FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
"COMPOSITIONS OF SATRANIDAZOLE"
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE OFFICE AT ALKEM HOUSE, DEVASH1SH, ADJACENT TO MATULYA CENTRE, S.B.MARG,
LOWER PAREL. MUMBA1 -400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED:
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ABSTRACT
The present invention concerns Novel Compositions of Satranidazole, suitable for once daily administration and it relates to a unit dosage form, such as a tablet or the like for delivering poorly water soluble drugs such as Satranidazole in to the body in a controlled release fashion. The invention also relates to the oral formulation for gastric retention for treating or preventing disease or disorders caused by or associated with certain bacterial infection, especially Helicobacter pylori and controlled delivery of an incorporated drug into gastric cavity, and thus administered, the tablet swells, produces effervescence and buoyant in the gastric juice and gradually releases the drug from the matrix by diffusion, erosion and dissolution.
BACKGROUND OF THE INVENTION
Amoebiasis is one of the important human protozoan infections. This disease is widespread throughout the world, being more common in tropical and subtropical zones. This infection is responsible for a high degree of morbidity and many a times mortality, if the infection spreads to extra-intestinal sites like liver etc.
Gastritis commonly refers to inflammation of the lining of the stomach. This form of non-erosive gastritis is the result of infection with Helicobacter pylori bacterium, a microorganism whose outer layer is resistant to the normal effects of stomach acid in breaking down bacteria.
Metronidazole, the new macrolides with long half-lifes, bismuth salts and Amoxycillin are the mainstay therapy for Gastritis caused by H.Pylori
Satranidazole, l-methylsulphonyl-3-(l-methyl-5-nitro-2-imidazolyl)-imidazolidinone is a novel nitroimidazole which differs from other 5-nitroimidazoles such as metronidazole, Ornidazole and Tinidazole in that the 2C of the imidazole ring is connected via a nitrogen to a substituted imidazolidinone moiety. It is a clinically
well-tolerated and highly active amoebicidal and may also be useful in the treatment of Gastritis caused by H.Pylori. Its comparison with other 2- and 5- nitroimidazoles
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indicate it may be more active towards anaerobes than many 5-nitroimidazoles because its relatively high redox potential may make it more resistant to inactivation
by oxygen.
Metronidazole is a drug of choice for vaginal trichomoniasis and amoebiasis, but treatment failures are known to occur and the drug is poorly tolerated. But Satranidazole is more active than other nitroimidazoles in experimental studies against amoebiasis and T. vaginalis and has less propensity towards neurological damage than metronidazole.
A particular aspect of the present invention is the preparation of a once daily dosage regimen for Satronidazole which currently is administered twice daily or more times as a 300mg tablet depending on the type of bacterial infection to be treated. The
exact site of Satronidazole absorption in vivo is unknown However, it is known that Satranidazole is very stable and soluble in the stomach (pH 1.2) and undergoes degradation at alkaline pH
Controlled release formulations have allowed the possibility of reducing dosage regimens for drugs, especially those administered orally to outpatients. The advantages of reduced dosage regimens for the outpatient are convenience and, more importantly, better assurance of compliance. The most convenient dosage form is a once daily dosage regimen.
Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. The use of floating dosage forms (FDFs) is one method to achieve prolonged gastric residence times (GRTs), providing opportunity for both local and systemic drug action.
U.S. Pat. No. 4,842,866 describes an extended release pharmaceutical formulation containing an active drug ingredient, sodium alginate and sodium-calcium alginate. The active drug ingredient is present in an amount up to 70% by weight of the formulation.
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US Pat No 4,389,393 describes a sustained release therapeutic composition containing an active agent and from 5 wt% to about 30 wt% of hydroxypropylmethyl cellulose or a mixture of hydroxypropylmethyl celluloses.
EP0799028B1 describes a controlled release; oral, solid, pharmaceutical composition for a reduced daily dosage regimen is described where the therapeutic ingredient is a poorly soluble basic drug. The formulation comprises the use of a water-soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid in admixture with the therapeutic drug.
WO9702020A1 describes an oral pharmaceutical composition of pantoprazole in pellet or tablet form, wherein the pantoprazole is at least partly in slow-release form, is distinguished, on combined administration with an antimicrobially active ingredient, by an enhanced action of rapid onset against disorders caused by Helicobacter.
WO04002445A2 describes an invention relates to a novel pharmaceutical composition containing an active ingredients(s) which is retained in the stomach or upper part of gastrointestinal tract for controlled delivery of medicament for improved local treatment, and/or better absorption from upper parts of gastrointestinal tract for effective therapeutic results.
US20030039688A1 describes an invention relates to drugs formulated as unit oral dosage forms by incorporating them in to polymeric matrices comprised of hydrophilic polymers that swell upon imbibition of water to a size that is large enough
to promote retention of the dosage form in the stomach during the fed mode.
WO03035041A1 describes an invention relates to controlled release oral dosage forms are provided for the continuous, sustained administration of a pharmacologically active agent to the upper gastrointestinal tract of a patient in whom the fed mode has been induced. The dosage form comprises a matrix of a biocompatible, hydrophilic, erodible polymer with an active agent incorporated therein, wherein the polymer is one that both swells in the presence of water and
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gradually erodes over a time period of hours, with swelling and erosion commencing upon contact with gastric fluid, and drug release rate primarily controlled by erosion rate.
US20030133985Al describes an invention relates to erodible, gastric-retentive dosage forms that are formulated using the in vitro drug release profile obtained with USP Disintegration test equipment rather the USP Dissolution Apparatus.
EP0744947B1 describes an invention relates to pharmaceutical compositions having a modified release profile for once daily dosing of metronidazole, methods for making the pharmaceutical compositions, and methods for treating a microbial infection with once daily dosing of the pharmaceutical compositions of the invention are provided. CN1593404A disclosed a metronidazole double layer laminated slow release tablet comprising two layers, the first layer being a slow release layer consisting of metronidazole, and the second layer being a quick release layer.
SUMMARY OF THE INVENTION
Satranidazole is a clinically well-tolerated and highly active amoebicidal and may also be useful in the treatment of Gastritis caused by H Pylori.
The present invention concerns to Novel Compositions of Satranidazole, suitable for once daily administration and also it relates to the oral controlled release formulation for gastric retention for treating or preventing disease or disorders caused by or associated with certain bacterial infection, especially Helicobacter pylori.
The compositions of the present invention comprise Satranidazole and excipients, are
Capable of being tabletted and of providing controlled release of Satranidazole for up
to 24 hours
The compositions of the invention comprise Satranidazole and pharmaceutically acceptable excipients such as binder, antiadherent, lubricant, Glidant, Hydrophilic
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polymer, gas producing agent (for gastroretentive), acidifying agent, aqueous soluble diluent, disintegrant and coating materials.
The present invention comprises most preferably Starch, Talc, and Magnesium Stearate, Colloidal Silicon Dioxide, Methocel K.IOOM, Calcium Carbonate, Calcium Carboxymethylcellulose, Sodium Starch Glycolate, Citric acid, Lactose, Hydroxypropylmethyl cellulose. Polyethylene Glycol 6000, Titanium dioxide and quinolline yellow.
The present invention also includes a method for making a composition of the invention, which method comprises producing satranidazole containing granules in a Fluidized bed Processor or Rapid Mixer Granulator employing aqueous binder. Then the use of Methocel K100M as a retarding agent at lubrication stage with other suitable excipients yields tablets which provide controlled release characteristics useful for once daily oral administration of Satranidazole
DETAILED DESCRIPTION OF INVENTION
In the context of the present invention a number of terms have been used. In order to provide a clear and consistent understanding of the specification, claims and the scope, the following definitions are provided. "Controlled release" as used herein, means sustained release or slow release or modified release or prolonged release or extended release or other similar terms used to indicate a composition providing an extended profile of drug release from the composition when exposed to aqueous environment either in-vitro or in-vivo as compared to an immediate release composition.
"Therapeutic agent, active agent or drug" as used herein, has been used interchangeably and have the meanings recognized by one skilled in the art.
One aspect of the present invention relates to a pharmaceutical composition for extended release derivative in the gastrointestinal environment, comprising a
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pharmaceutical salt and a pharmaceutically acceptable polymer, so that upon oral ingestion, maximum peak concentrations of the satranidazole are statistically significantly lower than those produced by an immediate release pharmaceutical
composition, and an area under the concentration - time curve and the minimum plasma concentration are substantially equivalent to that of the immediate release pharmaceutical composition.
Matrix Systems - Matrix Systems can be subdivided into different categories, these being dispersed and porous systems where the matrix-forming material does not undergo dimensional changes in contact with the gastric fluid. The advantage of non-erodible dispersed matrix systems over reservoir and credible systems is that they are relatively insensitive to changes in mixing and stirring conditions because diffusion is the rate- controlling factor. Conventional dispersed systems suffer from non-linear concentration-time release, due to the longer distance that the drug in deeper layers of the matrix must travel to exit the delivery system. During both drug dissolution and diffusional process, the boundary layer moves back in to the matrix while its surface area is maintained.
Drug release from the invention is based upon the fact that the dissolution medium surrounding the matrix device initially dissolves and leaches out drug from the surfaces of the dosage form, but at this process continues with time, the dissolution medium travels further into the matrix and the drug then has to dissolve into the medium and then leave via diffusion along the porous water filled paths, created by the gradual ingress of the dissolution medium.
In addition to the Satranidazole and polymer component, the invention may contain one or more excipients. Examples of such excipients are glidants, binders, diluents, solubilizers, antiadherents, preservatives, disintegrants , film formers, plasticizers, pigments etc. The sustained release characteristics for the release of the Satranidazole from the compositions of the invention may be varied by changing the type or amount of polymer component and/or the type or amount of excipients, which may be present.
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The pharmaceutically acceptable polymer component comprises at least one hydrophilic polymer Preferred hydrophilic polymers for use in the invention are water soluble and include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethylethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, polyvinyl alcohol, sodium alginate, polyvinyl pyrrolidone, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, methyl methacrylic ester copolymers,
maleic anhydride/methyl vinyl ether copolymers and poly(ethylene oxide). More preferably, the polymer is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose and poly (ethylene oxide).
Fillers or diluents are typically added to a small amount of the active drug to increase the size of the tablet. Examples of fillers or diluents include, but are not limited to, spray-dried or anhydrous lactose, sucrose, dextrose, starch, pregelatinized starch, mannitol, sorbitol and xylitol, microcrystalline cellulose, dibasic calcium phosphate. Preferably, the filler or diluent is lactose monohydrate.
Binders are used as a wet granulation excipient to agglomerate the active pharmaceutical ingredient and the other excipient. A binder is selected to improve powder flow and to improve compactibility. Examples of binders include, but are not limited to, cellulose derivative, such as microcrystalline cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose; polyvinyl pyrrolidone; gelatin; natural gums, such as acacia, tragaeanth, guar gum and pectin, starch paste, pregelatinized starch; sucrose, corn syrup; polyethylene glycols and sodium alginate; ammonium calcium alginate; magnesium aluminium silicate; and polyethylene glycols and sodium alginate; polyethylene glycols. Several co-processed filler-binders are commercially available, including cellacose (α-lactose monohydrate and powdered cellulose 75:25), microcelac, ludipress (93% β-lactose monohydrate, 3.5% polyvinylpyrrolidone and 3.5% crospovidone) and pharmatose DCL 40 (95% lactose and 5% lactitol).
Disintegrants are included in the invention include, but are not limited to, starch,
starch derivatives, sodium starch glycolate, croscarmellose sodium, Calcium Carboxymethyl cellulose, crospovidone and microcrystalline cellulose.
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The organic acid required in the control release formulation of the present invention is an amount of acid effective to create a microenvironment of low pH, in the vicinity
of the hydrating dosage form Viewed differently, an effective amount of organic
acid is the amount that facilitates dissolution of the basic drug throughout the GI tract. The precise amount may vary depending on the acid used and the choice of basic drug as will be known to one skilled in the art.
The organic acid for purposes of the present invention includes any organic carboxylic acid, preferably an aliphatic organic carboxyl acid having anywhere from C3-C20 carbon atoms. Preferred are, for example, tartaric acid, malic acid, succinic acid, glutaric acid, glutamic acid, maleic acid, mandelic acid and citric acid. The most preferred acid is citric acid.
The excipient used for producing effervescence includes any CO2 releasing pharmaceutically acceptable materials, preferably Sodium Bicarbonate or Calcium Carbonate but most preferably Calcium Carbonate.
In one of its aspects the invention provides sustained release, Satranidazole-containing compositions that permit a slow release of Satranidazole into the blood stream over a 24-hour period. The pharmaceutical compositions of the present invention that is capable of being compressed into a sustained release, once daily dosage form.
The compositions of present invention release greater than about 90% of their total Satranidazole content at a controlled rate over a 24-hour period.
The present invention also includes a method for making a composition of the invention, which method comprises producing satranidazole containing granules in a Fluidized bed Processor or Rapid Mixer Granulator employing aqueous binder. Then the use of HPMC as a retarding agent at lubrication stage with other suitable excipients yields tablets that provide controlled release characteristics useful for once daily oral administration of Satranidazole.
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The pharmaceutical composition of the present invention may include other drugs alone or in combination wherever known combination is required or beneficial.
Thus, for example, Satranidazole may be formulated in combination with a preparation for standard therapy of gastritis, ulcers or gastroesophagal reflux disease (GERD), preparations containing anti-ulcer or anti-gastritis medicaments; e.g., selected among gastric secretion inhibiting compounds such as omeprazole, cimetidine, ranitidine, lansoprazole, patoprazole, sucralfate, famotidine or nizatidine, or antacids such as magnesium hydroxide, aluminium hydroxide, sodium carbonate, sodium hydrogen carbonate, simethicone or aluminium magnesium hydroxide or hydrate thereof (such as the monohydrate known as magaldrate).


Dated this the 21st day of December 2006.

To:
The Controller of Patents, Patent Office, Mumbai 400 037