WO2009078034A2

WO2009078034A2 - Oral disintegrating tablets of ropinirole hydrochloride

Info

Publication number: WO2009078034A2
Application number: PCT/IN2008/000787
Authority: WO
Inventors: Pratibha S. Pilgaonkar; Maharukh T. Rustomjee; Anilkumar S. Gandhi; Atul Kelkar
Original assignee: Rubicon Research Private Limited
Priority date: 2007-11-26
Filing date: 2008-11-26
Publication date: 2009-06-25
Also published as: WO2009078034A3

Abstract

The present invention relates to a solid pharmaceutical composition comprising ropinirole, which dissolves or disintegrates in the oral cavity within about sixty (60) seconds. The present invention further discloses orally disintegrating tablets of ropinirole of optimal mechanical strength comprising taste-masked ropinirole and at least one pharmaceutically acceptable excipient.

Description

ORAL DISINTEGRATING TABLETS OF ROPINIROLE HYDROCHLORIDE

Field of the invention

The present invention relates to a solid pharmaceutical composition comprising ropinirole, which dissolves or disintegrates in the oral cavity within about sixty (60) seconds.

The present invention also relates to a process for the preparation of a taste-masked pharmaceutical composition of ropinirole of optimal mechanical strength comprising ropinirole along with a taste-masking agent and at least one pharmaceutically acceptable excipient.

Background of the Invention

The geriatric population, composed of people aged sixty-five (65) years and over, is rapidly growing in the United States and throughout the world. According to the United Nations World Prospects published in 2005, the global population of people over the age of sixty (60) in 2005 was estimated to be 672 million out of a total of approximately 6.5 billion and is expected to reach 1.9 billion by 2050 (cited in: Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat. The World Population Prospects: the 2004 revision). This population presents unique treatment challenges for caregivers and physicians. The prevalence of psychiatric illness ranges from 65-90%, with dementia complicated by depression, psychosis, and behavioral disturbances, the most common disorder. Majority of them also suffer from movement disorders, which 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.

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.

Further, Restless Leg Syndrome (RLS), also known as Ekbom's Syndrome 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, leading to significant discomfort.

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. Fibromyalgia patients experience a range of symptoms of varying intensities that wax and wane over time. 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.

Such type of movement disorders and impairments further complicate the administration of medication to the elderly population. Most commonly employed solid pharmaceutical preparations such as tablets or capsules are not suitable for this population as they may have difficulty in swallowing them. With liquid dosage forms, administration and stability of the drug and the dosage form can be a major concern. An ideal solid dosage form for these patients includes a formulation that simply melts in the mouth without any extra effort.

Further, taste is an important parameter governing the compliance of patients of any age group. With unpleasant tasting drugs, the disagreeable taste of the drug can lead to low patient compliance. Such reduced compliance, especially in case of Parkinson's patients can lead to severe complications.

Hence there exists a need to design taste-masked solid dosage forms of unpleasant tasting drugs for patients suffering from Parkinson's disease that dissolves or disintegrates in the oral cavity without the need for water providing a more convenient dosage form encouraging adherence to the daily medication regimen.

Ropinirole, 4-[2-(dipropylamino)ethyl]-l,3-dihydro-2H-indol 2-one, used commonly as hydrochloride salt, is a selective non-ergoline dopamine agonist used mainly in the treatment of Parkinson's disease. Dopamine agonists function by increasing the dopamine levels in the brain. This helps to lessen the symptoms of Parkinson's disease. 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.

Treatment with ropinirole is- also desirable in pediatric patients suffering from Restless Leg Syndrome (RLS) and Attention Deficit Hyperactivity Disorder (ADHD), and study shows that it resulted in significant improvement (Reference: Ropinirole in a Child With Attention- Deficit Hyperactivity Disorder and Restless Legs Syndrome. Pediatric Neurology, Volume 32, Issue 5, Pages 350-351 E. Konofal, I. Arnulf, M. Lecendreux, M. Mouren). Such pediatric populations also present a unique challenge to caregivers in terms of ease of administration, patient comfort and compliance with the prescribed dosing regimen.

Presentation of ropinirole in conventional solid dosage forms or liquid orals, having their own limitations, are not ideal for use in pediatric or geriatric patients or in patients suffering from various movement disorders like Parkinson's Disease. The unpleasant taste of ropinirole is another reason for development of alternate formulations that are palatable and • patient-friendly such as orally disintegrating tablets of ropinirole.

Attempts have been made to provide immediate or 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.

^• U.S. Patent Application 20070059365 describes a monolith or a double layer tablet 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. When the formulation was 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 syndrome.

Multi-layer controlled-release tablet comprising an active layer and a barrier layer, useful for the treatment of Parkinson's Disease is disclosed in U.S. Patent Application 20030180359. The invention relates to a tablet formulation comprising a mixed matrix of hydrophilic and lipophilic components able to control the release rate of ropinirole from the formulation.

Thus, even though there have been attempts in the prior art to control the release rate of ropinirole from the formulation, no efforts have been made to mask its unpleasant (tingling) taste or increase its palatability or provide patient friendly dosage forms such as rapidly disintegrating tablets. Accordingly, there exists a need for the development of taste-masked dosage forms of ropinirole using appropriate taste-masking technology such that the unpleasant taste of ropinirole is completely masked and the dosage form is convenient to consume.

The present invention addresses this need and discloses, after thorough experimentation, - taste-masked ropinirole formulations that rapidly disintegrate in the oral cavity. These tablet compositions have a pleasant mouth feel and good mechanical strength. These tablets are robust (e.g., low friability, low ejection forces, hardness) enough to be processed in high speed tableting machines and shipped in low cost packages, and at the same time retain rapid disintegration or dissolution properties.

Summary of the invention The present invention provides an orally disintegrating tablet formulation of ropinirole or a pharmaceutically acceptable salt thereof comprising: a. taste-masked ropinirole; and b. at least one pharmaceutically acceptable excipient. Detailed Description

Ropinirole is a non-ergoline dopamine agonist, marketed as Requip®. It is used in the treatment of Parkinson's Disease and is also one of two medications in the United States with an FDA-approved indication for the treatment of Restless Legs Syndrome (RLS). Ropinirole acts as an agonist at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4. It is available as tablets, strengths are distinguished by colour; 0.25 mg (white), 0.5mg (yellow), 1.0 mg (green), 2.0 mg (pink) and 5.0 mg (blue). Since ropinirole is indicated for Parkinson's Disease and RLS, there is a need for dosage forms which can be administered to these subjects with minimum difficulty. Such novel dosage forms like orally disintegrating tablets can also significantly improve patient compliance and thereby improve the conditions of patients with Parkinson's Disease and RLS.

The unpleasant taste of ropinirole poses a great challenge for the development of orally disintegrating tablet formulations. Thus, rigorous experimentation, with respect to development of taste-masking technology for a particular drug providing palatable formulations becomes essential, such that the invitro dissolution profile as desired is achieved without compromising on the stability or shelf-life of the drug and the dosage form.

The present invention provides taste-masked pharmaceutical compositions of ropinirole that dissolve or disintegrate in the oral cavity without water, within about sixty (60) seconds. The bitter taste of ropinirole in the compositions of the present invention is masked by coating

(such as using polymeric or non-polymeric pharmaceutically acceptable excipients), complexation (such as with ion-exchange resins, cyclodextrins, carbomers), adsorption (such as using magnesium aluminium silicate), salt formation (such as with sodium saccharin), use of sweeteners or flavors or the like, or any combinations thereof.

The present invention further provides orally disintegrating compositions of taste-masked ropinirole using co-processed excipients. The present invention also further provides orally disintegrating tablet compositions of ropinirole in controlled release form. Ropirύrole may be used in the form of a pharmaceutically acceptable salt. Further, 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. Thus the term "ropinirole" as used in the present invention relates to either the free base or pharmaceutically acceptable salts thereof.

The tablet compositions of the present invention include about 0.02% to about 20% by weight of ropinirole. In one embodiment of the present invention, the compositions of the present invention include about 0.1% to about 10% by weight of ropinirole.

The present invention is also applicable to combinations of ropinirole with other drugs. In one embodiment of the present invention, taste-masked orally disintegrating compositions of the present invention comprise ropinirole or an analog thereof in combination with other active agents selected from, but not limited to, aplindore, apomorphine, bromocriptine, cabergoline, dihydroergocryptine mesylate, fenoldopam, Hsuride, pergolide, piribedil, pramipexol, propylnorapomorphine, quinpirole, rotigotine, selegiline, rasagiline, levodopa, carbidopa, benztropin, procyclidine, amantadine, entacapone, tolcapone carmoxirole, (S)- didesmethylsibutramine, dopexamine, ibopamine, memantine, mesulergine, quinagolide, roxindole, talipexole, tandospirone, ipsapirone, gepirone, fibnaserin, flesinoxan, sarizotan, repinotan or tiotropium. Orally disintegrating tablets (ODTs) disintegrate/dissolve in the mouth rapidly without administering extra water, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation. Such dosage forms, due to their ease of administration and pleasant mouth feel, may encourage patients especially the elderly patients and children who have difficulty in swallowing conventional tablets to adhere to daily medication regimens and also allow the luxury of much more accurate dosing than oral liquids. Such tablets are also useful where water may not be readily available to assist in swallowing the tablet in specific conditions or the patient is not in a condition to use water and swallow the conventional tablet.

The unpleasant taste of ropinirole poses a great challenge for the development of orally disintegrating tablet formulations. The present invention employs a number of approaches including, but not limited to, using coating, complexation, salt formation, adsorbents, sweeteners, flavours and the like for masking of the unpleasant taste of ropinirole.

In an embodiment of the present invention, taste-masking is achieved by coating. Ropinirole in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like can be taste-masked by coating. In an aspect of the present invention, ropinirole can be loaded on an inert carrier before taste-masking by coating. The inert carrier as used herein includes beads, pellets, spheres or similar particles that do not contain an active ingredient. Non- limiting examples of inert carriers include microcrystalline cellulose, sugar or silicon dioxide.

In an embodiment of the present invention, ropinirole is taste-masked by coating with at least one pharmaceutically acceptable coating agent. Coating can be achieved using a pharmaceutically acceptable coating agent including, but not limited to, polymeric or non- r polymeric coating agents or any combinations thereof. Polymeric coating agents for taste-masking ropinirole as employed in the present invention include, but are not limited to, cellulose derivatives, saccharides or polysaccharides, polyhydric alcohols, poly(oxyethylene)-poly(oxypropylene) block copolymers (poloxamers), vinyl derivatives or polymers or copolymers thereof, a acrylic acid derivatives or the like or any combinations thereof.

Cellulose derivatives, include but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or combinations thereof.

Saccharides or polysaccharides include but are not limited to, guar gum, xanthan gum, gum arabic, tragacanth or combinations thereof. Polyhydric alcohols include but are not limited to, polyethylene glycol (PEG) or polypropylene glycol.

Vinyl derivatives, polymers arid copolymers thereof include but are not limited to polyvinylacetate aqueous dispersion (Kollicoat SR 30D), copolymers of vinyl pyrrolidone, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP) or combinations thereof.

Acrylic acid derivatives include but are not limited to, methacrylic acids, polyrήethacrylic acids, polyacrylates, especially polymethacrylates like a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters b) copolymer formed from monomers selected from butyl methacrylate, (2- dimethylaminoethyl)methacrylate and methyl methacrylate c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride or d) copolymers of acrylate and methacrylates with/without quarternary ammonium group in combination with sodium carboxymethylcellulose, e.g. those available from Rohm GmbH under the trademark Eudragit ^® like Eudragit EPO (dimethylaminoethyl methacrylate copolymer; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethylacrylate methymethacrylate copolymer), Eudragit RD 100 (ammoniomethacrylate copolymer with sodium carboxymethylcellulose); or the like or any combinations thereof.

According to the present invention, non-polymeric coating agents for taste-masking ropinirole include, but are not limited to, fats, oils, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols and their esters, phospholipids, terpenes or combinations 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 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, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof.

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 are 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 palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dirhyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, and combinations thereof.

Fatty acids 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 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 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, and stearyl alcohol and mixtures thereof.

In one embodiment, the non-polymeric coating agents employed include, but 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), Akofine (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), and Geleol (glyceryl stearate), and mixtures thereof.

Coating of the active ingredient can be done by any of the techniques known in the art, such as microencapsulation, hot melt granulation, melt extrusion, physical mixing, fluid bed coating, wet granulation or spray drying. Further, the taste-masking coatings, based on lipids or waxes, require that the melting point of the lipid be sufficiently high to prevent melting in the mouth and not be so high that the active ingredient itself melts or is chemically degraded during preparation of the formulation. Lipids or waxes can also be employed in the form of an aqueous dispersion stabilized by surfactants and suitable stabilizers. Coating can be carried out in the range from about 1% to about 80% weight gain, preferably from about 2% to about 60%, more preferably from about 5 to about 50%. The coating may be partial or complete, yet sufficient to mask the bitter taste of ropinirole.

In one embodiment of the present invention, coating for taste-masking ropinirole is done by physical mixing of the active with a pharmaceutically acceptable polymeric or non-polymeric coating agent or any combinations thereof. In case of physical mixing the ratio of ropinirole to coating agent may be from about 1 :0.1 to 1 : 100.

In another embodiment of the present invention, ropinirole is taste-masked by complexation using cyclodextrins or ion-exchange resins or carbomers or the like or any combinations thereof.

Ion-exchange resins are solid and suitably insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium and are not absorbed by the body. The resulting ion exchange is reversible and stoichiometric with the displacement of one ionic species by another. The drug-resinates effectively mask the taste of a bitter or unpleasant tasting drug within the matrix of the ion-exchange material. Appropriate selection of the ion-exchange resin is important so that the drug is not released in the mouth, leading to perception of the bitter taste of the drug.

The present invention provides a taste-masked ropinirole formulation wherein taste-masking is achieved by reversibly binding the active compound onto an ion-exchange resin, wherein the polymeric matrix of the ion-exchange resin has functional groups including, but not limited to, anionic groups, e.g., weakly acidic- carboxylic, esteric and phosphonic; strongly acidic- sulfonic and cationic groups, e.g , weakly basic- tertiary amine; strongly basic- quaternary amine. Additionally suitable polymeric matrices include copolymers of acrylic and substituted acrylic acids; styrene and styrene derivatives; cellulose esters; vinyl and substituted vinyl esters; and polysulfonic acids and polysulfonic acid esters. An ion-exchange resin having the polymeric matrix with an anionic functional group is a cation exchange resin and that having a cationic functional group is an anionic exchange resin. The mobile or exchangeable moieties, depending on the type of resin used, includes, but is not limited to, sodium, hydrogen, potassium, chloride or the like.

In yet another embodiment of the present invention, a cationic exchange resin is used to mask the bitter taste of ropinirole. The cationic exchange resin used includes, but is not limited to, those offered by Rohm and Hass under the brand names Amberlite^® IRP64, Amberlite^® IRP69, Amberlite^® IRP88 and the like; those offered by Dow under the brand names DOWEX^® RTM resins and the like; those offered by Thermax under the brand names Tulsion^® 335, Tulsion^® 344 and the like; those offered by Ion Exchange India under the brand names Indion^® 204, Indion^® 214, Indion^® 234, Indion^® 234S, Indion^® 294 and the like; those offered by Purolite under the brand names Purolite^® Cl 15 HMR, Purolite^® Cl 15 E, Purolite^® ClOO HMR, Purolite^® 100 MR and the like or any combinations thereof.

Several cyclodextrin derivatives may also be employed for complexation and hence taste- masking of active agents. Cyclodextrins are crystalline, cyclic oligosaccharides derived from starch. Examples of cyclodextrin derivatives which can be employed for ropinirole taste- masking include, but are not limited to, hydroxy propyl β-cyclodextrin and 7-sulphobutyl ether of cyclodextrin. Cyclodextrin makes an inclusion complex with the ropinirole molecule by acting as a hydrophobic host cavity. Such complexes for taste-masking purposes can be processed by mixing, grinding, solid dispersion, kneading, spray drying and melting method.

Ropinirole can be taste-masked by complexation with carbomers such as carbomer 934, carbomer 971, carbomer 974 or the like wherein the complex is held together by ionic bonding and gel properties of the carbomer, providing stable and palatable compositions. These complexes can be prepared by mixing, blending or slurrying ropinirole and carbomer together to allow the desired complex formation.

Further, the bitter taste of ropinirole can also be masked by formation of adsorbates, by adsorbing or partially or significantly blending ropinirole with an adsorbent such as, but not limited to, magnesium aluminum silicate, zeolite, activated granular carbon, silica gel, active aluminum, clay and mixtures thereof. These adsorbent materials surround the drug particles by forming a physical bond, by Van der Waals interactions, and hydrogen bonding force of attraction, so that the bitter taste of the drug is not perceived. The adsorbate of ropinirole can be formed by mixing or blending the active with the adsorbent in high or moderate shear mixers like planetary mixer or rapid mixer granulator. Alternatively, the_adsorbate can be formed by wet granulation involving the adsorbent and ropinirole in any conventional granulation equipment.

Taste-masking of ropinirole can also be achieved by formation of salt with equimolar amounts of sugar substitutes like cyclamate, saccharin, acesulfame or a mixture of at least two of the sugar substitutes. This results in the formation of a taste-masked ropinirole salt. The ropinirole salt has reduced bitter taste and thus results in improved patient compliance. Such a taste-masked salt can be compressed in the form of a tablet. Masking of the bitter taste of ropinirole is also achieved using at least one sweetening agent such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; and one or more flavors, e g , mint flavour, orange flavour, lemon flavors, strawberry aroma, vanilla flavour, raspberry aroma, cherry flavor, rutty frutty flavor ,magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts.

Design of orally disintegrating tablet requires a significant amount of research work in order to develop a process that maintains enough porosity inside the compressed tablets for fast dissolving or fast melting while maintaining the mechanical strength of the tablet. Orally disintegrating tablets can be prepared by any of the known non limiting technologies such as freeze drying, molding and sublimation, compression, cotton candy process, mass extrusion, etc or use of specialized excipients such as effervescent couple, highly micronized agents, coprocessed excipients or the like.

In one embodiment of the present invention, directly compressible excipient employed for orally disintegrating tablets is a coprocessed or composite excipient as described in PCT Application WO2007052289,- the entire contents of which are incorporated herein by reference. This coprocessed excipient comprises of at least one water soluble excipient and water insoluble inorganic excipient such as calcium silicate. The water soluble excipient can be a carbohydrate selected from monosaccharide, disaccharide, oligosaccharide or polysaccharide. Examples of carbohydrates include, but are not limited to, monosaccharides such as sorbitol, glucose, dextrose, fructose, maltose or xylitol, disaccharides such as sucrose, trehalose, lactose, glucose, galactose or mannitol, and oligosaccharides and polysaccharides such as dextrates and maltodextrins. Preferably, the water soluble excipient is mannitol. The water soluble and water insoluble excipients in the directly compressible excipient can be in a ratio of water-soluble excipient to water insoluble excipient of from about 50:1 to about 1:50. In one embodiment of the present invention, this ratio is about 30:1 to about 1:30. In a further embodiment of the present invention, this ratio is from about 20:1 to about 1:20. The amount of directly compressible coprocessed excipient employed in the composition is about 5% to about 95 % by weight of the said dosage form. The term 'coprocessed excipient', 'composite excipient' and 'directly compressible excipient' has been employed interchangeably for the purpose of this invention.

The tablets of the invention may include, in addition to the taste-masked active ingredient and directly compressible composite excipient, one or more binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, viscosity builders, glidants or lubricants, solubilizers, and stabilizers.

The compositions of the invention also include at least one superdisintegrant including, but not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems. In one of the embodiment, disintegrants employed are crospovidone and starch. The amount of superdisintegrant employed in the composition is about 2 to about 30 % by weight of the said dosage form.

Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts. Examples of suitable diluents include, but are not limited to, starch, dicalcium phosphate, microcrystalline cellulose and the like.

Examples of the lubricant include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. 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. Compositions of the present invention may also include salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica to improve the disintegration properties of the said compositions.

Examples of solubilizers include, but are not limited to, cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and mixtures thereof. The tablet compositions of the present invention may also include stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like. 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.

^"Souring agents include, but are not limited to, monosodium fumarate and/or citric acid. The tablet compositions of the present invention may optionally include viscosity building agents such as, but not limited to, polyalkylene oxides; polyols; starch and starch-based polymers; chitosan; polysaccharide gums; polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, gum acacia, gum tragacanth, xanthan gum, guar gum and polyvinyl alcohol and copolymers and mixtures thereof.

In one embodiment of the present invention, the orally disintegrating tablets of the present invention comprise a composition wherein taste-masked ropinirole is released in a controlled manner over a period of time, for example, from about 2 to about 24 hours. In such a formulation, ropinirole is coated with polymeric, non-polymeric coating agents described above or any combinations thereof. The amount of such release retardants for coating not only ensures the taste-masking but also controls the release of ropinirole. Any of the taste- masking approaches described above can be used in combination with a coating agent for the purpose of achieving a controlled release orally disintegrating tablets of ropinirole.

In another embodiment of the present invention, pellets or granules or the like of ropinirole are prepared comprising at least one release retardant in combination with one or more pharmaceutically acceptable excipients. Suitable release retardants, as discussed above can be polymeric or non-polymeric and include, but are not limited to, cellulose ethers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethyl cellulose and carboxymethylcellulose sodium; polysaccharides, such as carageenan, guar gum, xanthan gum, tragacanth and ceratonia; polymethacrylates, such as copolymers of acrylic and methacrylic acid esters containing quarternary ammonium groups; cellulose esters, such as cellulose acetate; acrylic acid polymers, such as carbomers; waxes, such as hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax; alginates, such as alginic acid and sodium alginate; and fatty acid derivatives, such as glyceryl monostearate and glyceryl palmitostearate. These pellets or granules or the like are further coated using agents described above in order to achieve taste- masking and controlled release of ropinirole.

The amount of release retardant in the formulation is from about 1 to 90% by weight of the dosage form. In one embodiment, the amount of release retardant in the formulation is about 5 to 80% by weight of the dosage form. In another embodiment, the amount of release retardant in the formulation is about 30 to 40% by weight of the dosage form.

The terms "solid dosage form," "tablet," and "solid preparation" are used synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry- granulation and extrusion/ melt granulation. In one embodiment of the present invention, tablets are prepared by direct compression, which involves compression of a taste-masked drug-excipient blend after mixing them for a definite time period.

The tablet may vary in shape such as oval, triangle, almond, peanut, parallelogram, round, pentagonal, hexagonal, and trapezoidal. The preferred shapes are round, oval and parallelogram forms.

The performance of the orally disintegrating tablets can be evaluated using a number of parameters namely wicking time, mouth dissolution time, in vitro disintegration time, etc. The term 'wicking time' as used here provides time (seconds) taken for water to wick into the tablet and completely wet the tablet core. The term 'mouth dissolution time' as used herein provides time (seconds) taken for tablet to completely dissolve/disintegrate in the mouth determined in and by human volunteers. The term 'in vitro disintegration time' as used herein refers to the time taken for complete disintegration of the tablet as determined using the USP disintegration apparatus. As per various embodiments of the present invention, in vitro disintegration time is less than 60 seconds. The orally disintegrating tablets of the present invention release not less than 85% of ropinirole within about thirty (30) minutes, preferably 15 minutes when tested for dissolution in USP Apparatus II with pH 4 citrate buffer. In another embodiment, the orally disintegrating tablets of the present invention, release in a controlled manner, not less than 75% of ropinirole in twenty-four (24) hours when tested for dissolution in USP Apparatus II with pH 4 citrate buffer.

While the present invention has been described in terms of its specifip 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 details of the invention, its objects and advantages are described below in the form of non-limiting exemplary illustrations.

EXAMPLES

Example 1: Taste-masking of ropinirole using Eudragit EPO Table 1: Composition of orally disintegrating tablets

Ropinirole was thoroughly dry mixed with Eudragit EPO and then blended with other excipients except lubricant in a blender to get a uniform powder mix. The mass was lubricated and compressed into tablets having following parameters: Hardness (N) : 30-50

Friability (%) : 0.25

Disintegration time (sec) : 10-20

Disintegration time in oral cavity (sec) : 20-30

In vitro release profile of ropinirole was studied in 900 ml of pH 4 citrate buffer using USP Type II dissolution apparatus with 50 rpm rotation speed at temperature 37.5 ± 0.5⁰C. Table 2: Dissolution data for ropinirole formulation

Tablets with desired taste-masking, friability disintegration time and in vitro release profile were obtained. The formulation was palatable with pleasant mouth feel.

Example 2: Taste-masking of ropinirole using Eudragit EPO

Ropinirole was dry mixed with Eudragit EPO and then blended with other excipients except lubricant in a blender to get a uniform powder mix. The blend was lubricated and compressed into tablets having following parameters:

Hardness (N) 20-40 Friability (%) 0.60 Disintegration time (sec) 12-18 Disintegration time in oral cavity (sec) 25-30

In vitro release profile of ropinirole was studied in pH 4 citrate buffer using USP Type II dissolution apparatus with 900 ml media at 50 rpm rotation speed at temperature 37.5 ± 0.5⁰C.

Table 4 Dissolution data of ropinirole tablets from Example 2

Tablets with desired taste-masking, friability, disintegration time and in vitro release profile were obtained. Tablets had acceptable taste with good mouth feel. Example 3: Taste-masking of ropinirole using ion-exchange resins Table 5: Composition of orally disintegrating tablet

Ropinirole was dissolved in water and to this solution a cationic ion exchange resin was added. The suspension was stirred for 3 hours and the complexed ropinirole was separated, dried and blended with other excipients in a blender to get a uniform mass except lubricant. The mass was lubricated and compressed into tablets having following parameters:

Hardness (N) 20-40 Friability (%) 0.20 Disintegration time (sec) 10-18 Disintegration time in oral cavity (sec) 26-31

Tablets with desired taste-masking, friability and disintegration time were obtained. Example 4: Taste-masking of ropinirole beads by polymer coating

Ropinirole was layered on non-pareil beads and these drug-loaded beads were further coated with a combination of ethyl cellulose and hydroxypropyl methylcellulose (20:80) to a weight gain of about 10%.

Table 6: Composition of orally disintegrating tablet

Coated ropinirole pellets were blended with other excipients in a blender to obtain a uniform mass. This mass was lubricated and compressed into tablets having following parameters:

Hardness (N) 50-65 Friability (%) 0.35 Disintegration time (sec) 20-25 Disintegration time in oral cavity (sec) 40-50

Tablets with desired taste-masking, friability and disintegration time were obtained.

Example 5: Taste-masking of ropinirole using cyclodextrin

Ropinirole was mixed with beta cyclodextrin (1 :2.5) in a ball mill for about 6 hours. Such treated ropinirole was then incorporated into an orally disintegrating tablet base.

Table 7: Composition of orally disintegrating tablet

Cyclodextrin treated ropinirole was blended with other excipients in a blender to obtain a uniform mass. This mass was lubricated and compressed into tablets having following parameters:

Hardness (N) 30-55 Friability (%) 0.61 Disintegration time (sec) 10-20 Disintegration time in oral cavity (sec) 30-40

Tablets with desired taste-masking, friability and disintegration time were obtained. Example 6: Formulation of taste-masked ropinirole using sodium saccharin Table 8: Composition of orally disintegrating tablet

Ropinirole hydrochloride was dissolved in water and reacted with saturated solution of sodium saccharin. This reaction produced salt of ropinirole saccharate which was incorporated in orally disintegrating tablets of ropinirole. Tablets with desired acceptable taste and disintegration time were obtained.

Example 7: Formulation of taste-masked coated ropinirole using aqueous wax composition

Table 9: Formulation of blend of ropinirole with microcrystalline cellulose

Table 10: Composition of coating solution

Procedure:

The drug was blended with microcrystalline cellulose (1:2 parts). Coating solution was prepared by melting Lubritab in water bath and adding Capmul in molten wax. Aspartame was dissolved in hot solution of Hydroxy propyl methyl cellulose E5 and this aqueous phase was added to oily phase of Lubritab and capmul. The system was homogenized and cooled to room temperature to which erythrocin colour, flavor and Aspartame were added to get a coating solution.

Drug blend was coated with coating composition using top spray assembly to weight gain of 40 %.

Table 11: Formulation of orally disintegrating tablets of taste-masked ropinirole

Procedure

A blend of coprocessed excipient, xylisorb and Kollidon CL were mixed with taste-masked coated ropinirole. This was mixed with colors, flavors and sweeteners to form a blend which was compressed to form mouth dissolve tablets of ropinirole hydrochloride. The tablets had desirable taste and pleasant mouth feel.

Example 8: Ropinirole melt extruded pellets coated using Kollicoat SR 30 D Table 12: Melt extruded pellets in orally disintegrating tablets

Ropinirole beads of controlled size and density using the extrusion technique was prepared by passing/ forcing a concentrated formulation of ropinirole and glyceryl behenate through a fine nozzle. The extruded mass was then cut and shaped, in a spheronization process, to produce beads suitable for formulation as controlled release multiparticulates. The resultant beads were further coated with Kollicoat SR 30 D to a weight gain of 20% by weight for additional release rate control and taste masking. These taste-masked ropinirole beads were mixed with other excipients and compressed into orally disintegrating tablets. Tablets with desired controlled release and acceptable mouth feel were obtained.

Example 9: Formulation of taste-masked ropinirole using Compritol Table 13: Composition of orally disintegrating ropinirole tablets

Ropinirole was dry mixed with Compritol and then blended with other excipients except lubricant in a blender to get a uniform powder mix. The blend was lubricated and compressed to get the tablets. The tablets had acceptable taste and pleasant mouth feel. Example 10: Formulation of taste-masked ropinirole using Eudragit RL/RS coating Table 14: Roll compaction of ropinirole

Ropinirole was mixed with microcrystalline cellulose and subjected to roll compaction followed by sifting to get ropinirole granules. Table 15: Coating of ropinirole granules by Eudragit RL/RS

Ropinirole granules were coated by Eudragit RL/RS suspension as per the composition to weight gain of 30 %.

Table 16: Formulation of ropinirole tablet

Coated ropinirole granules were blended with composite excipient comprising mannitol and calcium silicate along with other excipients and compressed to get orally disintegrating tablet. The tablets with desirable controlled release and pleasant mouth feel were obtained.

Claims

1) An orally disintegrating tablet composition of ropinirole, or a pharmaceutically acceptable salt thereof, comprising: (a) taste-masked ropinirole; and

Xb) at least one pharmaceutically acceptable excipient.

2) The tablet composition of claim 1 wherein said ropinirole is taste-masked by coating, complexation, salt formation, or use of adsorbents, sweeteners or flavors.

3) The tablet composition of claim 2 wherein said ropinirole is taste-masked by coating ^• with at least one pharmaceutically acceptable coating agent.

4) The tablet composition of claim 3 wherein said coating agent is a polymeric coating agent, a non-polymeric coating agent, or a combination thereof.

5) The tablet composition of claim 4 wherein said non-polymeric coating agent 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 tridocόsanoate, 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. 6) The tablet composition of claim 4 wherein said polymeric coating agent is a cellulose derivative, a saccharide or polysaccharide, a polyhydric alcohol, a poly(oxyethylene)- poly(oxypropylene) block copolymer (poloxamer), a vinyl derivative or polymer or copolymer thereof, a acrylic acid derivative or a combination thereof. 7) The tablet composition of claim 6 wherein said cellulose derivative is ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose

^■ (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxy ethylcellulose, carboxymethyl ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxy methyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose acetate ^* succinate, hydroxypropylmethylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, or a combination thereof.

8) The tablet composition of claim 6 wherein said vinyl derivative or polymer or copolymer thereof is polyvinylacetate aqueous dispersion (Kollicoat SR 30D), copolymers of vinyl .pyrrolidone, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinylpyrrolidone (PVP) or a combination thereof.

9) The tablet composition of claim 6 wherein said acrylic acid derivative is methacrylic acid, polymethacrylic acid, polyacrylate, polymethacrylate or a combination thereof.

10) The tablet composition of claim 9 wherein said polyacrylate is a) copolymer formed from monomers selected from the group consisting of methacrylic acid, methacrylic acid esters, acrylic acid and acrylic acid esters; b) copolymer formed from monomers selected from the group consisting of butyl methacrylate, (2- dimethylaminoethyl)methacrylate and methyl methacrylate; c) copolymer formed from monomers selected from the group consisting of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride; or d) copolymer of acrylate and methacrylates with/without quarternary ammonium group in • combination with sodium carboxymethylcellulose.

11) The tablet composition of claim 2 wherein said ropinirole is taste-masked by complexation using an ion-exchange resin, said ion-exchange resin is a cationic ion exchange resin.

12) The tablet composition of claim 2 wherein said ropinirole is taste-masked by complexation with cyclodextrins or its derivatives or with carbomers, said carbomers being carbomer 934, carbomer 971 or carbomer 974, or a mixture thereof.

13) The tablet composition of claim 2 wherein said ropinirole is taste-masked by preparing a pharmaceutically acceptable salt of ropinirole and a sugar substitute, said sugar substitute being saccharin sodium, cyclamate or acesulfame, or a mixture thereof.

14) The tablet composition of claim 2 wherein said ropinirole is taste-masked by preparing a pharmaceutically acceptable adsorbate of ropinirole and an adsorbent, said adsorbent being magnesium aluminum silicate, zeolite, activated granular carbon, silica gel, active aluminum or clay, or a mixture thereof. 15) An orally disintegrating tablet composition of ropinirole, or a pharmaceutically acceptable salt thereof, comprising taste-masked ropinirole wherein said ropinirole is taste-masked by coating using_v a pharmaceutically acceptable polymeric coating agent, said coating agent being basic butylated methacrylate copolymer.

16) The tablet composition of claim 1 wherein said excipient is a directly compressible excipient, binder, disintegrant, superdisintegrant, diluent, salivating agent, surfactant, flavor, sweetener, colorant, souring agent, viscosity builder, glidant, lubricant, solubilizer, or stabilizer.

17) The tablet composition of claim 16 wherein said directly compressible ^ι excipient comprises mannitol and calcium silicate. 18) The tablet composition of claim 1 wherein the in vitro disintegration time is less than 60 seconds.

19) The tablet composition of claim 1 further comprising an additional active agent.

20) The tablet composition of claim 19 wherein said active agent is aplindore, 5 apomorphine, bromocriptine, cabergoline, dihydroergocryptine mesylate, fenoldopam, lisuride, pergolide, piribedil, pramipexol, propylnorapomorphine, quinpirole, rotigotine, selegiline, rasagiline, levodopa, carbidopa, benztropin, procyclidine, amantadine, entacapone, tolcapone carmoxirole, (S)- didesmethylsibutramine, dopexamine, ibopamine, memantine, mesulergine, 10 quinagolide, roxindole, talipexole, tandospirone, ipsapirone, gepirone, fibnaserin, flesinoxan, sarizotan, repinotan or tiotropium.

21) The tablet composition of claim 1 wherein said composition readily disintegrates in the oral cavity within about 60 seconds, releasing controlled release, taste-masked ropinirole.

-15 22) A process for preparing an orally disintegrating tablet composition of ropinirole, or a pharmaceutically acceptable salt thereof, comprising:

(a) coating ropinirole by physically mixing ropinirole with a basic butylated methacrylate copolymer;

(b) blending the physical mix of step (a) with other excipients,. except lubricant, to 20 get a uniform powder mix;

(c) lubricating the powder mix of step (b); and

(d) compressing the powder mix of step (c) into an orally disintegrating tablet composition.

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