FIELD OF THE INVENTION:

The present invention relates to sustained release formulation of Nitazoxanide and Tizoxanide. The present invention specifically relates to tablet formulations, and more particularly to a sustained-release tablet composition of Nitazoxanide formulations and a process for preparing the formulation and method of using the formulations in the treatment of Cyclosporiasis, Isosporiasis and Amebiasis.

BACKGROUND OF THE INVENTION:

Nitazoxanide is, chemically known as 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide represented by a structural formula I

Nitazoxanide is the first thiazolide as an anti-protozoal agent, approved by the USFDA in 2002 and marketed as ALINIA®. Alina tablets contain 500 mg of Nitazoxanide and Alinia for Oral Suspension contains 100 mg Nitazoxanide per 5 mL.

Nitazoxanide was originally discovered in the 1980s by Jean Francois Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. In vitro studies demonstrated much broader activity. Dr. Rossignol co-founded Romark Laboratories, with the goal of bringing Nitazoxanide to market as an anti-parasitic drug.

Romark Laboratories has announced encouraging results from international Phase I and II clinical trials evaluating a controlled release version of Nitazoxanide in the treatment of chronic hepatitis C virus infection. The company used 675 mg and 1,350 mg twice daily doses of controlled release Nitazoxanide controlled release Nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events.

It is known that US 5,578,621 discloses Tizoxanide, which is chemically known as 2-hydroxy-N-(5-nitro-2-thiazolyl)benzamide, and US 3,950,351 discloses Nitazoxanide chemically known as 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide, which possess potent activity against parasites, bacteria, viruses and fungi.

US 4,315,018; 5,578,621 and 5,856,348 disclose the method of treating various diseases in humans using Nitazoxanide.

US 3,950,351, assigned to S.P.R.L. Phavic first discloses Nitazoxanide and a process for the preparation thereof.

For example EP 0 114 277 discloses compositions for expelling or destroying parasitic worms in the intestine. Said compositions in the form of an aqueous paste contain Febantel and Praziquantel as active agent, and Polysorbate 80 RTM as wetting agent.
GB 2,252,730 teaches pharmaceutical compositions for the treatment of helminthiasis in warm-blooded animals. The compositions which are administered in a liquid form contain for example Praziquantel, benzimidazole, viscosity agents, surfactants, sanitizers, acidifiers and stabilizers.

US 5,387,598 assigned to the Jean-Francois Rossignol, relates to a composition and a galenic formulation suitable for combating affections of the lower abdomen, for example intestinal conditions such as diarrhea, said composition or formulation containing: (a) an effective amount of Nitazoxanide (b) at least one wetting agent, and preferably (c) a starch derivative.

US 5,968,961 assigned to Romark Laboratories, relates to a pharmaceutical composition containing as active agent, solid particles of Nitazoxanide, said particles having a particle size smaller than 200 um, the mean particle size of the said active solid particles being greater than 10 um. It also relates to a pharmaceutical composition which contains at least one pharmaceutically acceptable acid.

US 6,117,894, assigned to Romark Laboratories, relates to a pharmaceutical composition containing as active agent, solid particles of Tizoxanide or Nitazoxanide and mixtures thereof said particles having a particle size smaller than 200 um, the mean particle size of the said active solid particles being greater than 10 um. It also relates to a pharmaceutical composition which contains at least one pharmaceutically acceptable acid.

The aim of the present invention is a pharmaceutical composition which is consistently and optimally effective against parasites, bacteria, fungi and viruses in animals and humans. Another aim of the present invention is a pharmaceutical composition that maintains its stability.

Formulation of pharmaceutical tablets typically involves mixing the active pharmaceutical ingredient (API) with one or more inactive ingredients (excipients). Formulations that contain low doses are often formulated with more excipient on a weight basis than the API to facilitate the manufacturing process like compaction, yet it results in small tablets that are easy for the patient to swallow. Since the excipient comprises a substantial portion of the total tablet weight, the processing and manufacturability of the tablets are readily adjusted regardless of the properties of the drug agent.

OBJECTIVE OF THE INVENTION;

The main object of the present invention is to provide a sustained release pharmaceutical composition comprising Nitazoxanide and a process for preparation thereof.

SUMMARY OF THE INVENTION:

The main aspect of the present invention is to provide the sustained release compositions comprising Nitazoxanide.

Second aspect of the present invention is to provide the sustained release tablets containing Nitazoxanide.

Third aspect of the present invention is to provide the sustained release composition, comprising 50-1500 mg of Nitazoxanide or its pharmaceutically acceptable salt thereof and 0% - 80% of pharmaceutical acceptable carriers.

Fourth aspect of the present invention is to provide sustained release composition according to claim 1, wherein said dissolution profile exhibits a release rate of not more than 50% in dissolution media at 3 hour of elapsed time.

DETAILED DESCRIPTION OF THE INVENTION;

The present invention relates to sustained release formulation of Nitazoxanide comprising as the active pharmaceutical ingredient. The current inventors have found the formulation of Nitazoxanide having excellent dissolution profiles and therapeutically desirable pharmacokinetic profiles.

The invention also relates to composition and process for making sustained release pharmaceutical compositions that exhibit one or more superior properties relative to other compositions comprising Nitazoxanide.

In the one preferred embodiment pharmaceutical compositions suited for oral administration like tablets, capsules, mups and sachets. Specifically the present invention relates to Sustained-Release tablets.

According to the embodiment of the present invention, the pharmaceutically acceptable carriers (excipients) include binders, diluents, disintegrants, surfactants and solubilizers.

In one aspect of the invention, a unit dosage form is provided having the following inactive ingredients: one or more disintegrants in an amount sufficient to facilitate break-up (disintegration) of the tablet after administration (e.g., provide an immediate release dissolution profile), one or more binders in an amount sufficient to impart adequate cohesiveness to the tablet and/or provide adequate free flowing qualities by formulation of granules of desired size/hardness, one or more diluents in an amount sufficient to impart satisfactory compression characteristics, one or more lubricants in an amount sufficient to provide an adequate flow rate of the granulation and/or prevent adhesion of the material to the die/punch, reduce interparticle friction, and/or facilitate ejection from the die, and if desired, optional ingredients.

When a dosage form such as a tablet is made by the compaction of a powdered formulation, the formulation is subjected to pressure from a punch and dye. Some excipients and active pharmaceutical ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the formulation to reduce adhesion and ease the release of the product from the dye.

The disintegration rate and often the dissolution rate of a compacted solid pharmaceutical formulation in an aqueous environment (e.g., the patient's stomach) may be increased by the addition of a disintegrant to the formulation.

According to one embodiment of the present invention disintegrants include, but are not limited to alginic acid, crosslinked polyvinyl pyrrolidone, com starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, maize starch and modified starches, methyl cellulose, microcrystalline cellulose, polyacrilin potassium, potato starch, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab), pregelatinized starch, starch and mixtures thereof.

According to one embodiment of the present invention binders include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioners sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxylpropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, sunflower oil, zein and mixtures thereof.

According to another embodiment of the present invention diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chaim glyceride, microcrystalline cellulose, polydextrose, polymethylacrylates, potassium chloride, powdered cellulose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizable maize, sucrose, sugar spheres, talc, tragacanth, trehalose, tribasic calcium phosphate, xylitol and mixtures thereof.

In another embodiment of the present invention lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

Yet another embodiment of the present invention glidants include, but are not limited to, calcium phosphate, calcium silicate, cellulose powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and mixtures thereof.

According to one more embodiment of the present invention surfactants comprises non-ionic surfactants like alkyl poly(ethylene oxide), a poly(ethylene oxide), Copolymers of poly(ethylene oxide) and poly(propylene oxide) (commercially called Poloxamers or Poloxamines), alkyl polyglucosides like octly glucoside, decyl maltoside, fatty alcohols like Cetyl alcohol, oleyl alcohol, Cocamide MEA, Cocamide DEA, Polysorbates like Tween 20, Tween 80; anionic surfactants such as Perfluorooctanoate, perfluorooctanesulfonate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauryl sulfate, alkyl benzene sulfonate, soaps or fatty acid salts and cationic surfactants such as Cetyl trimethylammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide, predorninantly CM alkyl).

The compressed tablet can also be film coated. Film coat concentration can be varied up to about 10% to complement the drug amount, and preferably about 3.1% to about 3.3%.
According to the another embodiment of the present invention the Film coating suspensions include combinations of one, two or three of the following components comprising carboxymethylcellulose sodium, carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner's sugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin, methyl cellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.

Four batches of sustained release tablets were made by progressive mixing and wet granulation with the following characteristics:

♦Note Qs represent quantity sufficient.

The following table represent the dissolution profile for the above mentioned sustained release tablets of Nitazoxanide:

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non-limiting examples.

EXAMPLES:

Example 1: Preparation of 1000 mg Nitazoxanide tablets:

Method of preparation:

1) Nitazoxanide, Microcrystalline cellulose and Crospovidone were sifted through 40 # separately and mixed in a rapid mixer granulator.

2) Binder solution was prepared by dissolving HPMC K 4M and Povidone in purified water.

3) The dry mix contents of step 1 were mixed for 6-8 minutes by using the binder
solution.

4) The wet granules were transferred to fluid bed dryer and dried at 50°C ± 5°C till
moisture content of the granules is maintained at 2.5 - 2.8%.

5) The dried granules were sifted through # 14 and lubricated with Magnesium stearate and Talc.

6) Nitazoxanide lubricated blend was compressed on 19.0 mm x 09.0 mm caplet shaped punches at optimum machine speeds.

In the appended table, the drag release of the sustained release 1000 mg Nitazoxanide tablets is listed:

Example 2: Preparation of Nitazoxanide 1000 mg tablets

Method of preparation:

1) Nitazoxanide, Microcrystalline cellulose, Povidone and Crospovidone were sifted
through 40 # separately and mixed in a rapid mixer granulator.

2) Binder solution was prepared by dissolving Povidone in purified water.

3) The dry mix contents of step 1 were mixed for 6-8 minutes by using the binder
solution.

4) The wet granules were transferred to fluid bed dryer and dried at 50°C ± 5°C till
moisture content of the granules was maintained at 2.5 - 2.8%.

5) The dried granules were sifted through #14 and lubricated with Crospovidone,
Magnesium stearate and Talc

6) Nitazoxanide lubricated blend was compressed on 19.0 mm x 09.0 mm caplet shaped punches at optimum machine speeds.

In the appended table, the drug release of the sustained release 1000 mg Nitazoxanide tablets is listed:

Example 3: Preparation of Nitazoxanide 500 mg tablets;



Method of preparation:

1) Nitazoxanide, Microcrystalline cellulose, Povidone and Crospovidone were sifted through 40 # separately and mixed in a rapid mixer granulator.

2) Prepare binder solution by dissolving Povidone in purified water.

3) The dry mix contents of step 1 were mixed for 6-8 minutes by using the binder solution.

4) Povidone The wet granules were transferred to fluid bed dryer and dried at 50°C ± 5°C till Moisture content of the granules is maintained at 2.5 - 2.8%.

5) The dried granules were sifted through #14 and lubricated with Magnesium stearate and Talc.

6) Nitazoxanide lubricated blend was compressed on 19.0 mm x 09.0 mm caplet shaped punches at optimum machine speeds.

7) Take Purified water in a clean SS Vessel and disperse all coating materials in under continuous stirring to get uniform dispersion.

8) Use above solution to coat the core tablets. Maintain the tablet bed temperature at 50+ 5°C.

We Claim:
1. The sustained release compositions comprising Nitazoxanide and/or its pharmaceutically acceptable salts thereof.

2. According to claim 1, the sustained release composition is selected from the group of tablets, capsules, mups and sachets.

3. The sustained release tablets comprising Nitazoxanide and/or its pharmaceutically acceptable salts thereof.

4. The sustained release composition tablet comprising 50-1500 mg of Nitazoxanide or its pharmaceutically acceptable salt thereof and 0% - 80% of pharmaceutical acceptable carriers.

5. The sustained release composition according to claim 1, is optionally film coated.

6. The sustained release composition according to claim 1, wherein said dissolution profile exhibits a release rate of not more than 50% in dissolution media at 3 hour of elapsed time.

7. The sustained release tablet according to claim 3, wherein said dissolution profile exhibits a release rate of not more than 50% in dissolution media at 3 hour of elapsed time.