FORM 2
THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION "EXTENDED RELEASE COMPOSITION"
We, EMCURE PHARMACEUTICAL LTD., of ARC-H, P-2, I.T.-B.T. Park Phase-II, M.I.D.C., Hinjwadi, Pune-411057, Maharastra, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

EXTENDED RELEASE COMPOSITION FIELD OF THE INVENTION
The present invention relates to an extended release metronidazole composition for
oral administration and methods of preparation of the same. In particular, it relates to an extended release metronidazole composition, which comprises of a combination of a water-insoluble polymer and a hydrophilic polymer in a ratio range of about one-to-one (1:1) to about one -to-six (1:6) by weight. BACKGROUND OF THE INVENTION
Extended release pharmaceutical formulations provide a significant advantage over immediate release formulations to both clinicians and their patients. Sustained release dosage forms are administered to patients in much fewer daily doses than their immediate release counterparts and generally achieve improved therapeutic effect and efficiency in the fewer daily doses.
For example, generally accepted treatment entails orally administering 250 mgs of metronidazole three times a day for a period of 7 days. This results in a series of three serum concentration profiles in the patient in which there is a rapid increase of drug due to immediate release followed by a similar rapid decrease. Such rapid increases and decreases provide a patient with a short window of appropriate blood concentration of the medicament for optimum therapy. Additionally patient compliance is a problem since patients can inadvertently forget to take one or more doses during the course of treatment, causing the plasma metronidazole levels to drop to below an acceptable therapeutic level for a period of several hours or more, which is not desired.
A 750 mg extended release dosage form, on the other hand, may only have to be administered to a patient once every 24 hours to achieve therapeutic effect. Sustained release dosage forms generally control the rate of active drug absorption, so as to avoid excessive drug absorption while maintaining effective blood concentration of the drug to provide a patient with a consistent therapeutic effect over an extended duration of time. Besides reducing the frequency of dosing and providing a more consistent therapeutic effect, sustained release dosage forms generally help reduce side effects caused by a drug. Because sustained release dosage forms deliver the drug in slow, incremental amounts versus the cyclic high and low concentrations of immediate release formulations, it is easier for a patient's body to digest the drug, thereby avoiding undesirable side-effects. For patients who self-administer therapies, sustained release dosage forms generally result in greater
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compliance due to the lower frequency of dosing, lower quantity of dosage units to be consumed, and reduced undesired side-effects.
Furthermore, every medicament has different solubility properties and pH dependencies which affect its dissolution rate, and hence its bioavailability. Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the granulation process, compression forces (in tablet manufacturing), surface area available for dissolution and environmental factors such as agitation in the stomach and the presence of food. Due to these numerous factors, specific formulations of a specific medicament play an important role in the preparation of prolonged or sustained action solid dosage forms and preparation of these solid dosage forms to achieve appropriate bioavailability for optimum therapeutic effect still remains a challenge.
Metronidazole is chemically known as l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, and has long been used for the treatment of trichomoniasis and more recently for the treatment of bacterial vaginosis. The use of metronidazole is also known for the treatment of various other conditions, including amebiasis (acute amebic dysentery), and Helicobacter pylori infections associated with duodenal ulcer disease, see, e.g., D. Graham, et al, Annals of Internal Medicine, 115, 266-269 (1991).
Metronidazole is known to be effective for killing such microorganisms as Trichomonas vaginalis, Entamoeba histolytica, Helicobacter species, such as Helicobacter pylori, anaerobic gram-negative Bacilli, including Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Fusobacterium species, anaerobic Gram-positive bacilli including Clostridium species and susceptible strains of Eubacterium, anaerobic gram-positive cocci including Peptococcus species and Peptostreptococcus species, and the like.
In order to reduce the number of daily doses of metronidazole needed to treat a microbial infection, while maintaining the benefits of making bioavailable effective amounts of the drug over an extended time period, it would be desirable to be able to deliver a therapeutically effective amount of metronidazole in a once daily dose. One such composition Flagyl ER presently in market make use of Poly methacrylic acid ester copolymer, which was approved by USFDA long back in the year 1997, belonging to G.D Searl LLC and disclosed by Desai etal. in US 6,103,262 patent.
US Pat. No. 6,103,262 describes a sustained release composition tablet comprising of about 59-79 wt % of metronidazole and 1.5 to 3.0 wt % of aqueous insoluble poly(meth)
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acrylic acid ester copolymer which is aqueous permeable, aqueous expandable and pH-independent.
US Pat. No 6,663,890 describes a pharmaceutical composition of Metronidazole comprising of first, second and third dosage form, wherein the first dosage form is an immediate release dosage form and the second and third dosage forms are delayed release
dosage forms. Said composition provides a pulsatile release of metronidazole and not a sustained release, wherein the delayed release dosage form are essentially immediate release dosage form, which provides time delayed release of metronidazole.
US Pat. Application. No 20020132002 now abandoned discloses a sustained release pharmaceutical dosage form comprising a water soluble medicament and a polymer mixture of water insoluble poly vinyl acetate combined with hydrophilic polymer poly vinyl pyrrolidone in a ratio of 1:0.25, additionally comprising of a cellulose ether polymer. This is in contrast to the present finding, wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
Heretofore, in the last decade there has only been a single modified release oral tablet dosage of metronidazole suitable for once daily dosing, even though metronidazole has been an accepted therapeutic treatment for trichomoniasis for over more then last three decades (35 years).
Thus, understanding the dire need, the present invention provides with an alternate once a day dosage form of Metronidazole composition which is capable of delivering acceptable bioavailability for up to 24 hours. The composition which is readily compressible such that the size of a single tablet is in the range of about 1000-1100 mg while providing about 750 mg of metronidazole and the entire dose may be provided in a single tablet suitable for oral administration. SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical composition for once daily dosing of metronidazole having substantial bioequivalence to immediate release metronidazole given three times per day. The compositions of the present invention comprise greater than 70% metronidazole and less than 30% excipient, yet, surprisingly, are capable of being tabletted and of providing modified release of metronidazole for up to 24 hours.
The present invention provides a pharmaceutical composition of metronidazole, the composition comprising: a first granular portion which comprises of,
i. about 40 wt % to about 75 wt % of metronidazole
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ii. a water-insoluble polymer and
iii. a hydrophilic polymer; and a second granular portion which comprises of about 0 wt % to about 35 wt % of metronidazole; wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
In another embodiment also provided is a method for preparation of said pharmaceutical composition.
The use of a combination of the water-insoluble polymer and a hydrophilic polymer in a ratio range of about one-to-one (1:1) to about one-to-six (1:6) as a rate retarding polymer combination unexpectedly provides both modified release characteristics useful for once daily oral administration of metronidazole and compressibility characteristics which allow the compositions of the invention to be compressed into tablet form.
The present invention also relates to a method for treating an infection caused by a microorganism which is susceptible to metronidazole, which method comprises administering to a patient having the infection an effective amount of a composition of the invention once daily for a number of days sufficient to eliminate or resolve the infection. DEFINITIONS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The term "pharmaceutically acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term "therapeutically effective amount" means the amount of a compound that, when administered for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
The term "subject" or "a patient" or "a host" as used herein refers to mammalian animals, preferably human.
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The term "Cmax" means the maximum plasma metronidazole concentration achieved after oral administration of metronidazole. The terms "AUC" or "area under the curve" mean the total amount of metronidazole absorbed by the bloodstream in a predetermined time, generally 24 hours. AUC is a measure of bioavailability which is calculated by integrating plasma metronidazole levels with respect to time.
As used herein unless otherwise stated, all percentages for ingredients are weight percentages, based on the total weight of the pharmaceutical composition.
The term "water-insoluble polymer" may include but are not limited to polyvinyl acetate, polyvinyl alcohol, vinyl chloride/vinyl acetate copolymers, acrylate polymers and copolymers, ethyl cellulose and hydrogenated castor oil.
The hydrophilic polymer are may include but are not limited to poly vinyl pyrrolidone, cellulose derivatives such as hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose, hydroxyl propyl cellulose, methyl cellulose or sodium carboxy methyl cellulose, Polyethylene glycols, Polyethylene oxide, modified starch derivatives, acrylic resin, hydrophilic gums such as acacia, gum tragacanth, xanthum gum and guar gum.
The term "diluent" as used herein means inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "binders" as used herein means substances used to cause adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art. If required, other binders may also be included in the present invention. Exemplary binders include, but are not limited to, starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC.TM. F68, PLURONIC.TM. fl27), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, polypropylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide), microcrystalline cellulose, combinations thereof and other such materials known to those of ordinary skill in the art.
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The term "detackifier" as used herein means agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to reduce the tackiness of granules. Such compounds include, by way of example and without limitation, magnesium stearate, calcium sulphate, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "glidant" as used herein means agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The terms "lubricant" or "lubricating agent" as used herein means substances used in tablet formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of
ordinary skill in the art.
Most of these excipients are described in detail in, e.g., Howard C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein. BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical depiction of in vitro dissolution rates for Flagyl ER RTM Vs. Example 1 comprising of a preformed mixture of Poly vinyl acetate and poly vinyl pyrollidone in a ratio of about 1: 1.6.
FIG. 2 is a graphical depiction of in vitro dissolution rates for Flagyl ER RTM Vs. Example 2 comprising of a preformed mixture of Poly vinyl acetate and poly vinyl pyrollidone in a ratio of about 1: 2. DETAILED DESCRD7TION OF THE INVENTION
The present invention provides with an extended release pharmaceutical composition of metronidazole for once daily dosing of metronidazole.
The compositions of the present invention comprise greater than 70% metronidazole and less than 30% excipient, yet, surprisingly, are capable of being tabletted and of providing modified release of metronidazole for up to 24 hours. The present invention provides a
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pharmaceutical composition for once daily dosing of metronidazole having substantial bioequivalence to immediate release metronidazole given three times per day.
In one embodiment, the present invention provides with an extended release pharmaceutical composition of metronidazole which permit a slow release of metronidazole into the bloodstream over a 24 hour period. The pharmaceutical compositions comprising of: a first granular portion which comprises of,
i. about 40 wt % to about 75 wt % of metronidazole
ii. a water-insoluble polymer and
iii. a hydrophilic polymer; and a second granular portion which comprises of about 0 wt % to about 35 wt % of metronidazole; wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
In a preferred embodiment the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about 1:1.25 to about 1: 5.50.
In a further preferred embodiment the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about 1:1.50 to about 1: 5.25.
Further the water-insoluble polymer is selected from the group comprising of polyvinyl acetate, vinyl chloride/vinyl acetate copolymers, acrylate polymers and copolymers, ethyl cellulose and hydrogenated castor oil.
The preferred water-insoluble polymer is Poly vinyl acetate.
Further the hydrophilic polymer is selected from the group comprising of poly vinyl pyrrolidone, cellulose derivatives such as hydroxy propyl methyl cellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose, methyl cellulose or sodium carboxy methyl cellulose, Polyethylene glycols, Polyethylene oxide, modified starch derivatives, acrylic resin, hydrophilic gums such as acacia, gum tragacanth, xanthum gum and guar gum. A preferred hydrophilic polymer is Poly vinyl pyrrolidone.
In another embodiment the compositions of the present invention may comprise, optionally, a second granular portion of metronidazole which is present in an amount of up to 35 wt %. Said optional second granular portion of metronidazole can optionally be utilized in forming the granules, preferably the second granular portion is mixed with the first granular portion after they are made. Said optional second granular portion of metronidazole can be referred to as an "immediate release component".
In yet another embodiment the compositions of the present invention comprises of a preformed combination of water-insoluble polymer and a hydrophilic polymer in a ratio
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range of about one-to-one (1:1) to about one-to-six (1:6) either as a solution, aqueous dispersion, emulsion or a suspension.
Further preferred is, wherein the pharmaceutical compositions comprises of:
a first granular portion which comprises of,
i. about 43 wt % to about 53 wt % of metronidazole
ii. a water-insoluble polymer and
iii. a hydrophilic polymer; and a second granular portion which comprises of about 22 wt % to about 32 wt % of metronidazole; wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
In yet another embodiment the compositions of the present invention further comprises of pharmaceutically acceptable adjuvant such as detackifier, diluent, binder, glidant, lubricant, sweeteners, colorants etc.
The detackifier is selected from the group comprising of talc, magnesium stearate, and calcium sulphate or the combinations thereof. A preferred detackifier is talc.
The pharmaceutically acceptable diluent is selected from the group comprising of lactose, sucrose, dextrose, mannitol, sorbitol, and the like. Further, the preferred pharmaceutically acceptable diluent is lactose.
The pharmaceutically acceptable diluent may comprise up to 40 wt % of the total weight of the pharmaceutical compositions of the invention. The first granular portion may comprise of the pharmaceutically acceptable diluent in an amount of from about 5% to about 15 % by weight, preferably from about 7% to about 13% by weight, based on the total weight of the pharmaceutical composition.
The pharmaceutically acceptable binder is selected from the group comprising of acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, poly vinyl pyrrolidone, compressible sugar (e.g., NuTab), ethyl cellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch or the combinations thereof. A preferred pharmaceutically acceptable binder is Poly vinyl pyrrolidone.
The glidant is selected from the group comprising of colloidal silicon dioxide, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch and talc or the combinations thereof. A preferred glidant is colloidal silicon dioxide.
The lubricant is selected from the group comprising of magnesium stearate, calcium stearate, mineral oil, stearic add and mm stearate or the combitMtifens tajtooC IhfcljUfd lubricant is magnesium stearate.
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The pharmaceutical composition of the present invention is in a Tablet form.
In yet another embodiment provided herewith is a method of preparation of said
composition comprising the steps of:
a) granulating (i) about 40 wt % to about 75 wt % of the first granular portion of metronidazole optionally comprising of up to 25 wt % of a pharmaceutically acceptable diluent with (ii) a preformed combination of water-insoluble polymer and a hydrophilic polymer , optionally supplemented with an effective amount of a detackifier, using a fluid bed granulator, under conditions suitable for producing granules; and optionally milling and sieving said granules to provide a first granular portion with a substantially uniform particle size.
b) granulating about 0 wt % to about 35 wt % of metronidazole to form a second granular portion
c) blending said first granular portion of step (a) with said second granular portion of step (b) to provide a blend;
d) combining said blend of step (c) with an effective amount of a pharmaceutically acceptable glidant;
(e) blending the mixture of step (d) with an effective amount of a pharmaceutically
acceptable lubricant and optionally up to 25 wt. % of a pharmaceutically acceptable diluent;
(f) compressing a predetermined amount of the blended mixture of step (e) to produce a tablet; and
(g) optionally coating the tablet.
wherein said preformed combination of water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
Preferred composition of the present invention comprises between about 600 mg and about 1000 mg of metronidazole, more preferably about 750 mg of metronidazole, so as to provide a once daily dosage of metronidazole suitable for administration for a period of several days. It will be appreciated, however, that the compositions may be tabletted into smaller weight units if it were desired to administer more than one tablet at a time.
In general the pharmaceutical dosage forms are acceptable for use in accordance with the present invention; the choice of which is well within the skill of a person of ordinary skill
in this art based upon the properties of the dosage forms provided herein. For example, orally
administered solid dosage forms include but are not limited to capsules, dragees, granules, pills, powders, and tablets.
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In yet another embodiment provided herewith is a method for treating a patient infected with a microorganism which is susceptible to metronidazole, which method comprises administering a pharmaceutical composition of the present invention.
In yet another embodiment provided herewith is a method for treating a patient infected with a microorganism which is susceptible to metronidazole, which method comprises administering once daily to the patient a pharmaceutical composition of the present invention for a number of days sufficient to eliminate the infection.
Among the diseases or conditions which may be treated with once daily administration of the compositions of the present invention are trichomoniasis, bacterial vaginosis and duodenal ulcer disease which is associated with the presence of Helicobacter pylori. With respect to H. pylori, it is well known to administer metronidazole in combination with other active ingredients such as bismuth and amoxicillin or bismuth and tetracycline. Chiba et al., Am. J. Gastroenterology, 87, 1716-1727 (1992); E. Herschel et al., New England J. Med., 328, 308-312(1993).
A therapeutically effective regimen for treating an infection caused by a microorganism which is susceptible to metronidazole entails once daily oral administration of a composition of the invention, which is between about 600 mg metronidazole and about 1000 mg metronidazole, preferably about 750 mg metronidazole for a period of between about 5 days and about 15 days or more. The clinical resolution of the infection or disease is readily determined by a clinician of ordinary skill in the art, such as by microbiological testing or disappearance of clinically characteristic symptoms. The dosage of metronidazole given and/or the length of treatment may be increased or decreased based on the type of infection, the degree of susceptibility of the microorganism to metronidazole, the age and general health of the patient, and like factors of which a clinician of ordinary skill in the art is aware and utilizes in the management of a patient.
The invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. EXAMPLES Process for the preparation of Extended Release Metronidazole Composition
Pre-milled metronidazole and lactose were sieved through 30 mesh screen and blended in a fluidized bed granulator. Said blend was granulated with a mixture of talc and a preformed dispersion of poly vinyl acetate and poly vinyl pyrollidone (Kollicoat SR 30 D) using fluidized bed granulator fitted with a single spray arm having a nozzle. Granulation was
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carried out a temperature of about 30 °C with the spray gun operating at an atomizing pressure of 11 to 15 psig and a spray rate of about 6 to 8 gm/minute. Fluidization was continued further to achieve the moisture content between 1 to 2.5 %. Granules so obtained
were further mixed with colloidal silicon dioxide & Lactose (pre sifted through 40 # sieve) which were further blended with magnesium stearate (pre sifted through 40 # sieve) to
provide a granular metronidazole composition ready for tableting.
The granular metronidazole composition was compressed using a rotary tablet press fitted with punches having predefined dimension. The tablet so obtained was coated with Opadry coating using perforated coating pan at a rate of 3 to 4 gm/min. Formulations so prepared are as follows Example 1

mg/tab % w/w
Metronidazole (Milled) 750.0 81.52
Lactose (Pharmatose DCL 21) 52.0 5.65
Povidone K 30 20.0 2.17
Kollicoat SR 30 D Solids
(30 % solid dispersion of polyvinyl acetate 15.0 1.63
with PVP & SLS )
Talc 3.0 0.33
Colloidal Silicon Dioxide (Aerosil 200) 1.0 0.11
Lactose (Pharmatose DCL 21) 74.0 8.04
Magnesium Stearate 5.0 0.54
920.0
Example 2

mg/tab % w/w
Metronidazole (Milled) 750.0 71.43
Lactose (Pharmatose DCL 21) 124.0 11.81
Colloidal Silicon Dioxide (Aerosil 200) 5.0 0.48
Povidone K 30 35.0 3.33
Kollicoat SR 30 D Solids 21.0 2.00
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(30 % solid dispersion of polyvinyl acetate
with PVP & SLS )
Talc 4.0 0.38
Colloidal Silicon Dioxide (Aerosil 200) 5.0 0.48
Lactose (Pharmatose DCL 21) 100.0 9.52
Magnesium Stearate 6.0 0.57
1050
In Vitro Dissolution of Extended Release Metronidazole Composition
The dissolution tests were performed using the standard USP XXII Dissolution Apparatus 2 (paddles), run at 75 RPM, in Distilled Water at 37.degree. C for 24 hours. Flagyl ER RTM. (G. D. Searle & Co.), 750 mg tablet was used as control and compared with two different extended release formulations of the present invention each containing 750 mg of metronidazole. Said two extended release formulations are as disclosed in Example 1 and 2 above. The results of the in vitro dissolution tests are given below:
Table-1

IN-VITRO DISSOLUTION DATA
Time in hr Percentage Release
Flagyl ER Example 1 Example 2
1 17.1 18.9 19.0
2 28.8 28.6 28.0
4 43.8 41.8 39.7
6 53.6 50.9 49.3
8 60.6 58.9 58.1
10 67.2 65.9 66.1
12 71.8 71.2 73.3
16 77.3 79.5 81.4
20 83.3 85.9 88.7
24 87.0 90.6 93.2
The above results clearly demonstrate that the dissolution rates for the compositions of the invention correlate to the in vitro dissolution of sustained release metronidazole formulations available as brand name Flagyl ER®.
As a comparison form FIG.l and 2 demonstrates a well correlated, desirable in vitro release rates for sustained release metronidazole compositions of
the invention, as compared to sustained release metronidazole formulations
available as brand name Flagyl ER®.
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As will be understood by a person skilled in the art, said therapeutic blood or tissue levels or reduction in frequency of dosing can be achieved by a composition which demonstrates a slow but continuous drug dissolution over a prolong period
of time over a period of 24 hours as reflected in the Table 1 and figure 1 amd z Conclusion: The comparative dissolution data of Example 1 and Example 2 with Flagyl ER shows that the composition of the present invention is a sustained release composition.
Although, the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
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We claim
1. A pharmaceutical composition of metronidazole, comprising:
a first granular portion which comprises of
(i) about 40 wt % to about 75 wt % of metronidazole
(ii) a water-insoluble polymer and
(iii) a hydrophilic polymer; and a second granular portion which comprises of about 0 wt % to about 35 wt % of metronidazole; wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
2. A pharmaceutical composition as claimed in claim 1 wherein said water-insoluble polymer and a hydrophilic polymer are present as preformed combination.
3. A pharmaceutical composition as claimed in claim 2, wherein said preformed combination is in the form of solution, aqueous dispersion, emulsion or a suspension.
4. A pharmaceutical composition as claimed in any one of claims 1 to 3 wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about 1:1.25 to about 1:5.5.
5. A pharmaceutical composition as claimed in claim 4 wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about 1:1.5 to about 1:5.25.
6. A pharmaceutical composition as claimed in any preceding claim wherein the water-insoluble polymer is selected from the group comprising of polyvinyl acetate, Vinyl chloride/vinyl acetate copolymers, acrylate polymers and copolymers, ethyl cellulose and hydrogenated castor oil.
7. A pharmaceutical as claimed in claim 6, wherein the water-insoluble polymer is poly vinyl acetate.
8. A pharmaceutical composition as claimed in any preceding claim wherein the hydrophilic polymer is selected from the group comprising of poly vinyl pyrrolidone,
cellulose derivatives such as hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose, hydroxyl propyl cellulose, methyl cellulose or sodium carboxy methyl cellulose, Polyethylene glycols, Polyethylene oxide, modified starch derivatives, acrylic resin, hydrophilic gums such as acacia, gum tragacanth, xanthum gum and guar gum.
9. A pharmaceutical composition as claimed in claim 8 wherein the hydrophilic polymer
is poly vinyl pyrrolidone
10. A pharmaceutical composition as claimed in claim 2 wherein said water-insoluble
polymer is Poly vinyl acetate and said hydrophilic polymer is Poly vinyl pyrrolidone.
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11. A pharmaceutical composition as claimed in claim 1, in a tablet dosage form.
12. A pharmaceutical composition as claimed in claim 11, wherein the dosage form comprises about 600-1000 milligrams, preferably, 750 milligrams of metronidazole.
13. A pharmaceutical composition as claimed in claim 12, wherein the pharmaceutical dosage form comprises about 750 milligrams of metronidazole.
14. A process for the preparation of pharmaceutical composition of claim 1, comprising the steps of:

a) granulating (i) about 40 wt % to about 75 wt % of the first granular portion of metronidazole optionally comprising of up to 25 wt % of a pharmaceutically acceptable diluent with (ii) a preformed combination of water-insoluble polymer and a hydrophilic polymer , optionally supplemented with an effective amount of a detackifier, using a fluid bed granulator, under conditions suitable for producing granules; and optionally milling and sieving said granules to provide a first granular portion with a substantially uniform particle size.
b) granulating about 0 wt % to about 35 wt % of metronidazole to form a second granular portion
c) blending said first granular portion of step (a) with said second granular portion of step (b) to provide a blend;
d) combining said blend of step (c) with an effective amount of a pharmaceutically acceptable glidant;
e) blending the mixture of step (d) with an effective amount of a pharmaceutically acceptable lubricant and optionally up to 25 wt. % of a pharmaceutically acceptable diluent;
f) compressing a predetermined amount of the blended mixture of step (e) to produce a tablet; and
g) optionally coating the tablet.
wherein said preformed combination of water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).
15. A pharmaceutical composition of Metronidazole, substantially as described herein


with respect to the foregoing examples and accompanying drawings.


Dated this the 26th day of December 2006
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ABSTRACT EXTENDED RELEASE COMPOSITION
A pharmaceutical composition of metronidazole, comprising a first granular portion
which consists of
(i) about 40 wt % to about 75 wt % of metronidazole (ii) a water-insoluble polymer and (iii) a hydrophilic polymer;
and a second granular portion which comprises about 0 wt % to about 35 wt % of metronidazole; wherein the water-insoluble polymer and a hydrophilic polymer are present in a ratio range of about one-to-one (1:1) to about one-to-six (1:6).