WO2008068778A2

WO2008068778A2 - Extended release pharmaceutical composition of pramipexole

Info

Publication number: WO2008068778A2
Application number: PCT/IN2007/000586
Authority: WO
Inventors: Rajesh Kshirsagar; Ashwin Rao; Nilesh Malaviya
Original assignee: Alembic Limited
Priority date: 2006-12-05
Filing date: 2007-12-05
Publication date: 2008-06-12
Also published as: WO2008068778A3; WO2008068778A8

Abstract

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

Description

EXTENDED RELEASE PHARMACEUTICAL COMPOSITION OF PRAMIPEXOLE

FIELD OF THE INVENTION

This invention relates to extended release pharmaceutical composition of pramipexole and compositions comprising pramipexole for achieving the extended release.

BACKGROUND OF THE INVENTION

Pramipexole, disclosed in US 4,886,812 is a dopamine D₂ receptor agonist approved for the treatment of Parkinson's disease and restless legs syndrome. Pramipexole is most commonly used as pramipexole dihydrochloride monohydrate which is (iS)-2-amino-4,5,6,7-tetrahydro- 6-(propylamino) benzothiazole dihydrochloride monohydrate (Figure 1). Its empirical formula is C₁₀H₁₇N₃S • 2 HCl • H₂O and molecular weight is 302.27. Pramipexole dihydrochloride monohydrate is a white to off-white powder substance and is commercially available as MIRAPEX^® tablets of Pharmacia & Upjohn. These are immediate-release tablets comprising pramipexole dihydrochloride monohydrate 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg and 1.5 mg, designed for oral administration of a single tablet three times per day to provide a daily dose of 0.375 to 4.5 mg.

A three times daily dosing regimen for immediate-release pramipexole dihydrochloride tablets is well tolerated. However the primary indication for the drug, Parkinson's disease, is seen more in the elderly population. An extended release composition which could be administered, for example, once daily would be especially useful in enhancing compliance among elderly patients.

Side effects of pramipexole have been reported to include orthostatic hypotension, the incidence of which is dose-related, and increased somnolence. An extended release dosage form of pramipexole may have the potential to avoid such side effects.

Pramipexole is a low dose, highly water soluble drug with a wide range of therapeutic dose strengths. Consistent in vitro and in vivo release profiles with reproducible absorption of pramipexole is desirable. Sustained release formulations of pramipexole have been described in the literature. For example, US 2005/0175691 discloses an orally deliverable pharmaceutical composition comprising a therapeutically effective amount of pramipexole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, the composition exhibiting at least one of (a) an in vitro release profile wherein on average no more than about 20% of the pramipexole is dissolved within 2 hours after placement of the composition in a standard dissolution test; and (b) an in vivo pramipexole absorption profile following single dose oral administration to healthy adult humans wherein the time to reach a mean of 20% absorption is greater than about 2 hours and/or the time to reach a mean of 40% absorption is greater than about 4 hours.

US 2005/0226926 describes a sustained-release pharmaceutical composition in a form of an orally deliverable tablet comprising a water-soluble salt of pramipexole, dispersed in a matrix comprising a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 fcN cm², preferably at least about 0.175 kN cm², and more preferably at least about 0.2 kN cm², at a solid fraction representative of the tablet. The disclosure provides for a composition with sufficient hardness yield during a high-speed tabletting operation, in particular to resist erosion during application of a coating layer.

However there is still a need in the art for extended release formulations of pramipexole which have improved patient compliance, reduced potential for side effects and which have consistent in vitro and in vivo release profiles.

OBJECTS OF THE INVENTION It is an object of the invention to provide an extended release pharmaceutical composition comprising pramipexole having a release profile in a dissolution medium which mimics the body environment such that not less than 25% of the total amount of pramipexole in the composition is released within one hour, no significant drug release takes place over the next at least one hour and not less than 80% of the total amount of pramipexole in the composition is released over a period of about 24 hours.

It is another object of the invention to provide an extended release pharmaceutical composition comprising pramipexole having a release profile such that a mean of about 20% of the pramipexole released from the composition is absorbed within about 2 hours and a mean of about 40% of the pramipexole in the composition is absorbed within about 4 hours after administration of the composition to a human.

Yet another object of the invention is to provide an extended release pharmaceutical composition comprising pramipexole which does not exhibit an adverse food effect and which can be administered to a mammal (including humans) in either the fed or fasting state.

Yet another object of the invention is to provide an extended release pharmaceutical composition comprising pramipexole wherein the release profile in vitro or in vivo is not adversely affected by the presence of alcohol.

Yet another object of the invention is to provide a method of treatment of a subject having a condition or disorder for which a dopamine receptor agonist is indicated, the method comprising orally administering to the subject, an extended release . pharmaceutical composition comprising a therapeutically effective amount of pramipexole.

SUMMARY OF THE INVENTION

The present invention provides an extended release pharmaceutical composition comprising pramipexole having a release profile in a dissolution medium which mimics the body environment such that not less than 25% of the total amount of pramipexole in the composition is released within one hour, no significant release of drug takes place over the next at least one hour and not less than 80% of the total amount of pramipexole in the composition is released over a period of about 24 hours. The present invention provides for an extended release pharmaceutical composition comprising pramipexole having a release profile such that a mean of about 20% of the pramipexole released from the composition is absorbed within about 2 hours and a mean of about 40% of the pramipexole in the composition is absorbed within about 4 hours after administration of the composition to a human.

The present invention provides an extended release pharmaceutical composition comprising pramipexole which does not exhibit an adverse food effect and which can be administered to a mammal (including humans) in either fed or fasting state.

The present invention also provides for an extended release pharmaceutical composition comprising pramipexole wherein the release profile in vitro or in vivo is not adversely affected by the presence of alcohol.

There is further provided a method of treatment of a subject having a condition or disorder for which a dopamine receptor agonist is indicated, the method comprising orally administering to the subject, an extended release pharmaceutical composition comprising a therapeutically effective amount of pramipexole.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the structure of Pramipexole dihydrochloride.

Figure 2 illustrates the comparative plasma level profile of equivalent doses of an extended release composition comprising pramipexole and an immediate release composition of pramipexole under fed state in healthy human volunteers.

Figure 3 illustrates the comparative plasma level profile of equivalent doses of an extended release composition comprising pramipexole and an immediate release composition of pramipexole under fasting state in healthy human volunteers. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to extended release of pramipexole and pharmaceutical compositions for achieving the same.

The term "extended release" for the purposes of this invention refers to one or more active pharmaceutical agents is released over a prolonged period of time, such as for example over a period of 8, 12, 16 or 24 hours.

The term "in vitro release profile" for the purposes of this invention refers to a dissolution profile exhibited by a composition in a suitable dissolution medium wherein the percentage of drug released from the composition is measured as a function of time.

The term "in vivo release profile" as used herein, refers to the profile obtained when an extended release pharmaceutical composition comprising pramipexole is administered to a human and is expressed as the percentage of pramipexole absorbed in the body as a function of time. The in vivo release profile can be obtained by applying a suitable deconvolution method to plasma concentration-time profiles obtained after administration of a composition to a mammal such as for example humans.

The term pramipexole for the purposes of this invention embraces pharmaceutically acceptable racemates, enantiomers, polymorphs, hydrates, salts, solvates and derivatives thereof. Pramipexole is used preferably in the form of its 5-enantiomer i.e. (5)-2-amino- 4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole.

It is preferred to use a salt of pramipexole, especially a salt exhibiting moderate to high solubility in water. A preferred salt of pramipexole is the dihydrochloride salt, most preferably in the form of the monohydrate. The term "pharmaceutically acceptable" as used herein, means those compounds which are, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit/risk ratio, and effective for their intended use.

In one embodiment, an extended release pharmaceutical composition comprising pramipexole of the invention exhibits a release profile in a dissolution medium which mimics the body environment such that not less than 25% of the total amount of pramipexole or a pharmaceutically acceptable salt thereof in the composition is released within one hour, no significant drug release takes place from the composition over the next at least one hour and not less than 80% of the total amount of pramipexole in the composition is released over a period of about 24 hours.

In a preferred embodiment, the release profile of the extended release pharmaceutical composition of the invention, comprising pramipexole is such that when tested in 900 ml of dissolution media at 37° C and in 40-mesh basket (USP Type 1) and rotated at 100 rpm with the dissolution media being varied with time such that the medium is 0.1N HCl for 0 to 2 hours, pH 4.5 acetate buffer for 2 to 4 hours, pH 5.5 acetate buffer for 4 to 8 hours and pH

6.8 phosphate buffer for 8 to 24 hours, the following release profile for pramipexole is obtained i. e. not less than 25% of the pramipexole is released in 2 hours, from 25 to 50% at the end of 4 hours, from 40 to 70% at the end of 8 hours and not less than 80% of the pramipexole is released in 24 hours.

In another embodiment, an extended release pharmaceutical composition comprising pramipexole exhibits a release profile such that about 20% of the pramipexole in the composition is absorbed within 2 hours and a mean of about 40% of the pramipexole in the composition is absorbed within 4 hours after administration of the composition to a human. In yet another embodiment; the present invention discloses an extended release pharmaceutical composition comprising pramipexole which does not exhibit an adverse food effect and therefore can be administered to a mammal either in the fasting or fed state. For the purpose of the present invention, an extended release composition comprising pramipexole is said to exhibit an adverse food effect if, after dosing a population, once fasted and once fed, the mean (AUCf_e(j)/ (AUCfasting) is below the value 0.80 and/or the lower 90% confidence limit for this ratio is below 0.75. Conversely, an extended release composition of pramipexole which does not exhibit an adverse food effect is one which, when tested on a test population, exhibits a value for (AUCfed)/ (AUCf_asting) of at least 0.80 and/or the lower 90% confidence limit for this value is at least 0.75. The value for mean (AUCf_ed)/ (AUC_fasti_ng) can be any value above 0.80 and still be within the scope of this invention, though it is preferred that it can have an upper (mean) limit of 1.25, and/or an upper 90% confidence limit of 1.40 or below.

The present invention, thus, provides for an extended release pharmaceutical composition comprising pramipexole which can be administered to a mammal (including humans) in either fed or fasting state and which exhibits a mean (AUCfed)/ (AUC_fasti_ng) of at least 0.80. In particular, the present invention provides an extended release pharmaceutical composition comprising pramipexole which can be administered to a mammal (including humans) in either fed or fasting state and which exhibits a mean (AUC_fed)/ (AUC_fasting) of at least 0.80 and/or with a lower 90% confidence limit of at least 0.75.

As used herein the term "AUC_fasti_ng" refers to the mean area under the plasma concentration- time curve, as calculated by the trapezoidal rule over the complete interval for a formulation administered in the fasting condition to a plurality of subjects i.e. subjects who have not eaten for at least eight hours, typically overnight, prior to ingestion of the dosage form. As used herein, "AUC _fed" refers to the mean area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete interval for all the formulations in fed condition to a plurality of subjects i.e. subjects who have eaten a Food and Drug Administration (FDA) recommended standard high fat breakfast within a period of twenty minutes, and then ingested the test dosage form essentially immediately thereafter.

The compositions of the present invention provide a therapeutically effective amount of pramipexole in one to a small plurality, for example two to about 4, of dosage units to be administered at one time. Preferably the full therapeutically effective dose is delivered in a single dosage unit. An amount of about 0.1 to about 10 mg per dosage unit will generally be suitable. Preferably an amount of about 0.2 to about 6 mg, more preferably an amount of about 0.3 to about 5 mg, pramipexole per dosage unit is present. Specific amounts per dosage unit contemplated herein include 0.375, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0 and 4.5 mg pramipexole dihydrochloride monohydrate.

A "therapeutically effective amount" of pramipexole herein is a daily dosage amount that, when administered as part of a regimen, provides therapeutic benefit in the treatment of a condition or disorder for which a dopamine receptor agonist is indicated. Suitable daily dosage amounts are likely to be found in a range from about 0.1 to about 10 mg, preferably about 0.3 to about 5 mg, for example about 0.375, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0 or 4.5 mg, expressed as pramipexole dihydrochloride monohydrate equivalent.

The extended release pharmaceutical composition comprising pramipexole can be any solid dosage form, for example, a tablet, a capsule and the like. The tablet dosage form can be for example a monolithic system, a bilayer system and so on. The capsule dosage form can be in the form of plurality of multiparticulates such as pellets, granules and mini-tablets filled in a capsule. Extended release from the composition can be achieved by any means like for example a matrix system, a coating system or combinations thereof.

In a preferred embodiment, the pharmaceutical composition which provides extended release of pramipexole as per the disclosures of the invention comprises of mini-tablets comprising pramipexole intimately mixed with one or more water-soluble, non-swellable excipients. These mini-tablets can be administered as such or can be further processed for example by filling into capsules.

The water-soluble, non-swellable excipients provides for consistent release of low dose pramipexole from the composition when extended release is required.

In a still preferred embodiment, a pharmaceutical composition comprising mini-tablets comprising pramipexole for extended release of pramipexole as per the disclosures of the invention consists essentially of two groups of mini-tablets wherein (a) said first group of functionally coated mini-tablets (Group a) comprises not less than 25% by weight of pramipexole which release essentially all the pramipexole contained within them within one hour of contacting a suitable release medium.

(b) said second group of functionally coated mini-tablets (Group b), which mini-tablets prior to coating comprise not less than 60% by weight of pramipexole intimately mixed with one or more water-soluble, non-swellable excipients which release pramipexole contained within them over a period of not less than 8 hours after contacting a suitable release medium

The term "group" as used herein can range from one to a plurality of units. As used herein, a suitable release medium can be a suitable in vitro dissolution medium or a suitable in vivo body fluid.

The term "mini-tablet" as used herein refers to any tablet of diameter between 2 to 5 mm.

Further, the release profile of such an extended release pharmaceutical composition of the invention, comprising pramipexole is such that when tested in 900 ml of dissolution media at 37° C and in 40-mesh basket (USP Type 1) and rotated at 100 rpm with the dissolution media being varied with time such that the medium is 0.1N HCl for 0 to 2 hours, pH 4.5 acetate buffer for 2 to 4 hours, pH 5.5 acetate buffer for 4 to 8 hours and pH 6.8 phosphate buffer for 8 to 24 hours, the following release profile for pramipexole is obtained i. e. not less than 25% of the pramipexole is released in 2 hours, from 25 to 50% at the end of 4 hours, from 40 to 70% at the end of 8 hours and not less than 80% of the pramipexole is released in 24 hours.

The term "intimate mixing" as used herein means mixing at a particulate level, which can be achieved, by means such as dry mixing with sifting, wet granulation, co-micronization, spray drying, adsorption and the like.

The term "water-soluble, non-swellable" excipient refers to any non-toxic pharmaceutically acceptable compound which has good aqueous solubility i.e. one part of excipient dissolves in 30 parts of water but which does not swell when it contacts water. The amount of the water-soluble, non - swellable excipient may be from about 10 to 95 wt % and preferably from about 40 to 80 wt % based on the total weight of the compressed core.

The water soluble, non-swellable excipients include but are not limited to water soluble organic acids, water soluble salts of organic acids, water soluble organic bases, water soluble salts of organic bases, inorganic salts, saccharides, water - soluble polymers, surfactants and the like. Saccharides include but are not limited to monosaccharides, disaccharides, oligosaccharides, polysaccharides or sugar alcohols and the like. Suitable water-soluble polymers include but are not limited to polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol and the like. Suitable surfactants include hydrophilic surfactants with a HLB value of atleast 10. The term hydrophilic surfactant also includes those anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.

In a preferred embodiment, the water-soluble excipient is polyethylene glycol. In a yet preferred embodiment the water soluble excipient is polyethylene glycol having molecular weight 4000, i.e. PEG 4000. The mini-tablets of the present embodiment can optionally contain one or more pharmaceutically acceptable excipients well known to those skilled in the art. Such excipients include without limitation diluents, binders, disintegrants, stabilizers, glidants, lubricants and the like.

Suitable diluents include but are not limited to calcium salts, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, saccharides, starch, starch derivatives and the like, or mixtures thereof. In preferred embodiments, the diluent is microcrystalline cellulose, starch or a mixture thereof

Suitable binders include but are not limited to alginic acid and alginates, cellulose and cellulose derivatives, gelatin, glycols, polyvinylpyrrolidone, starch, pregelatinized starch and the like. In preferred embodiments, polyvinylpyrrolidone and the water soluble, non- swellable excipient such as for example polyethylene glycol 4000 act as binders.

Suitable disintegrants include but are not limited to alginic acid and alginates, cellulose and cellulose derivatives, crospovidone, starch, starch derivatives and the like.

Stabilizers used in the present invention include, but are not limited to dextrins, polyacids and mixtures thereof. In preferred embodiments, cyclodextrin, more preferably, β- cyclodextrin is used as a stabilizer.

Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate and the like. In one embodiment, colloidal silicon dioxide is included as a glidant in an amount up to about 2%, preferably about 0.2% to about 0.6%, by weight of the tablet.

Suitable lubricants include stearic acid and stearates, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycols, sodium lauryl sulfate, sodium stearyl fumarate, talc and the like. In one embodiment, magnesium stearate is included as a lubricant in an amount of about 0.1% to about 1.5%, preferably about 0.3% to about 1%, by weight of the tablet.

In a preferred embodiment of the present invention the mini-tablets can further comprise a coating which may be a functional coating, an enteric coating, a compression coating or combinations thereof.

The functional coating may be used for extending the release of pramipexole from the composition and/or enhancing the stability of pramipexole and may comprise water soluble polymers/excipients, water insoluble polymers or combinations thereof. The water insoluble polymer may be, for example, but not limited to, cellulose ethers such as ethylcellulose, cellulose esters such as cellulose acetate, methacrylic acid derivatives (such as the polymers marketed under the trade name of Eudragit^® RL, RS) and the like. The water soluble polymers / excipients may be, for example, but not limited to hydroxypropyl methylcellulose, graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (such as marketed under the trade name of Kollicoat Protect^®), polyethylene glycol, copovidone (Plasdone S-630 ), hydrated colloidal silica, sucrose, mannitol or any other substance capable of playing the same role.

The functional coating typically constitutes about 1-20% by weight of the tablet on which the coating is being performed.

The enteric coating polymer may comprise one or more polymers for example, but not limited to, shellac, methacrylic acid copolymers (such as Eudragit^® S or L grades) cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate and the like. Typically the enteric coating constitutes about 1-20% by weight of the tablet on which the coating is being done.

In a preferred embodiment, the coating on the mini-tablet comprising pramipexole intimately mixed with one or more water soluble, non-swellable excipients comprises of a combination of one or more functional coatings and enteric coating for extending the release and enhancing the stability of the pramipexole contained within the mini-tablet while the mini- tablets which release pramipexole within an hour are coated with a functional coating which enhances the stability of the mini-tablets.

In a still preferred embodiment, a pharmaceutical composition comprising mini-tablets comprising pramipexole for extended release of pramipexole as per the disclosures of the invention consists essentially of a pharmaceutical gelatin capsule containing two groups of functionally coated mini-tablets wherein, (a) said first group of functionally coated mini-tablets (Group a) comprises not less than 25% by weight of pramipexole which release essentially all the pramipexole contained within them within one hour of contacting a suitable release medium and which are coated with a functional coating comprising a graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (for example marketed as Kollicoat Protect^®) at a level of 2-8% and

(b) said second group of functionally coated mini-tablets (Group b) which mini-tablets prior to coating comprise not less than 60% pramipexole intimately mixed with one or more water- soluble, non-swellable excipients coated with (i) a functional coating comprising a mixture of ethylcellulose and copovidone (Plasdone S- 630) at a level of 5% to 15% by weight of the core tablet and subsequently

(ii) an enteric coating comprising methacrylic acid copolymer type C such as for example marketed under the trade name of Acryl EZE^® at a level of 5-15% by weight of the functional coated tablet and finally (iii) a functional coating comprising a graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (Kollicoat Protect^®) at a level of 2- 8% and which release pramipexole over a period of not less than 8 hours after contacting a suitable release medium.

The coating, if present, can optionally contain additional pharmaceutically acceptable excipients such as plasticizers, colors, etc well known to the person of skill in the art.

Plasticizers can include but are not limited to citrates, phthalate, glycols and the like.

It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each type of additive employed may vary within ranges conventional in the art.

The mini tablets of the present invention can be prepared by any of the granulation methods known in the art, e.g., dry granulation, wet granulation, melt granulation or direct compression using equipment well known to a person having skill in the art. hi a preferred embodiment, fluid bed wet granulation is used to prepare the mini-tablets.

Dosage unit compositions of the present invention can be packaged in a container, accompanied by package insert providing pertinent information such as, for example, dosage and administration information, contraindications, precautions, drug interactions and adverse reactions.

In a preferred embodiment the extended release pharmaceutical composition comprising pramipexole can be packaged in a suitable packaging sytem which can also comprise means for reducing the oxygen content of the packaging system containing the extended release pharmaceutical composition comprising pramipexole. Examples of such means may include but are not limited to oxygen absorbers, inert gases such as nitrogen, argon and the like or combinations thereof. Oxygen absorbers reduce the oxygen concentration in a sealed container creating a very low-oxygen environment. Examples of oxygen absorbers which are commercially available include but are not limited to O- busters^® and the like. These means can be introduced into the packaging system containing the extended release pharmaceutical composition comprising pramipexole using techniques and equipments well known to those skilled in the art.

In another embodiment, the present invention discloses a pharmaceutical composition comprising mini-tablets comprising pramipexole for extended release of pramipexole as per the disclosures of the invention which consists essentially of two groups of mini-tablets wherein (a) said first group of functionally coated mini-tablets (Group a) comprises not less than 25% by weight of pramipexole which release essentially all the pramipexole contained within them within one hour of contacting a suitable release medium.

(b) said second group of functionally coated mini-tablets (Group b) comprises functionally coated mini-tablets, which mini-tablets prior to coating comprise not less than 60% by weight of pramipexole intimately mixed with one or more water-soluble, non-swellable excipients which release the pramipexole contained within them over a period of not less than 8 hours after contacting a suitable release medium wherein the in vitro release profile and/or the in vivo release profile of the composition is not adversely affected by the presence of alcohol. By "adverse effect" is meant an effect like dose dumping or a significant increase in the rate of release of pramipexole from the composition.

The following are few representative examples of the invention and in no way construed as being limited to the invention.

EXAMPLES Table 1: Composition of Pramipexole dihydrochloride mini-tablets

EXAMPLE 1

Pramipexole dihydrochloride monohydrate mini-tablets were prepared having compositions shown in Table 1. The finished dosage form consists of a hard gelatin capsule containing two types of mini-tablets of pramipexole corresponding to 0.75 mg pramipexole dihydrochloride monohydrate per capsule. Group (a) mini-tablets β-cyclodextrin and maize starch were sifted and mixed properly to form a blend. Part quantity of microcrystalline cellulose was added to this blend. Pramipexole dihydrochloride monohydrate and povidone K-30 were dissolved in a mixture of ethanol and water. The blend was granulated using this solution. The granules were dried and sifted and the remaining half quantity of microcrystalline cellulose was added to it. The mass was mixed with colloidal silicon dioxide and magnesium stearate. Mini-tablets were compressed to an average weight of 40 mg using 4 mm multitip punches. Group (b) mini-tablets

Polyethylene Glycol 4000 was sifted and mixed with microcrystalline cellulose (Avicel PH

101) to form a blend. Pramipexole dihydrochloride monohydrate was dissolved in minimum quantity of water and ethanol was added to it. The blend was granulated using this solution. The granules were dried and sifted. The mass was mixed with colloidal silicon dioxide, talc and magnesium stearate. Mini-tablets were compressed to an average weight of 40 mg using

4 mm multitip punches.

Coat

The prepared mini-tablets were functionally coated with ethylcellulose and Plasdone S-630 to a weight gain of about 9% of the weight of the core tablet. The tablets were further enteric coated using an aqueous dispersion of methacrylic acid copolymer Type C (Acryl EZE)

(20% solid content) to a weight gain of 8% of the weight of the functionally coated tablets.

Capsule

One immediate release mini-tablet and one extended release mini-tablet was filled into a hard gelatin capsule to get the finished extended release pharmaceutical composition.

EXAMPLE 2

The two groups of mini-tablets were prepared as mentioned in example 1.

Preparation of blend for conventional tablet Cross Carmellose sodium was sifted and mixed with microcrystalline cellulose (Avicel PH 101) to form a blend. Povidone K-30 was dissolved in purified water and the blend was granulated using this solution. The granules were dried and sifted. Microcrystalline cellulose (Avicel PH 102) and Talc were added to the granules and mixed followed by lubrication with magnesium stearate. This blend was used to compression coat one mini-tablet of each group together to provide a single tablet of size 19 X 8 mm.

EXAMPLE 3

Mini-tablets of group (b) were prepared as mentioned in example 1.

Preparation of granules Cross carmellose sodium was sifted and mixed with microcrystalline cellulose (Avicel PH 101) to form a blend. Pramipexole dihydrochloride monohydrate was dissolved in water along with polyvinylpyrolidone. The blend was granulated using this solution. The granules were dried and sifted. Microcrystalline cellulose (Avicel PH 102) and Talc were added to the blend and mixed followed by lubrication with magnesium stearate.

The prepared granules were used to compression coat mini-tablets of group (b) using 13/32" standard concave punches.

EXAMPLE 4

Group (a) minitablets

Pramipexole dihydrochloride was sifted and mixed with macrocrystalline cellulose to form a blend, β-cyclodextrin and Maize starch were sifted and mixed well with the blend. Povidone K-30 was dissolved in Isopropyl alcohol. The blend was granulated using this solution in fluid bed processor. The dried blend was sifted and mixed with colloidal silicon dioxide and magnesium stearate. The lubricated blend was compressed using 4 mm multitip punches. The mini-tablets were coated with aqueous solution of graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (Kollicoat Protect^®) up to a weight gain of 3 % of the weight of the core tablet.

Group (b) mini-tablets

Pramipexole dihydrochloride was mixed with microcrystalline cellulose and polyethylene glycol 4000 using a combination of dry mixing and sifting. The blend was granulated using ethanol in Fluid bed processor. The dried blend was sifted and mixed with colloidal silicon dioxide, talc and magnesium stearate. The lubricated blend was compressed using 4 mm multitip punches. The core tablets were functionally coated using ethylcellulose and Plasdone S-630 up to a level of 9% by weight of the core tablets. These tablets were enteric coated using methacrylic acid copolymer Type C (Acryl EZE ) up to a level of 8 % by weight of the functional coated tablets. Finally the mini-tablets were coated with graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (Kollicoat Protect^®) up to level of 3 % of the weight of enteric coated tablets. Capsule One immediate release mini-tablet and one extended release mini-tablet was filled into a hard gelatin capsule to get the finished extended release pharmaceutical composition.

Dissolution Method

The extended release dosage forms of Example 1 to Example 4 were tested for dissolution of pramipexole dihydrochloride in 900 ml of dissolution media at 37° C and in 40-mesh basket (USP Type 1) and rotated at 100 rpm. The dissolution media was varied with time beginning with 0.1N HCl for 0 to 2 hours. From 2 to 4 hours the media was pH 4.5 acetate buffer. From 4 to 8 hours the media was pH 5.5 acetate buffer and from 8 to 24 hours the media was pH 6.8 phosphate buffer.

Table 2: In vitro dissolution profile Example 1-4

Thus, from the dissolution profile present in Table 2, it is clear that no significant release of the drug takes place for at least one hour after the initial drug release (within one hour) takes place.

The extended release tablets of Example 1 were also tested for dissolution of pramipexole dihydrochloride in the presence of ethanol in 900 ml of dissolution media at 37° C and in 40- mesh basket (USP Type 1) and rotated at 100 rpm. The dissolution media was diluted with 10% ethanol (95%) and was varied with time beginning with 0.1N HCl for 0 to 2 hours. From 2 to 4 hours the media was pH 4.5 acetate buffer. From 4 to 8 hours the media was pH 5.5 acetate buffer and from 8 to 24 hours the media was pH 6.8 phosphate buffer. Table 3: In vitro dissolution profile of Example 1 (with 10% ethanol)

From this data, it can be concluded that the presence of alcohol does not induce any dose dumping from the extended release composition.

Pharmacokinetic study

An in vivo study was conducted in healthy human volunteers to assess bioavailability of the pharmaceutical composition of Example 1 by comparison with a reference treatment with immediate release pramipexole tablets.

Table 3: Descriptive analysis of pharmacokinetic parameters for pramipexole (n=10)

T- test (Example 1); R-reference (immediate release)

*- All readings are Mean±S.D

-K n= Il

++- n= 10

Table 4: Bioequivalence Table

*- All readings are Mean±S.D

Table5: Percent Rate of Absorption for Pramipexole in Fasting state (Ref)

Method

The study followed an open label, balanced, randomized, two period, two treatment, two sequence, cross over, oral bioavailability study comparing pramipexole dihydrochloride monohydrate 0.75 mg extended release capsules of example 1 (Test) with Mirapex^® 0.25 mg immediate release tablets (Reference) given thrice a day in healthy human subjects under fasted/fed condition. Plasma pramipexole concentrations were quantified by HPLC method. Samples were not diluted prior to analysis as all sample concentrations were within the limits of quantitation. Pharmacokinetic parameters for pramipexole were estimated by non compartmental methods. The parameters T_max, C_max, AUC_0→t (area under plasma concentration vs. time curve from 0 hours to the time last sample collected) and AUCo_→∞ (area under plasma concentration vs. time curve from 0 hours to infinity i. e. extent of absorption) were estimated during the studies and recorded in Table 3.

Statistical analysis of the generated data is shown in table 4 from which it can be seen that the extended release composition administered once daily is bioequivalent to the immediate release composition given in three divided doses as per the US-FDA guidelines.

It is surprising that an extended release composition having the dissolution profiles disclosed can be bioequivalent to the immediate release tablets since an extended release profile with a continuous release of drug is usually preferred.

As can be seen from the above data, the (AUCf_ed/AUC_fast_ed) for example 1 is 1.04 for AUCo_→t and 1.12 for AUCo_→∞. This shows that food has no effect on the above formulations of pramipexole.

Deconvolution of the generated data by Numerical Wagner-Nelson method is presented in Table 4 and 5 from which it can be seen that a mean of about 20% of the pramipexole in the composition is absorbed in vivo within about two hours and a mean of about 40% of the pramipexole in the composition is absorbed in vivo within about 4 hours. It is preferred that the composition, following single administration of 0.75 mg, exhibits a maximum plasma concentration (C_max) of pramipexole that is not greater than about 1200 ng/ml. Where a higher dose is administered, the preferred upper limit of C_max is proportionately greater; it being known that pharmacokinetics of pramipexole is substantially linearly dose-related up to a daily dose of 4.5 mg. Wright et al (1997), Journal of Clinical Pharmacology 37, 520-525. "C_max" as used herein, means maximum concentration observed representing peak exposure of active pharmaceutical ingredient (or metabolite) in plasma, serum or whole blood.

Thus it is preferred that the composition, following single dose administration, exhibits a time to reach maximum plasma concentration (T_max) of pramipexole that is at least about 6 hours. "T_max" as used herein, means time after administration of the drug at which maximum plasma concentration (C_max) is observed.

A composition having the in vitro release and/or in vivo PK parameters specified above is advantageous in having reduced potential to cause undesirable side effects that may be related to a combination of high C_max and short T_max. Preferably the incidence of side effects is no greater than with an immediate-release dosage form such as Mirapex^® tablets administered in a three times daily regimen. More preferably, the incidence of side effects is even lower than with such an immediate-release regimen. It is contemplated that these advantages become more pronounced with increase in daily dosage.

While the invention has been described in detail with respect to specific embodiments thereof, it will be apparent that numerous modifications and variations are possible without departing from the scope of the invention as defined by the following claims.

Claims

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

2. The extended release composition of claim 1 wherein the composition is in the form of mini-tabletscomprising pramipexole for extended release of pramipexole consisting essentially of two groups of mini-tablets wherein

(a) said first group of functionally coated mini-tablets (Group a) comprises not less than 25% by weight of pramipexole which release essentially all the pramipexole contained within them within one hour of contacting a suitable release medium

(b) said second group of functionally coated mini-tablets (Group b), which mini-tablets prior to coating comprise not less than 60% by weight of pramipexole intimately mixed with one or more water-soluble, non-swellable excipients which release the pramipexole contained within them over a period of not less than 8 hours after contacting a suitable release medium.

3. An extended release pharmaceutical composition comprising pramipexole having a release profile such that a mean of about 20% of the pramipexole released from the composition is absorbed within about 2 hours and a mean of about 40% of the pramipexole in the composition is absorbed within about 4 hours after administration of the composition to a human.

4. The extended release composition of claim 3 wherein the composition is in the form of mini-tablets comprising pramipexole for extended release of pramipexole consisting essentially of two groups of mini-tablets wherein; (a) said first group of functionally coated mini-tablets (Group a) comprises not less than 25% by weight of pramipexole which release essentially all the pramipexole contained within them within one hour of contacting a suitable release medium.

5. An extended release pharmaceutical composition comprising pramipexole which does not exhibit an adverse food effect and can be adapted to be administered to a mammal (including humans) in either fed or fasting state, said composition exhibiting a value of (AUCfed)/(AUCfasted) of at least 0.80 with a lower 90% confidence limit of at least 0.75.

6. The extended release composition of claim 5 wherein the composition is in the form of mini-tablets comprising pramipexole for extended release of pramipexole consisting essentially of two groups of mini-tablets wherein;

(a) said first group of functionally coated mini-tablets (Group a) comprises not less than 25% by weight of pramipexole which release essentially all the pramipexole contained within them within one hour of contacting a suitable release medium (b) said second group of functionally coated mini-tablets (Group b), which mini-tablets prior to coating comprise not less than 60% by weight of pramipexole intimately mixed with one or more water-soluble, non-swellable excipients which release the pramipexole contained within them over a period of not less than 8 hours after contacting a suitable release medium.

7. An extended release pharmaceutical composition comprising pramipexole wherein the release profile in vitro or in vivo is not adversely affected by the presence of alcohol.

8. An extended release composition of claim 7 wherein the composition is in the form of mini-tablets comprising pramipexole for extended release of pramipexole consisting essentially of two groups of mini-tablets wherein;

9. An extended release pharmaceutical composition comprising mini-tablets of pramipexole consisting essentially of two groups of mini-tablets wherein;

10. An extended release pharmaceutical composition according to claim 9 wherein (group a) mini-tablets are coated with a functional coating comprising a graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (Kollicoat Protect^®) upto a level of 2-8% of the weight of the core tablets

11. An extended release pharmaceutical composition according to claim 9 wherein the (group b) mini-tablets are coated with (a) a functional coating comprising a mixture of ethylcellulose and copovidone (Plasdone S- 630) at a level of 5% to 15% by weight of the core tablets and subsequently

(b) an enteric coating comprising methacrylic acid copolymer type C such as for example marketed under the trade name of Acryl EZE^® at a level of 5-15% by weight of the functional coated tablets and finally

(c) a functional coating comprising a graft copolymer of polyethylene glycol and polyvinyl alcohol mixed with polyvinyl alcohol and silicon dioxide (Kollicoat Protect^®) upto a level of 2-8% by weight of the enteric coated tablets.

12. An extended release pharmaceutical composition comprising pramipexole substantially as herein described with reference to Example 4.