COMPLETE SPECIFICATION
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 cefuroxime and quinolone antibiotic ofloxacin.
The present invention relates to formed particles comprising cefuroxime and ofloxacin, the particles being obtained by wet granulation.
The tablets containing cefuroxime 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.
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.
It is an object of the invention to provide particles comprising Cefuroxime and ofloxacin, which are suitable for the preparation of stable pharmaceutical compositions of Cefuroxime and ofloxacin.
DESCRIPTION OF THE INVENTION
The combination has dual mode of action which helps to kill bacteria like double edged sword, cefuroxime works by inhibiting bacterial cell wall synthesis causing cell death and Ofloxacin kills bacteria by inhibiting nucleic acid synthesis. Both cefuroxime and Ofloxacin are bactericidal in nature and both are killing the bacteria by two different mechanisms. Therefore the combination therapy of Cefuroxime and Ofloxacin will lead to minimal bacterial resistance.
1. The combination would be given twice daily because cefuroxime and ofloxacin are given twice.
2. Ofloxacin has coverage with Staphylococcus aureus, 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 Cefuroxime is resistant to above mentioned bacteria.
3. The combination could 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 aerunginosa.
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 Cefuroxime 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.
Cefuroxime is a semi-synthetic analog of cephalosphorin. It is a second-generation antibiotic. Cefuroxime is for parenteral use while cefuroxime axetil is of oral administration. Cefuroxime axetil is hydrolyzed to free cefuroxime, whose in vitro antimicrobial activity is similar to that of cefuroxime. Cefuroxime axetil has a broader spectrum of activity than cephalexin (first-generation). Cefuroxime is active against beta lactamase producing strains of H.influenzae and N.gonorrhoeae, which are normally resistant to ampicillin and penicillin, respectively.
The particles of the invention are obtained by wet granulation method. For granulation pharmaceutically acceptable organic solvents or mixtures thereof, or binder dispersion in an organic solvent are used. Preferred solvents include acetone, ethanol and acetonitrile, in particular acetone. The particles may be spherical or irregular in shape.
Cefuroxime may be in the form of its pharmaceutically accepted salts. The range of Cefuroxime varies from 100 mg to 750 mg, preferably 200 mg to 500mg, while the range of ofloxacin varies from 50 mg to 400 mg preferably 100mg to 400mg.
The compositions of the present invention may preferably contain from 250 to 500 mg of Cefuroxime and the 200mg to 400mg of ofloxacin. They may be prepared, for example as 250/200, 500/200, 250/400, 500/400 unit dosage forms.
The release of Cefuroxime and ofloxacin from the pharmaceutical formulations of the present invention can be immediate or modified, controlled, delayed, sustained, 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 Cefuroxime and ofloxacin.
The present invention also relates to the process for the preparation of the formed particles regular and irregular in shape. They are prepared by the wet granulation with organic solvent. For granulation either a solvent or binder dispersion in an organic solvent may be used.
The present invention can be formulated, but not limited to, in the following manner.
• Following ingredients are weight accurately for tablet (500 Tablets)-
(Table Removed)
For coating material-
(Table Removed)
PART-A
1) The following materials are taken, dried and sifted-
(Table Removed)
2) The sifted materials of step 2 are transferred in p.p bags and the
mixture was manually mixed for 10 minutes.
3) BINDER PREPARATION:
A) Take 60 ml purified water and heat it to boil.
B) Add Sodium benzoate 1 gm to the boiled water.
C) Make the slurry of 8 gm starch by dispersing it into 40 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.
4The binding agent is mixed with the sifted material.
1. The wet mass so obtained is passed through sieve # 8 manually.
2. Dry the wet milled material in FBD/Tray drier at a temperature 55°C. Air dry for 90 minutes to get moisture content NMT 1%.
3. Sift the dried granules through sieve # 20.

PART B- SLUGGING
(Table Removed)
Sift the granules through sieve no. 18
LUBRICATION FOR BOTH PART A AND PART B
Take the granules obtained from Part A and Part B, add to it the sieved
materials of the following table and mixed manually in PP bags for 10
minutes.
(Table Removed)
Compress the lubricated granules using required dies and punches. Process for film coating
(Table Removed)
1) Dissolve HPMC (E-15) 18 gm in to 100 ml isopropyl alcohol and 100 ml methylene chloride.
2) Disperse 3.6 gm and talcum 3 gm into 100 ml isopropyl alcohol.
3) Dissolve polyethylene glycol-6000 3 gm in 150 ml methylene chloride.
4) Mix the products of step 1, 2, and 3 and stir the mixture for 30 minutes.
5) Filter with nylon cloth #200.
6) The solution obtained in step 5 is used to coat the tablets.

CLAIMS
1) A pharmaceutical formulation comprising Cefuroxime and Ofloxacin
wherein Cefuroxime varies from 100 mg to 750 mg, preferably 200
mg to 500mg, while the range of ofloxacin varies from 50 mg to 400
mg preferably 100mg to 400mg, along with pharmaceutically
acceptable excipients; useful for the treatment of a variety of
bacterial infections.
2) The pharmaceutically acceptable excipients as claimed in claim 1 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.