WO2010012482A1

WO2010012482A1 - Ropinirole composition

Info

Publication number: WO2010012482A1
Application number: PCT/EP2009/005559
Authority: WO
Inventors: Jernej Zadnik; Franc Vrecer
Original assignee: Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority date: 2008-08-01
Filing date: 2009-07-31
Publication date: 2010-02-04
Also published as: SI2323634T1; EA023340B1; SI22849A; PL2323634T3; ES2659369T3; EP2323634B1; HRP20180222T1; EA201100287A1; HUE036279T2; EP2323634A1

Abstract

The present invention relates to novel pharmaceutical composition comprising ropinirole or its salt, hydrophilic matrix former, hydrophilic release rate modifier and optionally other excipients.

Description

ROPINIROLE COMPOSITION

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutical composition comprising ropinirole.

BACKGROUND OF THE INVENTION

Ropinirole is a dopamine D₂ agonist used in the treatment of Parkinson's disease and restless legs syndrome. Ropinirole and its hydrochloride salt were first disclosed in EPl 13964. Later were published many more patent applications concerning ropinirole, such as EP266033, EP299602, EP300614, WO9415918, EP831810, EP1272167, EP1435921, EP1656118,

WO2005040115 and WO2005074387.

EP 1 272 167 describes the preparation of a multi-layer tablet, in particular a multi-layer controlled release tablet, comprising one active layer containing an active substance, hydrophilic polymeric substances, lipophilic substances and adjuvant substances; and one or more barrier layers containing hydrophilic polymeric substances, lipophilic substances, and adjuvant substances. The drawback of the multy-layered tablets according to EP 1 272 167 is, that they are rather complicated to produce, as the dissolution rate is controlled with the position of the separate layers, their thickness, as well as their composition, including many different pharmaceutical excipients.

WO 03/035042 also relates to a multi layer controlled-release tablet, comprising an active layer containing ropinirole or a pharmaceutically acceptable salt thereof, hydrophilic polymeric substances, lipophilic substances, and adjuvant substances; and one or more barrier layers containing hydrophilic polymeric substances, lipophilic substances and adjuvant substances. Again, the drawback of this invention is, that the tablets are rather complicated to produce, as the dissolution rate is controlled with the position of the separate layers, their thickness, as well as their composition, including many different pharmaceutical excipients.

WO 2005/018605 provides a controlled release oral dosage form comprising a therapeutically effective amount of ropinirole or a salt thereof, in a matrix. The first drawback of the process disclosed there is, that still it is preferable to form a double layer tablet. The second drawback of the process and compositions of WO 2005/018605 is, that the best performing formulation according to Example 8 requires a rather complicated preparation process including high- shear mixing of the active ingredient with a first part of the diluent, after which the blend is low shear-mixed with the second part of the diluent. Only after the same time consuming procedure has been applied on the second blend, can a rotary double layer press be used to form double layer tablets.

DETAILED DESCRIPTION OF THE INVENTION

The problem solved by the present invention was thus to provide a pharmaceutical composition of ropinirole or its pharmaceutically acceptable salts which allows a straightforward, time- and money-saving process of preparing a sustained- release solid oral dosage form.

The composition according to present invention is simple for manufacturing and does not need any specially designed equipment (e.g. no rotary double layer press) as the tablets do not comprise separate layers, and enables the prolonged release of ropinirole from the composition suitable for once-a-day application to the patients.

More specifically, the present invention relates to a pharmaceutical solid matrix composition such as tablet, or capsule containing two or more micro or mini tablets, comprising: a.) ropinirole or its salt, b.) one or more hydrophilic matrix formers, c.) one or more hydrophilic release rate modifiers, and d.) optionally other excipients.

Further preferred embodiments of the present invention are described in the dependent claims.

Ropinirole according to present invention is preferably in salt form, especially in the form of the hydrochloride salt. More preferably ropinirole hydrochloride of crystalline form I according to WO 2005/080333 is used.

The pharmaceutical composition according to the present invention can be formulated in different dosage forms such as tablets or capsules. Preferably, the composition according to the present invention is in the form of a matrix tablet which can be manufactured by direct compression or via granulation. The term matrix tablet is used to designate a tablet whose core is homogeneous mixture of active pharmaceutical ingredient and excipients and which does not comprise separate layers, as stated above. In other words, it means a single layer tablet.

Optional excipients which can be used in the composition additionally to above mentoned under point b and c are diluents disintegrants, hydrophobic agents, antioxidants, binders, surfactants, glidants or lubricants.

The matrix tablet core can optionally be coated with a coating improving the appearance and physical-chemical characteristics of the matrix tablet core without influence on the release profile of ropinirole.

The hydrophilic matrix former can be selected from the group consisting of cellulose ethers such as hydroxypropylmethyl cellulose (HPMC), ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and/or carboxymethylcellulose sodium; polyethylene oxides; polysaccharides such as alginates, tragacanth, carageenan, ceratonia, xanthan gum, guar gum, locus bean gum, starch derivatives; polymethacrylates such as copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups. The hydrophilic matrix former can be used in a concentration of up to 80% (w/w). Preferably the concentration is from 20% to 80% (w/w), more preferably from 40% to 60% (w/w), based on the total weight of the composition (i.e. without the coating in case of coated tablets).

Preferably the hydrophilic matrix former is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carrageenan, alginate and/or xanthan gum.

Particularly preferred hydrophilic matrix formers are hydroxypropylmethyl celluloses which contain a methoxyl content of 19 to 24 % and a hydroxypropoxyl content of 4 to 12 %. These conform to the US Pharmacopeia requirement for type 2208 substitution of hypromellose. More preferred are hydroxypropylmethyl celluloses having a viscosity of 4 000 mPa.s to 250,000 mPa.s determined in 2% aqueous solution of the polymer at 2O⁰C according to USP method such as hydroxypropymethyl celluose available under the commercial names Hypromellose K4M, Hypromellose KlOOM and Hypromellose K250M. Also preferred hydrophilic matrix formers are water-soluble poly(ethylene oxide) polymers having an average molecular weight within the range from 100,000 to 8,000,000 g/mole which are available under the commercial name Polyox®, such as Polyox resin PEO WSR 303.

The hydrophilic release rate modifiers can be selected from the group consisting of nonionic and/or ionic polymers. They can be selected from water soluble nonionic polymers having an average molecular weight of below 20,000 g/mole such as polyethylene glycols (PEG) with an average molecular weight in the range from 190 to 15,000 g/mole, preferably in the range from 4,000 to 8,000 g/mole and most preferably 5,000 to 6,200 g/mole such as PEG 6000 and/or from anionic polymers having a pH, as aqueous dispersions in a concentration range from 0.1 to 10% (w/w) in the range from 1 to 6 such as carbomers (high molecular mass polymers of acrylic acid cross-linked with alkenyl ethers of sugars or polyalcohols such as in particular allyl sucrose or allyl ethers of pentaerythritol). Anionic polymers can be selected from the group consisting of carbomer, xantan, carrageenan and/or acrylic acid derivatives. Preferred anionic polymers are acrylic acid polymers usually known under their commercial name Carbopol® , especially carbomer homopolymers of type A which have a viscosity range of 4000-11000 cP (test according to USP/NF: Brookfϊeld RVT spindle no. 5, 20 rpm, neutralized to pH 7.3 to 7.8 at 0.5wt%), such as Carbopol 71G NF and/or Carbopol 971 P. They are also characterized by a low residual content of ethyl acetate, such as below 0.5 %(w/w). Their carboxylic acid content is in the range of 52 to 68% (w/w), calculated on the dry basis.

The hydrophilic release rate modifiers can be used in the concentration range 3 to 40% (w/w), preferably 10 to 30% (w/w) of the total weight of the composition.

As used herein, "release rate modifier" means substances which serve to modify the rate of release of therapeutic. agents. The release rate modifier will assist in providing a controlled release of the therapeutic agent and can cooperate with other components in the formulation preferably with hydrophilic matrix former.

Optionally the hydrophilic matrix former and the hydrophilic release rate modifier can be the same, and its/their weight ratio in the formulation is accordingly increased. Typically in such a case the hydrophilic matrix former, e.g. HPMC, is used in a weight ratio of between 40-80% (w/w), preferably 45-60%, most preferably 50% (w/w).

Hydrophobic agents can be selected from cellulose esters such as cellulose acetate; hydrophobic cellulose ethers such as ethylcellulose; waxes and fats such as hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax; alginates such as alginic acid and sodium alginate and fatty acid derivatives such as glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate or the like. Preferred hydrophobic agents are glyceryl behenate and in particular hydrogenated castor oil. Hydrophobic agents can be used in the concentration range from 5 to 40% (w/w), preferably 10 to 30% (w/w) of the total weight of the composition.

Diluents can be selected from sucrose, lactose, mannitol, dextrose, sorbitol, trehalose, starch and its derivatives, microcrystalline cellulose, calcium salts of phosphoric acid such as calcium hydrogen phosphate in anhydrous or hydrated state or a combination thereof. Diluents are preferably used in the range 5 to 50% (w/w), more preferably in the range 10 to 40% (w/w). Lactose and microcrystalline cellulose are being preferred. Also preferred are mixtures of lactose and in particular lactose monohydrate and cellulose, more preferred is ^"a spray-dried compound consisting of alpha-lactose monohydrate and cellulose powder, most preferably a compound consisting of 70% (w/w) alpha-lactose monohydrate and 25 % (w/w) cellulose powder. Such mixtures are commercially available as Cellactose®. The most preferred diluent is lactose monohydrate.

Binders can be selected from water soluble polymers such as soluble cellulose ethers such as hydroxypropylmethyl cellulose (having a viscosity as 2% solution in water at 20°C of below

20 cps (determined according to USP method), preferably below 15 cps and most preferably below lOcps), hydroxypropyl cellulose, which contains not less than 52.0% (w/w) and not more than 81.0%(w/w) of hydroxypropoxy groups ( — OCH₂CHOHCH₃), hydroxyethyl cellulose, methyl cellulose, povidone, copovidone, polyvinyl alcohol and/or water insoluble such as starch and its derivatives, microcrystalline cellulose. Binders are preferably used in an amount of up to 10% (w/w), more preferably from 1 to 8% (w/w) and most preferably from 2 to 6% (w/w). Disintegrants can be selected from crospovidone, carboxymethylcellulose sodium, carboxymethylcellulose calcium, sodium starch glycolate, low substituted hydroxypropyl cellulose which contains not less than 5.0% (w/w) and not more than 16.0% (w/w) of hydroxypropoxy groups ( — OCH₂CHOHCH₃), polacryline potassium; carboxymethylcellulose sodium being preferred.

Antioxidants can be selected from alpha tocopherol, butylated hydroxytoluene; butylated hydroxyanisole, sodium metabisulfite, potassium metabisulfite, alpha tocopherol, sodium ascorbate, ascorbic acid, ascorbyl palmitate, rutin, quercetin, coffee acid, fumaric acid, citric acid monohydrate or similar; butylated hydroxytoluene and butylated hydroxyanisole being preferred.

Surfactants can be selected from anionic surfactants such as sodium lauryl sulphate and/or non-ionic surfactants such as polysorbates, sugar esters, poloxameres or the like.

Glidants can be selected from colloidal silicon dioxide (Aerosil), talc, magnesium trisilicate, magnesium silicate, calcium phosphate, powdered cellulose or magnesium oxide.

Lubricants can be selected from metal stearates such as magnesium, calcium, zinc or aluminium stearate, sodium starch fumarate, hydrogenated vegetable oils, stearic acid.

Preferred are compositions comprising:

Composition A ropinirole hydrochloride 0.3 to 3.2 wt.-% hydrophilic matrix former/ hydrophilic release rate modifier 40 to 80 wt.-% diluent 6 to 50 wt.-% lubricant 0.1 to 5 wt.-%.

Composition A represents an embodiment of the invention where the hydrophilic matrix former also functions as hydrophilic release rate modifier. If the total amount of ingredients is less than 100%, additional excipients are added, such as disintegrants, hydrophobic agents, antioxidants and/or glidants Also preferred are compositions comprising:

Composition B ropiniro Ie hydrochloride 0.3 to 3.2 wt.-% hydrophilic matrix former 38 to 60 wt.-% diluent 6 to 44 wt.-% lubricant 1 to 2 wt.-% hydrophilic release rate modifier 2 to 16 wt.-% hydrophobic agent 5 to 12 wt.-% disintegrant 1 to 10 wt.-% antioxidant 0.01 to 0.3 wt.-% glidant 0.6 to 1 wt.-%.

Particularly preferred are compositions comprising:

Composition C ropinirole hydrochloride 0.3 to 3.2 wt.-% hydrophilic matrix former 40 to 60 wt.-%, in particular 45-55 wt.-% diluent 20 to 40 wt.-%, in particular 25 to 35 wt.-% lubricant 1 to 2 wt.-%. hydrophilic release rate modifier 2 to 6 wt.-%, in particular about 4 wt.-% hydrophobic agent 10 to 12 wt.-%, in particular about 10 wt.-% glidant 0.6 to 1 wt.-%.

Most particularly preferred compositions are:

Composition D ropinirole hydrochloride 0.3 to 3.2 wt.-% hydroxypropylmethyl cellulose 45-55 wt.-% lactose monohydrate 25 to 35 wt.-% magnesium stearate about 2 wt.-%. carbomer about 4 wt.-% hydrogenated castor oil about 10 wt.-% colloidal silica 0 -1% wt.-%. The uncoated tablet cores preferably have a weight in the range of 300 to 600 mg and can be optionally coated with a film coating.

The drug containing core can be manufactured by the state of the art processes such as direct compression, compression of granulate obtained by the state of the art processes such as wet granulation, hot melt granulation and/or dry granulation.

In one embodiment of the present invention the ropinirole hydrochloride containing matrix tablet core is produced by direct compression of the powder mixture containing ropinirole hydrochloride, a hydrophilic matrix former and at least one further ingredient selected from hydrophilic release rate modifiers, hydrophobic agents, diluents, binders, disintegrants, antioxidants, glidants and lubricants, where hydrophilic matrix former is used in the ratio to drug from 40:1 to 190:1. In another embodiment of the invention the ropinirole hydrochloride containing matrix tablet core can be produced via granulation, where the granulation process can be performed in the presence of solvent, such as the wet granulation processes in fluid bed, or in high shear granulators, where water and/or organic solvents, or their mixtures can be used as vehicles for the preparation of a granulation liquid, or in the absence of a granulation liquid, such as a dry granulation process, like roller compaction, or slugging, or melt granulation process. The granulation liquid for wet granulation can be composed of vehicle alone or pharmaceutical acceptable excipients selected from diluent, binder, antioxidant, surfactant can be dissolved, suspended and/or emulsified in the vehicle forming a granulation liquid.

In a special embodiment of the present invention when granulation is performed by a hot melt procedure, at least one component, preferably a binder, is used having melting or glass transition or softening point below 150°C, preferably below 120°C and most preferably in the range 35 to 90°C.

In another embodiment of the invention hot melt granulation can be performed using at least one substance, preferably a polymer with an average molecular weight of from 20,000 to 8,000,000 g/mol, preferably 30,000 to 7,000,000 g/mol, having a melting or glass transition or softening point below 200°C, preferably below 180°C. The glas transition and/or softening point of the polymer can be decreased by using a suitable plasticizer such as low molecular polyethylene glycol with an average molecular weight of below 10,000 g/mol, preferably below 8,000 g/mol, polysorbate, propylene glycol, alkyl esters of carboxylic and/or hydroxycarboxylic acids such as triethylcitrate or glycerol behenate.

The granulate is formulated by transformation of the powder mixture containing ropinirole hydrochloride, one or more hydrophilic matrix formers, one or more hydrophilic release rate modifiers, and at least one further ingredient selected from diluents, binders, disintegrants, glidants, lubricants or surfactants into granules by the before mentioned state of the art processes such as dry, wet or melt granulation. The obtained granulate is mixed with extragranular excipients selected from hydrophilic release rate agents, diluents, disintegrants, glidants and lubricants and compressed into tablet cores.

The average particle size of granulate obtained by wet granulation can be in the range of 50 to 400 μm.

Preferably, ropinirole hydrochloride and a part of the excipients are sieved and homogenously mixed in a high-shear granulator prior granulation. As the vehicle for the preparation of granulation liquid most preferably purified water is used. The water is added to the dry powder mixture by spraying nozzles, an atomizing air spraying nozzle being preferred. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which are mixed with additional excipients. The mixture is treated with a tablet machine to thereby give uncoated tablets each weighing in the range from 300-600 mg.

Low melting point binders are used in case of hot melt granulation of ropinirole. A homogenous mixture of ropinirole hydrochloride and at least one excipient selected from hydrophilic matrix formers, hydrophilic release rate modifiers, hydrophobic agents, diluents, disintegrants, antioxidants is granulated with molten or softened binder, where melting and/or softening of a binder can be achieved by in situ by heating the powder mixture including low melting binder to the melting temperature of binder or by adding of molten binder. Low melting binder can be selected from excipients having melting point below 100°C, preferably below 80⁰C and most preferably between 35 and 7O⁰C such as poloxamers, polyethylene glycols with MW below 10,000 g/mol, partial glyceride, macrogol glyceride esters with fatty acids with 10 to 22 C atoms, sugar esters or the like. A polymer having a softening point of below 200°C can be selected from povidone with K values from 12 to 90, copovidone, ethylcellulose, hydroxypropylmethyl cellulose, cellulose acetate phthalate, block copolymer of polyvinyl alcohol and polyethyleneglycol, polyvinyl alcohol. An especially preferred method of granulation using softening polymers described above is melt extrusion known from the state of the art.

Hydrophilic matrix formers, hydrophilic release rate modifiers, hydrophobic agents, diluents, binders, disintegrants, antioxidants can be used exclusively intra granularly, or exclusively extra granularly or can be used partially intra and partially extra granularly.

In a special embodiment of the invention drug containing tablet core can optionally be coated with water soluble coatings based on water soluble polymers selected from cellulose ethers such as low viscosity grades of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium carboxymethylcellulose, block copolymer of polyvinyl alcohol and polyethyleneglycol sold as Kollicoat IR and/or Kollicoat Protect. Such coating can optionally contain further ingredients such as stabilizers, antitacking agents, plasticizers, pigments and colorants. Coating can improve physical appearance such as colour, smoothness of the surface, which is important for processability during packaging of tablets into primary packaging such as blisters of the coated tablet and easiness of swallowing of tablets by patients, it reduces sorption of water (moisture) and the diffusion of oxygen into the core. Coating can be performed by the state of the art equipment such as perforated and non-perforated coating pans and fluid bed coaters.

A preferred coating agent is based on HPMC with addition of plasticizer and opacifier which is commercially available as Opadry® coating, such as Opadry y- 1-7000. The coating preferably contains pigments such as red iron oxide, yellow iron oxide and/or black iron oxide. The coating is preferably applied in an amount of 1 to 6 % (w/w), preferably 2 to 4 % (w/w) based on the weight of the tablet core. The thickness of the coating can be in the range from 5 to 50 μm, preferably 10 to 30 μm.

Particularly preferred coated compositions according to the invention are obtained by coating compositions C and D as defined above with a coating of Opadry y- 1-7000 and optional addition of iron oxides.

The formulation comprising ropinirole or its salt and suitable excipients prepared according to the above described possible technological procedures exhibits, when measured by the USP Basket method (10 mesh) at 200 rpm in 500 ml of phosphate buffer pH 6.8, the following in- vitro dissolution rate:

10 - 30 % of ropinirole released by 2 hours 35 - 70 % of ropinirole released by 8 hours 55 - 85 % of ropinirole released by 12 hours and at least 70 % of ropinirole released by 20 hours.

Humidity and water content is a highly important parameter to control in order to achieve a stable final solid dosage formulation. Consequently, the water content in the solid dosage form should be limited to be below 2.5% w/w determined by the pharmacopoeial Karl-Fisher method. Besides, the primary packaging material should therefore protect the formulation from the ambient humidity. Tablets containing ropinirole hydrochloride can be packed in air tight containers such as high density polyethylene (HDPE) containers with closure such as polypropylene (PP) closure and with or without desiccator, aluminium foil blisters or polychlorotrifluoroethylene (Aclar®) blisters or any other suitable water vapour impermeable packaging. Additionally inert gases such as nitrogen, argon or helium or vacuum can be used to assure inert atmosphere in the dosage form, such as tablet or capsule, environment in the sealed primary packaging. Inert atmosphere according to present invention mean that concentration of oxygen in the atmosphere around the solid dosage form such as tablet containing ropirinole or its salt packed in the primary packaging is less than 10 % (v/v), preferably less than 5 % (v/v) and most preferably less than 2 % (v/v). The concentration of oxygen in the atmosphere surrounding the tablet can be determined by gas chromatography.

Ropinirole used in the present invention can be prepared according to already known methods such as methods disclosed in EPl 13964, EP266033, EP300614, EP526529, WO9415918,

WO2005040115, WO2005067922, WO2005105741, WO2005080333, EP1568689,

CN1754874, WO2006123356, WO2007010557, WO2007110880, WO2007110879,

CN1958570, CN1974553, WO2008075169, WO2008084499 and/or US20090043111. It can also be further recrystallized and/or purified to a purity level of more than 99%, 99.5% or 99.9 %.

The invention is illustrated by reference to the following examples. However, the examples are not intended to limit any scope of the claim in any way. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.

EXAMPLES

Example 1: Formulation containing ropinirole hydrochloride prepared by direct compression

Ropinirole hydrochloride, hypromellose K250M, cellactose, and magnesium stearate are sieved and mixed. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 2: Formulation containing ropinirole hydrochloride prepared by direct compression

Ropinirole hydrochloride, hypromellose K250M, cellactose, hydrogenated castor oil, and magnesium stearate are sieved and mixed. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 3: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose K250M, lactose monohydrate, and hydrogenated castor oil are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose K250M and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 4: Formulation containing ropinirole hydrochloride prepared by direct compression

Composition

Example 5: Formulation containing ropinirole hydrochloride prepared by direct compression

Ropinirole hydrochloride, hypromellose K250M, cellactose, glyceryl behenate, and magnesium stearate are sieved and mixed. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 6: - Formulation containing ropinirole hydrochloride prepared by wet granulation

Composition

Example 7: - Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose K250M, lactose monohydrate, and hydrogenated castor oil are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose K250M, Carbopol 71G NF, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Com osition

Example 8: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose K250M, and lactose monohydrate are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose K250M, glyceryl behenate, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Com osition

Example 9: - Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose K250M, and lactose monohydrate, are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose K250M, Carbopol 71G NF, hydrogenated castor oil, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 10: Formulation containing ropinirole hydrochloride prepared by direct compression

Ropinirole hydrochloride, hypromellose K250M, and cellactose are sieved and mixed. The obtained mixture is mixed with glyceryl behenate, and magnesium stearate The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 11: - Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, and lactose monohydrate, are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, Carbopol 71 G NF, hydrogenated castor oil, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 12: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, and microcrystalline cellulose are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, carboxymethylcellulose sodium (CMC-Na 7LF), polyethylene glycol (PEG 6000), colloidal silicon dioxide (Aerosil 200), and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg. Composition

Example 13: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM and lactose monohydrate are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with Polyox resin PEO WSR 303, polyethylene glycol (PEG 6000), butylated hydroxytoluene and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 14: - Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM and lactose monohydrate are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, Carbopol 71 G NF, polyethylene glycol (PEG 6000), colloidal silicon dioxide (Aerosil 200), hydrogenated castor oil, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 15: - Formulation containing ropinirole hydrochloride prepared by wet granulation

Example 16: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose K250M, lactose monohydrate, and microcrystalline cellulose are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose K250M, colloidal silicon dioxide, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 17: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, and microcrystalline cellulose are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, carboxymethylcellulose sodium (CMC-Na 7LF), polyethylene glycol (PEG 6000), colloidal silicon dioxide (Aerosil 200), and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 475.0 mg.

Example 18: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, additional colloidal silicon dioxide (Aerosil 200), Carbopol 71 G NF, hydrogenated castor oil, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg. Composition

Example 19: Coating

779.85 g of Opadry y-1-7000, 1.34 g of red iron oxide, and 1.56 g of yellow iron oxide are dissolved and/or dispersed in 4441.25 g of purified water. The uncoated tablets obtained in Example 17 are coated with above dispersion in coating pan. Thus coated tablets weighing 489.3 mg were obtained.

Example 20: Coating

447.76 g of Opadry y-1-7000, 1.34 g of red iron oxide and 0.90 g of yellow iron oxide are dissolved and/or dispersed in 2550.0 g of purified water. The uncoated tablets obtained in Examples 11 and 18 are coated with above dispersion in coating pan. Thus coated tablets weighing 515.0 mg were obtained.

Example 21; - Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, lactose monohydrate, colloidal silicon dioxide (Aerosil 200), and butylated hydroxytoluene are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, additional colloidal silicon dioxide (Aerosil 200), Carbopol 71 G NF, hydrogenated castor oil, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg. Composition

Example 22: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) are sieved and mixed together. To the obtained mixture an aqueous mixture 50 % ethanol with dissolved butylated hydroxyanisole is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, additional colloidal silicon dioxide (Aerosil 200), Carbopol 71G NF, hydrogenated castor oil and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Composition

Example 23: Formulation containing ropinirole hydrochloride prepared by wet granulation

Ropinirole hydrochloride, hypromellose KlOOM, lactose monohydrate, hydroxypropyl cellulose (HPC Klucel EF), colloidal silicon dioxide (Aerosil 200), are sieved and mixed together. To the obtained mixture purified water is added. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, additional colloidal silicon dioxide (Aerosil 200), Carbopol 71G NF, hydrogenated castor oil, and magnesium stearate. The mixture is treated with a tablet machine to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Com osition

Example 24: Composition

Ropinirole hydrochloride, hypromellose KlOOM, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) are sieved and mixed together. To the obtained mixture purified water is added using atomizing air nozzle. The resulting mixture is granulated, dried and passed through an 18-mesh sieve to give granules, which were mixed with additional hypromellose KlOOM, additional colloidal silicon dioxide (Aerosil 200), Carbopol 71G NF, hydrogenated castor oil, and magnesium stearate. The mixture is treated by a tablet machine with oval 15mm x 8mm punches to thereby give uncoated tablets of the following composition each weighing 500.0 mg.

Coating

Opadry y- 1-7000, red iron oxide, yellow iron oxide and optionally black iron oxide are dissolved and/or dispersed in purified water. The uncoated tablets obtained are coated with prepared dispersion in coating pan. Thus coated tablets weighing 515.0 mg are obtained.

Ropinirole hydrochloride used in examples 1-24 was in a crystalline form I according to WO2005080333. Particle size distribution of different batches is shown in table bellow:

The size distribution of ropinirole hydrochloride particles was determined by laser diffraction using a Malvern Mastersizer 2000 laser diffraction instrument. The samples for analysis were prepared by dispersing a weighed amount of ropinirole hydrochloride particles in vegetable oil. With batch 1 two minute sonnication was also used. The term "average particle size" represents the mean particle diameter.

Trade name definitions

Claims

1. A pharmaceutical solid matrix composition comprising a) ropinirole or its salt; b) one or more hydrophilic matrix formers; c) one or more hydrophilic release rate modifiers; and d) optionally other excipients.

2. The pharmaceutical composition according to claim 1, wherein ropinirole is in the form of ropinirole hydrochloride.

3. The pharmaceutical composition according to claim 1, wherein the hydrophilic matrix former is selected from the group consisting of cellulose ethers, polyethylene oxides, polysaccharides and/or polymethacrylates.

4. The pharmaceutical composition according to claim 3, wherein the hydrophilic matrix former is selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropylcellulose, carrageenan, alginate and/or xanthan gum.

5. The pharmaceutical composition according to claim 1 or any of claims 2 to 4, wherein the hydrophilic release rate modifier is selected from the group consisting of ionic polymers and/or nonionic polymers.

6. The pharmaceutical composition according to claim 5, wherein the hydrophilic release rate modifier is a water soluble polymer having an average molecular weight below 20,000 g/mol and/or an anionic polymer having a pH within the range of 1 to 6 determined in an aqueous dispersion in a concentration range from 0.1 to 10 %.

7. The pharmaceutical composition according to claim 6, wherein the hydrophilic release rate modifier is PEG and/or carbomer.

8. The pharmaceutical composition according to claim 7, wherein hydrophilic release rate modifier is PEG 6000 and/or carbomer homopolymer type A.

9. The pharmaceutical composition according to any one of claims 1 to 4 comprising:

ropinirole hydrochloride 0.3 to 3.2 wt.-% hydrophilic matrix former/ hydrophilic release rate modifier 40 to 80 wt.-% diluent 6 to 50 wt.-% lubricant 0.1 to 5 wt.-%.

10. The pharmaceutical composition according to any one of claims 1 to 8 comprising:

ropinirole hydrochloride 0.3 to 3.2 wt.-% hydrophilic matrix former 38 to 60 wt.-% diluent 6 to 44 wt.-% lubricant 1 to 2 wt.-% hydrophilic release rate modifier 2 to 16 wt.-% hydrophobic agent 5 to 12 wt.-% disintegrant 1 to 10 wt.-% antioxidant 0.01 to 0.3 wt.-% glidant 0.6 to 1 wt.-%.

11. The pharmaceutical composition according to any one of claims 1 to 8 comprising:

ropinirole hydrochloride 0.3 to 3.2 wt.-% hydrophilic matrix former 40 to 60 wt.-%, in particular 45-55 wt.-% diluent 20 to 40 wt.-%, in particular 25 to 35 wt.-% lubricant 1 to 2 wt.-%. hydrophilic release rate modifier 2 to 6 wt.-%, in particular 4 wt.-% hydrophobic agent 10 to 12 wt.-%, in particular 10 wt.-% glidant 0.6 to 1 wt.-%.

12. The pharmaceutical composition according to any one of claims 1 to 8 comprising:

ropinirole hydrochloride 0.3 to 3.2 wt.-% hydroxypropylmethyl cellulose 45-55 wt.-% lactose monohydrate 25 to 35 wt.-% magnesium stearate 2 wt.-%. • carbomer 4 wt.-% hydrogenated castor oil 10 wt.-% colloidal silica 0-1 wt.-%.

13. The composition of any one of the previous claims comprising a water soluble coating.

14. The composition of claim 13, wherein the coating is selected from cellulose ethers, low viscosity grades of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose polyvinyl alcohol, sodium carboxymethyl cellulose.

15. The pharmaceutical composition according to any one of the previous claims, which exhibits the following in-vitro dissolution profile:

10 - 30 % of ropinirole released by 2 hours; 35 - 70 % of ropinirole released by 8 hours; 55 - 85 % of ropinirole released by 12 hours; at least 70 % of ropinirole released by 20 hours

measured by the USP Basket method (10 mesh) at 200 rpm in 500 ml of phosphate buffer pH 6.8.

16. The pharmaceutical composition according to any one of the previous claims, which uses a hydroxypropylmethyl cellulose as the hydrophilic matrix former and hydrophilic release rate modifier.

17. The pharmaceutical composition according to any one of the previous claims, which is present in the form of a tablet which does not comprise separate layers.