DESCRIPTION
FIELD OF THE INVENTION
The present invention is related to a synergistic pharmaceutical formulation
comprising ofloxacin and Racecadotril, for the treatment of diarrhea caused due
to bacterial infection. The unit oral dosage formulation is also formulated
comprising the above combination as well as pharmaceutically acceptable
excipients.
RELEVANT PRIOR ART
US 2009/0186084 relates to a new racecadotril formulation in the form of
tablets, the preparation process thereof and the use thereof to treat diarrhoea.
WO 2001/097803 discloses a new pharmaceutical granulate formulation
comprising the anti-diarrhoeal agent racecadotril comprising at least one
diluent, at least one lubricant, and an intragranular disintegrant having defined
characteristics.
The above prior art have the following drawbacks-
They only control diarrhoea and does not treat the underline cause of
diarrhoea.
As soon as the administration of the drug is stopped, diarrhoea again
appears.
Thus there is a need for a formulation which not only stops diarrhoea but also treats the underline causes of diarrhoea.
OBJECT OF THE INVENTION
The object of the present invention is to provide a safe, tolerable and effective
treatment of diarrhoea.
Yet another object of the invention is to provide a formulation comprising
ofloxacin and racecadotril, which helps in treating diarrhoea.
Another object of the invention is to provide method of formulation of ofloxacin
and racecadotril.
SUMMARY OF THE INVENTION
The present invention discloses the pharmaceutical formulation comprising
ofloxacin and a peripherally enkephalinase inhibitor for the treatment of
diarrhoea due to bacterial infections. The enkephalinase inhibitor is preferably

racecadotril. The method of formulation of the said composition is also
disclosed.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses the pharmaceutical formulation comprising
ofloxacin with racecadotril and the method of formulation of the said
combination for the treatment of the diarrhoea caused due to bacterial infection.
Diarrhea is an increase in the frequency of bowel movements or a decrease in
the form of stool (greater looseness of stool). Although changes in frequency of
bowel movements and looseness of stools can vary independently of each
other, changes often occur in both.
Antimicrobial agents are considered "miracle drugs" that are our leading
weapons in the treatment of infectious diseases. Antimicrobial resistance is the
ability of certain microorganisms to withstand attack by antimicrobials, and the
uncontrolled rise in resistant pathogens threatens lives and wastes limited
healthcare resources (Reference- WHO).
Ofloxacin is highly active against most pathogens causing bacterial enteritis.
High faecal levels are achieved readily following a single oral dose and may
persist for up to five days despite partial binding by faeces. In addition,
adequate ofloxacin levels persist in pancreatic secretions and bile for 12 to 14 h
following oral administration. Clinical data from various centres demonstrate a
prompt response when ofloxacin is administered once-daily for shigellosis,
salmonellosis and various other enteric pathogens. These theoretical
observations and clinical data suggest a potential for once-daily oral ofloxacin
therapy for bacterial diarrhoea.
In case of diarrhoea, oral rehydration therapy must be provided so as to cover
up the losses of electrolytes and liquid. However, there must be some steps
taken to reduce or stop the losses of those essential electrolytes and liquid.
There comes the need of anti-diarrhoeal drugs.
Various anti-diarrhoeal drugs are used either to treat diarrhoea or other
complications related to diarrhoea. The drugs can be used are electrolytes,
bulk-forming agents, absorbent, anti-inflammatory substances, and opioids use
to treat the pain.
In addition to above drugs, there requires an agent that will reduce diarrhoea or
stops the loss of important salts from the body..

Enkephalinases are the enzymes which degrade endogenous enkephalin opioid peptides, a penapeptide which regulates the nociception of the body. They include: Aminopeptidase N (APN), Neutral endopeptidase (NEP) and Dipeptidyl peptidase 3 (DPP3).
Racecadotril, a prodrug of thiorphan, is a enkephalinase inhibitor. The free thio group of thiorphan binds tightly to the zinc in the active site of the enzyme and inhibits its proteolytic action. Orally dosed racecadotril causes its antidiarrhoel
effects by inhibition Of intestinal Secretion. (Foye's principles of medicinal chemistry By William 0. Foye, Thomas L. Lemke, David A. Williams)
The present invention comprises of the combination of Ofloxacin and
Racecadotril with pharmaceutically acceptable excipients used in the
preparation of the formulation containing the above active pharmaceutical
ingredients.
Ofloxacin or its pharmaceutically acceptable salt is present in the range 50 mg
to 250 mg, preferably 100 mg to 200 mg, whereas racecadotril or its
pharmaceutically acceptable salt is present in the range 75 mg to 250 mg, more
preferably 100 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 Ofloxacin and Racecadotril 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 Ofloxacin and Racecadotril.
The dosage formulation of the combination may be orally administered or injectable.

We Claim:
1)A pharmaceutical formulation comprising Ofloxacin or its pharmaceutically acceptable salt, present in the range 50 mg to 250 mg, preferably 100 mg to 200 mg, and racecadotril or its pharmaceutically acceptable salt, present in the range 75 mg to 250 mg, more preferably 100 mg, useful for managing diarrhoea due to 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 can be oral or injectable, preferably oral.