FORM 2
The Patents Act, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION
[See, section 10]
"Once a Day Formulations of Antiprotozoal Agents"
APPLICANT
Ajanta Pharma Limited
An Indian Company,
Registered under Companies Act, 1956
and having its Registered Office at:
Ajanta House, 98 Govt. Industrial Area,
Charkop, Kandivli (W), Mumbai - 400 067,
Maharashtra, India
INVENTORS
The inventors under Sec.28 are:
BIYANI, Milind Kesharlal; JATHAR Shripad Rhushikesh;
all working as Research Scientists at Research Centre,
Ajanta Pharma Limited, Ajanta House, Charkop, Kandivli (W),
Mumbai - 400 067, Maharashtra, India
Nationality: Indian.
BAJAJ Amrita;
Working as - Reader in Pharmaceutics, C.U. Shah college of Pharmacy, S.N.D.T. Women's University, Juhu Tara Road, Santacruz (West), Mumbai -400049.
Nationality: Indian.
The following specification describes the nature of the invention;

Field of the Invention:
The present invention relates to once a day formulations of antiprotozoal agent. More particularly the present invention relates to the controlled release once a day formulations of tinidazole for amoebiasis and giardiasis.
Background of the Invention:
Wide varieties of protozoal parasites are the cause of pathological consequences of infection in human beings. Some of the most common protozoal infections seen in developed and developing countries are amoebiasis and girardiasis caused by anaerobic protozoa.
Amoebiasis is a type of gastroenteritis (gastro) caused by protozoan parasites Entemobacter histolytica minuta and Entamobacter histolytica histolytica of these, former is not the cause of serious effects but can be converted to pathogenic form, whereas the later is the cause of very common complications of amoebiasis, and may migrate into the liver or lungs or even the brain. They penetrate the intestinal mucous membrane and are responsible for the propagation of the disease, in both the upper as well as lower part of intestine, in the form of cysts. These cysts which are present in the lower part of the gastrointestinal tract of the infected individuals are excreted in their faeces. The lack of personal and collective hygiene leads to further spread of the disease as well as self re-infection of the individual. Individuals affected by these protozoas experience varying degree of symptoms from mild ones like

nausea, loose stools, weight loss, abdominal tenderness, occasional fever to sever ones like liver abscess, sever colitis.
Giardiasis is the most commonly reported intestinal protozoal infection, caused by the flagellated protozoa Giardia lamblia. Infection results from ingestion of cysts, most commonly from fecal contamination of water or food. Cysts change into motile trophozoites in the upper small intestine where they may or may not produce the disease. Most infected individuals are asymptomatic however; there could be isolated cases of epidemics of diarrhoea that is transient or persistent. Malabsorption manifested by steatorrhea and weight loss is also observed.
Various drugs are used to treat amoebiasis and giardiasis. The drugs, which are used to treat amoebiasis, can be categorized as luminal, systemic, or mixed amoebicides. Luminal amoebicides like diloxanide furoate, are active against intestinal forms of amoebae. These compounds can be used by themselves to treat asymptomatic or mild intestinal forms of amoebiasis only, however to eliminate the infection they are required to be used in conjunction with a systemic or mixed amoebicide. Systemic amoebicides are effective only against invasive forms of amoebiasis. These agents have been employed primarily to treat severe amoebic dysentery (dehydroemetine) or hepatic abscesses (dehydroemetine or chloroquine), but they are rarely used now unless other drugs fail or cause unacceptable side effects. Mixed amoebicides are active against both intestinal & systemic forms of amoebiasis. Drugs belonging

to 5-nitroimidazole class are the prototypical mixed amoebicide, and their use has revolutionized the treatment of this infection. 5-nitroimidazole derivatives are also used for the treatment of giardiasis.
Drugs belonging to the 5-nitroimidazole class are metronidazole, tinidazole, secnidazole, ornidazole, and the like. Of these, metronidazole was considered to be prototypical mixed amoebicide. However metronidazole and some other 5-nitroimidazole are well absorbed in the stomach and therefore may fail to reach the large intestine in therapeutic concentrations, hence are not very effective for the treatment of cysts and therefore are likely to be more effective against systemic than intestinal amoebiasis. Moreover the recent studies have shown tinidazole to be more effective, better tolerated drug, with fewer side-effects and with a more rapid therapeutic effect as a result shorter course of treatment than metronidazole. Therefore in view of these studies tinidazole appears to be a better choice as a mixed amoebicide.
Tinidazole is an antiprotozoal drug widely used as treatment for a variety of amoebic and parasitic infections. A large body of clinical data exists to support its use as a treatment for amoebas, giardia and vaginal trichomonas. It is chemically l-[2-(ethylsulphonyl) ethyl]-2-methyl-5-nitroimidazol.
The dose of tinidazole varies depending upon the type and severity of infection. For amoebiasis the standard dose is 4 tablets of 2 grams daily for three to five days and for a severe case of amoebiasis, treatment has to be

extended to 9 days at the same dosage. For giardiasis the dose of tinidazole is 4 tablets of 2 grams for one day. The conventional tinidazole tablet is absorbed from the stomach, enters systemic circulation and through enterohepatic circulation, it reaches into small intestine and then acts on the trophozoites present in the large intestine. Due to such indirect and lengthy route of absorption, though tinidazole is absorbed rapidly from the stomach, the local action required at the large intestine is protracted. Furthermore it is required in large doses, hence would not be cost effective and convenient to the patients in the need thereof. Moreover such large quantity of conventional dose which are absorbed in the upper part of the gastrointestinal tract can produce undesirable side effects such as from metallic taste in the mouth, mild nausea, headache, vomiting, to even toxic effects.
Therefore in view of the afore mentioned disadvantages associated with conventional formulations of antiprotozoal drug tinidazole, there is a need of the formulations of tinidazole with reduced dose, dosing frequency and most significantly which can produce the local action at intestine even with reduced dose and for prolonged period to show the therapeutic effect. All these parameters are well achieved with once a day, controlled release formulation of tinidazole of the present invention which comprises of tinidazole in as less dose as 500 mg, has to be taken only once a day, gives plasma concentrations of the drug in the blood to achieve both systemic as well as local action, maintained in therapeutic levels for about 24 hours to provide better therapeutic effects and are with lesser side effects.

Prior Art:
United States Patent no. 5549911 granted to Leduc, et al on August 27, 1996 discloses a galenic form of 5-nitroimdazole derivatives, which is characterized in that it comprises a combination of microgranules of 5-nitroimidazole derivatives consisting on the one hand, of gastroresitant microgranules and, on the other hand, of prolonged release microgranules, the pharmaceutical compositions comprising them and the microgranules as intermediates in the preparation of the form according to the invention.
Above prior art uses altogether different technology of providing galenic forms in the form of microgranules. Formulation of such galenic forms would be very tedious, lengthy and complex especially at industrial level. Moreover microgranules of the prior art are prepared by using more number of ingredients especially polymers, hence would not be cost effective. Moreover the does of the drug as given in the clinical trial is 1.5 gm a day, given as 3 daily doses of two gelatin capsules containing 250 mg of metronidazole as against present invention dose of tinidazole which is as less as 500 mg per day. Furthermore the release profile which is the main aspect of the any controlled release systems, is notably different of the prior art from that of the present invention once a day formulations. As per the release profile of the prior art, more than 70 percent of the drug is released at the end of 8th hour only, thus the major amount of the drug would be released in the small intestine, whereas the drug is actually required to be absorbed at the large intestine for the local action on

protozoas as well as cysts for providing better therapeutic effect and preventing relapse of the infection.
Thus it is obvious from the forgoing that the present invention once a day controlled release formulations of antiprotozoal agent tinidazole is entirely different from the prior art with respect to composition, dose of tinidazole, dosage form, formulation process and the release profile.
Objects of the Invention:
Therefore it is an object of the present invention to provide once a day controlled release formulations of antiprotozoal, agent for amoebiasis and giardiasis.
It is also an object of the present invention to provide once a day formulations of antiprotozoal agent tinidazole specifically designed so as to give plasma concentrations of the drug in the blood to achieve both systemic as well as local action, maintained in therapeutic levels for about 24 hours for providing better therapeutic effects.
It is also an object of the present invention to provide once a day formulations of antiprotozoal agent, tinidazole with reduced daily dose of drug thereby providing better treatment regimen.

It is also an object of the present invention to provide once a day formulations of antiprotozoal agent, tinidazole with reduced frequency of dosing thereby providing better patient compliance.
It is also an object of the present invention to provide once a day formulations of antiprotozoal agent tinidazole in the form of enteric coated matrix tablets avoiding the absorption of the drug in the upper part of the gastrointestinal tract thereby reducing the undesirable side effects such as metallic taste in the mouth, mild nausea, headache, vomiting, and even toxic effects.
It is also an object of the present invention to provide process for preparation of once a day controlled release formulations of antiprotozoal agent for amoebiasis and giardiasis.
It is also an object of the present invention to provide process for preparation of once a day formulations of antiprotozoal agent tinidazole specifically designed so as to give serum plasma concentrations of the drug in the blood to achieve both systemic as well as local action, maintained in therapeutic levels for about 24 hours for providing better therapeutic effects.
It is .also an object of the present invention to provide process for preparation of once a day formulations of antiprotozoal agent, tinidazole with reduced daily dose of drug thereby providing better treatment regimen.

It is also an object of the present invention to provide process for preparation of once a day formulations of antiprotozoal agent, tinidazole with reduced frequency of dosing thereby providing better patient compliance.
It is also an object of the present invention to provide process for preparation of once a day formulations of antiprotozoal agent tinidazole in the form of enteric coated matrix tablets avoiding the absorption of the drug in the upper part of the gastrointestinal tract thereby reducing the undesirable side effects such as metallic taste in the mouth, mild nausea, headache, vomiting, and even toxic effects.
Detailed description of the Invention:
The present invention provides controlled release once a day formulations of antiprotozoal agent, tinidazole for amoebiasis and giardiasis.
The present invention provides controlled release once a day formulations antiprotozoal agent comprises of active drug tinidazole, a release retarding agent and inert, safe pharmaceutically accepted excipients.
In accordance with the present invention tinidazole may be employed in a single oral dosage within the range from about 200 mg to 2000 mg, preferably from about 300 mg to about 1500 mg, more preferably from about 400 mg to about 700 mg.

The release rate retarding polymer that may be used in accordance with the present invention can be selected from methyl cellulose, ethyl cellulose, hydroxy ethylcellulose, hydroxy propylcellulose, hydroxypropyl methylcellulose or the like and or combination thereof of different grades of varying viscosity. Further it is preferable to use the lower alkyl ethers of cellulose, which shows the viscosity ranging from 4000 to 100,000 centipoises, more preferably from 15,000 to 30,000 centipoises.
The formulations in accordance with the present invention in addition to active drug, and release rate retarding polymer also comprises of other safe inert pharmaceutically accepted excipients like carrier, vehicle, binder, lubricant, diluent, preservative, coating material or the like.
In accordance with the present invention the once a day controlled release formulations described above are prepared in the form of suitable dosage forms for oral administration such as tablets, capsules, powders, granules, oral solutions or suspensions or the like.
In accordance with the present invention the once a day controlled release formulations in the form of matrix tablets are enteric coated to prevent the release of the drug in stomach thereby avoiding the undesirable side effects like metallic taste in the mouth, mild nausea, headache, vomiting, and even toxic effects.

In accordance with the present invention there has been also provided a
process for preparation of once a day controlled release formulations of
antiprotozoal agent, which is simple and easy to adopt for manufacturing at
large scale.
Dated this 14th day of August 2002.
For Ajanta Pharma Limited
Dr. BIYANI Milind K.
Vice President - Scientific Affairs
Ajanta Pharma Limited
98, Govt. Industrial Area,
Charkop, Kandivli (W),
Mumbai - 400 067
The Controller of Patents,
The Patent Office Branch, at Mumbai-400 013