COMPLETE SPECIFICATION
FIELD OF THE INVENTION
The present invention relates to the pharmaceutical dosage form comprising a cephalosporin and a fluoroquinolones, 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 cefixime and fluoroquinolones antibiotic levofloxacin.
The present invention relates to formed particles comprising cefixime and levofloxacin, the particles being obtained by wet granulation.
The tablets containing cefixime and levofloxacin 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 cefixime and levofloxacin, which are suitable for the preparation of stable pharmaceutical compositions of cefixime and levofloxacin.
DESCRIPTION OF THE INVENTION
Use of cefixime in combination with levofloxacin for treatment of infectious diseases caused by Gram-positive and Gram-negative pathogens. The present invention relates to the use of the fluoroquinolones levofloxacin in combination with the 3rd generation cephalosporin cefixime to treat infectious diseases caused or accompanied by a Gram-positive and/or Gram-negative pathogen like Streptococcus pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. Since the introduction of the fluoroquinolones in the 1980s, the use of this class of drugs has rapidly increased to become one of the more common choices of antimicrobials for various types of bacterial infection [I]. This widespread use has had its consequences, as selective pressure has increased resistance for some species over the years. The combination has dual mode of action which helps to kill bacteria like double edged sword. Cefixime works by inhibiting bacterial cell wall synthesis causing cell death and levofloxacin kills bacteria by inhibiting nucleic acid synthesis. Both Cefixime and levofloxacin are bactericidal in nature and both are killing the bacteria by two

different mechanisms. Therefore the combination therapy of Cefixime and Levofloxacin will lead to minimal bacterial resistance.
1. Excretion of Cefixime and Levofloxacin in active has great importance to treat urinary tract infections. Cefixime has 50% active excretion through urinary tract whereas Levofloxacin has active excretion via urine is 57% to 86%. 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 once daily because cefixime 400 mg and levofloxacin 400 mg are given once.
3. Levofloxacin has coverage with Aerobic Gram-Positive Microorganisms Enterococcus faecalis (many strains are only moderately susceptible) Staphylococcus aureus (methicillin-susceptible strains) Staphylococcus epidermidis (methicillin-susceptible strains) Staphylococcus saprophyticus Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]*) Streptococcus pyogenes and Aerobic and facultative gram-negative microorganisms Haemophilus influenza, Moraxella catarrhalis, Bordetella pertussis, Legionella pneumophila , Neisseria meningitides, Helicobacter pylori, Listeria monocytogenes, Gardnerella vaginalis, Bacteroides fragilis, Vibrio cholera, Clostridium spp. Pasteurella multocida and Anaerobic microorganisms Clostridium perfringes "Other" microorganisms includes Treponema pallidum, Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma pneumonia etc. whereas cefixime is resistant to above mentioned bacteria.

4. In pediatric shigellosis cefixime is drug of choice whereas in Inhalational Anthrax (Post-Exposure) levofloxacin gives an excellent result.
5. 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 marcescehs 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 Fluoroquinolones.
Levofloxacin is a Fluoroquinolones group antibiotic while cefixime is a cephalosporin antibiotic.
Levofloxacin is effective in Chlamydia and mycolplasma. 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.Levofloxacin is also effective in Gonorrhoea and also useful in nongonococcal urethritis. It has got relatively long post antibiotic effect on enterobacteriaceae, Pseudomonas and Staphylos.
Cefixime is highly effective against enterobacteriaceae, H.influenzae, Strep, pyogenes, Streptococcus pneumoniae, and is resistant to various B-lactamases. However, it is not active on Staphhylococcus aureus and Pseudomonas.
In some diseases like Typhoid fever, Uncomplicated UTI, and Gonorrhoea, both are having relatively similar capacity but the combination of levofloxacin and cefixime may be helpful in reducing the doses. Thus by forming the combination of levofloxacin and cefixime, the MIC (Minimum Inhibitory

Concentration) of both the drug reduces; leading to the patient''s compliance and antibiotic side effects gets reduced.
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.
Cefixime may be in the form of cefixime trihydrate. The range of cefixime varies from 50 mg to 400 mg, preferably 100 mg to 400 mg, while the range of levofloxacin varies from 100 mg to 600 mg preferably 250 mg to 550 mg.
The release of cefixime and Levofloxacin 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 cefixime and Levofloxacin.
The present invention can be formulated, but not limited to, in the following manner.
1) Following ingredients are weight accurately for tablet-
(Table Removed)

For coating material-
(Table Removed)
2) The following materials are taken, dried and sifted-
(Table Removed)
3) The sifted materials of step 2 are transferred in p.p bags
and the mixture was manually mixed for 10 minutes.
4) BINDER PREPARATION:

A) Dissolve PVPK-30 10.6 gm in 100 ml purified water.
5) The binding agent is mixed with the sifted material. 50 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 50°C. Air dry for 60 minutes.
8) Sift the dried granules through sieve # 18.
9) Take the dried sifted granules of step 8 and to it add sieved
material of following table and mixed manually in PP bag for
10 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 Cefixime and Levofloxacin wherein range of cefixime varies from 50 mg to 400 mg, preferably 100 mg to 400 mg, while the range of levofloxacin varies from 100 mg to 600 mg preferably 250 mg to 550 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.
9) The formulation as claimed in claim 1 may be preferably
oral dosage form.