DESCRIPTION
FIELD OF THE INVENTION
The present invention is directed to a pharmaceutical formulation and the
method of preparation comprising the combination of amoxicillin, clavulanic acid
and ornidazole.
RELEVANT WORK DONE PRIOR TO INVENTION (PRIOR ART) US 4997830 discloses a pharmaceutical combination of Metronidazole and Amoxicillin for the treatment of periodontitis. Conventional therapeutic doses of both the Metronidazole and Amoxicillin given as a combination therapy has been unexpectedly found to effectively treat periodontitis. The in vitro activity of tinidazole against anaerobic periodontal pathogens (25 Prevotella buccae, 18 Prevotella denticola, 10 Prevotella intermedia, 6 Prevotella melaninogenica, 5 Prevotella oralis, 10 Fusobacterium nucleatum and 8 Veillonella spp.) was determined by agar dilution. MIC90 values (minimum inhibitory concentration for 90% of the organisms) were 8ug/mL for Veillonella spp., 4ug/mL for P. intermedia, 2ug/mL for P. buccae, 1ug/mL for Fusobacterium spp. and 0.5ug/mL for other Prevotella spp. Cidal activity was studied by killing curves with tinidazole and amoxicillin (alone and in combination) at concentrations similar to those achieved in crevicular fluid (41.2µg/mL tinidazole and 14.05µg/mL amoxicillin) against an inoculum of ca. 107colony-forming units/mL of four bacterial groups, each one composed of four different strains of the following periodontal isolates: Prevotella spp., Fusobacterium spp. and Veillonella spp. (anaerobes) and one amoxicillin-susceptible Streptococcus spp. (facultative) in a proportion of 1:1:1:1. When only ß-lactamase-negative Prevotella or Fusobacterium strains were tested, significantly higher reductions were found with amoxicillin (>4log reduction at 48h) versus controls. The presence of ß-lactamase-positive Prevotella spp. or F. nucleatum strains rendered amoxicillin inactive (no reductions at 48h), with no differences from controls. Amoxicillin+tinidazole produced >3log reduction at 24h and >4log reduction at 48h regardless of the presence or not of ß-lactamase-positive strains. The presence in crevicular fluid of ß-lactamases produced by p-lactamase-positive periodontal pathogens may have ecological and therapeutic consequences since it may protect ß-lactamase-negative

periodontal pathogens from amoxicillin treatment. In vitro, tinidazole offered high antianaerobic activity against ß-lactamase-positive and -negative periodontal pathogens, avoiding amoxicillin inactivation. (Ref- international Journal of
Antimicrobial Agents, Volume 33, Issue 5, Pages 449-452 (May 2009))
The drawbacks in the prior art were-
5. There was increasing bacterial resistance towards amoxicillin.
6. Higher MIC was required to treat the infection.
7. The combination in the prior art were of narrow spectrum and treating only specific or very less variety of infection.
Thus there is need of a pharmaceutical formulation which is having a broad spectrum and provides a little resistance to bacteria. The present invention fulfils the above need.
OBJECTIVE OF THE INVENTION
The object of the present invention is to provide a pharmaceutical formulation
which is effective against a variety of bacterial and protozoal infections.
Yet another object of the present invention is to provide the combination which
works at the lower Minimum Inhibitory Concentration (MIC), thereby reducing
the side effects.
Another objective of the present invention is to reduce the bacterial resistance.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical formulation and the method of preparation comprising the combination of amoxicillin, clavulanic acid and ornidazole. The invention is used to treat a variety of disease caused by anaerobic as well as aerobic bacteria and also been effective to treat the protozoal infections. The combination also acts at a lower MIC and also reduces the bacterial resistance.
DETAILED DESCRIPTION OF THE INVENTION
Amoxicillin is a moderate-spectrum, bacteriolytic, ß-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral

administration, than other ß-lactam antibiotics. Amoxicillin is one of the most common antibiotics prescribed for children.
Amoxicllin is used in the treatment of a number of infections including: acute otitis media, streptococcal pharyngitis, pneumonia, skin infections, urinary tract infections, salmonella, lyme disease, and chlamydia infections. It is used to prevent bacterial endocarditis in high risk people who are having dental work done, to prevent strep pneumococus infections in those without a spleen, and for both the prevention and treatment of anthrax. It is also a treatment for cystic acne.
Clavulanic acid is a beta-lactamase inhibitor (marketed by GlaxoSmithKline, formerly Beecham) combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most penicillins.
Amoxicillin is susceptible to degradation by ß-lactamase-producing bacteria, which are resistant to a broad spectrum of ß-lactam antibiotics, such as penicillin. For this reason, it is often combined with clavulanic acid, a ß-lactamase inhibitor, and marketed under one name. This increases effectiveness by reducing its susceptibility to ß-lactamase resistance. Ornidazole is an antiprotozoal and antibacterial agent; it is a derivative of 5-nitroimidazole. It is effective against Trichomonas vaginalis, Entamoeba histolitica, Giardia lamblia (Giardia intestinalis) and some other anaerobic bacteria, such as Gardnerella vaginalis, Bacteroides and Clostridium spp., Fusobacterium spp., and anaerobic coccus.
By mechanism of action ornidazole is a DNA-tropic agent with selective activity against microorganisms, which have enzyme systems able to renew nitro group and catalyze an interaction of ferredoxin proteins with nitrocompounds. After preparation penetration into microbial cell the mechanism of its action is cause by renovation of nitro group under an influence of nitroreductase of microorganism and activity of renewed nitroimidazole. Products of renovation form complexes with DNA, causing its degradation, disturb processes of replication and transcription of DNA. In addition, products of preparation metabolism have cytostatic properties and disturb processes of cell respiration.

Pharmacokinetics: After per oral intake ornidazole is quickly absorbed in GIT. In
average absorption is 90%. Maximal concentration in plasma is within the limits
of 3 hours.
Ornidazole binding to plasma proteins is approximately 13%. Active substance
penetrates into cerebrospinal fluid and other fluids of the organism and tissues.
Amoxicillin is present in its pharmaceutically acceptable salt and is in the range
100 mg to 875 mg, preferably 250 mg to 500 mg, more preferably 250 mg.
Clavulanic is present in its pharmaceutically acceptable salt and present in the
range 70 mg to 150 mg, more preferably 125 mg.
Ornidazole is present in the range 250 mg to 600 mg, more preferably 500 mg.
The present formulation is prepared by using the suitable pharmaceutical
excipients, along with the said quantity of Active Pharmaceutical Ingredients.
The excipients used may be selected from the group of diluents, binding
agents, disintegrants, and lubricants.
The diluents can be selected from lactose, sucrose, glucose, mannitol, sorbitol,
calcium carbonate, and magnesium stearate.
The binding agents can be selected from polyvinylpyrrolidone (PVP),
polyethylene glycol (PEG), xylitol, sorbitol and maltitol which are mixed with the
appropriate solvent.
The solvent can be selected from purified water or isopropyl alcohol or the
mixture of both.
The disintegrants can be selected from polyvinylpyrrolidone (crospovidone),
crosslinked sodium carboxymethyl cellulose (croscarmellose sodium) and
sodium starch glycolate.
The lubricants can be selected from talc or silica, and fats, e.g. vegetable
stearin, magnesium stearate or stearic acid.
The formulation may be coated or uncoated.
The formulation can be coated with Hydroxypropyl Methyl Cellulose, along with
suitable plasticizer, opacifier, coloring agent and the solvent.
The release of amoxicillin, clavulanic acid and ornidazole from the
pharmaceutical formulations of the present invention can be immediate or
modified, controlled, delayed, sustained, or 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 amoxicillin, clavulanic acid and ornidazole

CLAIMS
1. A pharmaceutical formulation comprising 100 mg to 875 mg, preferably
250 mg of Amoxycillin, 70 mg to 150 mg, preferably 125 mg of clavulanic
acid, and Ornidazole 250 mg to 600 mg, preferably 500 mg, along with
pharmaceutically acceptable excipients.
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 can be oral or injectable,
preferably oral.