EP2833872A1 - Tablet formulations comprising cefpodoxime proxetil and clavulanic acid - Google Patents

Tablet formulations comprising cefpodoxime proxetil and clavulanic acid

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Publication number
EP2833872A1
EP2833872A1 EP13721136.3A EP13721136A EP2833872A1 EP 2833872 A1 EP2833872 A1 EP 2833872A1 EP 13721136 A EP13721136 A EP 13721136A EP 2833872 A1 EP2833872 A1 EP 2833872A1
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EP
European Patent Office
Prior art keywords
disintegrant
formulation according
pharmaceutical formulation
range
weight
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP13721136.3A
Other languages
German (de)
French (fr)
Inventor
Mahmut Bilgic
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Individual
Original Assignee
Individual
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Filing date
Publication date
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Publication of EP2833872A1 publication Critical patent/EP2833872A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/41—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to pharmaceutical formulations comprising cefpodoxime proxetil and clavulanic acid for use in the treatment of upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media; lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.
  • upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media
  • lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.
  • Said formulations are characterized in that they are in tablet form.
  • Cefpodoxime proxetil was first disclosed in the application numbered EP00491 18. It has been disclosed in said document that use of cefpodoxime proxetil is effective in treatment of infection related diseases caused by gram positive and gram negative bacteria.
  • Cefpodoxime proxetil is found in the form of granules for oral suspension comprising 40 mg / 5 ml, 50 mg / 5 ml and 100 mg / 5 ml cefpodoxime; powder for oral suspension comprising 40 mg / 5 ml cefpodoxime and tablet comprising 100 mg, 200 mg cefpodoxime on the market.
  • cefpodoxime proxetil The solubility of cefpodoxime in aqueous media is very low due to its hydrophobic characteristic.
  • formulations comprising cefpodoxime proxetil are compressed in tablet form, it has been observed that the active agent in said tablet form cannot be dissolved completely in the body fluid. Therefore, tablets comprising cefpodoxime proxetil cannot be easily and quickly dissolved in the body. This results in a decrease in the absorbance and the bioavailability of the drug and impedes the efficiency of the treatment.
  • a cephalosporin antibiotic such as cefpodoxime proxetil and a beta- lactamase inhibitor such as clavulanic acid are used together as a combination.
  • said low solubility and slow disintegration problems of formulations comprising cefpodoxime proxetil known in the state of the prior art, become more apparent in the presence of clavulanic acid as second active agent.
  • Clavulanic acid is known as a hygroscopic and moisture absorbent molecule.
  • tablet formulations comprising cefpodoxime proxetil and clavulanic acid combination dissolve easily in the body, disintegrate in a period of time less than 5 minutes and are quite stable in the case that formulations comprise a combination of disintegrant composed of at least two different disintegrants wherein ⁇ the amount of the first disintegrant is more than 5% and
  • the amount of the second disintegrant is less than 10% in proportion to total formulation amount.
  • the present invention relates to pharmaceutical tablet formulations comprising cefpodoxime proxetil and clavulanic acid combination characterized in that said formulation comprises a combination of disintegrant composed of at least two different disintegrants wherein
  • tablet formulations comprising cefpodoksime proxetil and clavulanic acid are characterized in that the amount of the first disintegrant is in the range of 5-20%, preferably in the range of 6-15% in proportion to total formulation weight.
  • tablet formulations comprising cefpodoxime proxetil and clavulanic acid are characterized in that the amount of the second disintegrant is in the range of 1 -10%, preferably in the range of 3-8% in proportion to total formulation weight.
  • the stability problems observed in cefpodoxime proxetil and clavulanic acid formulations decrease solubility of the drug in the body hence totality of the drug is not absorbed. This case leads to low bioavailability of the drug and low efficiency of the treatment.
  • the ratio of the first disintegrant to second disintegrant used in said formulations should be optimized. Accordingly, during the studies conducted for solving this problem, the inventors have found that if the ratio of the first disintegrant to the second disintegrant in the formulations prepared in accordance with the present invention is in the range of 5: 1 to 1 :5, preferably in the range of 4: 1 to 1 :3 by weight, more stabile and more soluble dosage forms in the body are obtained.
  • the ratio of the first disintegrant to the second disintegrant is in the range of 5: 1 to 1 :5, preferably in the range of 4: 1 to 1 :3 by weight.
  • the first disintegrant can be selected from a group comprising croscarmellose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, methylcellulose and/or combinations thereof.
  • the first disintegrant is croscarmellose calcium.
  • the second disintegrant is selected form group comprising carboxymethyl cellulose sodium, microcrystalline cellulose, hydroxypropyl cellulose, methylcellulose, starch and/or combinations thereof.
  • the second disintegrant is starch.
  • the ratio of croscarmellose calcium to starch can be in the range of 5: 1 to 1 :5, preferably in the range of 4: 1 to 1 :3 by weight.
  • cefpodoxime proxetil formulations Another problem observed in cefpodoxime proxetil formulations is the formation of aggregates during the preparation of the tablet form. If these aggregates are not eliminated, they prevent the formation of a homogenous mixture and destroy the uniform distribution of the active agent in the formulation. Studies conducted for solving said problem showed that not only the ratio of the disintegrants to each other but also the amount of cefpodoxime proxetil in proportion to the amount of disintegrant combination plays an important role in preparation of said formulations.
  • the inventors have found out that if the ratio of cefpodoxime proxetil to the disintegrant combination is in the range of 6: 1 to 1 :6, preferably 3:1 to 1 :3 by weight, no agglomeration is observed and the uniform distribution of the active agent is can be provided.
  • the ratio of cefpodoxime proxetil to the disintegrant combination is in the range of 6: 1 to 1 :6, preferably 3:1 to 1 :3 by weight.
  • Clavulanic acid comprised in the pharmaceutical formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, racemates, organic salts, inorganic salts and free base form or combinations thereof in respect to its chemical structure; in crystalline, amorphous form or combinations thereof in respect to its polymorphic structure.
  • clavulanic acid used as second active agent is in the potassium salt form.
  • the pharmaceutical formulation of the present invention comprising cefpodoxime proxetil and clavulanic acid can comprise at least one excipient selected form a group comprising antiadherant, glidant, diluent, surfactant, lubricant, humectant and film-coating agent in addition to the disintegrant combination.
  • the antiadherant that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising talc, starch, colloidal starch, leucine, sodium sulfite, stearates and/or combinations thereof.
  • the glidant that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate and/or combinations thereof.
  • the diluent that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising D- mannitol, xylitol, microcrystalline cellulose, crospovidon, dibasic calcium phosphate anhydrous, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and/or combinations thereof.
  • the surfactant that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising cetrimide, docusate sodium, glycerol monooleate, sorbital esters and sodium lauryl sulfate and/or combinations thereof.
  • the lubricant that can be used in the pharmaceutical formulations of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl sulphate fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate and/or combinations thereof.
  • the humectant that can be used in the pharmaceutical formulations of the present invention can be selected from a group comprising silica, colloidal silica, magnesium trisilicate, powder cellulose, magnesium oxide, calcium silicate, starch, microcrystalline cellulose and talc and/or combinations thereof.
  • the ratio of potassium clavulanate to humectant is 1 : 1.
  • the film coating agent that can be used in the pharmaceutical formulations of the present invention can be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin, hydroxypropyl cellulose and/or combinations thereof.
  • a film coating agent marketed under the trademark of Opadry Yellow can be used.
  • the pharmaceutical formulation of the present invention can be prepared in any tablet form such as conventional tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, prolonged release tablet, modified release tablet, delayed release tablet.
  • the pharmaceutical formulation of the present invention is preferably in the form of film coated tablet.
  • the pharmaceutical formulation of the present invention can comprise cefpodoxime proxetil in the range of 5-70%, preferably 10- 60%, more preferably 20-50%.
  • the pharmaceutical formulation of the present invention can comprise the mixture of potassium clavulanate-humectant in the range of 10-70% by weight.
  • the pharmaceutical formulation of the present invention comprises 5-70% cefpodoxime proxetil, 10-70% potassium clavulanate-humectant mixture, 1-30% disintegrant, 0.5-2.5% surfactant, 5-25% diluent, 0.1 -2% antiadherant, 0.1-2% glidant, 0.1-2% lubricant, 0.5-3.5% film coating agent.
  • the preparation method of the pharmaceutical formulation of the present invention preferably involves the following steps:
  • Step IV Coating the tablet form obtained in Step IV with a coating colution comprising a film- coating agent.
  • the pharmaceutical formulation of the present invention can be used in the manufacturing of a drug for use in the treatment of upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media; lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.
  • upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media
  • lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.
  • Example I Tablet formulation comprising cefpodoxime proxetil and clavulanic acid

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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)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to pharmaceutical formulations comprising cefpodoxime proxetil and clavulanic acid for use in the treatment of upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media; lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections. Said formulations are characterized in that they are in tablet form.

Description

TABLET FORMULATIONS COMPRISING CEFPODOXIME PROXETIL AND
CLAVULANIC ACID
The present invention relates to pharmaceutical formulations comprising cefpodoxime proxetil and clavulanic acid for use in the treatment of upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media; lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections. Said formulations are characterized in that they are in tablet form.
Cefpodoxime proxetil was first disclosed in the application numbered EP00491 18. It has been disclosed in said document that use of cefpodoxime proxetil is effective in treatment of infection related diseases caused by gram positive and gram negative bacteria.
Cefpodoxime proxetil is found in the form of granules for oral suspension comprising 40 mg / 5 ml, 50 mg / 5 ml and 100 mg / 5 ml cefpodoxime; powder for oral suspension comprising 40 mg / 5 ml cefpodoxime and tablet comprising 100 mg, 200 mg cefpodoxime on the market.
The solubility of cefpodoxime in aqueous media is very low due to its hydrophobic characteristic. Thus, when formulations comprising cefpodoxime proxetil are compressed in tablet form, it has been observed that the active agent in said tablet form cannot be dissolved completely in the body fluid. Therefore, tablets comprising cefpodoxime proxetil cannot be easily and quickly dissolved in the body. This results in a decrease in the absorbance and the bioavailability of the drug and impedes the efficiency of the treatment.
On the other hand, in order to prevent the bacterial resistance and present a more effective antibiotic treatment, a cephalosporin antibiotic such as cefpodoxime proxetil and a beta- lactamase inhibitor such as clavulanic acid are used together as a combination. However, said low solubility and slow disintegration problems of formulations comprising cefpodoxime proxetil, known in the state of the prior art, become more apparent in the presence of clavulanic acid as second active agent. Clavulanic acid is known as a hygroscopic and moisture absorbent molecule. Hence, stability problems seen during the storage and usage of formulations comprising cefpodoxime proxetil and clavulanic acid and incomplete dissolution of the active agent due to these problems results in a decrease of the bioavailability and inefficient treatment.
Accordingly, it is required to prepare formulations comprising cefpodoxime and clavulanic acid which dissolve quickly, have high solubility in the body and provide an efficient treatment.
Surprisingly, the inventors have seen that tablet formulations comprising cefpodoxime proxetil and clavulanic acid combination dissolve easily in the body, disintegrate in a period of time less than 5 minutes and are quite stable in the case that formulations comprise a combination of disintegrant composed of at least two different disintegrants wherein · the amount of the first disintegrant is more than 5% and
• the amount of the second disintegrant is less than 10% in proportion to total formulation amount.
In this regard, the present invention relates to pharmaceutical tablet formulations comprising cefpodoxime proxetil and clavulanic acid combination characterized in that said formulation comprises a combination of disintegrant composed of at least two different disintegrants wherein
• the amount of the first disintegrant is more than 5% and
• the amount of the second disintegrant is less thanl 0% in proportion to total formulation amount. According to another embodiment of the invention, tablet formulations comprising cefpodoksime proxetil and clavulanic acid are characterized in that the amount of the first disintegrant is in the range of 5-20%, preferably in the range of 6-15% in proportion to total formulation weight. In another embodiment of the present invention, tablet formulations comprising cefpodoxime proxetil and clavulanic acid are characterized in that the amount of the second disintegrant is in the range of 1 -10%, preferably in the range of 3-8% in proportion to total formulation weight. The stability problems observed in cefpodoxime proxetil and clavulanic acid formulations decrease solubility of the drug in the body hence totality of the drug is not absorbed. This case leads to low bioavailability of the drug and low efficiency of the treatment. In order to prevent this problem, the ratio of the first disintegrant to second disintegrant used in said formulations should be optimized. Accordingly, during the studies conducted for solving this problem, the inventors have found that if the ratio of the first disintegrant to the second disintegrant in the formulations prepared in accordance with the present invention is in the range of 5: 1 to 1 :5, preferably in the range of 4: 1 to 1 :3 by weight, more stabile and more soluble dosage forms in the body are obtained.
In this regard, another characteristic feature of the present invention is that the ratio of the first disintegrant to the second disintegrant is in the range of 5: 1 to 1 :5, preferably in the range of 4: 1 to 1 :3 by weight.
According to another embodiment of the present invention, the first disintegrant can be selected from a group comprising croscarmellose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, methylcellulose and/or combinations thereof.
In a preferred embodiment of the present invention, the first disintegrant is croscarmellose calcium.
In another preferred embodiment of the invention, the second disintegrant is selected form group comprising carboxymethyl cellulose sodium, microcrystalline cellulose, hydroxypropyl cellulose, methylcellulose, starch and/or combinations thereof.
In a more preferred embodiment of the invention, the second disintegrant is starch.
In another aspect, the ratio of croscarmellose calcium to starch can be in the range of 5: 1 to 1 :5, preferably in the range of 4: 1 to 1 :3 by weight.
Another problem observed in cefpodoxime proxetil formulations is the formation of aggregates during the preparation of the tablet form. If these aggregates are not eliminated, they prevent the formation of a homogenous mixture and destroy the uniform distribution of the active agent in the formulation. Studies conducted for solving said problem showed that not only the ratio of the disintegrants to each other but also the amount of cefpodoxime proxetil in proportion to the amount of disintegrant combination plays an important role in preparation of said formulations. Accordingly, the inventors have found out that if the ratio of cefpodoxime proxetil to the disintegrant combination is in the range of 6: 1 to 1 :6, preferably 3:1 to 1 :3 by weight, no agglomeration is observed and the uniform distribution of the active agent is can be provided.
In this aspect, another feature of the present invention is that the ratio of cefpodoxime proxetil to the disintegrant combination is in the range of 6: 1 to 1 :6, preferably 3:1 to 1 :3 by weight.
Clavulanic acid comprised in the pharmaceutical formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, racemates, organic salts, inorganic salts and free base form or combinations thereof in respect to its chemical structure; in crystalline, amorphous form or combinations thereof in respect to its polymorphic structure.
In a preferred embodiment of the present invention, clavulanic acid used as second active agent is in the potassium salt form.
The pharmaceutical formulation of the present invention comprising cefpodoxime proxetil and clavulanic acid can comprise at least one excipient selected form a group comprising antiadherant, glidant, diluent, surfactant, lubricant, humectant and film-coating agent in addition to the disintegrant combination.
The antiadherant that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising talc, starch, colloidal starch, leucine, sodium sulfite, stearates and/or combinations thereof. The glidant that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate and/or combinations thereof.
A further problem seen in formulations comprising cefpodoxime proxetil and clavulanic acid in addition to low stability and low solubility problems is that a proper flow cannot be provided. RSD% (relative standard deviation) value is above 2% in obtained formulations and this shows that the weight uniformity is lost. The inventors, based on the studies conducted, observed that if the pharmaceutical formulations of the present invention comprise 0.1-5%, preferably 0.2-3% glidant and 0.2-6%, preferably 0.3-4% antiadherant by weight, the optimum flow rate is ensured and the desired weight uniformity is obtained.
The diluent that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising D- mannitol, xylitol, microcrystalline cellulose, crospovidon, dibasic calcium phosphate anhydrous, lactose, starch, maltose, dextrin, maltodextrin, magnesium carbonate, talc and/or combinations thereof.
The surfactant that can be used in the pharmaceutical formulations of the present invention comprising cefpodoxime and clavulanic acid can be selected from a group comprising cetrimide, docusate sodium, glycerol monooleate, sorbital esters and sodium lauryl sulfate and/or combinations thereof. The lubricant that can be used in the pharmaceutical formulations of the present invention can be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl sulphate fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate and/or combinations thereof.
The humectant that can be used in the pharmaceutical formulations of the present invention can be selected from a group comprising silica, colloidal silica, magnesium trisilicate, powder cellulose, magnesium oxide, calcium silicate, starch, microcrystalline cellulose and talc and/or combinations thereof.
In another preferred embodiment of the pharmaceutical formulation of the present invention is that the ratio of potassium clavulanate to humectant is 1 : 1. The film coating agent that can be used in the pharmaceutical formulations of the present invention can be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin, hydroxypropyl cellulose and/or combinations thereof. For example, a film coating agent marketed under the trademark of Opadry Yellow can be used.
The pharmaceutical formulation of the present invention can be prepared in any tablet form such as conventional tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, prolonged release tablet, modified release tablet, delayed release tablet.
The pharmaceutical formulation of the present invention is preferably in the form of film coated tablet. In another embodiment of the present invention, the pharmaceutical formulation of the present invention can comprise cefpodoxime proxetil in the range of 5-70%, preferably 10- 60%, more preferably 20-50%.
In another preferred embodiment of the invention, the pharmaceutical formulation of the present invention can comprise the mixture of potassium clavulanate-humectant in the range of 10-70% by weight.
The pharmaceutical formulation of the present invention comprises 5-70% cefpodoxime proxetil, 10-70% potassium clavulanate-humectant mixture, 1-30% disintegrant, 0.5-2.5% surfactant, 5-25% diluent, 0.1 -2% antiadherant, 0.1-2% glidant, 0.1-2% lubricant, 0.5-3.5% film coating agent. The preparation method of the pharmaceutical formulation of the present invention preferably involves the following steps:
I. Mixing cefpodoxime proxetil, the disintegrant combination composed of two disintegrants, glidant and surfactant,
II. Compacting the mixture obtained in Step I at least two times,
III. Adding surfactant, diluent, antiadherant, glidant, second disintegrant and mixture of potassium clavulanate-humectant into the compacted mixture obtained in Step II and mixing them to form a blend,
IV. Adding lubricant to the blend obtained in Step III and compressing the final blend into tablet form,
V. Coating the tablet form obtained in Step IV with a coating colution comprising a film- coating agent.
The pharmaceutical formulation of the present invention can be used in the manufacturing of a drug for use in the treatment of upper respiratory infections such as tonsillitis, sinusitis, pharyngitis, otitis media; lower respiratory tract infections such as uncomplicated upper and lower urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.
The pharmaceutical formulations of the present invention can be prepared as described below, but not limited to the examples given. Example I. Tablet formulation comprising cefpodoxime proxetil and clavulanic acid
For the preparation of the formulation given above, dry granulation is used. Based on this method, cefpodoxime proxetil and the disintegrant combination composed of the first disintegrant and second disintegrant are mixed. The mixture is sieved, compacted and then sifted again. Surfactant, diluent, antiadherant, glidant and potassium clavulanate-humectant mixture is added, mixed and sieved again. Finally, lubricant is added and the final mixture is compressed into tablet forms and obtained tablets are coated with a film-coating solution comprising a film-coating agent.

Claims

1. A pharmaceutical formulation comprising cefpodoxime and clavulanic acid combination characterized in that said formulation comprises a combination of disintegrant composed of at least two different disintegrants wherein
• the amount of the first disintegrant is more than 5% and
• the amount of the second disintegrant is less thanl 0% in proportion to total formulation amount.
2. The pharmaceutical formulation according to claim 1 characterized in that the amount of the first disintegrant is in the range of 5-20% in proportion to total formulation weight.
3. The pharmaceutical formulation according to claim 2 characterized in that the amount of the first disintegrant is in the range of 6-15% in proportion to total formulation weight.
4. The pharmaceutical formulation according to claims 1-3 characterized in that the amount of the second disintegrant is in the range of 1-10% in proportion to total formulation weight.
5. The pharmaceutical formulation according to claim 4 characterized in that the amount of the second disintegrant is in the range of 3-8% in proportion to total formulation weight.
6. The pharmaceutical formulation according to claims 1-5 characterized in that the ratio of the first disintegrant to the second disintegrant is in the range of 5:1 to 1 :5 by weight.
7. The pharmaceutical formulation according to claim 6 characterized in that the ratio of the first disintegrant to the second disintegrant is 4:1 to 1 :3 by weight.
8. The pharmaceutical formulations according to claims 1-8 characterized in that the first disintegrant is selected form a group comprising croscarmellose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, methylcellulose and/or combinations thereof.
9. The pharmaceutical formulation according to claim 8 characterized in that the first disintegrant is croscarmellose calcium.
10. The pharmaceutical formulation according to claims 1-9 characterized in that the second disintegrant carboxymethyl cellulose sodium, microcrystalline cellulose, hydroxypropyl cellulose, methyl cellulose, starch and/or combinations thereof.
1 1. The pharmaceutical formulation according to claim 10 characterized in that the second disintegrant is starch.
12. The pharmaceutical formulation according to any preceding claims characterized in that the ratio of croscarmellose calcium to starch is in the range of 5: 1 to 1 :5.
13. The pharmaceutical formulation according to any preceding claims characterized in that the ratio of cefpodoxime proxetil to the disintegrant combination is in the range of 6: 1 to 1 :6.
14. The pharmaceutical formulation according to claim 13 characterized in that the ratio of cefpodoxime proxetil to the disintegrant combination is in the range of 3:1 to 1 :3.
15. The pharmaceutical formulation according to any preceding claims characterized in that the form of clavulanic acid is selected from a group comprising salts, hydrates, solvates, esters, enantiomers, racemates, organic salts, inorganic salts and in free base form or combinations thereof in respect to its chemical structure; in crystalline, amorphous form or combinations thereof in respect to its polymorphic structure.
16. The pharmaceutical formulation according to claim 15 characterized in that the clavulanic acid is in the potassium salt form.
17. The pharmaceutical formulation according to any preceding claims characterized in that said formulation comprises, in addition to the disintegrant combination, at least one excipient selected form a group comprising antiadherant, glidant, diluent, surfactant, lubricant, humectant and film-coating agent.
18. The pharmaceutical formulation according to claim 17 characterized in that the antiadherant is selected from a group comprising talc, starch, colloidal starch, leucine, sodium sulfite, stearates and/or combinations thereof.
19. The pharmaceutical formulation according to claim 17 characterized in that the glidant magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate and/or combinations thereof.
20. The pharmaceutical formulation according to any of the preceding claims characterized in that said formulation comprises glidant in the range of 0.1-5% by weight.
21. The pharmaceutical formulation according to claim 20 characterized in that said formulation comprises glidant in the range of 0.2-3% by weight.
22. The formulation according to any of the preceding claims characterized in that said formulation comprises antiadherant in the range of 0.2-6% by weight.
23. The formulation according to claim 22 characterized in that said formulation comprises antiadherant in the range of 0.3-4% by weight.
24. The formulation according to any of the preceding claims characterized in that said formulation is prepared in any tablet form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, prolonged release tablet, modified release tablet, delayed release tablet.
25. The formulation according to claim 24 characterized in that said formulation is prepared in film coated tablet form.
26. The formulation according to any preceding claims characterized in that said formulation comprises cefpodoxime proxetil in the range of 5-70% by weight.
27. The formulation according to any preceding claims characterized in that said formulation comprises the mixture of potassium clavulanate-humectant in the range of 10-70% by weight.
28. The formulation according to any preceding claims characterized in that said formulation comprises 5-70% cefpodoxime proxetil, 10-70% potassium clavulanate- humectant mixture, 1-30% disintegrant, 0.5-2.5% surfactant, 5-25% diluent, 0.1-2% antiadherant, 0.1-2% glidant, 0.1-2% lubricant, 0.5-3.5% film coating agent.
29. A preparation method for a pharmaceutical formulation according to any of the preceding claims characterized in that said method involves the following steps:
• Mixing cefpodoxime proxetil, the disintegrant combination composed of two disintegrants, glidant and surfactant,
• Compacting the mixture obtained in Step I at least two times,
• Adding surfactant, diluent, antiadherant, glidant, second disintegrant and mixture of potassium clavulanate-humectant into the compacted mixture obtained in Step II and mixing them to form a blend,
• Adding lubricant to the blend obtained in Step III and compressing the final blend into tablet form,
• Coating the tablet form obtained in Step IV with a coating colution comprising a film-coating agent.
EP13721136.3A 2012-04-04 2013-04-03 Tablet formulations comprising cefpodoxime proxetil and clavulanic acid Withdrawn EP2833872A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201203837 2012-04-04
PCT/TR2013/000108 WO2013151517A1 (en) 2012-04-04 2013-04-03 Tablet formulations comprising cefpodoxime proxetil and clavulanic acid

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EP2833872A1 true EP2833872A1 (en) 2015-02-11

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Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4486425A (en) 1980-09-30 1984-12-04 Sankyo Company Limited 7-[2-(2-Aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylates
US5837292A (en) * 1996-07-03 1998-11-17 Yamanouchi Europe B.V. Granulate for the preparation of fast-disintegrating and fast-dissolving compositions containing a high amount of drug
EP2575812A2 (en) * 2010-06-03 2013-04-10 Mahmut Bilgic Pharmaceutical composition comprising cefpodoxime proxetil and clavulanic acid
EP2575777A1 (en) * 2010-06-03 2013-04-10 Mahmut Bilgic Formulation comprising cefpodoxime proxetil and clavulanic acid
TR201009168A2 (en) * 2010-11-05 2012-05-21 Bi̇lgi̇ç Mahmut Water dispersible cefpodoxime proxetil formulations.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2013151517A1 *

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