WO2010044108A2

WO2010044108A2 - Controlled release formulations of ropinirole

Info

Publication number: WO2010044108A2
Application number: PCT/IN2009/000592
Authority: WO
Inventors: Pratibha Sudhir Pilgaonkar; Maharukh Tehmasp Rustomjee; Anilkumar Surendrakumar Gandhi; Atul A. Kelkar
Original assignee: Rubicon Research Pvt Ltd
Current assignee: Rubicon Research Pvt Ltd
Priority date: 2008-10-17
Filing date: 2009-10-16
Publication date: 2010-04-22
Anticipated expiration: 2011-04-17
Also published as: WO2010044108A3

Abstract

The present invention relates to non-swelling controlled release dosage forms comprising a therapeutically effective amount of ropinirole or a pharmaceutically acceptable salt thereof and at least one non-swelling release retardant. Further, the non-swelling controlled release dosage forms of the present invention provide effective plasma levels of ropinirole over a period of up to about 24 hours or more after administration.

Description

CONTROLLED RELEASE FORMULATIONS OF ROPINIROLE

Field of the Invention

The present invention relates to non-swelling controlled release dosage forms of ropinirole comprising at least one non-swelling release retardant. The present invention also relates to a process for the preparation of such non-swelling controlled release pharmaceutical formulations of ropinirole.

Background of the Invention

Ropinirole, used commonly as its hydrochloride salt, is a selective non-ergoline dopamine D₂ agonist indicated for use in the treatment of Parkinson's Disease. Dopamine agonists function by increasing the dopamine levels in the brain. Ropinirole overcomes the limitations of L-dopa therapy in the treatment of Parkinson's Disease and has been identified as a more specific dopamine D₂ agonist than dopamine agonists such as pergolide and bromocriptine.

Ropinirole has also been disclosed as being of potential use in the treatment of a variety of other conditions, such as fibromyalgia (U.S. Patent No. 6,277,875) and chronic fatigue syndrome (U.S. Patent No. 6,300,365). Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 -2 hours after administration.

Movement disorders are neurological conditions that affect the speed, fluency, quality, and ease of movement. Abnormal fluency or speed of movement (dyskinesia) may involve excessive or involuntary movement (hyperkinesia) or slowed or absent voluntary movement (hypokinesia). Non-limiting examples of movement disorders include ataxia (lack of coordination, often producing jerky movements), dystonia (causes involuntary movement and prolonged muscle contraction), Huntington's Disease (chronic progressive chorea), multiple system atrophies (e.g., Shy-Drager Syndrome), myoclonus (rapid, brief, irregular movement), Parkinson's Disease, progressive supranuclear palsy (rare disorder that affects purposeful movement), Restless Leg Syndrome (RSD) and periodic limb movement disorder (PLMD), tics (involuntary muscle contractions), Tourette's Syndrome, tremor (e.g., essential tremor, resting tremor), Wilson Disease (inherited disorder that causes neurological and psychiatric symptoms and liver disease). These excessive or otherwise abnormal involuntary movements may vary significantly in rate, frequency, periodicity and progression character and can present difficulty in the conventional multiple dose regime.

Parkinson's Disease is a progressive disorder of the nervous system that affects about 10 million people world-wide and is of increasing occurrence in aging populations. It is a highly specific degeneration of dopamine-containing cells of the substantia nigra of the midbrain causing a dopamine deficiency in the striatum. It affects neurons in the part of the brain that controls muscle movement and causes symptoms such as trembling, muscle rigidity, difficulty in walking, and problems with balance and coordination. These conditions result in poor patient compliance with multiple dosing regimes. Effective management of a patient with Parkinson's Disease is possible in the first 5-7 years of treatment, after which time a series of often debilitating complications, together referred to as Late Motor Fluctuations (LMF) occur (Lancet II: 345-349, 1997). Dopamine agonists like ropinirole that provide symptomatic benefit by directly stimulating post-synaptic striatal dopamine receptors are employed as monotherapy treatment alternative. They do not undergo oxidative metabolism and are not thought to accelerate the disease process.

Restless Leg Syndrome (RLS), also known as Ekbom's Syndrome is a fairly common sensorimotor disorder, characterized in that it typically gives the individual who suffers from

RLS an unpleasant sensation in the legs at rest, causing what is often described as an irresistible desire to move, which generally alleviates the discomfort. Ropinirole also has been shown to be effective in the treatment of RLS but the formulations need to release the drug in a controlled manner providing initial rapid relief followed by a sustained drug release profile to address continual symptomatic relief in RLS.

Movement disorders like restless leg syndrome and periodic limb movement during sleep are common in patients with fibromyalgia and chronic fatigue syndrome. Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal aches, pain and stiffness, soft tissue tenderness, general fatigue, and sleep disturbances. Chronic fatigue syndrome is a disorder that causes extreme fatigue that lasts longer with symptoms that include widespread muscle and joint pain, cognitive difficulties, chronic, often severe mental and physical exhaustion. Dopamine D2/D3 receptor agonists are used for the treatment of fibromyalgia and chronic fatigue syndrome. Ropinirole has also been investigated for the treatment of fibromyalgia and chronic fatigue syndrome and formulations capable of controlled release over a 24 hour period can ensure optimal control of the symptoms of both cases.

Ropinirole is presently marketed as its hydrochloride salt in an immediate-release tablet for the treatment of Parkinson's Disease (see European Patent Application EP-A-0299602). The drawback with this multiple dose regimen is that the "peak and trough" blood levels produced by multiple daily doses results in fluctuating stimulation of the dopaminergic neurons. These fluctuations may contribute to the pathogenesis of the motor complications in Parkinson Disease and reappearance of discomfort in RLS, fibromyalgia or other movement disorders. Therefore, there is a need to develop new and improved controlled release dosage forms of ropinirole capable of releasing the drug in a programmed manner either over a prolonged period of up to about 12 or up to about 24 hours or more after administration, or in a manner that would avoid peak and trough phenomenon for up to about 12 to up to about 24 hours to treat such a disease.

Attempts have been made to provide controlled release compositions of Ropinirole. Ropinirole hydrochloride has been disclosed as a 24-hour controlled release formulation (PCT Publication WO 01/78688). This multi-layer controlled-release tablet comprises: (a) one active layer containing: (i) an active substance (ropinirole), (ii) hydrophilic polymeric substances which swell and/or gel and/or erode upon contact with aqueous liquids, (iii) lipophilic substances, and (iv) adjuvant substances, wherein the weight ratio of the hydrophilic polymeric substances to the lipophilic substances contained in said active layer is in the range of 10: 1 to 0. 5: 1 and (b) one or more barrier layers containing one or more of hydrophilic polymeric substances which swell and/or gel and/or erode upon contact with aqueous liquids, lipophilic substances, and adjuvant substances. This formulation allows a constant and/or lower systemic concentration over a 24-hr period for Parkinson's Disease and avoids the necessity with the immediate release tablet of taking ropinirole three times a day. Though the formulation releases about 90 % drug in 24 hours, this is a technologically demanding composition involving special equipment such as multiple layer compression machine and a number of inactive excipients which makes the technology tedious and expensive. Moreover the dosage form is multiple layer formulation wherein the upper and lower barrier layers function to block drug release. Due to development of internal pressure by swelling of hydrophilic polymers of intermediate drug layer or due to peristaltic movement of stomach, there exists a possibility of separation of one or both of the barrier layers resulting in much faster drug release and associated adverse effects.

U.S. Patent Application 20070059365 describes a monolithic or a double layer tablet of ropinirole designed using a controlled release matrix comprising one or more dissolution rate controlling polymers like cellulose ethers, polysaccharides, polymethacrylates, cellulose esters, acrylic acid polymers, waxes, alginates and fatty acid derivatives, in combination with one or more pharmaceutically acceptable excipients. The formulation, when taken early evening, about 40 to 50 % drug is released by one hour to provide rapid relief from initial symptoms; followed by 95 % of drug release by 10 hours which was useful to take care of night-time RLS. U.S. Patent Application 20040247676A1 discloses the use of a dosage formulation or tablet comprising a mixed matrix of hydrophilic and lipophilic components able to control the release rate of ropinirole This multi-layer controlled-release tablet comprises: (a) one active layer comprising: (i) ropinirole or a pharmaceutically acceptable salt thereof, (ii) two or more hydrophilic polymeric substances, (iii) one or more lipophilic substance, and (iv) one ore more optional adjuvant substances and (b) one or more barrier layer. Compositions of this invention need to utilize at least two hydrophilic polymers, preferably hydroxymethylcellulose and sodium carboxymethylcellulose which due to their swelling and viscosity-increasing properties respectively are said to provide the desired controlled release profile. Both of the above patent applications describe use of hydrophilic polymers for retarding the release of ropinirole. Hydrophilic polymers, although employed widely provides first order release profile with burst effect and due to their swelling nature may lead to unpredictable and variable gastrointestinal transit indicated by lack of IVIVC. Such limitations may also result in variability in drug response. Further it is difficult to arrive at a constant release (zero order) formulation using these polymers.

Thus, though there have been attempts to control the release rate of ropinirole, the resulting formulations have been either technologically demanding requiring special equipments for manufacturing or employ hydrophilic swelling polymers as release retardants which does not provide a zero order constant release rate. With both these technologies there exists a possibility of higher burst release which is of a great concern considering potency of ropinirole and associated adverse effects such as nausea and vomiting. Hence there exists a need to develop controlled release dosage forms of ropinirole based on a process that is simple, reproducible and amenable to large scale manufacture using conventional equipment and which provides the desired release profile without rapid burst release. There also exists a need for dosage forms that are non-swelling, exhibit pH-independent release profile and retain their size substantially throughout the gastrointestinal tract in order to achieve better reproducibility and predictability in release rates.

Summary of the Invention

The present invention relates to non-swelling controlled release dosage forms comprising a therapeutically effective amount of ropinirole, or a pharmaceutically acceptable salt thereof, and at least one non-swelling release retardant. The non-swelling controlled release dosage forms of the present invention provide effective plasma levels of ropinirole over a period of up to about 12 hours or more after administration. The formulations of the present invention can be used for the manufacture of a medicament for the treatment of movement disorders such as, for example, Parkinson's Disease, Restless Leg Syndrome and fibromyalgia. Detailed Description of the Invention

Restless Leg Syndrome, a neurologic condition, presents sensory and motor symptoms which include leg discomfort and deep paresthesia leading to motor restlessness to relieve symptoms, disruption of sleep onset, multiple awakenings, and varying degrees of arousal. Symptoms may occur in the evening and night-time, and some patients experience daytime symptoms. Quality of life of these patients is negatively impacted. There exists a need, therefore, for controlled release formulations which when taken at late evenings can provide symptomatic relief to patients with initial rapid relief followed by sustained relief throughout the night. Parkinson's Disease is a chronic, progressive, neurodegenerative disorder with symptoms that include tremors, slowness of movement, stiffness, gait and posture problems. There exists a need for controlled release formulations that can significantly reduce 'off time when Parkinson's Disease symptoms return, allowing patients to continue their daily activities for a longer period of time. The oral controlled release tablet formulation of ropinirole for the treatment of Parkinson's Disease and Restless Leg Syndrome, marketed under the tradename REQUIP®XL™ and developed by GlaxoSmithkline, is based on the use of swelling polymers in the active layer of their multilayered dosage form Fibromyalgia is a chronic condition characterized by widespread pain in muscles, ligaments and tendons, as well as fatigue and multiple tender points. Need exists for once-a-day formulations which could address the waxing and waning symptoms associated with the disease.

The disorders referred to above pose separate demands regarding drug release profiles and it is difficult for a composition to conform to these diverse needs. The present invention addresses the need for developing a non-swelling controlled release dosage form providing effective plasma levels of ropinirole over a period of up to about 24 hours or more after administration, having great utility for the treatment of disorders like Parkinson disease, Restless Leg Syndrome or fibromyalgia. It was surprisingly found that the much desired drug release over a period of up to about 12 hours or up to about 24 hours after administration of the dosage form was achieved using at least one non-swelling release retardant. In one embodiment of the present invention, ropinirole is used in the form of a pharmaceutically acceptable salt thereof. Suitable salts include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid. The term "salt" or "salts" also include addition salts of free acids or free bases. All such salts are acceptable provided that they are non-toxic and do not substantially interfere with the desired pharmacological activity. Additionally, polymorphs, hydrates and solvates as well as amorphous forms of ropinirole can be utilized for the purpose of the present invention. The term "ropinirole" as used in the present invention relates to either the free base or pharmaceutically acceptable salts thereof.

The compositions of the present invention include about 0.01% to about 50% by weight of ropinirole. In one embodiment of the present invention, the compositions of the present invention include about 0.05% to about 35%. In another embodiment, the compositions of the present invention include about 0.05% to about 10% by weight of ropinirole.

The term "non-swelling controlled release dosage form" as used herein refers to a dosage form that is substantially non-swellable and also significantly non-eroding during the release of ropinirole at a predetermined rate, thereby maintaining its size during drug release. The term "substantially non-swellable" as used herein refers to a dosage form that does not swell to more than 20% of the total volume of the dosage form in about one hour in an aqueous buffer system simulating physiological gastrointestinal environment. In one embodiment of the present invention, the dosage form does not swell to more than 15% of the total volume of the dosage form in about one hour in an aqueous buffer system simulating physiological gastrointestinal environment. In another embodiment of the present invention, the dosage form does not swell to more than 10% of the total volume of the dosage form in about one hour in an aqueous buffer system simulating physiological gastrointestinal environment. The term 'non-swelling release retardant' as used herein refers to any excipient that does not swell in water or swells only moderately with its swelling index (swelling volume in ml per 1.0 gm of excipient determined using the method laid down in European Pharmacopoeia 6.0) being not more than 15 and can retard the release of an active pharmaceutical ingredient from a dosage form. In one embodiment of the present invention the non-swelling release retardant does not swell in water or swells only moderately with its swelling index being not more than 10. In another embodiment of the present invention the non-swelling release retardant does not swell in water or swells only moderately with its swelling index being not more than 5. In a still another embodiment of the present invention the non-swelling release retardant does not swell in water or swells only moderately with its swelling index being not more than 3. The terms "formulation", "dosage form" and "composition" are used interchangeably herein and denote the non-swelling controlled release dosage form of the present invention comprising a therapeutically effective amount of ropinirole, or a pharmaceutically acceptable salt thereof, and at least one non-swelling release retardant. The term "therapeutically effective amount" as used herein refers to a nontoxic but sufficient amount of the active agent required to provide the desired therapeutic, preventive and/or beneficial effect. The amount of active agent that is "effective" will vary from subject to subject, depending on the age, type of disorder and general condition of the individual, and the like. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

In order to achieve controlled release properties of the compositions of the present invention, ropinirole is incorporated in the dosage form with at least one non-swelling release retardant. Non-swelling release retardants are excipients which by way of various mechanisms retard release of the active ingredient. The release retardants used in the present invention prevents rapid release of the so as to result in a drug overdose nor do they retard drastically resulting in very slow release to achieve the desired biological effect. The non-swelling release retardants for formulating the controlled release dosage form of the present invention include, but are not limited to, non-swelling polymeric release retardants and non-swelling non-polymeric release retardants.

Non-swelling non-polymeric release retardants are those release retardants which do not comprise repeating units of monomers. According to the present invention, non-swelling non-polymeric release retardants include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, or combinations thereof. Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids useful in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol and mixtures thereof.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low-melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols. Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof. Mixtures of these waxes with the fatty acids may also be used.

Waxes are also monoglyceryl esters, diglyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol is substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleyl macrogolglycerides, stearoyl macrogolglycerides, and the like, and mixtures thereof.

In the one embodiment the non-swelling non-polymeric release retardant employed includes, but is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean oil), Castorwax® (Hydrogenated castor oil, Croduret® (Hydrogenated castor oil), Carbowax®, Compritol (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil, Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofϊne® (Hydrogenated cottonseed oil), Softtisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol® diisostearique (Polyglyceryl Diisostearate), Geleol® (Glyceryl Stearate), and mixtures thereof. In a further embodiment the non-polymeric release retardant employed includes, but is not limited to, Compritol®, Sterotex®, Lubritab®, stearic acid, cetyl alcohol, and mixtures thereof. According to the present invention, non-swelling polymeric release retardant can be pH independent or pH dependent. Non-swelling polymeric release retardants that are pH dependent exhibit pH dependent solubility, and hence their performance depends on the pH of the environment they encounter. Non-swelling polymeric release retardants that are pH independent exhibit solubility that is independent of pH and hence its performance does not depend on the pH of the environment they encounter. The non-swelling polymeric release retardants employed in the present invention tend to have lower variability compared to swelling polymeric systems.

Non-swelling pH independent polymeric release retardants employed in the present invention include, but are not limited to, polyvinyl acetate, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon® SR), polymethacrylic acid derivatives, cellulose derivatives, and combinations thereof. Cellulose derivatives that may be employed include, but are not limited to, ethyl cellulose. Polymethacrylic acid derivatives that may be employed include, but are not limited to, ammonio methacrylate copolymer (e.g., Eudragit® RLPO, Eudragit® RSPO available from Rohm Pharma), ethylacrylate^'methylmethacrylate copolymer (e.g., Eudragit® NE3 OD available from Rohm Pharma) and the like, or combinations thereof. In one embodiment, the non-swelling polymeric release retardant employed is Kollidon® SR.

Kollidon® SR is a sustained release matrix forming agent consisting of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w). Kollidon® SR has free-flowing, non- hygroscopic and directly compressible properties (high dry binding capacity). Further, in vitro drug release profiles of tablet formulations with Kollidon SR as sustained release matrix forming agent are not influenced by pH of dissolution media, ionic strength of dissolution media, speed of agitation and compression force. This unique property of Kolidon® SR makes it one of the most promising sustained release matrix forming agents especially where pH independent release is desired. However Kollidon® SR based formulations have tendency to show higher burst release (excessive drug release in initial hours) by dissolution of drug remaining on the tablet surface as soon as the tablet comes in contact with aqueous media/fluid, thus deviating the drug release kinetics far away from zero order kinetics (linear release). Thus, higher burst release poses major limitation on use of Kollidon® SR as sustained release matrix forming agent whenever lower burst release is desired/ required. Compositions of the present invention can address this limitation and control burst release as desired.

In one embodiment, non-swelling pH dependent polymeric release retardants employed include, but are not limited to, polymethacrylic acid derivatives, cellulose derivatives, acrylic acid derivatives, maleic acid copolymers, polyvinyl derivatives, and combinations thereof.

Cellulose based pH dependent release retardants include, but are not limited to, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxy ethylcellulose phthalate and the like, and combinations thereof.

Acrylic copolymer based pH dependent release retardant includes, but is not limited to, styrene^' acrylic acid copolymer, methyl acrylate^' acrylic acid copolymer, methyl acrylate^'methacrylic acid copolymer, butyl acrylate^'styrene^'acrylic acid copolymer, methacrylic acid^'methyl methacrylate copolymer {e.g., Eudragit® L 100 and Eudragit® S, available from Rohm Pharma), methacrylic acid^'ethyl acrylate copolymer (e.g., Eudragit® L 100-55, available from Rohm Pharma), methyl acrylate^'methacrylic acid^'octyl acrylate copolymer and the like, and combinations thereof.

Maleic copolymer based pH dependent release retardant includes, but is not limited to, vinylacetate^'maleic acid anhydride copolymer, styrene^'maleic acid anhydride copolymer, styrene^'maleic acid monoester copolymer, vinylmethylether^'maleic acid anhydride copolymer, ethylene^'maleic acid anhydride copolymer, vinylbutylether^'maleic acid anhydride copolymer, acrylonitrile^'methyl acrylate^'maleic acid anhydride copolymer, butyl acrylate^'styrene^'maleic acid anhydride copolymer and the like, and combinations thereof.

Polyvinyl derivative based pH dependent release retardants includes, but is not limited to, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate and the like, and combinations thereof.

In one embodiment, non-swelling pH dependent polymeric release retardant employed is methacrylic acid^'methylmethacrylate copolymer and methacrylic acid^'ethylacrylate copolymer available under the brand name Eudragit®.

The amount of non-swelling release retardant used in the formulation may vary depending upon the degree of controlled release desired. In an embodiment, non-swelling release retardant is present in the formulation in an amount from about 2% to about 95% by weight of the dosage form. In another embodiment, non-swelling release retardant is present in the formulation in an amount from about 5% to about 85% by weight of the dosage form. In a further embodiment, non-swelling release retardant is present in the formulation in an amount from about 5% to about 80% by weight of the dosage form.

In an embodiment of the present invention one or more non-swelling release retardants can be combined with at least one swelling release retardant. The swelling release retardant that can be incorporated in the compositions of the present invention includes, but is not limited to, polymers that are nontoxic and swell in a dimensionally unrestricted manner upon imbibition of fluids. Swelling release retardants which can be used include, but are not limited to, polyalkylene oxides, cellulosic polymers, acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers, polymaleic acid, poly(acrylamides), poly(olefinic alcohol)s, poly(N-vinyl lactams), polyols, polyoxyethylated saccharides, polyoxazolines, polyvinylamines, polyvinylacetates, polyimines, starch and starch-based polymers, polyurethane hydrogels, chitosan, polysaccharide gums, zein, shellac- based polymers. In a further embodiment, swelling release retardants that can be optionally included in the dosage forms of the present invention include, but are not limited to, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch and polyvinyl alcohol, copolymers and mixtures thereof.

The composition of the present invention further typically includes at least one pharmaceutically acceptable excipient to ease the manufacturing process as well as to improve the performance of the dosage form. Common excipients that may be employed include, but are not limited to, diluents, lubricants, binders, colorants, flavorants, surfactants, pH adjusters, anti-adherents, gildants and the like.

The present invention may additionally include one or more diluents including, but not limited to, lactose, lactose monohydrate, sugar, dextrate, dextrate hydrated, dextrins, fructose, lactitol, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose, or mixtures thereof in an amount within the range of from about 0 to about 90% by weight. In another embodiment, the filler may be present in an amount of about 1% to about 80% by weight.

Binders employed in the dosage form include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, copovidone, polymethacrylic acid derivative, ethyl cellulose, cross-linked carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, natural or synthetic gums and the like or mixtures thereof. In one embodiment, the binder is copovidone. Binders may be incorporated into the system in an amount of about 0.5% to about 20% by weight of the dosage form. In another embodiment, the binder may be incorporated in an amount of about 1% to about 10% by weight of dosage form. In a further embodiment, the binder may be present in an amount of about 2% to about 7.5% by weight of the dosage form.

Lubricants employed in the dosage form include, but are not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof. Lubricants may be employed in an amount of from about 0.2 to about 8% by weight of the dosage form. In another embodiment, lubricants may be employed in an amount of from about 0.5 to about 2% by weight of the dosage form. Compositions of the present invention may optionally also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. Anti-adherents employed in the dosage form include, but are not limited to, talc, magnesium stearate or finely divided silica, or combinations thereof. Examples of surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof. pH adjusters include, but are not limited to, sodium citrate, magnesium oxide, citric acid or combinations thereof. One or more flavorants employed, include but are not limited to, mint flavor, orange flavor, lemon flavors, strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor, tutty frutty flavr, magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts. One or more colorants employed, include, but are not limited to, titanium dioxide, dyes, lake pigments or natural colors.

The dosage form of present invention is a solid dosage form such as, but not limited to, tablet, granule, spheroid, bead, pellet or capsule. In one embodiment, the solid dosage form is a tablet which may vary in shape such as oval, triangle, almond, peanut, parallelogram, pentagonal, hexagonal, and trapezoidal. In one embodiment, the dosage form shapes are oval and parallelogram. In another embodiment, the tablet dosage form may be monolithic or multilayered. In one embodiment, a solid pharmaceutical composition in the form of a multilayer system for oral administration may be adapted to deliver one more active agent in addition to ropinirole, selected from, but not limited to, levodopa, carbidopa, clenbuterol, fenoterol, formoterol, [R, R]-formoterol, metaproterenol, picumeterol, pirbuterol, procaterol, reproterol, rimiterol, hexoprenaline, isoetharine, isoprenaline, salbutamol, [R]-salbutamol, salmeterol, [R]- salmeterol, terbutaline, tulobuterol, TA-2005, or combinations thereof. In an embodiment, the system may also be adapted to deliver base and salt form of ropinirole to achieve controlled release over a period of 24-hours. In a further embodiment a solid pharmaceutical composition in the form of a multilayer system for oral administration is adapted to deliver ropinirole from a first layer immediately upon reaching the gastrointestinal tract, and to deliver a further pharmaceutical agent which may be ropinirole or another active agent from a second layer, in a controlled manner over a specific time period.

In one of the embodiment of the present invention, the dosage form may be optionally coated. Surface coating may be employed for aesthetic purposes or for dimensionally stabilizing the compressed dosage form. The coating may be carried out using any conventional technique employing conventional ingredients suitable for oral use. A surface coating can, for example, be in the form of a film using conventional polymers including, but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol polymethacrylates and the like, and combinations thereof. In another embodiment of the present invention, the composition may be optionally coated with a functional coat. The functional coat may be applied using coating agents including, but not limited to, hydrophilic polymers, hydrophobic polymers, waxes, and the like, or mixtures thereof, either alone or in combination, along with plasticizers, colorants, opacifiers etc. Non- limiting examples of such coating agents include, but are not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethylcellulose, polymerthacrylates and the like, and combinations thereof. The functional coat may help provide the desired drug release profile. The functional coat may also inhibit the release of ropinirole in the stomach, if so desired. In one embodiment, non-swelling dosage form formulated according to the invention allows for controlled release of ropinirole following oral administration, with the in vitro release rate corresponding to the following % rate of active agent released as shown in Table A:

TABLE A

In another embodiment the dosage form for controlled release has an in vitro release rate corresponding to the following % rate of ropinirole released as shown in Table B:

TABLE B

In a further embodiment, the non-swelling dosage form of the present invention for controlled release has an in vitro release rate corresponding to the following % rate of ropinirole released as shown in Table C: TABLE C

A yet another embodiment, the dosage form in accordance with the invention for controlled release has an in vitro release rate corresponding to the following % rate of ropinirole released as shown in Table D:

TABLE D

In a further embodiment, the dosage form in accordance with the invention for controlled release has an in vitro release rate corresponding to the following % rate of ropinirole released as shown in Table E: TABLE E

In a still another embodiment, the in vitro dissolution release of the controlled release dosage form of the present invention for administration once daily is between 5 and 50% (by weight) ropinirole released after 1 hour, between 10 and 75% (by weight) ropinirole released after 2 hours, between 20 and 95% (by weight) ropinirole released after 4 hours, between 40 and 100% (by weight) ropinirole released after 8 hours, more than 50% (by weight) ropinirole released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) ropinirole released after 24 hours.

The dosage form of the present invention can be prepared by direct compression or granulation techniques. Direct compression technique involves compression of active agent and at least one non swelling release retardant alone or in combination with other release retardants after mixing them for a definite time period with other excipients. This technique can be applied effectively as the said non swelling release retardants are directly compressible. Granulation is any process of size enlargement whereby small particles are gathered together into larger, permanent aggregates to render them into a free flowing state. Either wet granulation or dry granulation or melt granulation methods can be used. In case of melt granulation, the non-polymeric release retardant is melted and the active agent is added and mixed with the molten mass effectively, allowed to solidify and thus producing drug granules. In another embodiment, the active agent is granulated using a molten non- polymeric release retardant. Drug granules thus obtained could be coated with a release retardant before incorporation into a dosage form. In case of wet granulation active agent is blended with a binder and granulation is carried out using a solvent. Alternatively a blend of active agent and other inactive excipients is granulated using a binder solution. Dry granulation process employs a roller compaction process. The composition of the present invention is easy to scale up as it involves processes routinely carried out in pharmaceutical industry.

In one embodiment, the method of preparing a non-swelling controlled release dosage form of ropinirole, or a pharmaceutically acceptable salt thereof, comprises the steps of:

(a) granulating ropinirole, or a pharmaceutically acceptable salt thereof, with at least one non-swelling release retardant to form drug granules;

(b) blending the drug granules of step (a) with at least one same or different non-swelling release retardant to form a blend; and

(c) compressing the blend of step (b) to form monolithic tablets.

In another embodiment, the method of preparing a non-swelling controlled release dosage form of ropinirole, or a pharmaceutically acceptable salt thereof, comprises the steps of: (a) granulating ropinirole, or a pharmaceutically acceptable salt thereof, with at least one non-swelling release retardant to form drug granules;

(b) blending the drug granules of step (a) with at least one same or different non-swelling release retardant to form a blend;

(c) compressing the blend of step (b) to form monolithic tablets; and (d) coating the tablets of step (c).

The preparation of the non-swelling dosage form of the present invention is technologically simple, being limited only to technological steps that are not demanding with respect to energy and time. The method of preparation and choice of supplemental substances according to the invention, described herein, also ensure very good stability and the desired physical properties of the drug form as well as the required dissolution profile.

As the non-swelling dosage form of the present invention employs non-swelling release retardants it is less affected by physiological variations and low patient-to-patient variability may be observed which is desirable for maximum therapeutic benefits.

A controlled release preparation according to the present invention is one which that achieves release of ropinirole over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. In an embodiment, composition of the present invention maintains drug concentration in the blood within the therapeutic range for up to about 12 hours or more. In another embodiment, composition of the present invention releases ropinirole or a pharmaceutically acceptable salt thereof for over a period of up to about 12 hours or more. In still another embodiment, composition of the present invention releases ropinirole or a pharmaceutically acceptable salt thereof for over a period of up to about 24 hours or more.

In a further embodiment is provided use of the non-swelling dosage form of the present invention for the manufacture of a medicament for the treatment of movement disorders such as but not limiting to, ataxia (lack of coordination, often producing jerky movements), dystonia (causes involuntary movement and prolonged muscle contraction), Huntington's Disease (chronic progressive chorea), multiple system atrophies (e.g., Shy-Drager Syndrome), myoclonus (rapid, brief, irregular movement), Parkinson's Disease, progressive supranuclear palsy (rare disorder that affects purposeful movement), Restless Leg Syndrome (RSD) and periodic limb movement disorder (PLMD), tics (involuntary muscle contractions), Tourette's Syndrome, Tremor (e.g., essential tremor, resting tremor), Wilson Disease (inherited disorder that causes neurological and psychiatric symptoms and liver disease) and/or fibromyalgia or chronic fatigue syndrome. In another embodiment of the present invention, there is provided a use of the non-swelling controlled release dosage form of the present invention for the manufacture of a medicament for the treatment of disorders like Parkinson's Disease, Restless Leg Syndrome or fibromyalgia.

In a still further embodiment, a method of treating movement disorder such as ataxia, dystonia, Huntington's Disease, multiple system atrophies, Shy-Drager Syndrome, myoclonus, Parkinson's Disease, progressive supranuclear palsy, Restless Leg Syndrome, periodic limb movement disorder, tics, Tourette's Syndrome, Tremor or Wilson Disease comprises administering to the subject in need thereof a non-swelling controlled release composition of the present invention.

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 invention is further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way.

EXAMPLES

Example 1

Ropinirole controlled release tablets using glyceryl behenate and Kollidon® SR Table 1 : Composition of ropinirole controlled release tablets

Weighed quantity of dextrate hydrated was mixed with ropinirole hydrochloride and added to molten glyceryl behenate to form a homogenous mixture that was allowed to cool to room temperature and sifted to obtain a granular mass. Ropinirole granules were blended with microcrystalline cellulose, Kollidon® SR and copovidone. This blend was lubricated using magnesium stearate and the lubricated blend was compressed to get the tablets.

Dissolution Study:

In vitro release profile of ropinirole was studied in pH 4 citrate buffer using USP Type II dissolution apparatus with 100 rpm rotation speed at temperature 37.5 ± 0.5⁰C. Table 2: Dissolution data of ropinirole controlled release tablet

Example 2

Ropinirole controlled release tablets using granule coating

Table 3: Composition of ropinirole granules prepared by melt granulation

Ropinirole hydrochloride was blended well with lactose monohydrate. Glyceryl behenate was melted and above blend was mixed with it. This mass was heated to 60° C with constant mixing for about 30 minutes. Resultant mass was cooled and sieved.

Table 4: Composition of coating solution

Methocel™ E-5 LV was dissolved in a part of water. To this solution Surelease® dispersion was added and finally balance quantity of water was added with stirring. Ropinirole granules were coated with above solution to a weight gain of 12% in a fluidized bed coater.

Table 5: Composition of controlled release tablet

Coated ropinirole granules were mixed well with Kollidon®SR, microcrystalline cellulose and copovidone and lubricated with magnesium stearate. The blend was compressed to get the tablets with optimum hardness and thickness.

Dissolution Study: In vitro release profile of ropinirole formulation was studied in pH 4 citrate buffer using USP Type II dissolution apparatus at temperature 37.5 ± 0.5⁰C.

Table 6: Dissolution data of ropinirole controlled release tablet

Example 3

Ropinirole controlled release tablets using Eudragit® RLPO and Kollidon® SR

Table 7: Composition of ropinirole controlled release tablets

Weighed quantity of ropinirole hydrochloride was mixed with Eudragit® RLPO, microcrystalline cellulose and was granulated using aqueous solution of copovidone. Ropinirole granules were blended with microcrystalline cellulose, Kollidon® SR and copovidone. This blend was lubricated using magnesium stearate and the lubricated blend was compressed to get the tablets.

Dissolution study:

In vitro release profile of ropinirole was studied in pH 4 citrate buffer using USP Type II dissolution apparatus with 100 rpm rotation speed at temperature 37.5 ± 0.5 C.

Table 8: Dissolution data of ropinirole tablet

Example 4

Ropinirole controlled release tablets using Eudragit® LlOO and ethylcellulose Table 9: Composition of ropinirole controlled release tablets

Weighed quantity of ropinirole hydrochloride was mixed with Eudragit® LlOO, microcrystalline cellulose and was granulated using aqueous solution of copovidone. Ropinirole granules were blended with microcrystalline cellulose, ethyl cellulose and copovidone. This blend was lubricated using magnesium stearate and the lubricated blend was compressed to get the tablets.

Example 5 Ropinirole controlled release tablets using glyceryl behenate and Kollidon® SR

Table 10: Composition of ropinirole controlled release tablet

Weighed quantity of ropinirole hydrochloride was mixed with dextrate hydrated and crospovidone. Glyceryl behenate was heated to about 70 C to melt and ropinirole and dextrate mixture was added to it and mixed well. This was cooled to room temperature to obtain a granular mass. Ropinirole granules were blended well with microcrystalline cellulose, Kollidon® SR and copovidone. This blend was lubricated using magnesium stearate and was compressed into tablets of optimum hardness.

Dissolution Study:

In vitro release profile of ropinirole formulation was studied in pH 4 citrate buffer using USP Type II dissolution apparatus at temperature 37.5 ± 0.5⁰C. Table 11 : Dissolution data of Ropinirole controlled release tablet

Example 6

Ropinirole controlled release tablets using glyceryl behenate and KoIIidon® SR

Table 12: Comopsition of ropinirole controlled release tablet

Weighed quantity of ropinirole hydrochloride was mixed with dextrate hydrated and Kollidon® SR. Glyceryl behenate was heated to about 70⁰C to melt and ropinirole and dextrate mixture was added to it and mixed well. This was cooled to room temperature to obtain a granular mass. Ropinirole granules were blended well with microcrystalline cellulose, Kollidon® SR and copovidone. This blend was lubricated using magnesium stearate and was compressed into tablets of optimum hardness. The tablets were coated with functional coat comprising of a combination of ethylcellulose and hypromellose and aesthetic coat of hypromellose to the final weight of 343mg.

Dissolution Study:

In vitro release profile of ropinirole formulation was studied in pH 4 citrate buffer using USP Type II dissolution apparatus with 100 rpm rotation speed at temperature 37 ± 0.5⁰C.

Table 13: Dissolution data of ropinirole controlled release tablet

Comparative oral bioavailability study:

A randomized, open-label study was designed to evaluate in vivo performance of ropinirole controlled release tablet of example 6 versus Requip® XL™ of GlaxoSmithKline in healthy adult male volunteers. Log transformed pharmacokinetic parameters such as Cmax and AUC were calculated from data.

Table 14: Summary statistics of pharmacokinetic parameters

From table 14 it is evident that the non-swelling controlled release test dosage form of the present invention is bioequivalent to marketed Requip® XL™.

Example 7

Comparative evaluation of the swelling of the controlled release dosage form of the present invention (of Example 6) and Requip® XL™ A comparative evaluation of the percent swelling of the controlled release dosage form of example 6 and the marketed formulation REQUIP^® XL™ was carried out. For both the tablets intial dimensions were measured using verier calipers and then placed in 500ml of pH 4.0 citrate buffer. After one hour, measurement of the relevant dimensions and volume of the tablets was again carried out and percent swelling was calculated by computing the increase in volume of the tablets against the initial value. Comparative results are as depicted beneath. Table 15: Summary of comparative percent swelling

Comparative Percent Swelling

Ropinirole XL Time (hr) Requip^® XL (Example 6)

0 0 0

1 91 0

The tablets of example 6 exhibited non swelling behaviour whereas Requip® XL tablets exhibited extensive swelling nature with more than 90% increase in volume of the dosage form.

Claims

1) A non-swelling controlled release dosage form comprising:

(a) a therapeutically effective amount of ropinirole or a pharmaceutically acceptable salt thereof; and

(b) at least one non-swelling release retardant.

2) The dosage form of claim 1 wherein ropinirole or a pharmaceutically acceptable salt thereof is present in an amount of about 0.01% to about 50% by weight of the dosage form.

3) The dosage form of claim 1 wherein said non-swelling release retardant is a non- polymeric release retardant; a polymeric release retardant, or a combination thereof.

4) The dosage form of claim 3 wherein said non-polymeric release retardant is spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, mineral waxes, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, cetyl alcohol, or stearyl alcohol, or a mixture thereof. 5) The dosage form of claim 4 wherein said non-polymeric release retardant is glyceryl behenate, hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated palm oil, stearic acid, palmitic acid, or a mixture thereof.

6) The dosage form of claim 3 wherein said polymeric release retardant is polyvinyl acetate, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w), ethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxy ethylcellulose phthalate, polymethacrylate, styrene^'acrylic acid copolymer, methyl acrylate^'acrylic acid copolymer, methyl acrylate^'methacrylic acid copolymer, butyl acrylate^'styrene^'acrylic acid copolymer, methacrylic acid^'methyl methacrylate copolymer, methacrylic acid^'ethyl acrylate copolymer, methyl acrylate^'methacrylic acid^'octyl acrylate copolymer, vinylacetate^'maleic acid anhydride copolymer, styrene^'maleic acid anhydride copolymer, styrene^'maleic acid monoester copolymer, vinylmethylether^'maleic acid anhydride copolymer, ethylene^'maleic acid anhydride copolymer, vinylbutylether^'maleic acid anhydride copolymer, acrylonitrile^'methyl acrylate^'maleic acid anhydride copolymer, butyl acrylate^'styrene^'maleic acid anhydride copolymer, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, or a mixture thereof.

7) The dosage form of claim 6 wherein said polymeric release retardant is polyvinyl acetate, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w), ethyl cellulose, methacrylic acid^'methyl methacrylate copolymer, methacrylic acid^'ethyl acrylate copolymer, or a mixture thereof. 8) The dosage form of claim 1 wherein said non-swelling release retardant is present in an amount of about 2% to about 95% by weight of the dosage form.

9) The dosage form of claim 8 wherein said non-swelling release retardant is present in an 5 amount of about 5% to about 85% by weight of the dosage form.

10) The dosage form of claim 9 wherein said non-swelling release retardant is present in an amount of about 5% to about 80% by weight of the dosage form.

10 11) The dosage form of claim 1 wherein said dosage form is present as a tablet, granule, spheroid, bead, pellet or a capsule.

12) The dosage form of claim 11 wherein said dosage form is a tablet.

15 13) The dosage form of claim 12 wherein said dosage form is a monolithic or multilayered tablet.

14) The dosage form of claim 1 further comprising at least one swelling release retardant.

20 15) The dosage form of claim 14 wherein said swelling release retardant is polyalkylene oxide, cellulosic polymer, acrylic acid and methacrylic acid polymer or ester thereof, maleic anhydride polymers, polymaleic acid, poly(acrylamides), poly(olefinic alcohol), poly(N- vinyl lactams), polyol, polyoxyethylated saccharide, polyoxazoline, polyvinylamine, polyvinylacetate, polyimine, starch and starch-based polymer, polyurethane hydrogel,

,25 chitosan, polysaccharide gum, zein, shellac-based polymer, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch and polyvinyl alcohol, or a mixture thereof. 16) The dosage form of claim 1 further comprising at least one pharmaceutically acceptable excipient, said excipient being diluent, lubricant, binder, colorant, flavorant, surfactant, pH adjuster, anti-adherent or glidant.

17) The dosage form of claim 1 wherein said dosage form is coated.

18) The dosage form of claim 17 wherein said dosage form is coated with hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvinyl alcohol or poly methacrylate, or a combination thereof.

19) The dosage form of claim 1 wherein said dosage form releases ropinirole or a pharmaceutically acceptable salt thereof for over a period of up to about 12 hours after administration.

20) The dosage form of claim 1 wherein said dosage form releases ropinirole or a pharmaceutically acceptable salt thereof for over a period of up to about 24 hours after administration.

21) A method of preparing a non-swelling controlled release dosage form of ropinirole comprising the steps of:

(b) blending the drug granules of step (a) with at least one same or different non-swelling release retardant to form a blend, and (c) compressing the blend of step (b) to form monolithic tablets.

22) A method of preparing a non-swelling controlled release dosage form of ropinirole comprising the steps of: (a) granulating ropinirole, or a pharmaceutically acceptable salt thereof, with at least one non-swelling release retardant to form drug granules;

(c) compressing the blend of step (b) to form monolithic tablets, and

(d) coating the tablets of step (c).