DESCRIPTION
FIELD OF THE INVENTION
The present invention is related to a synergistic pharmaceutical formulation
comprising Ornidazole and Racecadotril, for the treatment of diarrhea caused
due to bacterial and protozoal 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.
WO 2009/022893 discloses a pharmaceutical composition comprising the
synergic combination of an antimicrobial agent such as ciprofloxacin and a
selective enkephalinase enzyme inhibitor such as racecadotril, as well as to
pharmaceutically acceptable excipients, which are formulated in a single
dosage unit to be administered orally. The invention is intended to control and
treat acute bacterial diarrhoea, providing an improved therapeutic effect, faster
onset of action and reduced risk of serious complications.
The above prior art have the following drawbacks-
5. They only control diarrhoea and does not treat the underline cause of diarrhoea.
6. As soon as the administration of the drug is stopped, diarrhoea again appears.
7. The combination of ciprofloxacin with racecadotril will be ineffective against the diarrhoea caused by protozoal infection.
Thus there is a need for a formulation which not only stops diarrhoea but also
treats the underline causes of diarrhoea including both the bacterial as well as
protozoal infection.
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 administered to
treat the diarrhoea caused by both bacteria as well as protozoa.
Yet another object of the invention is to provide a formulation comprising
Ornidazole and racecadotril, which helps in treating diarrhoea.
Another object of the invention is to provide method of formulation of Ornidazole
and racecadotril.
SUMMARY OF THE INVENTION
The present invention discloses the pharmaceutical formulation comprising
Ornidazole and a peripherally enkephalinase inhibitor for the treatment of
diarrhoea due to bacterial as well as protozoal 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
Ornidazole with racecadotril and the method of formulation of the said
combination for the treatment of the diarrhoea caused due to bacterial as well
as protozoal 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.
Protozoan infections are a group of the diseases caused by unicellular
organisms. Protozoal infections are especially common for poorly developed
tropical or subtropical countries where hygiene and sanitatory conditions are
inappropriate. Protozoa are eukaryotic unicellular organisms. The structure and
metabolism of eukaryotic cells are very close to those in human host.
Therefore, protozoal infections are hardly treated and have a high rate of
toxicity. Evolution has developed in mammals many efficient protective
mechanisms to deal with protozoa and other invading parasites. However,
many of parasites developed their own tactics to escape the defensive
responses of the host. Some of the parasites penetrate human host cells where
antibodies are not able to reach them.
Ornidazole is an anti infective / antibacterial and antiprotozaol drug. It is used in
the treatment of anaerobic infections both pre& post operatively, bacterial

vaginosis, amoebic dysentery, amoebic liver abscess, hepatic and intestinal
amoebiasis, and other protozoan infection like giardiasis, trichomoniasis.
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 O. Foye, Thomas L. Lemke, David A. Williams)
The present invention comprises of the combination of Ornidazole and
Racecadotril with pharmaceutically acceptable excipients used in the
preparation of the formulation containing the above active pharmaceutical
ingredients.
Ornidazole or its pharmaceutically acceptable salt is present in the range 150
mg to 500 mg, preferably 500 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 Ornidazole 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 Ornidazole and Racecadotril.
The dosage formulation of the combination may be orally administered or
injectable.

We Claim:
1) A pharmaceutical formulation comprising Ornidazole or its
pharmaceutically acceptable salt, present in the range 150 mg to 500 mg, preferably 500mg, 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.