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Home , Aplindore, Budipine, Etybenzatropine, Mazaticol, Phenglutarimide, Piroheptine

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 1 /1 1 December 2011 (01.12.2011) 2U11/148243 Al

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/20 (2006.01) A61K 31/428 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/IB20 11/001099 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 23 May 201 1 (23.05.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Langi English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 567/KOL/2010 24 May 2010 (24.05.2010) IN (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): LUPIN GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, LIMITED [IN/IN]; 159 CST Road, Kalina, Santacruz ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (East), State of Maharashtra, 400 098 Mumbai (IN). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (75) Inventors/ Applicants (for US only): KULKARNI, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Shirishkumar [IN/IN]; Lupin Limited (Research Park), GW, ML, MR, NE, SN, TD, TG). 46A/47A, Village Nande, Taluka Mulshi, Maharashtra, 4 11 042 Pune (IN). KULKARNI, Rajesh [IN/IN]; Lupin Declarations under Rule 4.17 : Limited (Research Park), 46A/47A, Village Nande, Talu — as to applicant's entitlement to apply for and be granted ka Mulshi, Maharashtra, 4 11 042 Pune (IN). JADHAV, a patent (Rule 4.1 7(H)) Pandharinath [IN/IN]; Lupin Limited (Research Park), 46A/47A, Village Nande, Taluka Mulshi, Maharashtra, — as to the applicant's entitlement to claim the priority of 4 11 042 Pune (IN). TIWARI, Ashish [IN/IN]; Lupin the earlier application (Rule 4.17(Hi)) Limited (Research Park), 46A/47A, Village Nande, Talu — of inventorship (Rule 4.1 7(iv)) ka Mulshi, Maharashtra, 4 11 042 Pune (IN). Published: (74) Agents: MAJUMDAR, Subhatosh et al; S. Majumdar & Co., 5, Harish Mukherjee Road, 700 025 Kolkata (IN). — with international search report (Art. 21(3))

(54) Title: EXTENDED RELEASE FORMULATION OF

(57) Abstract: An extended release formulation comprising pramipexole or pharmaceutically acceptable salts; derivatives; sol vates; and isomers thereof, a weak acid and an extended release polymer. The formulation provides pH independent release profile of pramipexole. EXTENDED RELEASE FORMULATION OF P A IPEXOLE

Field of the Invention The present invention is directed to an extended release formulation of anti- drug comprising pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof, a weak acid and an extended release polymer.

Background of the Invention Parkinson's disease is a movement disorder of increasing occurrence in aging populations. It is a progressive neurodegenerative disorder affecting the mobility and control of the skeletal muscular system. The disease is associated with the depletion of from cells in the corpus striatum. Parkinson's disease is a common disabling disease of old age affecting about one percent of the population over the age of 60 in the United States. The incidence of parkinson's disease increases with age and the cumulative lifetime risk of an individual developing the disease is about 1 in 40. Symptoms include pronounced tremor of the extremities, bradykinesia, rigidity and postural change. A perceived pathophysiological cause of Parkinson's disease is progressive destruction of dopamine-producing cells in the basal ganglia which comprise the pars compartum of the substantia nigra, basal nuclei located in the brain stem. Loss of dopamineric neurons results in a relative excess of . Parkinson's disease often begins with mild limb stiffness and infrequent tremors and progresses over a period of ten or more years to frequent tremors and memory impairment, to uncontrollable tremors and dementia.

Based on the mechanism the anti-parkinson's drugs can be classified as dopamine precursors or , agonists, monoamine oxidase-B inhibitors, catechol-O-methyl transferase inhibitors, aromatic L-amino acid decarboxylase inhibitors, , N-methyl D-aspartate receptor inhibitors etc. Drugs such as ; droxidopa; levodopa; ; ; ; ; ; ; ; ; ; pramipexole; ropinarole; ; ladostigil ; ; ; ; ; ; ; ; ; ; ; ; ; chlorphenxamine; cyrimine; ; ; diphenylhydramine; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and the like are used for the treatment of parkinson's disease.

Most common adverse events in early parkinson's disease without levodopa were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema.

Pramipexole is a non-ergot with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptor, binding with higher affinity to D3 than D2 or D subtypes. The precise mechanism of action of pramipexole as a treatment for parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum an the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in parkinson's disease is unknown. The pramipexole is a basic drug and its chemical name is (S)-2-amino-4, 5,6,7- tetrahydro-6-(propylamino) benzothiazole. Its empirical formula is C10H17N3S. The salt form commonly used is pramipexole dihydrochloride monohydrate.

The pramipexole as its dihydrochloride monohydrate salt is approved in United States as MIRAPEX ® (immediate release tablets) and as MIRAPEX®ER (extended release tablets) for the treatment of early as well as advanced idiopathic parkinson's disease. MIRAPEX® is also approved for the treatment of moderate-to-severe primary (RLS). MIRAPEX ®ER tablets are taken orally once daily. US 4,886,812 discloses tetrahdro-benzthiazole compounds (pramipexole). US6, 001 ,861 & US 6,194,445 disclose use of pramipexole for the treatment of restless legs syndrome.

The starting dose of pramipexole is 0.375 mg/day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg/day and then by 0.75mg increments up to a maximum recommended dose of 4.5 mg/day.

As is commonly known, extended release of active ingredient(s) allows simplification of the patient's administration scheme by reducing the amount of recommended daily intakes, improves patient's compliance, and attenuates adverse events, e.g., related to high plasma peaks. Extended release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise formulations with controlled, prolonged, sustained, delayed, 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. There are a number of approaches described in prior art to provide extended release tablet compositions of pramipexole.

US 7,695,734 discloses an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water swelling hydrophilic polymers other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer and the other is a substantially neutral polymer.

US 2005/0175691 discloses the orally deliverable pharmaceutical once daily sustained release composition comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof , a starch preferably pregelatinized starch, a hydrophilic polymer such as hydroxypropylmethyl cellulose and at least one pharmaceutically acceptable excipient.

US 2005/0226926 discloses a sustained-release pharmaceutical composition in a form of an orally deliverable tablet comprises 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. 5 N cm 2 at a solid fraction representative of the tablet.

US 2009/0281 153 discloses 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 pregelatinized starch.

US 2009/0182024 discloses 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. US 2009/0130197 disclose an extended release pellet comprising an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least one release-modifying excipient.

US 2008/02541 17 disclose a process for preparing tablets of pramipexole dihydrochloride wherein the tablets exhibit enhanced stability properties.

WO 2007/090882 discloses an extended release composition which comprises the active compound pramipexole and provides a selected release profile. Preferably, the composition does not exhibit a lag phase of more than 1 hour. The composition is for suitable for oral administration. It also discloses a method for achieving a 5 selected release profile, optionally by combining an extended release dose fraction and an immediate release dose fraction.

US 2003/01 33982 discloses zero-order sustained release solid dosage forms suitable for administration of a wide range of therapeutically active medicaments, especially those that are water-soluble comprises (a) a matrix core comprising ethylcellulose and the active agent and (b) a hydrophobic polymer coating encasing the entire matrix core.

US 2008/0248107 discloses a controlled release formulation comprising an therapeutically effective amount of pharmacologically active substance having high water solubility, at least one non-polymeric release retardant, and at least one pH independent non-swelling release retarding polymer. The said dosage form provides controlled release of the active agent with reduced initial burst release.

US 2006/01 10454 discloses an extended release composition of Pramipexole or a pharmaceutical acceptable salt thereof, wherein the active agent is coated on a non pareil inert core, the drug loaded core is further coated with a polymeric layer which enables the release of the active agent over an extended period and optionally the extended release pellets being further blended with suitable excipients and compressed into a multi unit tablet and processes for the preparation of the said composition.

WO 2008/068778 discloses an extended release pharmaceutical composition comprising pramipexole having an extended release profile such that not less than 25% of the total amount of pramipexole or a pharmaceutically acceptable salt thereof in the composition is released within one hour no, significant release of the drug takes place over the subsequent one hour and not less than 80% of the total amount of pramipexole or a pharmaceutically acceptable salt thereof in the composition is released over a period of about 24 hours.

US 2009/0304794 disclose a controlled release pharmaceutical formulation of pramipexole for once-a-day administration comprising a therapeutically effective amount of pramipexole, and an osmotic agent, wherein pramipexole is released from the formulation along a pre-determined release profile. The controlled release formulation of the invention is osmotic formulation

US 2009/01 10728 discloses the solid dosage form for delivery of water soluble pharmaceutical agents comprises a matrix core containing the pharmaceutical agent and a hydrophobic material, and a coating containing a hydrophilic pore-forming agent and a hydrophobic polymer. The dosage form exhibits a zero-order release profile upon dissolution.

US 2009/0053310 discloses novel sustained release dosage form comprising an active agent and a combination of a non-swelling pH dependent release retardant and a non swelling pH independent release retardant polymer which provides pH- independent drug release for a considerable period of time after administration.

WO 2007/002518 disclose delayed-release (DR) pramipexole pharmaceutical composition in an once - daily orally deliverable form, comprising an enteric coating, a pramipexole core, and pharmaceutically acceptable carriers and excipients, wherein the enteric coating substantially eliminates the release and/or absorption of pramipexole in the upper gastrointestinal (Gl) tract.

US 2004/0228915 disclose an extended release multiparticulate formulation of a therapeutic agent, wherein coated core multiparticulate particles of the therapeutic agent are overcoated with a binder-dispersing agent, such as povidone or cross- povidone. The binder-dispersing agent in the formulations of the present invention ensure that compressed tablets formed therefrom will remain intact through oral administration, and dissolve shortly thereafter, enabling the multiparticulates to release the therapeutic agent contained therein over an extended period of time.

Although number of approaches has already been developed for extended release of pramipexole, we have found that the presence of weak acid in the formulation provides a pH independent release profile for pramipexole dihydrochloride monohydrate.

Pramipexole is a basic drug. The presence of two or more basic centres in pramipexole and 2-aminobenzothiazole structure is the reason for the strong basic character of this drug.

Basic and acidic drugs exhibit pH-dependent solubility profiles varying by more than 2 orders of magnitude in the physiological pH range. A basic drug's solubility decreases as it proceeds distally towards the large intestine (pH 8.0) while it is soluble in the stomach and the upper or proximal region of the small intestine. Thus, a poorly soluble basic drug will lead to less drug being available for absorption in the lower or distal intestine.. While not intending to be bound by any particular theory, it is believed that the formulation with the weak acid creates a microenvironment of low pH to enhance the solubility of the drug within the dosage form as it moves down the Gl tract.

Thus the oral extended release formulations comprise of pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof, a weak acid and an extended release polymer would provide an extended release of pramipexole. The release profile is found to be pH independent.

Objects of the Invention: An extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer.

An extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, wherein the extended release formulation exhibits a pH independent release profile.

Summary of the Invention: One embodiment disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer.

Other embodiment disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, providing therapeutically effective concentration of pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof for a period of at least 8 hrs.

Another embodiment disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, wherein the extended release formulation exhibits a pH independent release profile.

Another embodiment disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, wherein the extended release formulation is gastroretentive.

Another embodiment disclose an extended release formulation comprising (i) Core comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, and (ii) Coating.

Another embodiment disclose an extended release formulation comprising (i) Core comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, and (ii) Coating, wherein the extended release formulation is gastroretentive.

Brief Description of the Drawing : FIG. 0 1 depicts the in vitro dissolution profile of pramipexole dihydrochloride monohydrate tablets of Example 0 1 in 0.1 N HCI, pH 4.5 acetate buffers and pH 6.8 phosphate buffers.

Detailed Description of the Invention: The present invention provides an extended release formulation of anti-parkinson drug preferably pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof, a weak acid and an extended release polymer.

As used herein, the term "pramipexole" is understood as covering all forms of pramipexole, the free base as well as pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof. The most preferred form is pramipexole dihydrochloride monohydrate. The term "therapeutically effective concentration" or "therapeutically effective amount" is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which are therapeutically effective in treating diseases.

The extended release formulation would release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time.

The term extended release formulation may also used synonymously with prolonged release formulation, programmed release formulation, timed release formulation, modified release formulation, site specific release formulation, sustained release formulation, controlled release formulation, slow release formulation, delayed release formulation, osmotic dosage form, bioadhesive formulation, orally disintegrating modified release formulation, gastroretentive formulation and other such dosage forms.

The term "pH independent release" means the release profile which does not vary much with changes in pH.

The term "pharmaceutically-acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular pramipexole active ingredient selected for use.

The extended release formulation includes tablets, coated tablets, layered tablets, particles, granules, pellets, powders, microparticles, capsules which may be hard gelatin or soft gelatin, caplets, sachets, pellets, spheroids, mini-tablets, beads, microcapsules, lozenges and pills. One of the embodiments disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer.

The weak acid may be selected from organic acids, inorganic acids or combination thereof. The organic acids may include, but are not limited to, citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, , mandelic acid, glutaric acid, and .

The inorganic acids may include, but are not limited to, hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.

The preferred weak acid is organic acid and the preferred organic acid is fumaric acid.

Weak acid provides acidic microenvironment and may avoid degradation of pramipexole when exposed to alkaline media. The weak acid used may also act as anti-oxidant to prevent oxidation of pramipexole at alkaline pH.

In another embodiment, the extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, providing therapeutically effective concentration of pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof for a period of at least 8 hrs. The extended release polymer used in the present invention may be selected from water soluble polymer, water insoluble polymer, waxy material or combination thereof. The extended release polymer may be added in the formulation in the range of about 1 to about 90%.

The water soluble polymer may be selected from the group consisting of alkyl celluloses such as methyl cellulose; pseudo ethylcellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose (hypromellose); carboxyalkyl cellulose esters; other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans; methacrylate copolymers; polyvinyl ; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

Water insoluble polymer may be selected from the group consisting of cellulose acylate; cellulose ethyl ether; cellulose diacylate; cellulose triacylate; cellulose acetate; cellulose diacetate; cellulose triacetate; mono-, di- and tricellulose alkan, mono-, di- and tricellulose aroyl; ethyl cellulose; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; cellulose acetate succinate; polyvinylacetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); poly vinyl alcohols; polyacrylamide derivatives poly (vinyl acetate); polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate- methacrylic acid-octyl acrylate copolymer, pH-independent acrylates such as ammonio methacrylate copolymer and the like; ethyl cellulose, crosslinked polymers such as styrene-divinylbenzene copolymer, polysaccharides having hydroxyl groups such as dextran, cellulose derivatives which are treated with Afunctional crosslinking agents such as epichlorohydrin, dichlorohydrin, 1, 2-, 3 , 4-diepoxybutane and the like.

Waxy material may be selected from carnauba wax; beeswax; Chinese wax; spermaceti; lanolin; bayberry wax; candelilla wax; castor wax; esparto wax; Japan wax; jojoba oil; ouricury wax; rice bran wax; ceresin waxes; montan wax; ozocerite; peat waxes; paraffin wax; polyethylene waxes; polyglycerol fatty acid esters; fatty alcohols; glyceryl esters of fatty acids; and mineral or vegitable oil.

The extended release formulation of the present invention may further contain pharmaceutically acceptable excipients such as binders; diluents; lubricants; disintegrating agents; glidants; stabilizers; osmotic agents and surface active agents.

The binders may include, but are not limited to, potato starch; modified starch; gelatin; wheat starch; corn starch; microcrystalline cellulose; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (hypromellose), ethyl cellulose and sodium carboxy methyl cellulose; natural gums such as acacia, alginic acid and guar gum; liquid glucose; dextrin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; gelatin; poly propylene glycol; tragacanth; hydrogenated vegetable oil; castor oil; paraffin; higher aliphatic alcohols; higher alphatic acids; long chain fatty acids; fatty acid esters; and wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, waxes, stearic acid and stearyl alcohol. The amount of binder present can vary from about 0.1% to about 25% by weight of the tablet dry weight, preferably about 0.5% to about 0%. The diluents may include, but are not limited to, pharmaceutically acceptable inert fillers such as microcrystalline cellulose; lactose; dibasic or tribasic calcium phosphate; saccharides confectioner's sugar; compressible sugar; dextrates; dextrin; dextrose; fructose; lactitol; mannitol; sucrose; starch (i.e. corn starch); xylitol; sorbitol; talc; calcium carbonate; and calcium sulphate. The diluent is preferably used in an amount of about 0 to 90% by weight.

The disintegrating agents may include, but are not limited to, cross-linked polymers such as crospovidone; starch or modified starch such as sodium starch glycolate; clays such as bentonite or veegum; celluloses or cellulose derivatives; and crosslinked cellulose such as croscarmellose sodium resins such as polacrillin potassium.

The lubricants may include, but are not limited to, Mg, Al or Ca or Zn stearate; polyethylene glycol; glyceryl behenate; glyceryl monosterate; mineral oil; sodium stearyl fumarate; stearic acid; hydrogenated vegetable oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; polyethylene glycol; ethylene oxide polymers; and colloidal silica.

The glidants may include, but are not limited to, trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; colloidal silicon dioxide; and silicon hydrogel.

The extended release formulation may optionally contain a surface active agent. The surface active agents may include, but are not limited to, fatty acid; olefin; alkylcarbonyl; silicon elastomer; sulfate ester; petty alcohol sulfate; sulfate pete and oil; sulfonic acid-base; fat sulfonate; alkylaryl sulfonate; ligmin sulfonate; phosphoric acid ester; polyoxyethylene; polyoxyethylene caster oil; polyglycerol; polyol; imidazol; altanolamine; hetamine; sulfobecamine; phosphotide; polyoxyethylene- sorbitan fat acid ester; and sorbitan ester.

The osmotic agents may include, but are not limited to sodium chloride; potassium chloride; magnesium sulfate; magnesium chloride; sodium sulfate; lithium sulfate; urea; inositol; sucrose; lactose; glucose; sorbitol; fructose; mannitol; dextrose; magnesium succinate; and potassium acid phosphate.

One embodiment disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer wherein the extended release formulation exhibits a pH independent release profile.

One embodiment disclose an extended release formulation comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, wherein the extended release formulation is gastroretentive.

Gastroretentive means a formulation which is remained in the stomach or upper part of the small intestine. The size of the extended release formulation will determine whether the formulation is gastroretentive.

Other embodiment disclose an extended release formulation comprising (i) Core comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, and (ii) Coating.

The coating may be functional, multifunctional or non-functional coating. It includes moisture barrier coatings; enteric polymeric coatings; extended release coating; sustained release coating; controlled release coating; and the like.

The functional coating comprise of extended release polymer which may affect the release of pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof from the extended release formulation.

The non-functional coatings have no affect on the release of pramipexole from the extended release formulation.

The coating composition may further include other pharmaceutically acceptable excipients such as plasticizer, pore forming agent or channeling agent, solvent system (i.e., water), a colorant and the like to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the overcoat. Suitable ingredients for providing color to the formulation include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating. Alternatively, any suitable method of providing color to the formulations of the present invention may be used.

The plasticizer may include, but not limited to polyethylene glycol; triethyl citrate; triacetin; diethyl phthalate; dibutyl stearate; dibutyl sebacate; oleic acid; alcohol; mineral oil; castor oil; lanolin; petrolatum; propylene glycol; glycerol; acetylated monoglyceride; rape oil; olive oil; sesame oil; acetyltributylcitrate; acetyltriethylcitrate; glycerin sorbitol; diethyloxalate; diethylmalate; diethylfumarate; dibutylsuccinate; diethylmalonate; dioctylphthalate; dibutylsebacate; triethylcitrate; tributylcitrate; glyceroltributyrate; and the like.

The pore forming agent which may be used are lactose, sodium chloride, sodium carbonate, polyethylene glycol etc.

Another embodiment disclose an extended release formulation comprising (i) core comprising (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, and (ii) coating, wherein the extended release formulation is gastroretentive.

The extended release formulation of the present invention may be manufactured by various methods known in the art such as by dry granulation, wet granulation, fluidized bed granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods. Aqueous and/or non-aqueous solvents may be used for granulation.

The wet granulation process comprises the admixing of the active ingredient with diluent(s) and/or extended release polymer, and granulation of the blend with the binder mass to form the wet mass followed by drying and sizing. The binder may optionally be admixed with the dry blend and granulation performed with aqueous or non-aqueous solvent. The solvent for the non-aqueous granulation is selected from methanol, ethanol, isopropyl alcohol and dichloromethane.

Alternatively pramipexole may also be dissolved in solvent and then used as granulating solution.

The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Examples: Formula:

Procedure: Microcrystalline cellulose, hypromellose & fumaric acid were sifted and mixed. This mixture was granulated with solution of pramipexole dihydrochloride monohydrate & povidone in methanol and water mixture. The granules were dried for desired loss on drying. The dried granules were sifted, lubricated and compressed into tablets. Dissolution study for pramipexole dihydrochloride monohydrate tablets of Example 0 1: The dissolution profile of the pramipexole dihydrochloride monohydrate tablets of

Example 0 1 was carried out in type 1 dissolution apparatus, basket, at 100rpm, at a temperature of about 37±0.5 °C, in 500ml of 0.1 N HCI, pH 4.5 acetate buffer and pH 6.8 phosphate buffer which may release not more than about 25% of pramipexole dihydrochloride monohydrate within 1 hour, from about 30% to about 70% of pramipexole dihydrochloride monohydrate is released within 4 hour and not less than about 75 % of pramipexole is released within 12 hours. The results of the in vitro dissolution profile are set forth in Table: .01 and illustrated in Figure 0 1. Table: 0 1 Dissolution profile of pramipexole dihydrochloride monohydrate tablets

of Example 0 1 % Drug Release

Time (Hrs) In 0.1 N HCI In pH 4.5 In pH 6.8 Acetate Buffer Phosphate Buffer 1 22.9 17.3 18.0 2 34.0 26.6 28.6

4 49.7 42.5 4 1.7

8 7 1. 1 6 1.6 60.9 12 84.7 77.3 75.5 14 90.9 85.3 80.8 16 93.6 90.7 84.9 18 97.2 100.4 89.6 20 99.7 102.1 94.0 CLAIMS

1. An extended release formulation comprising: (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer.

2. The extended release formulation as defined in claim 1, wherein the weak acid is organic acid, inorganic acid or combination thereof.

3. The extended release formulation as defined in claim 2 , wherein the organic acid is citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, mandelic acid, glutaric acid or glutamic acid.

4. The extended release formulation as defined in claim 2, wherein the inorganic acid is hydrochloric acid, phosphoric acid, nitric acid or sulfuric acid.

5. The extended release formulation as defined in claim 2 , wherein the organic acid is fumaric acid.

6. The extended release formulation as defined in claim 1, wherein the extended release polymer is water soluble polymer, water insoluble polymer, waxy material or combination thereof.

7. The extended release formulation as defined in claim 6 , wherein the water soluble polymer is selected from the group consisting of methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxyalkyi cellulose esters, galactomannans, tragacanth, agar, guar gum, polyfructans, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyethylene oxide and copolymers of ethylene oxide and propylene oxide.

The extended release formulation as defined in claim 6 , wherein the water insoluble polymer is selected from the group consisting of cellulose acylate, cellulose ethyl ether, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetatephthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, ammonio methacrylate copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, ethyl cellulose, styrene-divinylbenzene copolymer, dextran, epichlorohydrin, dichlorohydrin, 1,2-,3,4-diepoxybutane hydroxypropylmethylcellulose acetate succinate, poly (vinyl acetate), poly vinyl alcohols and polyacrylamide derivatives.

The extended release formulation as defined in claim 6 , wherein the waxy material is selected from the group consisting of carnauba wax, beeswax, Chinese wax, spermaceti, lanolin, bayberry wax, candelilla wax, castor wax, esparto wax, Japan wax, jojoba oil, ouricury wax, rice bran wax, ceresin waxes, montan wax, ozocerite, peat waxes, paraffin wax, polyethylene waxes, and polyglycerol fatty acid esters. 10. An extended release formulation comprising: (a) pramipexole or pharmaceutically acceptable salts; derivatives; solvates; and isomers thereof; (b) a weak acid; and (c) an extended release polymer, wherein the extended release formulation exhibits a pH independent release profile.

11.The extended release formulation as defined in claim 0, wherein the extended release formulation of pramipexole releases not more than about 25% of pramipexole within 1 hour, from about 30% to about 70% of pramipexole within 4 hour and not less than about 75% of pramipexole within 12 hours when tested according to USP type 1 dissolution apparatus at 100rpm and 37±0.5 °C temperature in 500ml of 0.1 N HCI.

A . CLASSIFICATION O F SUBJECT MATTER INV. A61K9/20 A61K31/428 ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

EPO-Internal , BIOSIS, EMBASE, WPI Data

C . DOCUMENTS CONSIDERED TO B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2006/015943 A2 (BOEHRINGER I NGELHEIM 1-11 INT [DE] ; BOEHRINGER I NGELHEIM PHARMA [DE] ; FRI ED) 16 February 2006 (2006-02-16) ci ted i n the appl i cati on cl aims ; exampl es

W0 2010/010138 Al (BOEHRINGER I NGELHEIM 1-11 INT [DE] ; BUERGER ERICH [DE] ; FERGER BORIS [DE] ; ) 28 January 2010 (2010-01-28) exampl es

US 6 287 599 Bl (BURNSIDE BETH A [US] ET 1-11 AL) 11 September 2001 (2001-09-11) cl aims ; tabl es 2 , 4

□ Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the principle o r theory underlying the considered to b e of particular relevance invention "E" earlier document but published o n o r after the international "X" document of particular relevance; the claimed invention filing date cannot be considered novel o r cannot b e considered to "L" documentwhich may throw doubts o n priority claim(s) o r involve a n inventive step when the document is taken alone which is cited to establish the publication date of another "Y" document of particular relevance; the claimed invention citation o r other special reason (as specified) cannot be considered to involve a n inventive step when the "O" document referring to a n oral disclosure, use, exhibition o r document is combined with one o r more other such docu¬ other means ments, such combination being obvious to a person skilled in the art. "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

25 July 2011 01/08/2011

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Zimrner, Barbara Patent document Publication Patent family Publication cited in search report date member(s) date

WO 2006015943 A2 16-02-2006 AU 2005271193 A l 16-02 2006 BR PI0513848 A 20- 05 2008 CA 2576386 A l 16-02 2006 CN 101022788 A 22-08 2007 CN 101849920 A 06-10 2010 CN 101843597 A 29-09 2010 EA 200700388 A l 31-08 2007 EC SP077243 A 29- 03 2007 EP 1778201 A2 02-05 2007 HK 1107780 A l 01-04 2011 JP 2008509193 A 27- 03 2008 KR 20070050081 A 14-05 2007 NZ 553645 A 30- 09 2010 SG 164375 A l 29-09 2010 US 2006051419 A l 09-03 2006 US 2009130197 A l 21- 05 2009 US 2010086589 A l 08-04 2010 ZA 200700313 A 28- 05 2008

W0 2010010138 A l 28-01-2010 NONE

US 6287599 B l 11-09-2001 AU 2002249881 B2 21-12-2006 CA 2432178 A l 01-08-2002 EP 1351668 A l 15-10-2003 JP 4340840 B2 07-10-2009 JP 2004518676 A 24-06-2004 W0 02058676 A l 01-08-2002