COMPLETE DESCRIPTION
FIELD OF THE INVENTION
The present invention relates to the pharmaceutical dosage form comprising a cephalosporin and a quinolone, which shows the synergistic effect against the infection caused by a variety of microorganisms.
BACKGROUND OF THE INVENTION
The present invention belongs to the field of pharmaceutical technology and relates to pharmaceutical compositions comprising a combination of the cephalosporin antibiotic cefpodoxime and quinolone antibiotic ofloxacin.
The present invention relates to formed particles comprising cefpodoxime and ofloxacin, the particles being obtained by wet granulation.
The tablets containing cefpodoxime and ofloxacin are usually prepared first by dry granulation (slugging, compacting) of the active substance and a portion of the excipients. The resulting granulate is then mixed with the remainder of the excipients and the mixture is compressed into tablets. The processes for the preparation of these tablets are described, for example, in patent applications WO 92/19227, WO 95/28927 and WO 98/35672.
Patent application WO 01/62231 discloses the pharmaceutical compositions which comprise at least four different types of pellets. Pellets containing both active drugs are not described. Because of different release rates of the active substances from the pellets, the preparation of the formulations having different release profiles is possible.
In a published document, the synergic effects of quinolones and oral cephem antibiotics on Serratia marcescens are discussed. (Journal of Antimicrobial Chemotherapy (1996) 38, 771-776, Masako Otsuki and Takeshi Nishino).
In a published document there is a Comprehensive evaluation of ciprofloxacin in combination with beta-lactam antibiotics against

Enterobacteriaceae and Pseudomonas aeruginosa (Haller.l. Arzneimittelforschung. 1986 Feb;36(2):226-9.)
In J Med Microbiol. 1989 Jul; 29(3):221-7, interactions of the 4-quinolones with other antibacterials, is discussed (Lewin CS, Smith JT.).
The above prior art has one or more of the following drawbacks-
1) The study comprising cefpodoxime and Ofloxacin was not done in-vivo, thus there was no known effect of the drug and its metabolism in the human body. Neither the safety profile nor the drug-drug interaction in the human body is known.
2) Some of the prior art are very narrow in approach and does not either teach or suggest beyond that.
3) The present invention is not available to the general public as a dosage formulation.
4) In some of the prior art, the study is done through parenteral formulations only and no focus was given to the oral formulation.
5) In some of the prior art, no synergy was found in the combination of new quinolones and beta lactam antibiotics.
Thus there is a need of a formulation that will be able to overcome the above drawbacks as well as to study the combination in the broader manner and to conduct the in-vivo of the oral formulation which was not done in the prior art.
OBJECTIVES OF THE INVENTION
The objective of the invention is to provide a combination which is effective against a large number of microorganisms.
Yet another objective of the invention is to minimize the bacterial resistance against the antimicrobial agents.
Yet another object of the invention is to provide a formulation that proves to be a safe alternative for the treatment of bacterial infections.

It is an object of the invention to provide particles comprising cefpodoxime and ofloxacin, which are suitable for the preparation of stable pharmaceutical compositions of cefpodoxime and ofloxacin.
DESCRIPTION OF THE INVENTION
It was surprisingly found that the FDC of Cefpodoxime and Ofloxacin, developed in order to further improve the efficacy of Ofloxacin and to promote compliance in patient who otherwise require the administration of two drugs, yields highly significant results. The FDC of Cefpodoxime and Ofloxacin is also comparable in terms of safety and tolerability profile with cefpodoxime alone in both patients and investigators global impression.
• The FDC of Cefpodoxime and Ofloxacin is significantly superior to cefpodoxime alone in terms of clinical outcomes and microbial eradication.
• 94% physician rated treatment with FDC of Cefpodoxime and Ofloxacin as excellent to good versus 76% with cefpodoxime alone.
• 92% patients rated the treatment as excellent to good in FDC of Cefpodoxime and Ofloxacin group versus 76% in the cefpodoxime alone group.
The combination has dual mode of action which helps to kill bacteria like double edged sword. Cefpodoxime works by inhibiting bacterial cell wall synthesis causing cell death and ofloxacin kills bacteria by inhibiting nucleic acid synthesis. Both Cefpodoxime and ofloxacin are bactericidal in nature and both are killing the bacteria by two different mechanisms. Therefore the combination therapy of Cefpodoxime and Ofloxacin will lead to minimal bacterial resistance.
1. Excretion of Cefpodoxime and ofloxacin in active has great importance to treat urinary tract infections. Cefpodoxime has 50% active excretion through urinary tract whereas ofloxacin has active excretion via urine is 65% to 85%.The combination could be drug of choice in complicated and uncomplicated urinary tract infections only because of active excretion of both the drugs.

2. The combination would be given twice daily because cefpodoxime and ofloxacin are given twice.
3. Ofloxacin has coverage with Staphylococcus saprophyticus, Staphylococcus epidermidis, Penicilline-resistant strains, Enterococcus faecalis, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Morganella morganii, Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomons maltophilia, bordetella pertussis, Acinetobacter calcoaceticus etc. whereas cefpodoxime is resistant to above mentioned bacteria.
4. In pharyngitis /tonsillitis and acute bacterial maxillary sinusitis, cefpodoxime is drug of choice whereas in prostatitis ofloxacin gives an excellent result.
5. The combination coulde be an ideal choice of drug for multidrug resistant typhoid fever, multidrug resistant tuberculosis and sever infection from head to toe.
Beta - Lactam antibiotics are among the safest and the most frequently prescribed agents in India and world wide. However, emergence of beta-lactam resistance coupled with extended spectrum betalactamase (ESBL) in clinically important pathogens have increasingly limited their use.
The emergence of ESBL producing Enterobacteriaceae, particularly Escherichia Choli and Klebsiella pneumonia, presents significant diagnostic and therapeutic challenges to the management of infection due to these organisms. ESBL bacteria that produce ESBL enzymes and that mediate resistance to extended spectrum cephalosporins. The presence of ESBL producing organism in a clinical infection can result in treatment failure if one of the above classes of the drug is used.
The ESBL enzymes are plasmid mediated enzymes capable of hydrolyzing and inactivating of wide variety of beta-lactam including third generation cephalosporin. The first ESBL isolates were discovered in Western Europe in mid 1980s and subsequently in the US in the late 1980s. The resistant organisms are now a worldwide problem. They can be found in a variety of Enterobacteriaceae species, however, the majority of ESBL producing

strains are K.pneomonia, K.oxytoca and E.Coli. Other organisms reported to harbour ESBL include Enterobacter species, Salmonella species, Morganella morganii, Proteous mirabilis, Serratia marcescens and Pseudomonas aeruginosa.
Major risk factors for colonization or infection with ESBL producing organisms are long term antibiotic exposure, prolonged ICU stay, nursing home residency, severe illness, residence in an institution with high rates of third generation cephalosporin use and instrumentation or catheterization.
It has been clinically proven in Roche Research Center, New Jersy to combat with ESBL infection the dual mode of action of combination antibiotics are required, especially Cephalosporin and Quinolone.
Ofloxacin is a flouroquinolone group antibiotic while cefpodoxime is a cephalosporin antibiotic.
Ofloxacin is effective in Chlamydia and mycoplasma., it is used as an alternative drug for nonspecific urethritis, cervictis and atypical pneumonia. It also inhibits M.tuberculae. it is also highly effective against M.leprae. It is particularly suitable for chronic bronchitis.Ofloxacin is also effective in Gonorrhoea and also useful in nongonococcal urethritis. It has got relatively long post antibiotic effect on enterobacteriaceae, Pseudomonas and Staphylos.
Cefpodoxime is highly effective against enterobacteriaceae, H.influenzae, Strep.pyogenes, Streptococcus pneumoniae, and is resistant to various B-lactamases. However, it is not active on Pseudomonas.
In some diseases like Typhoid fever, Uncomplicated UTI, and Gonorrhoea, both are having relatively similar capacity but the combination of ofloxacin and cefpodoxime may be helpful in reducing the doses. Thus by forming the combination of ofloxacin and cefpodoxime, the MIC (Minimum Inhibitory Concentration) of both the drug reduces; leading to the patient's compliance and antibiotic side effects gets reduced.
Cefpodoxime may be in the form of cefpodoxime trihydrate. The range of cefpodoxime varies from 50 mg to 400 mg, preferably 100mg to 200mg,

while the range of ofloxacin varies from 50 mg to 400 mg preferably 100mg to 200mg.
Suitable fillers may be microcrystalline cellulose, powdered cellulose, lactose, starch, pregelatinized starch, or sucrose preferably microcrystalline cellulose and lactose.
Suitable binders are starch, polyvinylpyrrolidone, alginic acid, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, and others preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
Suitable disintegrants are starch, pregelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, alginic acid, sodium alginate, and others preferably sodium starch glycolate, cross-linked sodium carboxymethylcellulose and cross-linked polyvinylpyrrolidone.
Suitable glidants are magnesium stearate, calcium stearate, aluminium stearate, stearic acid, palmitic acid, cetanol, stearol, colloidal silicon dioxide, talc, powdered cellulose, starch and others, preferably, colloidal silicon dioxide.
Suitable lubricants are stearic acid, calcium, magnesium, zinc or aluminium stearate, siliconized talc, glycerol monostearate, and others. Preferred lubricants are calcium or magnesium stearate and stearic acid.
The release of cefpodoxime and ofloxacin from the pharmaceutical formulations of the present invention can be immediate or modified, controlled, delayed, sustained, and extended. The release rate for both active drugs can be the same or different.
The pharmaceutical formulations of the present invention may comprise formed particles with the same composition or formed particles with different composition and different release rate of cefpodoxime and ofloxacin.
The present invention can be worked upon, but not limited to, in the following manner-

Following ingredients are weighed accurately for tablet-

WEIGHMENT SHEET FOR COATING MATERIAL

(Table Removed)
STEPS
1. WEIGHING: Weigh all the ingredients and mark as given in weighment sheet
2. SIFTING:

(Table Removed)
3) DRY MIXING:
The sifted materials of step 2 are transferred in p.p bags and the mixture was manually mixed for 10 minutes.
4) BINDER PREPARATION:
(I) AQUEOUS
A) Dissolve PVPK-30 15 gm in 50 ml/purified water.
B) Take 60 ml purified water and heat it to boil.
C) Make the slurry of 13.5 gm starch by dispersing it into 20 ml purified water.
D) Pour the slurry of step (C) in boiled water of step (B) stir well to get a translucent / fluffy paste, cool this paste at room temperature.
E) To the paste of step (D) add solution of step (A).
5) The binding agent is mixed with the sifted material. 30 ml water can be added to the mixture if required.
6) The wet mass so obtained is passed through sieve # 8 manually.
7) Dry the wet milled material in FBD/Tray drier at a temperature 55°C. Air dry for 60 minutes to get moisture content NMT 1%.
8) Sift the dried granules through sieve # 20.
9) Take dried granules of step 8, to it add sieved material of following table and mixed manually in PP bag for 15 minutes.

(Table Removed)
10)The granules so obtained are compressed using required dies and punches and are coated by using the coating material.

CLAIMS
1) A pharmaceutical formulation comprising 50 mg to 400 mg of Cefpodoxime, preferably 100 to 200 mg, and ofloxacin 50 mg to 400 mg, preferably 100 to 200 mg, along with pharmaceutically acceptable excipients; useful for the treatment of a variety of bacterial infections.
2) The pharmaceutically acceptable excipients are selected from diluents, binding agents, disintegrants, and lubricants.
3) The diluents as claimed in claim 2 can be selected from lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate.
4) The binding agents as claimed in claim 2 can be selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), xylitol, sorbitol and maltitol which are mixed with the appropriate solvent.
5) The solvent as claimed in claim 4 can be selected from purified water or isopropyl alcohol or the mixture of both.
6) The disintegrants as claimed in claim 2 can be selected from polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium) and sodium starch glycolate.
7) The lubricants as claimed in claim 2 can be selected from talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid.
8) The formulation as claimed in claim 1 can be coated with Hydroxypropyl Methyl Cellulose, along with suitable plasticizer, opacifier, coloring agent and the solvent.