FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
PHARMACEUTICAL COMPOSITION COMPRISING ROPINIROLE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957
and having its registered office at
Glenmark House, HDO - Corporate Bldg,
Wing -A, B.D. Sawant Marg,
Chakala, Andheri (East),
Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF INVENTION:
The present invention relates to pharmaceutical compositions and more particularly to a pharmaceutical composition containing ropinirole or a pharmaceutically-acceptable salt thereof.
BACKGROUND OF INVENTION:
Ropinirole, 4-[2-(dipropylamino) ethyl]-1, 3-dihydro-2H-indol-2-one, is a potent anti-parkinson's disease drug developed by SmithKline Beecham Pharmaceuticals. In United States of America Ropinirole is sold as Ropinirole Hydrochloride, under the tradename of Requip. US patent 4452808 assigned to the SmithKline Beecham describes the Ropinirole as a therapeutic agent. Another patent US 4824860 describes the use of Ropinirole in Parkinson's disease. Smithkline Beecham sells Requip Tablets since 1997.
Enough information is available in the prior art on various aspects of Ropinirole, which include, its use in parkinson's disease and restless leg syndrome , its synthesis on commercial scale, polymorphism exhibited by Ropinirole, and structurally related impurities which are associated with Ropinirole the synthesis of Ropinirole.
The presence of certain structurally related impurities in the Ropinirole is well known in prior art, moreover there are certain articles which describes the method of the separation and estimation of these impurities. Coufal, et al. in Journal of Chromatography: Biomedical Sciences and Applications, described the method to separate and quantify ropinirole and some impurities using capillary liquid chromatography applications.
In accordance with the present invention, while developing the pharmaceutical composition of Ropinirole HC1, we came across few other impurities additional to that of already known structurally similar impurities of Ropinirole. The present invention provides the solution towards the instability of pharmaceutical composition of Ropinirole HC1 and provides a pharmaceutical composition with acceptable storage life.
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OBJECTIVE OF INVENTION:
The objective of present invention is to provide a substantially stable pharmaceutical composition comprising Ropinirole or pharmaceutically acceptable salts thereof.
Another objective of the present invention is to provide a substantially stable pharmaceutical composition comprising Ropinirole or pharmaceutically acceptable salts thereof, and at least one stabilizer which controls an unknown individual impurity below 0.15%, more preferably below 0.1%.
Another objective of the present invention is to provide a substantially stable pharmaceutical composition comprising Ropinirole or pharmaceutically acceptable salts thereof, and at least one stabilizer, preferably a citric acid, which controls an unknown individual impurity below 0.15%, more preferably below 0.1%.
DETAILED DESCRIPTION OF INVENTION:
For the purpose of present invention the term "substantially stable pharmaceutical composition" represents the pharmaceutical composition wherein an unknown individual impurity is controlled below 0.15%, more preferably below 0.1%. The above said quantities of unknown impurities are calculated based on the dose of Ropinirole in each unit.
The stabilizer of present invention is a pharmaceutically acceptable material which controls the unknown individual impurity of the pharmaceutical composition of Ropinirole or pharmaceutically acceptable salts thereof, below 0.15%, more preferably below 0.1%.
A problem associated with the pharmaceutical composition of Ropinirole, is that during the accelerated stability testing conditions the unknown impurities at certain RRT values exceeds than 0.1%, which makes the formulation unacceptable with respect to the guidelines led by FDA for the approval of generic drug product. During the course of the development of pharmaceutical composition of Ropinirole HCl in the absence of any prominent stabilizer, we observed that unknown impurities more than 0.1% generates in the compositions, at the end of first or second month, at the storage condition of 40° C and 75% relative humidity. The impurities eluted at relative retention time 0.58, 0.85 and 2.93 were observed to be produced
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more than 0.1% in the formulation. In order to control the unknown impurities, the stabilizer was incorporated in the formulation which stabilized the formulation with respect to the quantity of unknown impurities.
Preferably the pharmaceutical composition of the invention is formulated into an oral dosage form, such as a tablet or capsule.
Accordingly a further aspect of the invention comprises a pharmaceutical composition comprising Ropinirole or pharmaceutically acceptable salt thereof, at least one stabilizer which is preferably an antioxidant and more preferably citric acid, and one or more fillers, disintegrate or lubricants and optionally a binder.
The stabilizer used for the purpose of present invention can be selected from the group comprising antioxidants not limited to Ascorbic acid (vitamin C), Tocopherol-derived compounds, Butylated hydroxyanisole (BHA), Butylated hydroxytoluene (BHT), ethylenediaminetetraacetic acid (EDTA), Tert-Butylhydroquinone, Citric acid. The most preferred stabilizer is Citric acid.
Suitable fillers include, for example, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose), calcium sulfate, xylitol and lactitol.
Suitable disintegrants include, for example, crosscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate.
Suitable binders include, for example, polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose,
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methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate.
Additional conventional excipients which may be added include preservatives, stabilizers, antioxidants, silica flow conditioners, antiadherents or glidants.
Typically the Ropinirole will be present in an amount within the range of 0.01 to 50%, for example 0.1 to 25%, such as 0.lto 20%, and particularly 0.1 to 18% by weight.
Typically one or more fillers will be present in an amount 2 to 50% by weight. Typically one or more binders will be present in an amount 2 to 50% by weight.
Typically one or more disintegrants will be present in an amount 1 to 10%, and especially 2 to 6% by weight.
Typically one or more lubricants will be present in an amount 0.5 to 3%, and especially 0.8 to 2% by weight.
The pharmaceutical composition of the invention may be prepared, using standard techniques and manufacturing processes generally known in the art, for example by sifting and dry blending the components.
In a preferred mode one or more fillers, one or more binders, as well as other additional excipients if desired are blended together. The components of the blend prior to blending, or the blend itself, may be passed through a mesh screen, for example a 40 mesh screen. The blend thus obtained was granulated with the aqueous solution of Citric Acid in Rapid Mixer Granulator (RMG). The wet granules were dried in Fluidized Bed Drier (FBD). The active ingredient and disintegrant were sifted through 40# and were mixed with the dried granules in blender for about 15 minutes. A lubricant, which may also be screened, is then added to the blend and blending continued until a homogeneous mixture is obtained. The mixture is then compressed into tablets.
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A tablet coating may then be applied, for example by spray-coating with a water-based film coating formulation. The coating of the tablets was done by Opadry suspension. The coating may comprise, for example, 0.5 to 10% by weight of the tablet composition, particularly 1 to 6%, and preferably 1 to 3%.
A further aspect of the present invention comprises a method of preparing a stabilized pharmaceutical composition which comprises incorporating aqueous solution of citric acid as granulating fluid.
The currently marketed composition Requip consist of croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.
The forthcoming section provides information regarding the analytical method that was used for the estimation of impurities associated with the Ropinirole HO.:
Mobile phase:
Mobile phase A: phosphate buffer pH 6.8
Mobile phase B: Acetonitrile
Phosphate buffer preparation: 6.8gm of potassium dihydrogen phosphate was weighed and transferred in l000ml of water, pH of buffer was adjusted to 6.8(±0.05) with triethylamine. The buffer solution was filtered through nylon 0.45u membrane filter, mixed and degassed.
Diluent preparation:
Methanol: Water (80:20v/v)
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Chromatographic conditions:
Column: X Terra RP18 (250x 4.6mm) 5μ Flow rate: 1.0 ml/min
Detection: 250 nm
Pump mode: Gradient
Injection volume: 25μL
Run time: 70 min
Column temperature: 40°C
Retention time: About 16 min (Ropinirole)
PREPARATION OF STANDARD SOLUTION (1.25PPM) 0.5%:
55mg of ropinirole hcl working standard (equivalent to 50mg of ropinirole base) was weighed and transferred to a 50ml volumetric flask.30ml of diluent was added and sonicated to dissolve the solids with occasional shaking and volume was made up by adding diluent.
5ml of the above mentioned solution was pipette out to a 100ml volumetric flask and diluted to volume with the diluent. Again 5ml of this solution was pipette out into 200ml volume flask and volume was made with diluent and mixed.
SAMPLE PREPARATION (250 ppm):
25 tablets were crushed and weighed accurately powder equivalent to 5mg ropinirole into 20ml volumetric flask. 15ml of diluent was added and sonicated for 20 minutes to disperse the powder completely. This solution was allowed to stand for 10 minutes. The volume was made up with diluent and mixed. This solution was centrifuged at about 2500rpm for 10 minutes. The supernatant liquid was filtered through Teflon 0.45u membrane filter and finally injected.
PLACEBO PREPARATION:
25 placebo tablets were crushed and weighed accurately powder equivalent to 5mg ropinirole into 20ml volumetric flask. 15ml of diluent was added and sonicated for 20 minutes to disperse
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the powder completely. This solution was allowed to stand for 10 minutes. The volume was made up with diluent and mixed. This solution was centrifuged at about 2500rpm for 10 minutes. The supernatant liquid was filtered through Teflon 0.45 membrane filter and finally injected.
The embodiments of the present invention are described according to the following examples. The advantages of the invention are illustrated by way of comparative data in tables that follow.
Example I:
In accordance with the present invention the pharmaceutical composition of Ropinirole HC1 was prepared by using excipients same as that of Requip tablets. Ropinirole was mixed with pharmatose 200M and lactose anhydrous (DCL 21). Further the blend was mixed with Avicel PH 112 and Ac Di Sol. Finally the obtained blend was lubricated with magnesium stearate. The blend was then compressed into tablets with the average weight of 150mg. Tablets were finally film coated with film forming coating agent i.e. hydroxypropyl methylcellulose. The coated tablets were then packed in the HDPE containers. Table 1 provides the quantitative formula of tablets produced in Example I.
Stability studies of the tablets produced in example I were initiated at accelerated conditions (40° C and 75% relative humidity) for three months. The results of the stability study are provided in table No 2. After the end of three months the unknown impurities at relative retention time (RRT) 0.85 and 2.93 were found to be more than 0.1%.
The marketed composition was also stored at same storage condition, which after the end of three months had unknown impurities more than 0.1%.
Example II:
DCL21, Pharmatose 200M & Avicel were sifted through 40#. The blend thus obtained was granulated with the aqueous solution of Citric Acid in Rapid Mixer Granulator (RMG). The wet granules were dried in Fluidized Bed Drier (FBD). Then Ropinirole HC1 and Ac-di-sol, sifted through 40#, were mixed with the dried granules in blender for 15 minutes. Finally the blend was
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lubricated with magnesium stearate. The lubricated blend was then compressed into the tablets with average weight 150mg. The tablets were coated with Opadry Suspensions. The coated tablets were packed in HDPE containers and subjected to the accelerated conditions (40°C and
75% relative humidity) for three months. Table 3 provides the quantitative formula of tablets produced in Example II.
The results of the stability data obtained after the end of three months has been provided in table
4.
Table 1: Quantitative Formula of Example I

Ingredients Quantity mg/tablet
Ropinirole HC1 0.285
Lactose Monohydrate (Pharmatose 200M) 15.000
Lactose Anhydrous (DCL 21) 58.715
Microcrystalline cellulose (Avicel PH 112) 70.000
Croscarmellose Sodium (Ac Di Sol) 4.500
Magnesium Stearate 1.500
HPMC 3.00
Total weight of tablet 153.000
Table 2: Stability Study for Example I

Time RRT 0.58 RRT 0.85 RRT 2.93
Initial 0.04 ND ND
1M 0.06 0.06 ND
2M 0.04 0.10 0.13
3M 0.05 0.23 0.25

Table 3: Quantitative Formula of Example II

Ingredients Mg /tablet
(DCL 21) Lactose Anhydrous 58.714
(Pharmatose 200M) Lactose Monohydarte 15.000
Microcrystalline celullose (Avicel PH 101) 68.50
Citric Acid 1.50
Ropinirole Hydrochloride 0.286
Croscarmellose Na (Ac-Di-Sol) 4.500
Mg Stearate 1.500
Weight of Core Tablet 150.000
Weight of Coating material 3.75
(Color of) Opadry film coats White
Table4: Stability Study for Example II

RRT 0.58 RRT 0.85 RRT 2.93
Initial 0.06 ND 0.05
IM 0.07 0.03 0.04
2M 0.10 ND 0.03
3M 0.06 0.02 0.05