INTRODUCTION

Aspects of the present application relate to pharmaceutical formulations comprising pramipexole or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof. Further aspects relate to extended release formulations for oral administration, comprising pramipexole or

pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof. In aspects, the present application further relates to stable extended release formulations for oral administration comprising pramipexole or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof.

The drug compound having the adopted name "pramipexole," disclosed in U.S. Patent No. 4,886,812, is a dopamine D2 receptor agonist. It is structurally different from the ergot-derived drugs, e.g., bromocriptine or pergolide. It is also pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine D2 family of dopamine receptors. Pramipexole is prescribed for the treatment of Parkinson's disease and restless legs syndrome. Pramipexole has a chemical name (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, and the salt form commonly used is pramipexole dihydrochloride monohydrate.

Pramipexole dihydrochloride monohydrate has the molecular formula

CioHi ₇ N ₃ S-2HCI I-l20, its molecular weight is 302.26, and the structural formula is represented below.

Pramipexole dihydrochloride monohydrate is a white to off-white powder substance. Water solubility is more than 20 mg/mL and solubility in buffer media is generally above 10 mg/mL between pH 2 and pH 7.4. Pramipexole

dihydrochloride monohydrate is not hygroscopic, and has a highly crystalline nature. Under milling, the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, yet in solution it is light sensitive. Pramipexole is a chiral compound with one chiral center. Pure (S)-enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during synthesis.

Pramipexole is the active ingredient in a product marketed by Boehringer

Ingelheim Pharmaceuticals, Inc. as immediate release (IR) tablets using the brand name MIRAPEX®, having mannitol, corn starch, colloidal silicon dioxide, povidone and magnesium stearate as the pharmaceutical excipients. Pramipexole immediate release (IR) tablets are prescribed in Europe and the U.S. for the treatment of signs and symptoms of either early Parkinson's disease or advanced Parkinson's disease in combination with levodopa. The IR tablets have to be taken three times a day. It has been found that compositions prepared using the ingredients of MIRAPEX® (Physicians Desk Reference, Edition 54, page 2467), when stored at 40±2°C and relative humidity of 75±5% for three months, show a decrease in the content of pramipexole dihydrochloride monohydrate, to below 95% of the label amount.

Pramipexole is the active ingredient in a product marketed as extended release tablets under the brand name MIRAPEX® ER, indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and containing the excipients hypromellose, corn starch, carbomer homopolymer, colloidal silicon dioxide, and magnesium stearate.

In Europe, pramipexole is marketed in prolonged release tablets, using the brand name MIRAPEXIN®. It can be used alone or in combination with levodopa. The tablets are taken once a day, with or without food.

In common with other anti-Parkinson's disease drugs, pramipexole has the potential to cause undesirable side effects. Side effects of pramipexole have been reported to include orthostatic hypotension, the incidence of which is dose-related. There are also reports of subjects using pramipexole medication experiencing increased somnolence, in particular "sleep attacks." Such attacks involve a subject falling asleep while engaged in activities of daily living, including operation of a motor vehicle, sometimes resulting in accidents.

As is commonly known, modifying the release of active ingredients sometimes allows simplification of a patient's administration scheme, by reducing the number of recommended daily intakes, improves patient's compliance, and attenuates adverse events, e.g., related to high drug plasma concentration peaks. Modified release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise formulations with a controlled, a prolonged, a sustained, a delayed, a slow or an extended release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms.

A number of approaches have been described in the literature to provide pharmaceutical formulations of pramipexole.

U.S. Patent Application Publication No. 2005/0226926 describes a sustained-release pharmaceutical composition in a form of an orally deliverable tablet comprising a water-soluble salt of pramipexole, dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kNcm ² , preferably at least about 0.175 kNcm ^"2 , and more preferably at least about 0.2 kNcm ^"2 , at a solid fraction representative of the tablet.

U.S. Patent Application Publication No. 2006/0051417 describes an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix, the matrix comprising at least two water swelling polymers, wherein one of the polymers is pregelatinized starch, and wherein another one of the polymers is an anionic polymer.

U.S. Patent Application Publication No. 2006/0198887 describes an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water swelling polymer other than pre-gelatinized starch. The composition comprises at least two water swelling polymers other than pre-gelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer.

U.S. Patent Application Publication No. 2007/0129329 discloses a stabilized pharmaceutical composition of pramipexole comprising one or more dextrins.

International Application Publication No. 2009/109990 describes a pharmaceutical composition comprising a mixture of pramipexole or its

pharmaceutically acceptable salts, or hydrates or solvates thereof, a sugar alcohol, and a pharmaceutically acceptable carrier medium, substantially free of polyvinylpyrrolidone. U.S. Patent Application Publication No. 2009/0130197 describes an extended release pellet formulation of pramipexole or a pharmaceutically acceptable salt thereof which may be filled in a capsule or compressed into a tablet and is suitable for once-daily oral administration.

There remains a need for developing stable extended release systems for pramipexole, which release the drug in a specific manner independent or dependent on the pH of the gastric environment. Also, controlling the initial burst release of pramipexole from the core formulation is highly desirable to provide a gradual release of the active agent over extended times. Formulating stable extended release dosage forms of pramipexole has not been an easy task for the formulators, since pramipexole is a low dose, highly water soluble drug with a wide range of therapeutic dose strengths. Hence, stable extended release dosage forms of pramipexole which provide consistent in vitro and in vivo release profiles with reproducible absorption are desirable.

SUMMARY

Aspects of the present application relate to pharmaceutical compositions of pramipexole comprising pramipexole or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof. Further aspects relate to extended release formulations for oral administration comprising pramipexole or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof.

An aspect provides stable extended release formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof, which is suitable for once-daily oral administration.

An aspect of the present application provides extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof that continuously provides a constant plasma level of the active ingredient over formulation passage through the gastrointestinal tract.

An aspect provides stable extended release formulations comprising pramipexole or a pharmaceutically acceptable salt thereof, wherein the

formulations provide either pH-independent or pH-dependent release profiles, or a combination of both. An aspect relates to stable extended release formulations comprising pramipexole or a pharmaceutically acceptable salt thereof, wherein the

formulations comprise at least one pH-independent polymer, or at least one pH- dependent polymer, or a combination of both.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof and at least one hydrophilic water-swellable polymer.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof and at least one water-insoluble polymer.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one hydrophilic water-swellable polymer, and at least one water-insoluble polymer.

An aspect of the present application relates to stable extended release formulations comprising pramipexole or a pharmaceutically acceptable salt thereof and microcrystalline cellulose.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable thereof and at least one cationic polymer.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof and at least one ion-exchange resin.

An aspect of the application relates to extended release formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof and at least one cationic ion-exchange resin.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof and at least one of unmodified starch or pre-gelatinized starch.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one water-swellable hydrophilic polymer, and at least one of unmodified starch or pre-gelatinized starch. An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one water-insoluble polymer, and at least one of unmodified starch or pre-gelatinized starch.

An aspect of the present application relates to extended release

formulations of pramipexole comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one of cationic polymer or cationic exchange resin, and at least one of unmodified or pre-gelatinized starch. DETAILED DESCRIPTION

Aspects of the present application relate to pharmaceutical formulations comprising pramipexole or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof. Further aspects relate to stable extended release formulations for oral administration comprising pramipexole or pharmaceutically acceptable salts thereof, methods for manufacturing the same, and uses thereof.

As used herein, the terms "composition," "formulation," and "dosage form" refer to preparations of pramipexole in a form suitable for administration to a human.

The term "stable" refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.

The term "label amount" refers to the dosage amount of therapeutically active ingredient present in a pharmaceutical product.

The term "pharmaceutically acceptable" as used herein, refers to materials that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit-risk ratio, and effective for their intended use.

The term "extended" release means the active ingredient is gradually, liberated over time, sometimes slower or faster, dependent or independent from the pH value and encompasses immediate extended release (IXR) or delayed extended release (DXR) patterns. Extended release is used synonymously with prolonged release, controlled release, sustained release, or modified release. The term "immediate release" refers to a release of the active substance that is not deliberately modified by a special formulation design and/or

manufacturing method and therefore occurs as quickly as is consistent with the properties of the active substance. The immediate release formulation may serve as a precursor to an extended release formulation, or may be used with extended release formulation.

The term "delayed" release means the release of the active ingredient is not immediate and will commence after about 1-2 hours, or later, following administration.

The term "mini-tablet" as used herein refers to any tablet having a maximum dimension between 2 and about 5 mm.

The term "pH-independent" indicates that the release characteristic is virtually the same in different pH media.

The term "pH-dependent" refers to a release to the active substance in a manner that is substantially dependent upon the pH of the surrounding medium within the pH ranges normally found in the human gastrointestinal tract.

The term "layer" in its broadest sense also includes a coating or film, or any type of partly or fully surrounding material used in the pharmaceutical sector.

The term "release retardant" refers to an excipient that can inhibit the release of an active pharmaceutical ingredient from a formulation.

The term "non-functional" means a coating having no substantial effect on drug release properties of the composition. Such a coating can impart a distinctive appearance to the composition, provide protection against attrition during packaging and transportation, improve ease of swallowing, and/or have other benefits.

The term "water-soluble" herein means having solubility of at least about 10 mg/mL. Unless otherwise specified, "solubility" herein means solubility in water at 20-25°C at any physiologically acceptable pH, for example at a pH in the range of about 4 to about 8.

It has now been discovered that pramipexole or its pharmaceutically acceptable salts can be stabilized in pharmaceutical compositions, through the incorporation of microcrystalline cellulose in the compositions. Embodiments of these compositions when subjected to exposure unpackaged, under conditions of about 40±2°C and relative humidity of about 75±5%, for one month, maintain their content of pramipexole dihydrochloride monohydrate ranging from about 95 to about 105% of the label amount of pramipexole dihydrochloride monohydrate, and total impurities (known and unidentified) are less than about 1 .5% of the label content of pramipexole dihydrochloride monohydrate.

The amount of microcrystalline cellulose used in the formulation may be from about 5% to about 90%, or about 15% to about 80, by weight of the formulation.

Microcrystalline cellulose is widely used in tablets because of its unique compressibility and carrying capacity. It exhibits excellent properties as an excipient for solid dosage forms. It compacts well under minimum compression pressures, has high binding capability, and creates tablets that are extremely hard and stable, yet disintegrate rapidly. Other advantages include low friability, inherent lubricity, and the highest dilution potential of all binders. These properties make microcrystalline cellulose particularly valuable as a filler and binder for formulations prepared by direct compression, though it also is used in wet or dry granulation and for spheronization and peptization.

An extended release dosage form of pramipexole may be in the form of tablets such as layered or monolithic tablet, mini-tablets, capsules, pellets, granules, beads, or other particles, nonpareil, patches, powders, and other dosage forms suitable for oral administration. In embodiments, a composition of the present application is in the form of layered or monolithic tablets or mini- tablets. In embodiments, a composition is an extended release pellet wherein the active ingredient is embedded within a matrix, or layered onto an inert core. A composition may also be formulated as layered tablets comprising at least two layers, wherein the layers may exhibit the same or different release profiles, or as a mantle formulation wherein one layer completely surrounds the other layer. A composition may also be formulated as a delayed release dosage form, wherein release in the upper part of the gastrointestinal tract is substantially decreased. A composition may also be in the form of a reservoir system, wherein a functional coating controls the release of the active ingredient.

A composition can be prepared by direct compression, dry compression (slugging), or by wet or melt granulation. Tablets can be prepared by a direct compression technique, using powder blends. Granules can be formed by any processes, using operations such as one or more of dry granulation, wet granulation, extrusion-spheronization, and the like. Granulation of active ingredients, optionally together with one or more pharmaceutically acceptable excipients such as diluents or fillers, can be carried out in equipment such as planetary mixers, rapid mixer granulators (RMG), fluid bed processors, and the like. Alternatively, powder blends can be compacted using a roller compactor and then milled to produce granules that are suitable for compression. The granules or pellets obtained may further be compressed into tablets or filled into capsules. Tablets and mini-tablets can be filled into capsules, using techniques that are known in the art. The granules or the dry blends formed may have bulk densities ranging from about 0.2 to 0.6 g/mL, tapped densities ranging from about 0.5 to 0.8 g/mL, and Carr indexes ranging from about 20 to 40%.

Melt extrusion can be achieved using either hydrophilic or lipophilic substances with melting points between about 40°C and 120°C. Suitable examples are polyethylene glycol 2000-10000, poloxamer 188, carnauba wax, hydrogenated castor oil, stearyl alcohol, cetyl alcohol, and any mixtures thereof. In order to achieve the desired release rates, other excipients, such as lactose, microcrystalline cellulose, starch, etc., can be added.

Equipment suitable for processing the pharmaceutical compositions of the present application include any of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, homogenizers, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans; tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

The compositions of the present application may be used in the treatment of, for example, Parkinson's disease, restless leg syndrome, cluster headache, and bipolar disorder. Pharmaceutical compositions of this application may be orally administered in any acceptable dosage forms, such as capsules and tablets.

Cores of the extended release tablet or pellet formulations of pramipexole may be a hydrophilic or hydrophobic matrix, or may be formed by combinations comprising at least one water-swellable or water-insoluble polymer. In embodiments, extended release tablet or pellet formulations of pramipexole may comprise an immediate release core, with the active ingredient layered onto the core or incorporated into the core, which is surrounded partially or completely by a functional or non-functional coating.

Tablets of the present application can be of any suitable sizes and shapes, for example round, oval, polygonal, or pillow-shaped, and optionally have nonfunctional surface markings. In embodiments of the present application, extended release tablets are white to off-white and of oval, round or biconvex, shape.

Extended release pellets can have sizes between 0.2 and 3 mm in diameter, or between 0.5 and 1.5 mm, or between 0.7 and 1 mm. Extended release capsules can be of any size and shape and color. Capsule shells can be made from hydroxypropyl methylcellulose (also called HPMC), vegetable substances, or gelatin.

In embodiments, an extended release composition of pramipexole comprises at least two of drug delivery components which are immediate release, pH-independent modified release, and pH-dependent modified release

components.

An immediate release component may comprise from about 1 % to about 40% of the total pramipexole in a dosage form. The immediate release component may further comprise binders, disintegrants, lubricants, etc.

A pH-dependent component may comprise from about 1 % to about 99% of the pramipexole in a dosage form. The pH-dependent component may be coated with an enteric coating. Such enteric coatings include polymeric materials containing weakly acidic functional groups, which are capable of ionizing at elevated pH. In the low pH of the stomach, the enteric polymers are un-ionized, and therefore are insoluble. As the pH increases in the intestinal tract, these functional groups ionize, and the polymer becomes soluble or decomposes in the intestinal fluids. The enteric coatings may comprise methacrylic acid copolymers, cellulose acetate phthalates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, hydroxypropyl methylcellulose acetate succinates, methacrylic acid ester copolymers, or other enteric polymers known in the art. Enteric coatings may also contain pharmaceutically acceptable plasticizers such as triethyl citrate, dibutyl phthalate, polyethylene glycols, or other plasticizers. Additives such as dispersants, colorants, and anti-tack and anti-foaming agents, may also be included.

Alternatively, a pH-dependent component may comprise pramipexole dispersed in a polymer matrix, wherein the polymer matrix comprises one or more polymers that allow for release of pramipexole in a pH-dependent manner. Useful polymers include, for example, cellulose acetate phthalates, hydroxypropyl methylcellulose phthalates, polyvinyl acetate phthalates, sodium alginate, hydroxypropyl methylcellulose acetate succinates, methacrylic acid copolymers, and polymethylvinyl ether-maleic acid copolymers.

A pH-independent component may comprise from about 0.1% to about

99% of the pramipexole in the dosage unit. The modified release component may be obtained by preparing a matrix using at least one water-swellable, water- soluble, or water-insoluble polymer, or non-polymeric release retardant, as a release sustaining material. Useful gel-forming polymers include, for example, hydrophilic polymers such as hydroxypropyl methylcelluloses, hydroxypropyl celluloses, methyl celluloses, hydroxyethyl celluloses, polyvinylpyrrolidones, polyethylene oxides, carboxymethylcelluloses, psyllium, and natural gums such as guar gum, gum Arabic, gelatin, locust bean, and acacia. Hydrophilic gel-forming polymers can be used alone or in combination with other hydrophilic polymers, such as propylene glycol, polyethylene glycols, polyvinylpyrrolidones,

microcrystalline cellulose, croscarmellose, starches, methacrylate polymers, dextrin, maltodextrin, dextran, glucomannans, galactomannans, pectin, block copolymers of ethylene oxide and propylene oxide, and polyvinyl alcohols, or in combination with hydrophobic polymers such as ethylcelluloses, chitin, cellulose acetates, cellulose acetate butyrates, cellulose acetate phthalates, cellulose acetate propionates, glyceryl behenate, glycerol palmitostearate, glycerol monostearate, waxes including carnauba, bee, and microcrystalline, polyvinyl acetates, and sulfonated divinylbenzene/styrene copolymers.

Alternatively, a pH-independent component may be coated with a material that functions to slow the release of the active ingredient from the component. Such coatings include, but are not limited to, for example, ethylcelluloses, polyvinyl acetates, cellulose acetates, cellulose acetate phthalates, cellulose acetate butyrates, shellac, methacrylate polymers and copolymers, hydroxypropyl methylcellulose phthalates, and waxes. The insoluble coatings may be used in conjunction with water soluble polymers and compounds to increase the permeability of the insoluble film. Such polymers and compounds include hydroxypropyl methylcelluloses, hydroxypropyl celluloses, methyl celluloses, hydroxyethyl celluloses, polyvinylpyrrolidones, polyethylene oxides,

carboxymethylcelluloses, guar gum, gum Arabic, gelatin, locust bean, acacia, sucrose, lactose, propylene glycol, polyethylene glycols, dextrin, maltodextrin, dextran, glucomannans, galactomannans, pectin, block copolymers of ethylene oxide and propylene oxide, polyvinyl alcohol polysorbates, and sodium lauryl sulfate. The coating layers may also contain any of pharmaceutically acceptable plasticizers, dispersants, colorants, and anti-tack and anti-foaming agents.

Polymers are natural or synthetic compounds, or mixtures of compounds, formed by the polymerisation of small, monomeric compounds and consisting essentially of repeating structural units derived from the monomeric compounds. The polymers or non-polymeric release retardants constituting a matrix or coating mainly provide for the controlled pharmacokinetic release profile of a formulation. Depending on the amount of polymeric or non-polymeric release retardants provided in a formulation, the release profile can be tuned, i.e., larger amounts of polymer lead to a more pronounced sustained release effect, and vice versa. In embodiments, the amount of polymeric or non-polymeric release retardant in a formulation ranges from about 10 to about 90% by weight.

When using a combination of polymers, the ratio of the polymers also influences the release profile of the preparation. A combination of different polymers offers the possibility of combining different mechanisms by which pramipexole is released. Such combination facilitates control of the

pharmacokinetic release profile of the preparation.

In embodiments, the application provides extended release dosage forms comprising pramipexole or its pharmaceutically acceptable salt thereof and at least one cationic polymer.

Cationic polymers according to the present application include chitosan and Eudragit™ E.

Chitosan is a deacetylated chitin. Chitin is a natural linear polysaccharide and has widespread distribution in nature. Chitosan itself is also found in nature in some instances, although it is industrially obtained by hydrolyzing the aminoacetyl groups of chitin from shells of crabs or shrimps in an aqueous alkali solution. It is a linear polyamine where amino groups are readily available for chemical reactions and salt formation with acids. It has a high charge density of one charge per glucosamine unit. The positive charge of chitosan interacts strongly with the negative charges typical in most natural waters. Chitosan is insoluble in water (pH>7) but soluble in aqueous acids such as acetic, adipic, formic, lactic, malic, malonic, propionic, pyruvic, succinic, and nitric acids, showing that its solubility is pH-independent.

Eudragit E 100, which is available from Evonik Industries, Darmstadt, Germany, is a cationic polymer based on dimethylaminoethyl methacrylate and neutral methacrylates. It becomes water soluble via salt formation with acids, thus providing gastro-soluble film coatings. Eudragit E films swell and are permeable in water and buffer solutions above pH 5 and are soluble in gastric fluid below a pH of 5. The average molecular weight of Eudragit E is about 150,000 and it neither contains any plasticizers nor requires their addition for processing.

Cationic polymers used in the composition may be present in a core or coating, and in embodiments cationic polymer comprises between 2% and 40% of the final dosage form, or between 10 and 20%.

In embodiments, the application provides extended release dosage forms comprising pramipexole or its pharmaceutically acceptable salt thereof and at least one pH-dependent polymer.

Useful pH-dependent polymers according to the present application include polyacrylates, methacrylic acid polymers, alginates, and carboxymethyl celluloses.

Carbomer polymers are cross-linked acrylic acid polymers. They are produced from primary polymer particles of about 0.2 to 6 pm average diameters. The flocculated agglomerates cannot be broken into the ultimate particles when produced. Each particle can be viewed as a network structure of polymer chains interconnected via cross-linking. Various useful carbomer polymers include, but are not limited to, Carbopol™ 71 G, 934, 934 P, 971 P, and 974P.

The pH-dependent polymers used in a formulation may be present in a core or coating and, in embodiments, the polymer comprises between about 2% and 40% of the final dosage form, or between about 10 and 20%.

Ion exchange resins that are useful in the present application, without limitation, include styrene-divinylbenzene based copolymers (e.g., Amberlite™ IRP-69, IR-120, IRA- 400 and IRP- 67), copolymers of methacrylic acid and divinylbenzene (e.g. IRP-64 and IRP-88), phenolic polyamines (e.g., IRP- 58), and styrene-divinylbenzene (e.g., colestyramine resin USP).

Ion exchange resins can have a mean particle sizes less than about 100 pm and particle size distributions where not less than 90% of the particles pass through a U.S. Standard 325 mesh sieve. In embodiments, an ion exchange resin comprises between about 5 and 35%, or between about 10 and 20%, of the final dosage form.

Matrix-forming polymer, pramipexole, and ion exchange resin components can be admixed in dry form, thus decreasing the time and expense involved in the formulation of a final dosage form. However, coating procedures and wet granulation techniques may optionally be employed.

In embodiments, the application provides extended release dosage forms comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one pH-independent water-swellable polymer, and at least one water-insoluble polymer.

Useful water-swellable polymers according to the present application include, but are not limited to: alkyl celluloses such as methyl celluloses;

hydroxyalkyl celluloses, for example, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, and hydroxybutyl celluloses; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl celluloses and hydroxypropyl methyl celluloses; carboxyalkyi cellulose esters; other natural, semi-synthetic, or synthetic di- and oligo- polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans; polyvinyl alcohols; polyvinylpyrrolidones; starches and pre- gelatinized starches; copolymers of polyvinylpyrrolidone with vinyl acetate;

combinations of polyvinyl alcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide, polypropylene oxide, and copolymers of ethylene oxide and propylene oxide; polyaminoacids (e.g., gelatin); methyl vinyl

ether/maleic anhydride copolymers; dextrin derivatives (e.g., dextrin); and copolymers of acrylic and methacrylic acid esters containing quaternary

ammonium groups.

Water-insoluble polymers suitable for use in the present application include methacrylic acid copolymers, ammonium methacrylate copolymers, ethyl acrylate and methyl methacrylate copolymers, microcrystalline cellulose, cellulose acetates, cellulose diacetates, cellulose triacetates, cellulose propionates, cellulose acetate butyrates, cellulose acetate propionates, cellulose tripropionates, cellulose ethers such as ethyl celluloses, nylons, polycarbonates,

poly(dialkylsiloxanes), poly(methacrylic acid) esters, poly(acrylic acid) esters, poly(phenylene oxides), aromatic nitrogen-containing polymers, polymeric epoxides, regenerated cellulose, agar acetate, amylose triacetate, beta glucan acetate, acetaldehyde dimethyl acetate, cellulose acetate methyl carbamate, cellulose acetate phthalates, cellulose acetate succinates, cellulose acetate dimethylamino acetates, cellulose acetate ethyl carbonates, cellulose acetate chloroacetates, cellulose acetate ethyl oxalates, cellulose acetate propionates, poly(vinylmethylether) copolymers, cellulose acetate butyl sulfonates, cellulose acetate octates, cellulose acetate laurates, cellulose acetate p-toluenesulfonates, triacetate of locust gum bean, hydroxylated ethylene-vinyl acetate, cellulose acetate butyrates, shellac, and zein.

Additional water-insoluble polymers according to the present application include fatty acids, long chain alcohols, fats and oils, waxes, and phospholipids.

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 application include hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated

cottonseed oil, hydrogenated sunflower oil, hydrogenated castor oil, and the like, and mixtures thereof. Other fatty acids include, for example, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof.

Useful long chain alcohols include excipients such as 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 useful in the present application include natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, and mineral waxes), and synthetic waxes that are edible and have melting points within the range from about 25°C to about 100°C. Specific examples of useful waxes are spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugar cane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, Carbowax™ polyethylene glycols and methoxypolyethylene glycols, and the like, and mixtures thereof.

The wax may also be a monoglyceryl ester, diglyceryi ester, or triglyceryl ester (glycerides), which are esters formed from fatty acids having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol react with the fatty acid. Examples of useful glycerides include 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, and the like, and mixtures thereof.

The wax products include Cutina™ (hydrogenated castor oil), Hydrobase™ (hydrogenated soybean oil), Castorwax™ (hydrogenated castor oil), Croduret™ (hydrogenated castor oil), Carbowax™ products, 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™ (lauroyl macrogolglycerides), Precirol™ (glyceryl

palmitostearate), Emulcire™ (cetyl alcohol), Plural™ (polyglyceryl diisostearate), Geleol™ (glyceryl stearate), and mixtures thereof.

The amounts of water-swellable and water-insoluble polymers used in the formulation may vary, depending upon the medicament employed and the degree of sustained release desired. In general, they may be present in a core or coating in an amount from about 2% to about 90%, or from about 5% to about 75%, or from about 5% to about 40%, by weight of the composition.

Coating involves the deposition of a thin, substantially uniform film onto the surface of a solid dosage form such as a tablet, powder, granule, nonpareil, capsule and the like. Coatings are generally applied continuously to a moving bed of material, usually by means of a spray technique, although manual application procedures also can be used. The coated dosage forms are then sometimes cured at an elevated temperature to provide a finished product.

The coating compositions employed in the present application may be aqueous, non-aqueous, or hydro-alcoholic systems. The solvents used to prepare a non-aqueous coating composition include, but are not limited to, dehydrated alcohol, isopropyl alcohol, methylene chloride, acetone, and mixtures thereof.

Suitable polymers for use in coating include hydroxypropylcelluloses, hydroxyethylcelluloses, hydroxypropyl methylcelluloses,

methylhydroxyethylcelluloses, methylcelluloses, ethylcelluloses, cellulose acetates, sodium carboxymethylcelluloses, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof (e.g., Eudragit™ RL, Eudragit RS, Eudragit L100, Eudragit S100, Eudragit NE), Acryl-eze™, polyvinylpyrrolidones, and polyethylene glycols. The polymers can be combined with water-soluble polymers, such as an HPMC or a polyethylene glycol, to form pores or channels in the coating to modify the release rate.

An aspect of the present application relates to extended release

formulations comprising pramipexole or a pharmaceutically acceptable salt thereof and at least one of an unmodified starch or pre-gelatinized starch.

An aspect of the present application relates to extended release

formulations comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one water-swellable hydrophilic polymer, and at least one of an unmodified starch or pre-gelatinized starch.

An aspect of the present application relates to extended release

formulations comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one water-insoluble polymer, and at least one of an unmodified starch or pre-gelatinized starch.

An aspect of the present application relates to extended release

formulations comprising pramipexole or a pharmaceutically acceptable salt thereof, at least one of a cationic polymer or cationic exchange resin, and at least one of an unmodified or pre-gelatinized starch.

Useful starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starces (commercially available as PCS PC10 from Signet Chemical Corporation) and starch 1500, starch 1500 L grade (low moisture content grade) from Colorcon, fully pregelatinized starch

commercially available as National 78-1551 from Essex Grain Products, and others.

Concentrations of unmodified starch or pre-gelatinized starch used according to the present application will frequently be less than the concentrations of water-swellable or water-insoluble polymers, when used in combination.

However, in embodiments, a starch is not used in tablet formulations according to the present application, as it may be replaced by one or more of the above-mentioned other excipients. Furthermore, a starch having a tensile strength of at least about 0.15 kNcm ^"2 in a solid fraction representative of the tablet as described according to WO 2004/010997 is not required according to the present application.

An amount of pramipexole salt, expressed as pramipexole dihydrochloride monohydrate equivalent, of about 0.1 to about 10 mg, or about 0.05% to about 5% by weight of the composition, will generally be suitable. Specific dosage amounts per unit, for example, include 0.375, 0.5, 0.75, 1 , 1.5, 3, and 4.5 mg of

pramipexole dihydrochloride monohydrate. The amount that constitutes a therapeutically effective amount varies according to the condition being treated, the severity of the condition, and the patient being treated.

Dosage forms can be subjected to in vitro dissolution evaluations, such as using the procedure of Test 71 1 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP") to determine the rate at which the active substance is released from the dosage forms, and the content of active substance can be determined in dissolution solutions using techniques such as high performance liquid chromatography (HPLC).

Compositions of the present application may have a pH-independent or a pH-dependent release profile, or may have a combination of both pH-dependent and pH-independent release profiles.

Formulations according to the present application release the active ingredient substantially completely over at least 4 hours, or at least 8 hours, or at least 12 hours, or at least 18 hours, or at least 24 hours. In embodiments, the drug is substantially completely released over times between 12 and 24 hours. As used herein, substantially complete release is defined as from about 90 to about 105% of the incorporated amount of active ingredient, according to a suitable assay.

Particle sizes of active pharmaceutical ingredient (API) can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle size and size distribution. This will be even more critical for low-dose drugs like pramipexole. Satisfactory dosage units of low doses cannot be manufactured from a drug that does not meet certain particle size and size distribution criteria.

Pramipexole as an active ingredient poses some problems, while processing into pharmaceutical compositions, particularly into tablets. It will give stickiness during compression, due to its having an electrical charge, and leads to various process related problems such as CU variation, which can make processes unacceptable.

The application includes controlled release pharmaceutical compositions comprising pramipexole and one or more polymers, wherein the pramipexole ingredient has particle size distributions with Dg ₀ (at least 90 volume percent of the particles) less than about 100 pm, or less than about 50 pm, or less than about 20 pm.

The Dio, D ₅₀ , and D ₉₀ values are useful ways for indicating a particle size distribution. D ₉₀ is a size value where at least 90 volume percent of the particles have sizes smaller than the said value. Likewise Dio refers to 10 volume percent of the particles having sizes smaller than the said value. D ₅₀ refers to at least 50 volume percent of the particles having sizes smaller than the said value and a D[4,3] value refers to the mean particle size. Methods for determining Di ₀ , D ₅₀ , D ₉₀ and D[4,3] include laser diffraction, such as using equipment sold by Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom.

The application includes pharmaceutical compositions comprising pramipexole and one or more pharmaceutical excipients to enhance

processability. Geometric mixing of pramipexole with other inactive ingredients will enhance the processability of the compositions.

One or more pharmaceutical excipients that can be used in the present application include adsorbents. Suitable adsorbents include, but are not limited to, colloidal silicon dioxide, calcium silicate, other silicates, kaolin, microcrystalline cellulose, bentonite, talc, sorbitol, clays, Fujicalin™, Neusilin™, Zeopharm™, magnesium carbonate, magnesium oxide, calcium carbonate, resins,

crospovidones, sugar, vinegar, diatomaceous earth materials, lactose, etc. used singly or in mixtures.

In addition to pramipexole or a salt thereof and the polymers or non- polymeric release retardants, formulations of the present application may also optionally comprise further excipients, i.e., pharmaceutically acceptable

formulating agents, in order to enhance properties such as the compressibility, appearance, and taste of the preparation. These formulating agents comprise, for example, any one or more of diluents or fillers, glidants, binding agents, granulating agents, anti-caking agents, lubricants, flavors, dyes, and

preservatives. Other conventional excipient types known in the art can also be included.

Diluents:

Various useful fillers or diluents include, but are not limited, to starches, lactose, mannitol (e.g., Pearlitol™ SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV) and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to CEOLUS™ KG801 , Avicel™ PH101 , PH102, PH301 , PH302 and PH-F20, PH-112 microcrystalline cellulose 114, and microcrystalline cellulose 112, and silicified microcrystalline cellulose (e.g., Prosolv™ supplied by JRS Pharma). Other useful diluents include but are not limited to carmelloses, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Binders:

Various useful binders include, but are not limited to, hydroxypropyl celluloses, also called HPC (Klucel™ LF, Klucel EXF) and useful in various grades, hydroxypropyl methylcelluloses, also called hypromelloses or HPMC (e.g., Methocel™) and useful in various grades, polyvinylpyrrolidones or povidones (such as grades PVP-K25, PVP-K29, PVP-K30, and PVP-K90), copovidones (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, methylcelluloses, polymethacrylates, starches, and pre-gelatinized starches.

Disintegrants:

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di- sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including but not limited to crosslinked povidone, Kollidon™ CL (manufactured by BASF, Germany),

Polyplasdone™ XL, XI- 0, and INF-10 (manufactured by ISP Inc., USA), and low- substituted hydroxypropylcelluloses. Examples of low-substituted

hydroxypropylcellulose include but are not limited to low-substituted

hydroxypropylcellulose LH11 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, and starches.

Lubricants:

An effective amount of a pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and combinations thereof. Glidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variation, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc and combinations thereof.

Coloring Agents:

Coloring agents can be used to color code compositions, for example, to indicate the type and dosage of the therapeutic agent therein. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural juice concentrates, pigments such as titanium oxide, iron oxides, silicon dioxide, and zinc oxide, combinations thereof, and the like. A buffer may be present to maintain a pH range wherein the active agent dispersed within the tablet core is stable. Examples of buffers suitable for use in tablet cores include phosphate, citrate, acetate, diethanolamine,

monoethanolamine, sodium bicarbonate, TRIS, and THAM. A buffer is usually not used, if the active agent is stable in the tablet core in the absence of a buffer, in order to minimize the size of the tablet core.

Suitable release enhancing agents may also be present in the formulation including wicking agents, such as high HLB surfactants, for example Tween™ 20, Tween 60 or Tween 80 polysorbates, ethylene oxide propylene oxide block copolymers, ionic surfactants such as sodium lauryl sulfate, sodium docusate, non-swelling hydrophilic polymers such as cellulose ethers, polyethylene glycols, complexing agents such as: polyvinylpyrrolidones, cyclodextrins, nonionic surface active agents, and micelle forming agents, which may be surface active agents such as poly(ethylene oxide) modified sorbitan monoesters , and Span™ products (fatty acid sorbitan esters).

Stabilizing agents may also be present in the formulation. Chelating agents such as EDTA (ethylenediaminetetraacetic acid) and complexing agents such as cyclodextrins may act as stabilizing agents.

Some excipients are frequently used as adjuvants for use in coating processes, include plasticizers, opacifiers, anti-adhesives, polishing agents, etc. Various useful plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.

Anti-adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of a useful antiadhesive for this purpose is talc. The anti-adhesive is frequently present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based upon the total weight of the coating.

Suitable polishing agents include polyethylene glycols, talc, surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax). In addition to the above coating ingredients, sometimes pre-formulated coating products such as Opadry™ products (supplied by Colorcon) or Tabcoat™ products can be used. Opadry compositions generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. Opadry products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures. Products sold in a dry form generally require only dispersion in a liquid before use.

The application includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum, high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, etc.

The application includes the optional inclusion of molecular sieves or silica gel in the containers, to reduce humidity levels. A molecular sieve is a material containing tiny pores of a precise and uniform size, used as an adsorbent for gases and liquids. Silica gel is a granular, vitreous, highly porous form of silica made synthetically from sodium silicate. Silica gel is most commonly encountered in everyday life as beads packed in a vapor-permeable pouch. In this form, it is used as a desiccant to control local humidity in order to avoid spoilage or degradation of products.

Mention of pramipexole is intended to include any of the alternative forms in which pramipexole can be administered, such as salts, esters, hydrates, solvates, crystalline or amorphous polymorphs, racemic mixtures, enantiomeric isomers, etc.

The following examples further describe certain specific aspects and embodiments, and demonstrate the practice and advantages thereof. It is to be understood that the examples are given only for the purpose of illustration and are not intended to limit the scope of the application in any manner. EXAMPLE 1 : Extended release pramipexole formulation.

Ingredient mg/T ablet

Pramipexole dihydrochloride monohydrate 0.375

Hydroxypropyl methylcellulose K100 M 185 HPMC K 15M CR 55

Povidone K 30 15

Anhydrous lactose 41.125

Colloidal silicon dioxide 2

Magnesium stearate 1.5

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC 100M, HPMC K15M, anhydrous lactose, povidone K-30, and colloidal silicon dioxide, and sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the material of step 1 with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets.

EXAMPLE 2: Extended release pramipexole formulation.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC 100M, HPMC K15M, anhydrous lactose, and colloidal silicon dioxide, and sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the material of step 1 with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets.

EXAMPLE 3: Extended release pramipexole formulation.

Ingredient mg/Tablet

Pramipexole dihydrochloride monohydrate 0.375 Hydrogenated castor oil and/or stearic acid 100

Mannitol 50

Lactose 145.625

Colloidal silicon dioxide 2

Talc 2

Manufacturing processes can include melt granulation or wax spray granulation.

A) Melt granulation:

1. Melt hydrogenated castor oil and/or stearic acid, and disperse pramipexole dihydrochloride monohydrate uniformly in the melt.

2. Adsorb the molten mass onto a mixture of mannitol, lactose, and colloidal silicon dioxide, previously sifted through an ASTM 40 mesh sieve, and screen through an ASTM 30 mesh sieve.

3. Blend the material from step 2 with talc, previously sifted through an ASTM 60 mesh sieve.

4. Compress the lubricated blend into tablets.

B) Wax spray granulation:

1. Hydrogenated castor oil and/or stearic acid are dissolved in hot methanol and dichloromethane.

2. Pramipexole dihydrochloride monohydrate is added and dissolved.

3. Mannitol and lactose are placed in a fluid bed processor and solution prepared in step 2 is sprayed onto the bed. Screen the granules through an ASTM 30 mesh sieve.

4. Blend colloidal silicon dioxide, previously sifted through an ASTM 40 mesh sieve, with the granules.

5. Blend talc, previously sifted through an ASTM 60 mesh sieve, with the material of step 4.

6. Compress the lubricated blend into tablets. EXAMPLE 4: Extended release pramipexole formulation.

Ingredient mg/Tablet

Pramipexole dihydrochloride monohydrate 0.375

Hydroxypropyl methylcellulose 140 Hydrogenated castor oil and/or stearic acid 76

Mannitol 50

Lactose 31.125

Colloidal silicon dioxide 1

Talc 1.5

Manufacturing process:

1. Melt hydrogenated castor oil and/or stearic acid and disperse pramipexole dihydrochloride monohydrate uniformly in the melt.

2. Adsorb the melt on to a mixture of HPMC, mannitol, lactose, and colloidal silicon dioxide, previously sifted through an ASTM 40 mesh sieve, and screen through an ASTM 30 mesh sieve.

3. Blend the material of step 2 with talc, previously sifted through an ASTM 60 mesh sieve.

4. Compress the lubricated blend into tablets.

EXAMPLE 5: Extended release pramipexole formulation.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC 100M, HPMC K15M, anhydrous lactose, pre-gelatinized starch, and colloidal silicon dioxide. Sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the material of step 1 with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets. EXAMPLE 6: Extended release pramipexole formulation.

Manufacturing process:

1 . Mix pramipexole dihydrochloride monohydrate geometrically with HPMC K 100M, Eudragit E 100, anhydrous lactose, pre-gelatinized starch, and colloidal silicon dioxide. Sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the material of step 1 with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets. EXAMPLE 7: Extended release pramipexole formulation.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC K 100M, Amberlite IRP 69, anhydrous lactose, pre-gelatinized starch, and colloidal silicon dioxide. Sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the material of step 1 with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets. EXAMPLE 8: Extended release pramipexole formulation.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC K15M, Carbopol 71 G, microcrystalline cellulose, pre-gelatinized starch, and Aerosil 200 W, and sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the step 1 ingredients with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets. EXAMPLE 9: Extended release pramipexole formulation.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC K15M, Carbopol 71 G, microcrystalline cellulose, lactose DCL-21 , pre- gelatinized starch, and Aerosil 200 W, and sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve. 3. Blend the step 1 ingredients with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets.

EXAMPLE 10: Extended release pramipexole formulation.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC K15M, Carbopol 71 G, lactose DCL-21 , pre-gelatinized starch, and Aerosil 200 W, and sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the step 1 ingredients with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets.

Stability testing is performed by storing formulations of Examples 8-10 and the commercial IMIRAPEX® ER product ("Ref.") unpackaged, at 40°C and 75% RH for 2 or 4 weeks. Impurities are analyzed and the results are given below, where values are percentages of the label pramipexole content.

Higher chemical stability is observed in formulations containing

microcrystalline cellulose than in formulations containing lactose, or a combination of lactose and microcrystalline cellulose. Particularly, the unidentified impurities increase to a greater extent in the presence of lactose.

EXAMPLE 1 1 : Extended release pramipexole formulations.

Manufacturing process:

1. Mix pramipexole dihydrochloride monohydrate geometrically with HPMC K15M, Carbopol 71 G, corn starch, lactose DCL-21 , pre-gelatinized starch, and Aerosil 200 W, and sift three times through an ASTM 40 mesh sieve.

2. Sift magnesium stearate through an ASTM 60 mesh sieve.

3. Blend the step 1 material with magnesium stearate of step 2.

4. Compress the lubricated blend into tablets.

Impurity analyses for the formulations, after storage at 40°C and 75% RH in closed 40 cc HDPE bottles for 3 months, are given below. Values are percentages of the label pramipexole content.

Parameter A B

Highest Unidentified Impurity 0.13 0.07

Total Impurities 0.62 0.25