DESCRIPTION
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 Cefpodoxime and fluoroquinolones antibiotic levofloxacin.
The present invention relates to formed particles comprising Cefpodoxime and levofloxacin.
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 Cefpodoxime and
levofloxacin, which are suitable for the preparation of stable pharmaceutical
compositions of Cefpodoxime and levofloxacin.
DESCRIPTION OF THE INVENTION
The present invention relates to the use of the fluoroquinolones levofloxacin in combination with the 3rd generation cephalosporin cefpodoxime 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. 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.
Cefpodoxime works by inhibiting bacterial cell wall synthesis causing cell death and levofloxacin kills bacteria by inhibiting nucleic acid synthesis. Both Cefpodoxime and levofloxacin are bactericidal in nature and both are killing the bacteria by two different mechanisms. Therefore the combination therapy of Cefpodoxime and Levofloxacin will lead to minimal bacterial resistance. Beta - Lactam antibiotics are among the safest and the most frequently prescribed agents in India and worldwide. 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 Coli 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, and 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 white Cefpodoxime 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.
Cefpodoxime is a third generation cephalosporin and is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below:
• Acute otitis media caused by Streptococcus pneumoniae , (excluding penicillin-resistant strains), Streptococcus pyogenes, Haemophilus influenzae (including beta-lactamase-producing strains), or Moraxella (Branhamella) catarrhalis (including beta-lactamase-producing strains).
• Pharyngitis and/or tonsillitis caused by Streptococcus pyogenes.
• Community-acquired pneumonia caused by Streptococcus pneumoniae or Haemophilus influenzae (including beta-lactamase-producing strains).
• Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae (non-beta-lactamase-producing strains only), or Moraxella catarrhalis . Data are insufficient at this time to establish efficacy in patients with acute bacterial exacerbations of chronic bronchitis caused by beta-lactamase-producing strains of Haemophilus influenzae .
• Acute, uncomplicated urethral and cervical gonorrhea caused by Neisseria gonorrhoeae (including penicillinase-producing strains).
• Acute, uncomplicated ano-rectal infections in women due to Neisseria gonorrhoeae (including penicillinase-producing strains).
• Uncomplicated skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains) or Streptococcus pyogenes. Abscesses should be surgically drained as clinically indicated.
• Acute maxillary sinusitis caused by Haemophilus influenzae (including beta-lactamase-producing strains), Streptococcus pneumoniae, and Moraxella catarrhalis .
• Uncomplicated urinary tract infections (cystitis) caused by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis , or Staphylococcus saprophytics .
In some diseases like Typhoid fever, Uncomplicated UTI, and Gonorrhoea, both are having relatively similar capacity but the combination of levofloxacin and cefpodoxime may be helpful in reducing the doses. Thus by forming the combination of levofloxacin 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 its pharmaceutically acceptable salt. The range of cefpodoxime 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.
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 levofloxacin 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 levofloxacin. The dosage formulation of the combination may be orally administered or injectable.

CLAIMS
1. A pharmaceutical formulation comprising 50 mg to 400 mg of
Cefpodoxime, preferably 100 to 400 mg, and Levofloxacin 100 mg to 600
mg, preferably 250 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.