs and they cause problems in use and carrying.
• the inventors have aimed to develop stable oral pharmaceutical formulations which comprise cefpodoxime proxetil and clavulanic acid derivatives together and eliminate the low solubility and gelling problems of cefpodoxime.
• the present invention relates to stable pharmaceutical compositions with good solubility characteristics in which cefpodoxime proxetil and clavulanic acid derivatives are formulated together.
• Said pharmaceutical composition is characterized by comprising 20% diluent at maximum in addition to cefpodoxim proxetil and clavulanic acid derivatives. It has surprisingly been seen that solid dosage forms which comprise the active agent cefpodoxime proxetil having rather low water solubility and are formulated by the formulation of the present invention have better solubility.
• the pharmaceutical composition comprising cefpodoxime proxetil and clavulanic acid derivatives in combination comprises a diluent in the range of 20% or less, preferably in the range of 2-15%, more preferably in the range of 4-8%.
• Cefpodoxime proxetil that can be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free base form and/or a combination thereof.
• Clavulanic acid that can be used in the pharmaceutical composition of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free base form and/or a combination thereof.
• Potassium clavulanate is preferably used in the present invention.
• the formulation of the present invention can comprise various excipients such as, but not limited to, glidants, lubricants, disintegrants, diluents, surfactants and optionally coating agents.
• the diluent that can be used in the pharmaceutical composition of the present invention can be selected from, but not limited to, a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or combinations thereof.
• starch is used as the diluent in the pharmaceutical composition of the present invention.
• the inventors have found that the ratio of cefpodoxime proxetil to the diluent is a factor affecting the dissolution of formulations comprising cefpodoxime proxetil and clavulanic acid or its derivatives. According to this, dissolution tests indicated that dissolution of cefpodoxime proxetil is at the desired level in the case that the ratio of cefpodoxime proxetil to the diluent is in the range of 10:1 to 1 :1, preferably in the range of 8:1 to 2:1, more preferably in the range of 6: 1 to 4: 1.
• compositions comprising cefpodoxime proxetil and clavulanic acid in which the ratio of cefpodoxime proxetil to the diluent is in the range of 10:1 to 1 :1, preferably in the range of 8:1 to 2:1, more preferably in the range of 6: 1 to 4: 1.
• the glidant that can be used in the pharmaceutical composition of the present invention can be selected from, but not limited to, a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof.
• silicon dioxide or talc or a combination thereof is used as the glidant in the pharmaceutical composition of the present invention.
• the inventors have found that use of a combination composed of talc and silicon dioxide yields more successful results in preventing antistatic adhesion. As a result of the studies they conducted, they have found that successful results are obtained in the case that the ratio of talc to silicon dioxide is in the range of 5:1 to 1:5, preferably in the range of 3:1 to 1 :3, more preferably 1:1.
• compositions composed of talc and silicon dioxide as the glidant.
• the present invention is pharmaceutical compositions comprising cefpodoxime proxetil and clavulanic acid or its derivatives which comprise a glidant composition wherein the ratio of talc to silicon dioxide is in the range of 5:1 to 1 :5, preferably in the range of 3 : 1 to 1 :3, more preferably 1 :1.
• compositions comprising cefpodoxime proxetil and clavulanic acid or its derivatives which include 0,6% talc and/or silicon dioxide at minimum in proportion to unit dose weight.
• the lubricant that can be used in the pharmaceutical composition of the present invention can be selected from, but not limited to, a group comprising calcium stearate, magnesium stearate, polyoxyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, talc, sodium benzoate or combinations thereof.
• magnesium stearate is used as the lubricant in the pharmaceutical composition of the present invention.
• the disintegrant that can be used in the pharmaceutical composition of the present invention can be selected from, but not limited to, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellululose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropylcellulose, methyl cellulose, povidone, magnesium aluminum silicate, starch or combinations thereof.
• croscarmellose sodium or microcrystalline cellulose or a combination thereof is used as the disintegrant in the formulation of the present invention.
• the surfactant that can be used in the pharmaceutical composition of the present invention can be selected from, but not limited to, a group comprising docusate sodium, sorbitan esters, cetrimide and sodium lauryl sulfate.
• sodium lauryl sulfate is preferably used as the surfactant.
• the pharmaceutical composition of the present invention can comprise 20-800 mg cefpodoxime proxetil or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an equal amount.
• the pharmaceutical composition of the present invention can comprise 50-500 mg clavulanic acid or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an equal amount.
• Clavulanic acid and its derivatives are extremely susceptible to moisture.
• potassium clavulanate in the pharmaceutical composition 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 used with microcrystalline cellulose preferably in the ratio of 1 : 1.
• the pharmaceutical composition of the present invention can comprise 5-60% cefpodoxime proxetil in proportion to total weight of unit dose or pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms thereof.
• the pharmaceutical composition of the present invention can comprise 5-50% clavulanic acid in proportion to total weight of unit dose or pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an equal amount.
• the pharmaceutical composition of the present invention can comprise 5-60% cefpodoxime proxetil; 5-50% potassium clavulanate; 0,5-5% glidant; 0,1-5% lubricant; 0-25% disintegrant and/or disintegrants; 0,5-20% diluent; 0,1-5% surfactant and optionally coating agent of 1-5% of the core weight.
• the pharmaceutical composition comprising cefpodoxim proxetil and clavulanic acid prepared according to the present invention can be in conventional tablet, film coated tablet, sachet or capsule form.
• the present invention relates to processes for preparation of pharmaceutical compositions comprising pharmaceutically acceptable excipients in addition to cefpodoxime proxetil and clavulanic acid or its derivatives as the active agents.
• the process of the present invention comprises the steps of granulating the active agents cefpodoxime proxetil and clavulanic acid or its derivatives by conventional wet and/or dry granulation methods; or powdering cefpodoxime proxetil, clavulanic acid derivatives and other excipients after mixing them by dry blending method and compressing the pharmaceutical composition of the present invention in tablet form and optionally coating the tablets with a coating agent in the case that the product is developed in tablet 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.
• the pharmaceutical composition prepared according to the present invention is used in the production 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 in the production of a medicament so as to be used in upper respiratory infections such as
• composition pertaining to the present invention can be prepared as described below, but not limited to the examples given.
• EXAMPLE 1 Formulation and process for preparation of film tablet comprising cefpodoxime proxetil and sodium clavulanate
• a process for preparation of pharmaceutical compositions of the present invention is composed of the steps of mixing and compressing cefpodoxime proxetil, the disintegrant and the diluent and then sieving them; adding the surfactant, potassium clavulanate, microcrystalline cellulose, disintegrant, glidant and lubricant into the granules obtained and mixing them; and then compressing tablets of the mixture obtained and coating the tablets with coating material.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Inorganic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 2011
  • 2011-06-02 EP EP11738841.3A patent/EP2575811B1/de active Active
  • 2011-06-02 WO PCT/TR2011/000147 patent/WO2011152807A1/en active Application Filing
  • 2011-06-02 EP EP11790098.5A patent/EP2575812A2/de not_active Withdrawn
  • 2011-06-02 WO PCT/TR2011/000144 patent/WO2011152805A2/en active Application Filing

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