HK1149481A - Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof - Google Patents

Description

Extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof

The present application is a divisional application of the chinese invention application (title of the invention: extended release tablet comprising pramipexole or a pharmaceutically acceptable salt thereof, application date: 25/7/2005; application No. 200580027635. X).

Technical Field

The present invention relates to extended release (extended release) tablets comprising pramipexole or a pharmaceutically acceptable salt thereof, a process for the preparation thereof and use thereof.

Background

Pramipexole is a known dopamine D2 receptor agonist. It differs structurally from ergot-derived drugs such as bromocriptine or pergolide. It is also pharmacologically unique in that it is a full agonist and is receptor selective for the dopamine D2 family of dopamine receptors.

The chemical name of pramipexole is: (S) -2-amino-4, 5, 6, 7-tetrahydro-6- (propylamino) benzothiazole with the molecular formula of C₁₀H₁₇N₃S, relative molecular weight 211.33. The chemical formula is as follows:

the pramipexole salt commonly used is pramipexole dihydrochloride monohydrate (formula C)₁₀H₂₁C₁₂N₃An OS; relative molecular weight 302.27). Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs at 296 ℃ to 301 ℃ with decomposition. Pramipexole is a chiral compound with one chiral center. The pure (S) -enantiomer is synthesized as an intermediate during the synthesis by chiral recrystallization.

Pramipexole dihydrochloride monohydrate is a highly soluble compound. The water solubility is greater than 20mg/ml, the solubility in a buffer medium from pH 2 to pH 7.4 is generally greater than 10 mg/ml. Pramipexole dihydrochloride monohydrate is non-hygroscopic and has high crystalline properties. Under milling, the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, while its solution is sensitive to light.

In 1997 pramipexole Immediate Release (IR) tablets were first approved in the united states and subsequently in the second year, market approval was obtained in european union ((EU), switzerland, canada and south america and in eastern european countries, the near east and asia, respectively.

Pramipexole IR tablets in combination with levodopa have been shown in the EU and US to be useful in the treatment of signs and symptoms of early or late stage parkinson's disease. The IR tablets must be taken 3 times a day.

From a pharmacokinetic point of view, pramipexole IR tablets are rapidly and completely absorbed after oral administration. Its absolute bioavailability is greater than 90%, with maximum plasma concentrations occurring within 1 to 3 hours. Since absorption is not performed to a full extent after ingestion of food, the absorption rate is lowered. Pramipexole showed linear kinetics with relatively minor changes in plasma levels in the patients. Its elimination half-life (t)_1/2[h]) In contrast, from 8 hours in young people to 12 hours in older people.

As is generally known, improving the release of the active ingredient by reducing the recommended daily intake simplifies the dosing regimen for the patient, increases patient compliance, and reduces side effects, such as those associated with high plasma peaks. Modified release (modified release) pharmaceutical formulations modulate the release of an added active ingredient or ingredients over time, including controlled, extended, sustained, delayed, slowed or extended release (extended) release, and thus achieve therapeutic or convenient objectives, unlike those provided by conventional dosage forms, such as solution or rapidly dissolving dosage forms.

Modified or prolonged release of the active ingredient from the pharmaceutical preparation can be obtained by uniformly embedding said active ingredient in a hydrophilic matrix which is a viscous hydrophilic polymer network which is soluble, partially soluble or insoluble, by physical or chemical entanglement, by ionic or crystalline interactions, by complex formation, by hydrogen bonding or van der waals forces. The hydrophilic matrix swells upon contact with water, thereby forming a protective gel layer from which the active ingredient is slowly, gradually, continuously, time-sequentially released by diffusion from the polymeric network, by erosion of the gel layer, by dissolution of the polymer, or by a combination of said release mechanisms.

However, it has proven difficult to prepare tablets having suitable combinations and handling properties for drugs having relatively high solubility, such as in the case of pramipexole dihydrochloride.

A number of methods for providing pramipexole extended release tablet compositions are described in the prior art:

WO2004/010997 describes an extended release pharmaceutical composition in the form of an oral delivery 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 0.15kNcm in a representative solid component of the tablet^-2Preferably at least about 0.175kN cm^-2More preferably at least about 0.2kN cm^-2. The disclosure therein aims to provide compositions which achieve sufficient hardness under high speed tabletting operations, especially against corrosion when applying coating layers. According to a preferred embodiment, there is provided a pharmaceutical composition in the form of an oral delivery tablet comprising an inner core comprising pramipexole dihydrochloride monohydrate in an amount of about 0.375, 0.75, 1.5, 3, or 4.5mg dispersed in a matrix comprising (a) HPMC type 2208 in an amount of about 35% to about 50% by weight of the tablet, and (b) pregelatinized starch having a tensile strength of at least about 0.15kN cm in a 0.8 solid component^-2From about 45% to about 65% by weight of the tablet; the core is substantially encapsulated in a coating comprising from about 2% to about 7% by weight of the tablet of an ethylcellulose-based hydrophobic or water-insoluble component and an HPMC-based pore-forming component in an amount of from about 10% to about 40% by weight of the ethylcellulose-based component.

Furthermore, WO 2004/010999 discloses an oral delivery pharmaceutical composition comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, said composition exhibiting at least one of the following properties: (a) in vitro release profile, in a standard dissolution test, wherein on average no more than about 20% of the pramipexole dissolves within 2 hours after placing the composition; and (b) in vivo pramipexole absorption profile which achieves an average 20% absorption time of greater than about 2 hours and/or an average 40% absorption time of greater than about 4 hours after a single dose oral administration to a healthy adult. However, in practical applications, it appears that any formulation with extended or controlled release properties designed for once-a-day application can meet the above requirements, but it lacks general teachings on how to modulate this property.

It is an object of the present invention to provide an extended release tablet composition of pramipexole or a pharmaceutically acceptable salt thereof, which is suitable for once daily oral administration. A further object is to provide a tablet composition comprising pramipexole or a pharmaceutically acceptable salt thereof which provides a therapeutic effect for up to one day and allows patients to treat their symptoms with a single daily dose, which makes it possible to modulate the release profile of the active ingredient according to a pH-related or unrelated selective release profile. Also, a process for preparing the tablet is provided.

Summary of The Invention

Surprisingly, it has been found that pramipexole or a pharmaceutically acceptable salt thereof can be used in formulations such as once daily extended or (slow) release tablets and that two different formulation principles result in different release rates, either related or independent of the pH value.

One embodiment of the present invention relates to an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix thereof comprising at least two water swellable polymers, wherein one of the polymers is pregelatinized starch, and wherein another of the polymers is an anionic polymer.

Preferably, the present invention relates to an extended release tablet formulation wherein the anionic polymer is selected from the group consisting of optionally cross-linked acrylic acid polymers, methacrylic acid polymers, alginates and carboxymethyl cellulose.

Also preferably, the present invention relates to an extended release tablet, wherein the anionic polymer is a cross-linked acrylic polymer, and the content of the optionally cross-linked acrylic polymer in the matrix is about 0.25 wt-% to about 25 wt-%, preferably about 0.5 wt-% to about 15 wt-%, preferably about 1 wt-% to about 10 wt-%.

Also preferably, the present invention provides an extended release tablet further comprising a water swellable polymer, wherein said polymer is not pregelatinized starch or an anionic polymer, and is preferably selected from hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

Particularly preferred are extended release tablets wherein the water swellable polymer other than pregelatinized starch or an anionic polymer is hydroxypropyl methylcellulose and the amount of hydroxypropyl methylcellulose in the matrix is from about 10wt. -% to about 75wt. -%, preferably from about 25wt. -% to about 65wt. -%.

Particularly preferably, the present invention provides an extended release tablet wherein the matrix comprises about:

(a) 0.05 to 5wt. -% of pramipexole or a salt thereof

(b) Anionic water-swellable polymer 0.25 to 25wt. -%)

(c) 10 to 75wt. -% of water-swellable polymers different from (b)

(d) Appropriate amount of other excipients to 100wt. -%)

Another embodiment of the present invention relates to an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising:

(a) at least one pregelatinized starch as a water-swellable polymer and optionally excipients, to give tablets with pH-independent in vitro release profile in the range of pH1 to 7.5, or

(b) At least one pregelatinized starch as a water-swellable polymer, a water-swellable anionic polymer, preferably an acrylic acid polymerization product, and optional excipients, the resulting tablet provides a pH-dependent release profile with a faster release profile at pH < 4.5 and a slower and otherwise pH-independent release profile in the range of pH4.5 to 7.5.

Designing an extended release formulation for oral administration according to the present invention requires selecting and evaluating the in vitro release profile and timing of the formulation to best suit the desired in vivo plasma profile, preferably once daily administration. Thus, two different formulation principles for a single unit matrix tablet have been investigated, i.e. to provide two formulations with different release rate profiles and different pH dependencies. These alternative formulations are beneficial to the patient, as extended release drug delivery allows patients to treat their symptoms with a single daily dose, thereby increasing patient convenience and compliance.

The term "in vitro release profile" as used above or in the following refers to a release profile obtained in an in vitro test in a type of commonly used liquid medium, in which test there is a release of the active ingredient from the extended release formulation, i.e. for example in an in vitro dissolution medium, but also in body fluids or simulated body fluids, more particularly in gastrointestinal fluids.

In the context of the present invention, the term "extended" release is to be understood as meaning a gradual, continuous release of the active ingredient over time, sometimes slower or faster, depending on or independently of the pH, as opposed to an immediate release. In particular, the term indicates that the formulation does not immediately release the full amount of active ingredient upon oral administration, and that the formulation allows a reduction in dosing frequency, this definition also being used interchangeably with the term extended release, and the term slow release. The use of slow or extended release is synonymous with having an extended action, the slow or modified release dosage form being one which allows at least a reduction in the frequency of administration or a significant improvement in patient compliance or therapeutic properties compared to conventional dosage forms (e.g. solution or immediate release pharmaceutical dosage forms, conventional solid dosage forms).

The pH independent release profile indicates that its release characteristics are virtually identical in different pH media.

According to the teachings of the present invention, two types of extended release tablets commercially available exhibit different in vitro release profiles.

The extended release tablet of the present invention uses a swellable and partially aggressive polymer matrix resulting in a square root of time to time release profile of the sample, formulation a) which release profile is generally independent of pH in the range of pH1 to 7.5, and formulation b) which release profile is (slightly) faster in simulated gastric fluid with pH < 4.5, but independent of pH in the range of 4.5 to 7.5. Faster release in simulated gastric fluid is more advantageous than slower release in intestinal fluid, in which case the dosage form loading dose effect is ideal, while the generally pH independent release profile is advantageous, which reduces dose dumping (dose doubling) and dietary impact.

According to the invention, "formulation a)" is understood to mean a tablet in which the matrix comprises the composition according to a) as defined above and "formulation b)" is understood to mean a tablet in which the matrix comprises the composition according to b) as defined above.

The water-swellable polymer present in the two alternative tablets a) and b) of the invention represents at least one pregelatinized starch as hydrophilic swellable polymer, constituting an extended release matrix, slowly releasing pramipexole or a salt thereof as an active ingredient. After administration, upon contact with aqueous fluids, the polymers swell to form a viscous gel layer that regulates the release of the drug.

Examples of polymers present in the formulations of the invention, other than pregelatinized starch, are water-swellable substantially neutral polymers or water-swellable anionic polymers.

The term "water-swellable substantially neutral polymer" of the present invention includes alkyl celluloses, such as methyl cellulose; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses, such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; carboxyalkyl cellulose esters; other natural, semi-synthetic or chemical synthetic di-, oligo-and polysaccharides such as galactomannans, tragacanth, agar, guar and fructans (polyfructans); a methacrylate copolymer; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate; a combination of polyvinyl alcohol and polyvinyl pyrrolidone; polyalkylene oxides, such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, preferably cellulose ether derivatives, such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, most preferably hydroxypropyl methylcellulose.

The term "water-swellable anionic polymer" in the present invention includes acrylic acid polymerization products, methacrylic acid copolymers, alginates, carrageenans, gum arabic, xanthan gum, polysaccharide derivatives such as chitosan, sodium carboxymethylcellulose and calcium carboxymethylcellulose, preferably acrylic acid polymerization products.

Hydroxypropyl cellulose and hydroxypropyl methylcellulose of different viscosity grades are commercially available. Preferably, the Hydroxypropylmethylcellulose (HPMC) used in the present invention has a viscosity grade of from about 3,500mpa.s to about 100,000mpa.s, particularly from about 4,000mpa.s to about 20,000mpa.s, most particularly a viscosity grade of from about 6,500mpa.s to about 15,000mpa.s (apparent viscosity in 2% aqueous solution at 20 ℃), such as hydroxypropylmethylcellulose 2208 or 2206(DOW, AntwerpBelgium). HPMC type 2208 contains 19-24% by weight methoxy groups and 4-12% by weight hydroxypropyl substituents.

Hydroxypropyl cellulose having an apparent viscosity of greater than 1,500mpa.s (at 20 ℃, 1% aqueous solution) is preferred, particularly hydroxypropyl cellulose having a viscosity of from about 1500 to about 3000mpa.s, preferably from 4000 to 6500mpa.s (2% aqueous solution), for example the Klucel series, for example Klucel m (Hercules, Wilmington, USA).

Without wishing to be bound by theory, it is believed that there are three main mechanisms for the release of pramipexole or a salt thereof from a hydrophilic matrix: dissolution, erosion and diffusion. Pramipexole or its salt is released by a dissolution mechanism when it is homogeneously dispersed in the matrix network of the soluble polymer. The network will gradually dissolve in the gastrointestinal tract, thereby gradually releasing its drug load. The matrix polymer may also gradually erode away from the matrix surface, also releasing pramipexole or its salts in time. When pramipexole is prepared in a matrix consisting of insoluble polymers, it will be released by diffusion: the gastrointestinal fluids penetrate the insoluble, sponge-like matrix, allowing diffusion of the loaded drug.

Thus, the water-swellable polymers that make up the matrix primarily provide the controlled release pharmacokinetic release profile to the formulation. Depending on the amount of water-swellable polymer included in the formulation, the release profile may be adjusted, i.e. a large amount of swellable polymer results in a more pronounced sustained release effect and vice versa. Preferably, the water-swellable polymer is present in the present formulation in an amount of about 30 to about 99% by weight.

Moreover, when polymer combinations are used, the ratio of the polymers also affects the release characteristics of the formulation. The combination of different polymers provides a possible combination of different mechanisms of pramipexole release from the matrix. These combinations help to control the pharmacokinetic release profile of the formulation at will. For example, when one or more water swellable polymers are utilized, particularly hydroxypropyl cellulose and hydroxypropyl methylcellulose, the weight percent of hydroxypropyl methylcellulose is preferably from 25 to about 62%; the preferred weight percent of hydroxypropyl cellulose is from about 0% to about 16%.

The release of pramipexole or a salt thereof from a matrix comprising hydroxypropyl cellulose and hydroxypropylmethyl cellulose occurs by a combination of a series of release mechanisms. Since hydroxypropylmethylcellulose has a higher solubility than hydroxypropylcellulose, it will gradually dissolve, eroding from the matrix, whereas the latter will act more as a sponge-like matrix, releasing the active ingredient mainly by diffusion.

The extended release tablets according to formulation a) are pH independent. Thus, the encountered dietary disadvantages associated with dose dumping can be avoided. In dining patients, the problem of diet-related dose dumping can be attributed to a number of factors, such as mechanical forces, which are exerted by the stomach on its contents and hence on the ingested formulation, and different pH sites of the gastrointestinal tract. Since the pH values encountered in the gastrointestinal tract vary not only with the location of the gastrointestinal tract, but also with the food intake, extended release formulations preferably must also provide extended release characteristics, and in particular must avoid dose dumping effects, whether the patient is in fasting or in dietary conditions.

According to the present invention, the oral extended release formulation a) can maintain the pharmacokinetic release profile during its passage through the gastrointestinal tract, avoiding undesired variations in the plasma concentration of the drug or complete dose dumping, in particular dose dumping at different parts of the gastrointestinal tract.

In addition to pramipexole or a salt thereof and the water-swellable polymer, the formulation of the present invention may optionally comprise additional excipients, i.e., pharmaceutically acceptable agents, in order to improve the preparation, compactibility, appearance and taste of the formulation. Such pharmaceutical agents include, for example, diluents or fillers, glidants, binders, granulating agents, anti-caking agents, lubricants, fragrances, colorant preservatives. Other conventional excipients known in the art may also be included.

The filler can be selected from soluble fillers such as sucrose, lactose, especially lactose monohydrate, trehalose, maltose, mannitol, sorbitol, inulin, and insoluble fillers such as dicalcium phosphate or tricalcium phosphate, talc. Different grades of lactose can be used. One preferred lactose for use in the present invention is lactose monohydrate 200 mesh (DMV, Veghel, the netherlands). Preferably, another lactose monohydrate that can also be used is lactose type DCL 11 (DMV, Veghel, The Netherlands). The notation (mutation) DCL refers to "direct compression lactose". Number 11 is the reference number of the manufacturer. In the case of water-soluble active ingredients, as described in the present invention, water-insoluble fillers, such as starch and starch derivatives, microcrystalline cellulose, dibasic calcium phosphate dihydrate and anhydrous dibasic calcium phosphate, which may be added in addition to or in place of the water-soluble filler, are more preferred. The total weight percent of filler is about 5% to about 75% by weight.

Glidants can be used to improve powder flow properties and reduce caking before and during tableting. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, calcium phosphate and the like. Preferably, the colloidal silicon dioxide is included as a glidant in an amount up to about 2%, preferably from about 0.2% to about 0.8% by weight of the tablet.

Lubricants may be used to facilitate release of the tablet from the formed device, for example to prevent sticking to an up-punch ("picking") or down-punch ("sticking") surface. Suitable lubricants include magnesium stearate, calcium stearate, canola oil (canola oil), palmitoyl stearyl glyceride, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate (sodium stearyl fumarate), stearic acid, talc, hydrogenated vegetable oil, zinc stearate, and the like. In one embodiment, magnesium stearate is included as a lubricant in an amount of from about 0.1% to about 1.5%, preferably from about 0.3% to about 1%, by weight of the tablet.

In the optional agents for formulation, which may be further included in the matrix formulation, agents such as povidone; copovidone; starch; acacia gum; gelatin; seaweed derivatives such as alginic acid, sodium alginate and calcium alginate; cellulose, preferably microcrystalline cellulose, cellulose derivatives, such as ethyl cellulose, hydroxypropyl methyl cellulose, cellulose having useful dry or wet binding and granulation properties; and antisticking agents such as talc and magnesium stearate.

According to a preferred embodiment of the invention, the matrix a) of the alternative extended release tablet comprises or essentially consists of pregelatinized starch, hydroxypropylmethylcellulose and excipients. The amount of pregelatinized starch is preferably from 10 to 75% by weight, particularly preferably from 25 to 65% by weight, most preferably from 45 to 55% by weight. The content of hydroxypropylmethylcellulose is preferably 10 to 75% by weight, particularly preferably 25 to 65% by weight, most preferably 35 to 55% by weight. The content of the other excipients is preferably from 0 to 30%, particularly preferably from 0.5 to 20%, most preferably from 1 to 10% by weight. The optional sodium carboxymethylcellulose may additionally preferably be present in an amount of from 5 to 50, particularly preferably from 10 to 40, most preferably from 15 to 30,% by weight.

The expression "essentially consists of" should be understood as meaning that it does not in principle exclude the presence of other components than the components mentioned, which other components present do not influence the essential properties of the formulation.

In the case of formulation b) of the present invention, which provides a pH dependent release profile, the release of pramipexole or a salt thereof from the tablet and subsequent absorption into the bloodstream may be altered during the passage of the dosage form along the gastrointestinal tract. Thus, it provides a pH dependent release profile, wherein the release profile is faster in the range of pH < 4.5 and slower in the range of pH 4.5-7.5, and further pH independent release profiles.

The above detailed description of the selection and type of water-swellable polymers and optional excipients also applies to formulation b).

Furthermore, anionic water-swellable polymers, preferably acrylic acid polymerizates, must be present in formulation b), which are preferably selected from carbomers or carbopols (carbopol)In series, acrylic acid polymerization products are known to have high molecular weights. Particularly preferred are, for example, carbomer 941 (carbopol)71G、carbopol971) And carbomer 934 (carbopol)974). Preferably, the content of the acrylic acid polymerization product is 0.25 to 25% by weight, particularly preferably 0.5 to 15% by weight, most preferably 1 to 10% by weight. The pH-dependent formulation b) is formed in the presence of acrylic acid polymerizates, which swell to a greater extent in acids in the pH range above pH4.5 and in the alkaline pH range.

Increasing the amount of acrylic acid results in a decrease in the release rate. Therefore, adjusting the amount of the acrylic acid polymerization product makes it possible to further arbitrarily adjust the desired dissolution characteristics. In the preferred range of 0.25 to 25% by weight, adjusting the amount of the acrylic acid polymerization product can further provide the following advantages: desirable, individually tailored, adjustable, individually maintained (resp. main) dissolution profiles for a variety of formulations that can be composed of varying amounts and/or types of gelling agents, water-swellable polymers, fillers, and anhydrous binders.

According to a preferred embodiment of the invention, the matrix b) of the alternative extended release tablet comprises or essentially consists of pregelatinized starch, hydroxypropyl methylcellulose acrylic acid polymer and excipients. The amount of pregelatinized starch is preferably from 10 to 75% by weight, particularly preferably from 25 to 65% by weight, most preferably from 45 to 55% by weight. The amount of hydroxypropylmethylcellulose is preferably 10 to 75, particularly preferably 25 to 65, and most preferably 35 to 55% by weight. The content of the acrylic acid polymerization product is preferably as mentioned above. The content of the excipient is preferably 0 to 30, particularly preferably 0.5 to 20, and most preferably 1 to 10% by weight. The optional sodium carboxymethylcellulose may also be present in an amount of from 5 to 50, particularly preferably from 10 to 40, most preferably from 15 to 30,% by weight.

As an active ingredient, pramipexole or a pharmaceutically acceptable salt thereof in the formulation according to the invention may be present in an amount suitable for the patient to obtain the desired treatment. The preferred salt of pramipexole is the dihydrochloride salt, most preferably in the form of the monohydrate. The amount of pramipexole salt is typically about 0.1 to about 5 mg. According to a particularly preferred embodiment, in an extended release tablet according to the invention, for example 0.750mg pramipexole dihydrochloride monohydrate, corresponding to 0.524mg anhydrous base, may be used. However, any other amount suitable for treatment may be used, provided that the amount of pramipexole or a salt thereof is capable of providing a daily dose in one to a few tablets at a time, e.g. 1 to about 4 tablets. Preferably, the entire daily dose is delivered in a single tablet. Amounts of pramipexole salt, as expressed as the equivalent pramipexole dihydrochloride monohydrate, of about 0.1 to about 10mg per tablet, or about 0.05% to about 5% by weight of the composition, are generally suitable. The preferred amount per tablet is from about 0.2 to about 6mg, more preferably from about 0.3 to about 5 mg. Specific dosages per tablet include, for example, 0.375, 0.5, 0.75, 1.0, 1.5, 3.0, and 4.5mg pramipexole dihydrochloride monohydrate. The amount that constitutes a therapeutically effective amount varies depending on the condition being treated, the severity of said condition and the patient being treated.

Preferably, the extended release tablet according to the invention has the following composition:

pramipexole or a salt thereof in an amount of 0.05 to 5% by weight

Pregelatinized starch 10 to 75% by weight

10 to 75% by weight of other water-swellable polymers

Acrylic acid polymerization product 0 to 25% by weight

An optional excipient is present in an amount up to 100% by weight.

Thus, particularly preferred extended release tablets of the invention are composed of:

0.1 to 2% by weight of pramipexole or a salt thereof;

25 to 65% by weight of hydroxypropyl methylcellulose;

0 to 40% by weight of sodium carboxymethylcellulose;

25 to 75% by weight of pregelatinized starch;

from 0 to 15% by weight of a polymerization product of acrylic acid, preferably carbomer 941;

0.5 to 50% by weight of other excipients, preferably selected from: colloidal silicon dioxide, magnesium stearate, lactose monohydrate, mannitol, microcrystalline cellulose, anhydrous dibasic calcium phosphate, hydroxypropyl cellulose, povidone, copovidone, talc, polyethylene glycol, sodium dodecyl sulfate, iron oxide, and titanium dioxide.

As described in accordance with WO2004/010997, the starch in a representative solid fraction of tablets has at least about 0.15kN cm^-2The tensile strength of (a) is necessary to practice the present invention.

It is particularly preferred according to the invention that no coating is present on the tablets. However, the extended release tablet of the present invention may comprise a non-functional coating. The non-functional coating may comprise a polymeric component, such as HPMC, optionally with other ingredients, such as one or more plasticizers, colorants, and the like. The term "non-functional" in the context of the present invention means that the release properties of the tablet are not substantially affected and that the coating serves an additional useful purpose. For example: such coatings may impart an identifiable appearance to the tablet, provide protection against wear during packaging and shipping, enhance ease of swallowing (ease), and/or have other benefits. The non-functional coating should be used in an amount sufficient to provide complete coverage of the tablet. Typically, it is suitable in an amount of about 1% to about 10%, more typically about 2% to about 5%, by weight of the total tablet.

The tablets of the invention may be of any suitable size and shape, for example circular, oval, polygonal or pillow-shaped, and optionally with non-functional surface markings. According to the present invention, it is preferred that the extended release tablet is white to off-white and has an oval or circular, biconvex shape.

The tablets of the invention may be packaged in a container with package inserts providing pertinent information, such as dosage and administration information, contraindications, precautions, drug interactions and side effects.

The invention also relates to the use of an extended release tablet formulation according to the invention for the preparation of a pharmaceutical composition for the treatment of parkinson's disease and related complications or disorders.

Also, preferably, the present invention relates to a process for preparing an extended release tablet via a direct compression method comprising the steps of:

(1) the active ingredient trituration is prepared by premixing the active ingredient with a portion of the water-swellable polymer and/or other excipients in a mixer, wherein the active ingredient is pramipexole or a pharmaceutically acceptable salt thereof, wherein the pramipexole or pharmaceutically acceptable salt thereof is milled, preferably peg-milled, prior to use.

(2) Premixing the active ingredient triturate in step (1), a major portion of the water-swellable polymer and/or excipients in a mixer to obtain a premix;

(3) optionally, dry-sieving the premix through a screen to separate cohesive granules and to improve the homogeneity of the contents;

(4) mixing the premix of step (2) or (3) in a mixer, optionally adding the remaining excipients to the mixture, and continuing the mixing; and

(5) matrix tablets are prepared by compressing the final blend in a suitable tablet press.

Thus, tablets were prepared via a direct compression method, which was applied to prepare two types of pramipexole extended release matrix tablets. In order to obtain sufficient content uniformity in the low drug load formulation, the active ingredient is preferably peg-milled. Preferably, the particle size distribution of the peg-milled drug substance, as determined by laser diffraction using a dry dispensing system, is characterized in that the 90% (V/V) particle fraction has a diameter of less than 100 μm, more preferably the 90% (V/V) particle fraction has a diameter of less than 75 μm.

Other methods may also be used to prepare pramipexole extended release tablets, such as conventional wet granulation and roller compaction. In the case of wet granulation, it is preferred to granulate pramipexole with suitable fillers, such as starch, microcrystalline cellulose, lactose monohydrate or anhydrous dibasic calcium phosphate, and wet binders, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, copovidone and starch paste, resulting in a concentration of the active ingredient, which, after drying and dry sieving, is mixed with the major part of the gelling excipient, as all the above mentioned delaying principles.

In the case of roller compaction, or in other words in the case of dry granulation, a pre-mixture of pramipexole with part of the excipients used in the direct compression process, or with the entire mixture comprising all the excipients, is prepared by means of a conventional roller compactor to form a ribbon, after which the granulate is screened and finally further mixed with other excipients, such as glidants, lubricants and antiadherents.

Brief description of the drawings

FIG. 1 is a flow diagram of a preferred embodiment of the direct compression process according to the present invention.

FIG. 2 illustrates the dissolution profile of a matrix tablet formulation according to the invention comprising 4% by weight of carbopol in 3 different pH media。

FIG. 3 is a diagram illustrating a method according to the present inventionThe amine respectively comprises 0%, 1% and 4% by weight of carbopolThe dissolution profile of the bone meal of (3).

In accordance with the flow chart, fig. 1 illustrates a preferred embodiment of the manufacturing process, wherein the preparation of the extended release tablets of examples 1 and 2 is exemplarily illustrated. FIG. 1 shows the detailed preparation steps performed and the program control (in process controls) performed.

Preparation step (1) relates to the active ingredient trituration, in which case pramipexole, pramipexole dihydrochloride monohydrate, of peg-milled nature, is premixed with a portion (part) of the water-swellable polymer, in this case with pregelatinized starch, in a generally known mixer. In this flow diagram, a Turbula free-settling mixer or blender is used. The stirring time is a few minutes, in the present case preferably 10 minutes.

In the preparation step (2) according to this flow chart, premixing is carried out in which the active ingredient trituration and the major portion of water-swellable polymer and excipients are premixed for several minutes to give a premix. In the present case, hydroxypropyl methylcellulose (hypromellose), the major part of pregelatinized starch, carbomer 941 and colloidal silicon dioxide are premixed for 5 minutes in the Turbula mixer or blender mentioned above.

According to the following preparation step (3), dry sieving may be optionally performed. The pre-mix may be manually screened through a screen, such as a 0.8mm mesh screen, to separate cohesive granules and improve the uniformity of the contents.

In the subsequent preparation step (4), after sieving, in a Turbula mixer, the main mixing step is carried out, in which the components are mixed for a few minutes, preferably 5 minutes. Optionally, other excipients may be added at this point, and in the flow chart the component magnesium stearate is added to the main mix and further mixing (final mixing) is carried out in a Turbula mixer for several minutes, e.g. 3 minutes, to give the final mix.

The preparation step (5) according to the method of the present invention is tableting. The final blend is compacted on a suitable tablet press to produce, for example, rectangular matrix tablets (ER tablets ═ extended release tablets). In order to control and maintain the desired properties, the resulting matrix tablet is subjected to the following processes: tablet mass, hardness, tablet height and friability.

The resulting pramipexole extended release tablets of the present invention may then be filled into, for example, High Density Polyethylene (HDPE) bottles. The bottles were sealed with screw caps and labeled appropriately, whereby all packaging and labeling activities were performed according to the cGMP protocol. Alternatively, a blister type package may be used, for example using an aluminium/aluminium foil blister.

Fig. 2 illustrates a graph of dissolution characteristics of a matrix tablet formulation according to the present invention. The matrix tablet comprises 4% by weight of carbopolA detailed composition is given in example 2, which corresponds to the above-mentioned formulation according to the invention. The release profile of the matrix disc in 3 different pH media is shown, namely pH 6.8, n ═ x in 0.05M phosphate buffer, pH 1.2, n ═ x in simulated gastric fluid, and pH4.5, n ═ x in McIlvaine buffer; (x represents the number of test units). The release percentage of the active ingredient is plotted against time (hours).

Fig. 3 illustrates a graph of dissolution characteristics of a 3-skeleton tablet formulation according to the present invention. The matrix tablets do not contain carbopolComprising 1% or 4% by weight of carbopolDetailed descriptions are given in examples 1, 2 and 4A composition is provided. The medium was 0.05M phosphate buffer, pH 6.8. The release percentage of the active ingredient is plotted against time (hours).

FIGS. 2 and 3 show the pH range from 1 to 7.5 and in the absence of carbopolIn vitro release characteristics independent of pH, and the presence of carbopolThe pH dependent release profile below, wherein the release profile at pH < 4.5 and below is faster. carbopolAn increase in the amount will result in a decrease in the release rate.

The benefits of the present invention are manifold:

in accordance with the teachings of the present invention, commercially available extended release tablets comprising pramipexole or a salt thereof exhibit different in vitro release profiles. It is possible to select tailored release profiles that meet the observed symptoms and clinical picture of the patient's needs.

The primary indication for pramipexole, parkinson's disease, is a condition that becomes more prevalent with aging and is often accompanied by memory decline. Thus, according to the present invention, there is provided a matrix tablet of pramipexole or a salt thereof with extended or reduced release, which reduces the recommended daily intake, simplifies the dosage regimen for the patient, and improves patient compliance, and is particularly suitable for use in elderly patients. Preferably, the extended release tablet of the present invention provides a daily dose upon administration of a single dose.

Furthermore, the tablets of the present invention may be prepared via direct compression, wet or dry granulation suitable for both types of extended release matrix tablets.

The description of the invention is now illustrated by the following examples of various other embodiments, which will be apparent to those skilled in the art from this description. It should be expressly noted, however, that the examples and descriptions are illustrative only and should not be construed as limiting the invention.

Examples

According to the present invention, extended release tablets of pramipexole have been prepared. The tablets of the examples are white to yellowish white, oblong, biconvex, 14X 6.8mm tablets. The tablet should be administered orally and should not be split into two halves (holves). The pramipexole tablet in the examples contained 0.75mg of pramipexole dihydrochloride monohydrate, which is equivalent to 0.524mg of pramipexole free, anhydrous base.

Example 1

In table 1 is shown an embodiment of a qualitative and quantitative composition of extended release tablets of pramipexole according to the present invention.

Table 1: qualitative and quantitative composition of pramipexole extended release tablets

Example 2

In table 2 another embodiment of the qualitative and quantitative composition of the pramipexole extended release tablets according to the invention is shown.

Table 2: qualitative and quantitative composition of pramipexole extended release tablets

Example 3

The batch formulations for the two pramipexole tablets of examples 1 and 2 are shown in table 3. The batch size of the final mixture corresponded to 2000 tablets per batch.

Table 3: composition of 0.75mg ER tablets per batch

Composition (I)	Grams per batch example 1	Grams per batch example 2
			Pramipexole dihydrochloride monohydrate, peg-grind	1.500	1.500
Hydroxypropyl methylcellulose 2208	315.000	315.000
			Pregelatinized starch	370.200	349.200
Carbomer 941	7.000	28.000
			Colloidal silicon dioxide	2.800	2.800
Magnesium stearate	3.500	3.500
			Total mass	700.000	700.000

Example 4

The following example shows pramipexole tablets conforming to formulation a) that provide a pH independent release profile in the range of pH1 to 7.5.

TABLE 4

Components	mg/tablet
		Pramipexole dihydrochloride monohydrate, peg-grind	0.750
Hydroxypropyl methylcellulose 2208(Methocel K100M)	175.000
		Pregelatinized starch	170.400
Colloid twoSilicon oxide	2.100
		Magnesium stearate	1.750
Total weight of matrix tablet	350.000

Claims (16)

1. An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix thereof, said matrix comprising at least two water swellable polymers, wherein one of said polymers is pregelatinized starch, and wherein another of said polymers is an anionic polymer.

2. The extended release tablet formulation of claim 1, wherein the anionic polymer is selected from the group consisting of optionally crosslinked acrylic acid polymers, methacrylic acid polymers, alginates, and carboxymethylcellulose.

3. The extended release tablet formulation of claim 2, wherein the anionic polymer is a cross-linked acrylic polymer, and wherein the content of the optionally cross-linked acrylic polymer in the matrix is about 0.25 to about 25wt. -%, and preferably about 0.5 to about 15wt. -%, and preferably about 1 to about 10wt. -%.

4. The extended release tablet formulation of any preceding claim, further comprising a water swellable polymer which is not pregelatinized starch or an anionic polymer, and is preferably selected from hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

5. The extended release tablet formulation of claim 4, wherein the water swellable polymer that is not pregelatinized starch or an anionic polymer is hydroxypropyl methylcellulose, and wherein the amount of hydroxypropyl methylcellulose in the matrix is from about 10-wt% to about 75 wt%, and preferably from about 25 wt.% to about 65 wt.%.

6. The extended release tablet formulation of claim 1, wherein the matrix comprises about:

(a) 0.05 to 5wt. -% of pramipexole or a salt thereof

(b) Anionic water-swellable polymer 0.25 to 25wt. -%)

(c) 10 to 75wt. -% of water-swellable polymers different from (b)

(d) Other excipients are in appropriate amounts up to 100wt. -%.

7. An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising:

(a) at least pregelatinized starch as a water-swellable polymer and optionally excipients, the resulting tablet providing a pH-independent in vitro release profile at a pH in the range from 1 to 7.5, or

(b) At least one pregelatinized starch as a water-swellable polymer, a water-swellable anionic polymer, and optional excipients, to provide tablets having a pH-dependent release profile with faster release profiles at a pH < 4.5 and slower and additional pH-independent release profiles at a pH in the range of 4.5 to 7.5.

8. The extended release tablet formulation according to claim 1 or claims 6 to 7, wherein the one or more other water swellable polymers are selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose and sodium alginate.

9. An extended release tablet formulation according to claim 7 or 8, wherein the matrix comprises or essentially consists of hydroxypropylmethylcellulose in an amount of 10 to 75% by weight, preferably 25 to 65% by weight, and excipients in an amount of 25 to 90% by weight, preferably 35 to 75% by weight.

10. An extended release tablet formulation according to any of the preceding claims wherein the anionic polymer is a polymerization product of acrylic acid selected from carbomers or carbopolAnd (4) series.

11. An extended release tablet according to claim 10, wherein the content of acrylic acid polymerization product is 0.25 to 25% by weight, preferably 0.5 to 15% by weight, most preferably 1 to 10% by weight.

12. An extended release tablet formulation wherein pramipexole or a pharmaceutically acceptable salt thereof is present in an amount sufficient to provide a daily dose for a single administration.

13. A process for preparing an extended release tablet according to any of the preceding claims via a direct compression process comprising the steps of:

(1) preparing an active ingredient trituration by premixing the active ingredient with a portion of the water-swellable polymer and/or excipients in a mixer, wherein the active ingredient is pramipexole or a pharmaceutically acceptable salt thereof, wherein the pramipexole or pharmaceutically acceptable salt thereof is milled, preferably peg-milled, prior to use;

(2) premixing the active ingredient triturate in step (1), a major portion of the water-swellable polymer and/or excipients in a mixer to obtain a premix;

(3) optionally, dry-sieving the premix through a screen to separate cohesive granules and to improve the homogeneity of the contents;

(4) mixing the premix of step (2) or (3) in a mixer, optionally adding the remaining excipients to the mixture, and continuing the mixing; and

(5) the final blend is compressed in a suitable tablet press to produce matrix tablets.

14. Process for the preparation of an extended release tablet according to any of the preceding claims 1 to 12 via wet granulation comprising the following steps:

(1) preparing an active ingredient trituration by mixing the active ingredient with a portion of the excipients in a mixer, wherein the active ingredient is pramipexole or a pharmaceutically acceptable salt thereof, wherein the pramipexole or a pharmaceutically acceptable salt thereof is milled, preferably peg-milled, prior to use;

(2) granulating the active ingredient trituration of step (1) by adding a granulating liquid, preferably water;

(3) drying the granules of step (2) in a fluid bed dryer or drying oven;

(4) mixing the dry particles of step (3) with the water-swellable polymer and/or excipients in a mixer to obtain a final mixture;

(5) compressing the final blend of step (4) in a suitable tablet press to produce matrix tablets.

15. Method for preparing an extended release tablet according to any of the preceding claims 1 to 12 via a dry granulation process comprising the steps of:

(1) mixing the active ingredient pramipexole or a pharmaceutically acceptable salt thereof, which is ground, preferably peg-ground, with part of the filler or all excipients in a mixer before use;

(2) compacting the mixture of step (1) on a suitable roller compactor;

(3) reducing the ribbon obtained in step (1) to small particles by a suitable grinding or sieving step;

(4) optionally mixing the granules in step (3) with the remaining excipients in a mixer to obtain a final mixture;

(5) tabletting the granules of step (3) or the final mixture of step (4) in a suitable tabletting machine to prepare matrix tablets.

16. Use of an extended release tablet formulation according to any one of the preceding claims 1 to 12 for the manufacture of a pharmaceutical composition for the treatment of parkinson's disease and related complications or disorders.