US20060051419A1 - Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof - Google Patents

Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof Download PDF

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US20060051419A1
US20060051419A1 US11/202,689 US20268905A US2006051419A1 US 20060051419 A1 US20060051419 A1 US 20060051419A1 US 20268905 A US20268905 A US 20268905A US 2006051419 A1 US2006051419 A1 US 2006051419A1
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Prior art keywords
extended release
coating
pellet
polymer
pramipexole
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Thomas Friedl
Rolf-Stefan Brickl
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Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRICKL, ROLF-STEFAN, FRIEDL, THOMAS
Publication of US20060051419A1 publication Critical patent/US20060051419A1/en
Priority to US12/276,610 priority Critical patent/US20090130197A1/en
Priority to US12/630,271 priority patent/US8715728B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention is directed to an extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof.
  • Pramipexole is a known dopamine D2 receptor agonist. It is structurally different from the ergot-derived drugs, e.g., bromocriptine or pergolide. It is also pharmacologically unique in that it is a full agonist and has receptor selectivity for the dopamine D2 family of dopamine receptors.
  • Pramipexole is designated chemically as (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole and has the molecular formula C 10 H 17 N 3 S and a relative molecular mass of 211.33.
  • the chemical formula is as follows:
  • Pramipexole dihydrochloride monohydrate (molecular formula C 10 H 21 Cl 2 N 3 OS; relative molecular mass 302.27).
  • Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296° C. to 301° C., with decomposition.
  • Pramipexole is a chiral compound with one chiral center. Pure (S)-enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during synthesis.
  • Pramipexole dihydrochloride monohydrate is a highly soluble compound. Water solubility is more than 20 mg/mL and solubility in buffer media is generally above 10 mg/mL between pH 2 and pH 7.4. Pramipexole dihydrochloride monohydrate is not hygroscopic, and has a highly crystalline nature. Under milling, the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, yet in solution it is light sensitive.
  • Pramipexole immediate release (IR) tablets were first authorized in the USA in 1997, followed over the course of the next years by marketing authorizations in the European Union (EU), Switzerland, Canada, and South America as well as in countries in Eastern Europe, the Near East, and Asia.
  • EU European Union
  • EU European Union
  • South America as well as in countries in Eastern Europe, the Near East, and Asia.
  • Pramipexole IR tablets are indicated in the EU and US for the treatment of signs and symptoms of either early Parkinson's Disease or advanced Parkinson's Disease in combination with levodopa.
  • the IR tablets have to be taken 3 times a day.
  • pramipexole IR tablets are rapidly and completely absorbed following oral administration.
  • the absolute bioavailability is greater than 90% and the maximum plasma concentration occurs within 1 to 3 hours.
  • the rate of absorption is reduced by food intake but not the overall extent of absorption.
  • Pramipexole shows linear kinetics and a relatively small inter-patient variation of plasma levels.
  • the elimination half-life (t 1/2 [h]) varies from 8 hours in the young to 12 hours in the elderly.
  • modified release of active ingredient(s) allows simplification of the patient's administration scheme by reducing the amount of recommended daily intakes, improves patient's compliance, and attenuates adverse events, e.g., related to high plasma peaks.
  • Modified release pharmaceutical preparations regulate the release of the incorporated active ingredient or ingredients over time and comprise formulations with a controlled, a prolonged, a sustained, a delayed, a slow or an extended release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving dosage forms.
  • a modified or extended release of active ingredient(s) from a pharmaceutical preparation may be accomplished by homogeneously embedding the active ingredient(s) in a hydrophilic matrix, being a soluble, partially soluble or insoluble network of viscous, hydrophilic polymers, held together by physical or chemical entanglements, by ionic or crystalline interactions, by complex formation, by hydrogen bonds or van der Waals forces.
  • the hydrophilic matrix swells upon contact with water, thereby creating a protective gel layer from which the active ingredient(s) are slowly, gradually, continuously released in time either by diffusion through the polymeric network, by erosion of the gel layer, by dissolution of the polymer, or by a combination of these release mechanisms.
  • WO 2004/010997 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 kN cm ⁇ 2 , preferably at least about 0.175 kN cm ⁇ 2 , and more preferably at least about 0.2 kN cm ⁇ 2 , at a solid fraction representative of the tablet.
  • the disclosure thereof is concentrated to provide a composition with sufficient hardness yield during a high-speed tabletting operation, in particular to resist erosion during application of a coating layer.
  • WO 2004/010999 discloses an orally deliverable pharmaceutical composition
  • 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 (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.
  • any formulation having a modified or controlled release profile designed for a once daily application would meet the above requirements for which a general teaching how to adjust such a profile is missing. All examples are directed to tablets and not to coated pellets.
  • an object of the present invention to provide an extended release pellet formulation of pramipexole or a pharmaceutically acceptable salt thereof which may be filled in a capsule and is suitable for once-daily oral administration. It is a further object to provide a pellet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof which may be filled in a capsule and is suitable to provide a day-long therapeutic effect and will allow patients to treat their symptoms with a single daily dose, and makes it possible to adjust the release profile of the active ingredient according to a selected release profile dependent or independent from the pH value. Furthermore, a method of manufacturing the pellet formulation shall be provided.
  • pramipexole or a pharmaceutically acceptable salt thereof may be used in formulations as once daily extended (or slow) release pellets and two alternative formulation principles allow different release rate types dependent or independent from the pH value.
  • One embodiment of the present invention relates to an extended release pellet comprising an active ingredient selected from pramipexole and the pharmaceutically acceptable salts thereof, and at least one release-modifying excipient.
  • the invention relates to an extended release pellet, wherein the active ingredient is embedded within a matrix formed by the at least one release-modifying excipient, which is preferably selected from the group of lipids, waxes, and water-insoluble polymers.
  • an extended release pellet comprising a core and a coating, wherein at least one release-modifying excipient is incorporated in the coating.
  • an extended release pellet wherein the active ingredient is incorporated in the core.
  • an extended release pellet wherein the coating comprises at least a first layer and a second layer surrounding the first layer, wherein the first layer comprises the active ingredient, and wherein the second layer comprises at least one release-modifying excipient, preferably selected from ethyl cellulose, cellulose acetate, polyvinylacetate, polyacrylates, polymethacrylates, and ammonio methacrylate copolymer.
  • the second layer further comprises at least one water-soluble excipient, preferably selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.
  • an extended release pellet wherein the second layer further comprises an enteric-coating polymer, preferably selected from methacrylic acid copolymers type A and B.
  • an extended release pellet wherein the second layer comprises from about 10 to about 85 wt.-% of the enteric-coating polymer and from about 15 to about 75 wt.-% of the water-insoluble polymer.
  • an extended release pellet wherein the core comprises a saccharide, such as saccharose, starch, cellulose, and a cellulose derivative, preferably microcrystalline cellulose.
  • a saccharide such as saccharose, starch, cellulose, and a cellulose derivative, preferably microcrystalline cellulose.
  • layer should be understood in its broadest sense also including a coating or a film or any kind of (partly or fully) surrounding material used in the pharmaceutical sector and having a defined thickness.
  • pellets can also be formed by extrusion of active principle together with excipients in a wet extrusion or melt extrusion process.
  • the extended release formulations (a) and (b) according to the present invention intended for oral administration allow to select and estimate which in vitro release characteristic and timing of a formulation is most suitable to achieve the desired in vivo plasma profiles preferably with a once daily application. Therefore, two different formulation principles have been developed for pellets. The two formulation principles have different release rate types and a different pH dependency is available. These alternative formulations are beneficial to patients as the extended release drug delivery will allow patients to treat their symptoms with a single daily dose, thereby increasing patient convenience and compliance.
  • in vitro release characteristic is directed to a release characteristic as obtained in a kind of normally used liquid medium for in vitro experiments wherein the release of active ingredient from the extended release formulation can occur, i.e., for example, in in vitro dissolution media, but also in body fluids or simulated body fluids, more in particular in the gastrointestinal fluids.
  • extended release should be understood in contrast to an immediate release, the active ingredient is gradually, continuously liberated over time, sometimes slower or faster, dependent or independent from the pH value.
  • the term indicates that the formulation does not release the full dose of the active ingredient immediately after oral dosing and that the formulation allows a reduction in dosage frequency, following the definition for extended release, interchangeable with slow release.
  • a slow or extended release dosage form is used synonymously with prolonged action, sustained release, or modified release dosage form.
  • the extended release dosage form allows at least a two-fold reduction in dosing frequency or a significant increase in patient compliance or therapeutic performance as compared to that presented as a conventional dosage form (e.g., as a solution or a prompt drug-releasing, conventional solid dosage form).
  • the two types of extended release pellet formulations are available showing different in vitro release characteristics.
  • the two types have the same structure, i.e., an inert pellet core and a first and a second layer applied thereon in this order, the first layer represents the active ingredient layer comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally a binder and further excipients, the second layer represents a functional coating either comprising a water-insoluble polymer with a pore former or a mixture of an enteric-coating polymer, i.e., which is resistant against gastric juice, and a non-dissolving water swelling polymer.
  • formulation (a) is understood the pellet formulation having the second layer as above-defined under (a) and under “formulation (b)” is understood the pellet formulation having the second layer as above-defined under (b) whereas the inert pellet core and first layer compositions of formulation (a) and (b) will be the same.
  • the extended release pellet formulation (a) of the present invention applies a water-insoluble polymer preferably with a pore former in the second layer leading to an exponential (1 st order) in vitro release characteristic, which is widely independent of the pH value.
  • the extended release pellet formulation (b) of the present invention applies a mixture of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer, the resulting layer having a close to zero order in vitro release characteristic over a broad period of time at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and an more accelerated release above pH 7.3.
  • the latter is furthermore characterized by a certain lag time until drug release becomes substantial and, after the main portion of drug is released, by a flattening of the release profile until an asymptote is reached. This results in a sigmoid profile, i.e., an S-shaped dissolution profile.
  • a close to zero order in vitro release characteristic indicates a curve which has a virtually constant ascending slope.
  • the inert pellet core present in both alternate pellet formulations (a) and (b) of the present invention comprises saccharides, preferably polysaccharides, cellulose or a cellulose derivative, starch, and/or waxes. It is preferred if the core consists of or essentially consists of a saccharide, preferably polysaccharide, or cellulose, particularly preferred saccharose or microcrystalline cellulose. Most preferred is microcrystalline cellulose.
  • the size of the cores may be sieve fractions between 0.1 and 3.0 mm, preferably between 0.5 and 1.5 mm.
  • the inert pellet core consists or essentially consists of microcrystalline cellulose it has been found that the thickness of the second layer applied thereon may be decreased to a great extent compared to the use of other core materials, e.g., if the core is composed of saccharose. Therefore, the amount of release controlling polymeric agents and overall spray volumes as well as process times to apply the coating dispersions or solutions may be reduced significantly while the release profile for the active ingredient may be maintained.
  • the related advantages are reducing the amount of excipient and solvent materials used, reducing the process times and the embodiment is cost-saving.
  • pellet formulations (a) and (b) of the present invention there is provided a first layer or coating on the inert core pellet comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally one or more binders and further excipients.
  • the first layer or coating normally has a thickness of 0.5 to 25 ⁇ m, preferably 1 to 5 ⁇ m.
  • pramipexole or a pharmaceutically acceptable salt thereof may be present in any amount suitable for the desired treatment of a patient.
  • a preferred salt of pramipexole is the dihydrochloride salt, most preferably in the form of the monohydrate. Usual amounts are from about 0.1 to about 5 mg pramipexole salt.
  • e.g. 0.750 mg pramipexole dihydrochloride monohydrate, corresponding to 0.524 mg anhydrous base is used in the extended release capsule or tablet formulation according to the present invention taking into account that all pellets which are filled in a capsule or compressed into a tablet are to give the desired dose strengths.
  • the extended release pellets are filled into hard capsules, but also compressing of the pellets together with further excipients into tablets is possible.
  • any other amount of active ingredient suitable for treatment may be used with the only proviso that the amount of pramipexole or salt, that is the whole number of pellets being present in one capsule, is sufficient to provide a daily dose in one to a small plurality, for example one to about 4, of capsules to be administered at one time.
  • the full daily dose is delivered in a single capsule.
  • An amount of pramipexole salt, expressed as pramipexole dihydrochloride monohydrate equivalent, of about 0.1 to about 10 mg per capsule, or about 0.05% to about 5% by weight of the composition will generally be suitable.
  • an amount of about 0.2 to about 6 mg, more preferably an amount of about 0.3 to about 5 mg, per capsule is present.
  • Specific dosage amounts per capsule e.g., include 0.375, 0.5, 0.75, 1.0, 1.5, 3.0, and 4.5 mg pramipexole dihydrochloride monohydrate.
  • the amount that constitutes a therapeutically effective amount varies according to the condition being treated, the severity of said condition, and the patient being treated.
  • the binder(s) present in the first layer may be any suitable wet binder(s) as used in the pharmaceutical sector.
  • suitable wet binder(s) examples are hydrophilic polymers which may swell and glue upon contact with water.
  • the viscosity of the polymers preferably ranges from 1 to 1,000 mPa.s (apparent viscosity of a 2% aqueous solution at 20° C.).
  • alkylcelluloses such as, methyl cellulose; hydroxyalkylcelluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses, such as, hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; carboxyalkylcelluloses, such as, carboxymethylcellulose; alkali metal salts of carboxyalkylcelluloses, such as, sodium carboxymethylcellulose; carboxyalkylalkylcelluloses, such as, carboxymethyl ethyl cellulose; carboxyalkylcellulose esters; other natural, semisynthetic, or synthetic polysaccharides, such as, alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabicum, guar gum, xanthan gum, starches, pect
  • Preferable binders are polysaccharides, in particular cellulose derivatives and more preferred cellulose ether derivatives.
  • a most preferred cellulose ether derivative is hydroxypropyl cellulose.
  • Hydroxypropyl methyl cellulose preferably used as a wet binder in the present invention has a viscosity grade ranging from about 3 mPa.s to about 1,000 mPa.s, in particular ranging from about 3 mPa.s to about 20 mPa.s and preferably a viscosity grade of about 4 mPa.s to about 18 mPa.s (apparent viscosity of a 2% aqueous solution at 20° C.), e.g., hypromellose 2910 (DOW, Antwerp, Belgium).
  • Hydroxypropyl cellulose having a viscosity lower than 1,500 mPa.s is preferred, in particular hydroxypropyl cellulose having a viscosity in the range from about 75 to about 150 mPa.s (5% aqueous solution), preferably from 300 to 600 mPa.s (10% aqueous solution), e.g., KLUCEL® EFO (Hercules, Wilmington, USA).
  • the amount of binder in the first layer of the pellet formulations (a) and (b) of the present invention ranges from 0 to about 30% by weight, preferably from about 10 to about 20% by weight.
  • a combination of binders may be used.
  • the first layer of the extended release pellet formulation of alternatives (a) and (b) comprises or consists of hydroxypropyl cellulose, pramipexole or a pharmaceutically acceptable salt thereof and excipients.
  • the amount of hydroxypropyl cellulose is preferably in the range from 1 to 30, particularly preferred from 5 to 25, most preferred from 10 to 20% by weight.
  • the amount of excipients is preferably in the range from I to 40, particularly preferred from 2 to 25, most preferred from 5 to 15% by weight.
  • Beside pramipexole or a salt thereof, and the binder(s), the first layer or coating of both formulations (a) and (b) of the present invention may also optionally comprise excipients, i.e., pharmaceutically acceptable formulating agents, in order to promote the manufacture and coating properties of the preparation.
  • excipients i.e., pharmaceutically acceptable formulating agents
  • These formulating agents comprise, for example, glidants, antiadherents, binding agents, granulating agents, anti-caking agents, and lubricants.
  • Other conventional excipients known in the art can also be included.
  • a glidant and antiadherent can be used to improve the manufacturing during the spray process and to prevent sticking and picking of the pellets to each other.
  • Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate and the like.
  • talc is included as a glidant/antiadherent in an amount up to about 25%, preferably about 5% to about 15%, by weight of the first layer.
  • waxes, lipids, and water-insoluble polymers may be used as release modifying agents.
  • Suitable waxes include compounds that are chemically defined as esters of fatty acids and fatty alcohols or sterols, as well as derivatives and functional analogues thereof. Usually, the chain length of the fatty acid moiety is at least about 8 carbon atoms, and more typically at least about 12 carbon atoms. Waxes are plastic solids at room temperature, but very often have a moderately low melting point, such as below about 80° C.-100° C. Waxes are usually somewhat more brittle than solid fats, and less greasy. More recently, also compounds which are chemically different from this definition but similar in their properties have been referred to as waxes. These waxes or functional analogues may also be used according to the present invention.
  • waxes and wax analogues examples include white and yellow beeswax, carnauba wax, microcrystalline wax, spermaceti wax, candellila wax, saturated fatty acid esters, sugar cane wax, paraffin wax, castor wax, and wax mixtures such as nonionic or anionic emulsifying wax, cetyl esters wax, and lanolin.
  • waxes are beeswax, carnauba wax, saturated fatty acid esters, and microcrystalline wax.
  • Suitable lipids include lipophilic compounds or mixtures of natural or synthetic origin that have similar properties as glycerides and other natural lipids, such as phospholipids, sphingolipids, ceramides, sterols, steroids, and carotenoids.
  • Lipids may be solid or liquid at room temperature, and may be viscous in their liquid state.
  • a lipid used to carry out the invention is solid at room temperature, even though a liquid lipid may also be used in mixtures, such as in a mixture with a solid lipid or wax.
  • lipids which may be found useful include mono-, di-, and glycerides of saturated or unsaturated fatty acids, such as—optionally hydrated or partially hydrated—vegetable oils (e.g., peanut, castor, coconut, cottonseed, palm, or soybean), edible fat, hard fat, glyceryl behenate, glyceryl stearate, glyceryl palmitate; fatty acids such as stearic acid, behenic acid, palmitic acid, oleic acid, lauric acid, myristic acid, arachidic acid, linolenic acid, linoleic acid, arachidonic acid, and erucic acid; fatty alcohols such as those corresponding to the previously mentioned fatty acids, in particular cetyl alcohol, stearyl alcohol, oleyl alcohol, and palmityl alcohol; glycerides, fatty acids, or fatty alcohols which are modified with sorbitan or polyoxyethylene; and phospholipids such as lecit
  • Particularly suitable lipids are solid or at least partially hydrated triglycerides including edible fat, hard fat, hydrated peanut-, castor-, coconut-, cottonseed-, palm-, and soybean oil, glyceryl behenate, glyceryl stearate, glyceryl palmitate, stearic acid, behenic acid, and palmitic acid.
  • Suitable water-insoluble polymers may comprise the water-insoluble polymers as defined below for the formulations according to the present invention.
  • agents such as polyvidone; starch; acacia gum; gelatin; seaweed derivatives, e.g., alginic acid, sodium and calcium alginate; cellulose, preferably microcrystalline cellulose, cellulose derivatives, e.g., ethyl cellulose, hydroxypropyl methyl cellulose, having useful binding and granulating properties.
  • the second layer is provided on the first layer, the second layer, a functional layer, being an extended release coating or film coating comprising at least one water-insoluble polymer and preferably a pore former, the resulting pellet having an pH-independent in vitro release characteristic. Therefore, the second layer is a non soluble diffusion lacquer with pores leading to an exponential (1 st order) release profile of the pellet formulation (a) which has practically a pH-independent in vitro release characteristic. A release characteristic which is pH-independent indicates that the release characteristic is virtually the same in different pH media.
  • the water-insoluble polymer according to the present invention is defined as a polymer having a water solubility which is lower than 1 part soluble in 1,000, preferably lower than about 1 part soluble in 10,000 parts of solvent.
  • the release-controlling second layer, coating or film according to pellet formulation (a) comprises one or more hydrophobic or water-insoluble polymers such as cellulosic polymers e.g., methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose esters such as cellulose acetate, polyvinyl acetate, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof, such as ammonio methacrylate copolymer, type B, and the like. Particularly preferred is ethyl cellulose.
  • cellulosic polymers e.g., methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose esters such as cellulose acetate, polyvinyl acetate, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof, such as ammonio methacrylate copolymer, type B, and the like.
  • ethyl cellulose is e
  • the hydrophobic or water-insoluble component typically constitutes about 1% to about 25%, preferably about 3% to about 10%, by weight of the pellet as a whole, provided that microcrystalline cellulose pellets are used as described above. In case sugar pellets are used higher amounts of ethylcellulose can become necessary.
  • the second layer can contain one or more pore formers, such as more water soluble polymers, like hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and highly water soluble polymers, like polyvinyl pyrrolidone and polyethylene glycol, or other water soluble excipients, such as lactose and mannitol.
  • Particularly preferred pore formers are polyethylene glycols (e.g., Macrogol 6000).
  • the amount of pore former is suitably up to 40 per cent by weight of the layer, coating or film, preferably up to 25% by weight.
  • Pore formers like polyethylene glycols also serve as plasticizers, i.e., the function of such excipients either as plasticizer and/or pore former can not be clearly differentiated.
  • the second layer can optionally contain additional pharmaceutically acceptable excipients as mentioned above, preferably used are plasticizers, dyes and antiadherents.
  • plasticizers are polyethylene glycols (e.g., Macrogol 6000), triacetin, and triethylcitrate.
  • the amount of plasticizer is suitably up to 25 per cent by weight of the layer, coating or film.
  • Anti-adherents, such as talc and magnesium stearate can be used.
  • the extended release pellet formulation according to formulation (a) is pH-independent. Therefore, the disadvantage that food related dose-dumping which may be encountered is avoided.
  • the problem of food related dose-dumping in fed patients can be attributed to a lot of factors such as the mechanical forces that are exerted by the stomach on its content and thus on an ingested preparation as well as the different pH regions of the gastrointestinal tract. Since the pH values encountered in the gastrointestinal tract vary not only with the region of the tract, but also with the intake of food, an extended release formulation preferably also has to provide a controlled release profile and in particular has to avoid dose-dumping regardless whether the patient is in fasted or fed conditions.
  • the oral extended release formulation (a) retains its pharmacokinetic release profile along its way through the gastrointestinal tract so as to avoid undesirable fluctuations in drug plasma concentrations or complete dose-dumping, in particular avoids dose-dumping in different regions of the gastrointestinal tract.
  • the alternate pellet formulation (b) has the same structure with regard to the inert pellet core and first layer composition as defined for formulation (a) but a different second layer or functional film coating composition.
  • the second layer of formulation (b) comprises or essentially consists of a mixture of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer, the resulting pellet having a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and a more accelerated release above pH 7.3.
  • the pH-dependent enteric-coating polymer is preferably an anionic polymer, more preferably an anionic carboxylic acrylic polymer soluble above a pH value of 5.5, preferably above a pH value of 7.0.
  • an anionic polymer is meant a polymer containing anionic groups after dissociation depending on pH.
  • such polymer should be soluble above pH 5.5, preferably above pH 7.0.
  • the anionic carboxylic acrylic polymer is selected from partly methyl esterified methacrylic acid polymers. Suitable partly methyl esterified methacrylic acid polymers are sold under the names EUDRAGIT® L and EUDRAGIT® S, preferably used are EUDRAGIT® S100 and L100.
  • the water-insoluble, pH-independent swelling polymer is preferably selected from quaternary ammonium substituted acrylic polymers.
  • Such polymers are sold under the names EUDRAGIT® RS and EUDRAGIT® RL having an ammonium substitution of about 5 and about 10 per cent by weight, respectively.
  • EUDRAGIT® RS 100 is used.
  • the layer or film coating comprises the enteric-coating polymer such as the anionic carboxylic acrylic polymer in an amount of 10 to 85 per cent by weight of the layer or coating and the water-insoluble, pH-independent swelling polymer, selected from quaternary ammonium substituted acrylic polymers, in an amount of 15 to 75 per cent by weight of the layer or coating.
  • the release profile can be tuned with regard to the release rate, that is the time to, e.g., reach a level of 50% of drug dissolved, and with regard to the extent of pH dependency.
  • an excess of the anionic carboxylic acrylic polymer, e.g., EUDRAGIT® S 100 over the quaternary ammonium substituted acrylic polymers is required to achieve the desired accelerated dissolution characteristic at a pH above 6.8,
  • the second layer, coating or film normally has a thickness of 5 to 80 ⁇ m, preferably 20 to 60 ⁇ m.
  • the second functional layer according to formulation (b) of the present invention takes advantage of the fact that the time of passage through the small intestine is rather constant, said time is about 2 to 5 hours.
  • the change of pH from acid to about neutral at the pylorus is employed as a trigger mechanism changing the physical condition of the layer and finally causing the accelerated release of the active substance. Therefore the formulation releases a major part of its drug contents in the small intestine, and in the lower part of the intestinal system preferentially in the large intestine, i.e., the colon.
  • a pore-forming component may be present in the second layer or film coating of formulation (b).
  • the pore-forming component may be selected from the group consisting of water soluble polymers, such as polyethylene glycols, polyvinyl pyrrolidone, and cellulose derivatives, such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose, preferably hydroxypropyl cellulose.
  • the pore-forming component is typically present in an amount of about 1% to about 25%, preferably about 2% to about 10%, by weight of the polymer mixture in the second layer.
  • a particular preferred pore-forming component is hydroxypropyl cellulose having a viscosity in the range from about 150 to about 700 mPa.s, preferably from 200 to 600 mPa.s, e.g., selected from the KLUCEL® series such as KLUCEL® EF or LF (Hercules, Wilmington, USA).
  • the polymer pore-forming component forms diffusion pores and leads to an accelerated hydration and an altering of the rebuffering characteristics of the layer or film coating with a change from acid to alkaline medium and results in an accelerated penetrability of the layer or coating for the active ingredient pramipexole or its salt in the pH range >7.3
  • the presence of a pore-forming component provides the further advantage that the release characteristic is accelerated and occurs more rapid, i.e., the effects of the second layer are enhanced significantly.
  • the first and second layers or coatings should be applied at as uniform a thickness as possible to provide optimum control of release rate of the pramipexole or pramipexole salt.
  • Microcrystalline cellulose, powdered cellulose or starch is mixed with pramipexole in ratios delivering the necessary amount of drug in a suitable number of pellets with regard to reproducibility of filling and acceptable capsule size. Extrusion is achieved by addition of water only or of water containing binders such as povidone or methyl cellulose, hydroxypropyl cellulose. In order to achieve the desired release rates, other excipients such as lactose, microcrystalline cellulose, starch, etc., can be added.
  • Melt extrusion is achieved either by hydrophilic or lipophilic compounds with melting points between 40° C. and 120° C. Suitable examples are polyethylene glycol 2000-10000, poloxamer 188, carnauba wax, hydrogenated castor oil, stearyl alcohol, cetyl alcohol and mixtures thereof. In order to achieve the desired release rates, other excipients such as lactose, microcrystalline cellulose, starch, etc., can be added.
  • pellets are then coated by retarding lacquers as described for the pellets consisting of inert starters with drug layers sprayed onto them.
  • excipients are suitable also to achieve extruded pellets with suitable extended release even without retarding lacquers. These are, e.g., carnauba wax, hydrogenated castor oil and mixtures thereof for lipophilic pellets or carbopol, anionic carboxylic acrylic polymer, e.g., partly methyl esterified methacrylic acid polymers. Suitable partly methyl esterified methacrylic acid polymers are sold under the names EUDRAGIT® L and EUDRAGIT® S, preferably used are EUDRAGIT® S100 and L100.
  • the extended release pellets can be of sizes between 0.2 and 3 mm in diameter, preferably between 0.5 to 1.5 mm, most preferred between 0.7 and 1.0 mm. According to the present invention the pellets are preferably filled in hard capsules.
  • the extended release capsules can be of any size and shape and color, e.g., for a 0.75 mg dose strengths preferably a size 3 capsule can be used.
  • the capsule shell is usually made from hydroxypropyl methyl cellulose (so-called HPMC or vegetable capsules) or gelatin.
  • HPMC hydroxypropyl methyl cellulose
  • the capsules according to the present invention are usually filled with pellets, for example, more than 150 extended release pellets. Each pellet is built up of an inert (starter) core pellet, an active ingredient layer and an extended or slow release film coating. In one capsule, the amount of pramipexole or the pharmaceutically acceptable salt thereof contained in the pellets may preferably be sufficient to provide a daily dose administered at one time.
  • the extended release pellets can be admixed with fillers and binders, such as microcrystalline cellulose, carrageenans, and alginates and disintegrants, such as sodium starch glycolate, sodium carboxymethyl cellulose (croscarmellose), further excipients, like glidants and lubricants, and be compressed into tablets.
  • fillers and binders such as microcrystalline cellulose, carrageenans, and alginates and disintegrants, such as sodium starch glycolate, sodium carboxymethyl cellulose (croscarmellose), further excipients, like glidants and lubricants, and be compressed into tablets.
  • the present invention is further directed to the use of the extended release pellet formulation or capsule according to the present invention for preparing a medical composition for the treatment of Parkinson's Disease and complications or disorders associated therewith.
  • a manual screening after process step (2) and/or process step (3) may be performed in order to remove agglomerates.
  • the solvents employed according to the process of the invention are solvents having a sufficient volatility to evaporate under the conditions of application, leaving a layer of the solute on the surface of the core or body or pellet prepared.
  • Organic solvents such as alcohols, hydrocarbons and esters may be used as well as derivatives thereof, such as chlorinated hydrocarbons. Particularly preferred are alcohol such as ethanol or alcohol/water mixtures.
  • the process of applying the coating may be carried out in an apparatus normally used in the pharmaceutical industry for coating of solid pharmaceutical preparations, preferably in a fluid bed apparatus. The process is normally carried out at 25° C. to 35° C. product temperature, however, temperature and pressure conditions may be varied within broad limits. In a fluid bed spraying process, the temperature of the inlet air is suitably about 20° C. to 60° C.
  • the obtained extended release pellets are filled in suitable capsules and the capsules of the invention can be packaged in a container, accompanied by a package insert providing pertinent information such as, for example, dosage and administration information, contraindications, precautions, drug interactions and adverse reactions.
  • the capsules are for example filled into High Density Polyethylene (HDPE) bottles. The bottles are closed tightly with screw caps and appropriately labeled. All packaging and labeling activities are performed according to cGMP regulations.
  • HDPE High Density Polyethylene
  • FIG. 1 is a flow diagram illustrating process step ( 1 ) of a preferred embodiment of the manufacturing process according to the present invention wherein the first layer is applied on inert starter core pellets;
  • FIG. 2 is a flow diagram illustrating process step ( 2 ) of a preferred embodiment of the manufacturing process according to the present invention wherein the second layer is applied on the first layer of the pellets;
  • FIG. 3 is a flow diagram illustrating process step ( 3 ) of a preferred embodiment of the manufacturing process according to the present invention wherein the pellets are filled in capsules;
  • FIG. 4 is a graph illustrating the dissolution profiles of a pellet formulation according to the present invention wherein the second layer is a diffusion lacquer composed of ethyl cellulose (formulation (a)) in 3 different pH media;
  • FIG. 5 is a graph illustrating the dissolution profiles of a pellet formulation according to the present invention wherein the second layer is a mixture of EUDRAGIT® S 100 and EUDRAGIT® RS 100 (formulation (b)) in 4 different pH media; and
  • FIG. 6 is a graph illustrating the dissolution profiles of a pellet formulation according to the present invention wherein the second layer is as defined in FIG. 5 , but a pore-forming component is additionally present (formulation (b)+pore-forming component) in 3 different pH media.
  • FIGS. 1 and 2 a preferred embodiment of the manufacturing process is illustrated with reference to a flow diagram wherein the manufacture of the pellet formulations D, E, F, G, H of Examples 1 to 5 is exemplarily shown.
  • the figures show the detailed process steps of the manufacturing process of the active ingredient pellets (first layer; FIG. 1 ) and of the slow or extended release pellets (second or functional layer; FIG. 2 ) and the in process controls performed.
  • FIG. 3 shows the filling of capsules with the obtained pellets.
  • microcrystalline cellulose pellets (Cellets 700) are used which represent the starting material for the subsequent coating step.
  • the same active ingredient pellets with a drug load of 1% (10 mg/g) can serve as starting material for the functional film-coating. Yet also other drug loads in the active ingredient pellets are suitable.
  • the active ingredient pellets are manufactured by spray-layering of an aqueous solution of pramipexole dihydrochloride monohydrate (active ingredient), unmilled quality, together with hydroxypropyl cellulose (binder) and talc (excipient) onto the surface of microcrystalline cellulose pellets (core, Cellets 700) in a bottom spray fluid bed equipment. Light protection of the spray suspension is normally required. After the spraying is completed, the pellets are dried at 35° C. for 1 hour in a tray dryer. After drying, the pellets are manually screened through a 1.12 mm mesh size screen in order to remove agglomerates.
  • the in process controls used are: active ingredient assay and loss on drying.
  • coating suspensions consisting of methacrylic acid copolymer (type B USP/NF)) and ammonio methacrylate copolymer (type B USP/NF)), or ethyl cellulose, and excipients selected from talc, triacetin or triethylcitrate and hydroxypropyl cellulose or macrogol 6000, are sprayed onto the active ingredient pellets in a bottom spray fluid bed equipment.
  • the solvent used is according to the described embodiment either Ethanol 96% or an Ethanol 96% mixture with water.
  • the extended or slow release pellets are dried at 40° C. for 12 to 48 hours in a tray dryer. After drying, the pellets are manually screened through a 1.12 mm mesh size screen in order to remove agglomerates.
  • the in process controls used are: active ingredient assay and loss on drying.
  • An appropriate amount of dried and screened pellets are filled into vegetable capsules (HPMC capsules) or gelatin capsules of size 3 to give the desired dose strengths using a suitable intermittent motion capsule filling machine.
  • the appropriate amount is calculated from the assay result found for the respective batch of slow or extended release pellets.
  • the in process controls used are: average mass of empty capsules, mass of filled capsule, and length of closed capsule.
  • FIG. 4 it represents a graph illustrating the release profiles of a pellet formulation according to the present invention.
  • the pellet contains an inert pellet core, a first layer comprising pramipexole hydrochloride monohydrate and binder and a second layer which represents a diffusion lacquer composed of ethyl cellulose.
  • the detailed composition of the pellet is given in Example 4.
  • the pellet meets the requirements as defined in the abovementioned formulation (a) according to the present invention.
  • the value percent of released active ingredient is plotted against the time (hours).
  • FIG. 4 clearly shows that said pellet formulation has a release characteristic being independent from the pH value.
  • FIG. 5 represents a graph illustrating the release profiles of a pellet formulation according to the present invention.
  • the detailed composition of the pellet is given in Example 2.
  • the pellet formulation has a second layer in accordance with formulation (b) which is composed of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer (EUDRAGIT® S100/EUDRAGIT® RS 100).
  • formulation (b) which is composed of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer (EUDRAGIT® S100/EUDRAGIT® RS 100).
  • the value percent of released active ingredient is plotted against the
  • FIG. 5 clearly shows that the pellet formulation has a release characteristic being dependent from the pH value, i.e., the resulting pellet shows a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, and an accelerated release at pH 7.5.
  • FIG. 6 represents a graph illustrating the release profiles of a pellet formulation according to the present invention.
  • the detailed composition of the pellet is given in Example 5.
  • the pellet formulation has a second layer in accordance with formulation (b) which is composed of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer (EUDRAGIT® S100/EUDRAGIT® RS 100) and contains additionally a pore-forming component (KLUCEL® EF) and a plasticizer (triethylcitrate).
  • formulation (b) is composed of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer (EUDRAGIT® S100/EUDRAGIT® RS 100) and contains additionally a pore-forming component (KLUCEL® EF) and a plasticizer (triethylcitrate).
  • the value percent of released active ingredient is plotted against the time (hours).
  • FIG. 6 clearly shows that the pellet formulation has a release characteristic being dependent from the pH value.
  • the presence of a pore-forming component and the use of a different plasticizer increases and accelerates the effects significantly, compared with the pellet formulation without pore-forming component as shown in FIG. 5 .
  • two types of extended release pellets containing pramipexole or a pharmaceutically acceptable salt thereof are available showing different in vitro release profiles.
  • the two types have the same structure, i.e., an inert starter pellet core and a first layer or coating and second layer or functional film coating provided on the core in this order.
  • the core and first layer or coating are identical and the second layer or coating allows to tune the releasing characteristic as desired.
  • At least one water-insoluble polymer is present in the second layer, the resulting pellet having a pH-independent in vitro release characteristic.
  • the second layer comprises a mixture of a pH-dependent enteric-coating polymer and a pH-independently water swelling polymer, the resulting pellet having a close to zero order in vitro release characteristic at acidic pH values up to pH 6.8, an accelerated release above pH 6.8 and a more accelerated release above pH 7.3.
  • the additional presence of a pore-forming component has the significant effect that the release characteristic is enhanced and accelerated compared with the same formulation without a pore-forming component.
  • the thickness of the second layer and the amount of release controlling excipients applied thereon may be decreased to a great extent compared to the use of other core materials, e.g., if the core is composed of saccharose.
  • the primary indication for pramipexole, Parkinson's Disease, is an affliction that becomes more prevalent with advancing age and is often accompanied by decline in memory. Therefore, the pellets according to the present invention providing an extended or slow release of pramipexole or a salt thereof allows to simplify the patient's administration scheme by reducing the amount of recommended daily intakes and improves patient's compliance, particularly relevant for elderly patients.
  • the inventive extended release pellet formulations provide a daily dose administered at one time. The amount that constitutes a therapeutically effective amount varies according to the condition being treated, the severity of said condition, and the patient being treated.
  • cap and body white opaque hydroxypropyl methyl cellulose capsules of size 3 are used, filled with extended release pellets.
  • the complete capsules are intended to be administered orally, and shall not be opened before use.
  • the pramipexole 5 pellets in the Examples contain 0.75 mg of pramipexole dihydrochloride monohydrate, corresponding to 0.524 mg of pramipexole free, anhydrous base.
  • ER Pellets consisting of: 88.458 Pramipexole dihydrochloride 0.750 Active ingredient Company monohydrate standard Microcrystalline cellulose pellets 73.980 Non-pareille carrier Ph.Eur./NF (Cellets 700) pellet Hydroxypropyl cellulose 0.150 Wet binder Ph.Eur./NF (KLUCEL ® EF) Talc 0.495 Glidant Ph.Eur./USP Methacrylic acid copolymer, 7.500 Functional coating Ph.Eur./NF Type B (EUDRAGIT ® S 100) Ammonio methacrylate 3.750 Functional coating Ph.Eur./NF copolymer, Type B (EUDRAGIT ® S 100) Ammonio methacrylate 3.750 Functional coating Ph.Eur./NF copolymer, Type B (EUDRAGIT ® S 100) Ammonio methacrylate 3.750 Functional coating Ph.Eur./NF copolymer, Type B (EUDRAGIT ® S 100) Ammonio methacrylate 3.750
  • Formulation F One embodiment of the qualitative and quantitative composition of pramipexole extended release pellets according to the present invention (Formulation F) is shown in Table 3. TABLE 3 Qualitative and Quantitative Composition of Pramipexole ER Capsule (Formulation F) mg per mg per 0.75 mg 0.75 mg Reference to Ingredient capsule capsule Function Standards ER Pellets consisting of: 80.063 Pramipexole dihydrochloride 0.750 Active ingredient Corporate monohydrate standard Microcrystalline cellulose pellets 73.980 Non-pareille carrier Ph.Eur/NF (Cellets 700) pellet Hydroxypropyl cellulose 0.150 Wet binder Ph.Eur./NF (KLUCEL ® EF) Talc 0.495 Glidant Ph.Eur./USP Ethyl cellulose (N14) 3.750 Functional coating Ph.Eur./NF Macrogol 6000 0.938 Plasticizer Ph.Eur./USP Ethanol (96%) 49.167* Solvent Ph.Eur. Purified water 32.583*
  • the batch formula for the two pramipexole extended release pellet formulations of Example 1 and 2 (Formulations D and E) is shown in Table 6.
  • the batch size for the active ingredient layering is 1 kg
  • the batch size for the functional slow release film-coating of the active pellets is 530.748 g (Formulation D) and 549.600 g (Formulation E), corresponding to a theoretical batch size of 6000 capsules each.
  • the batch formula for the two pramipexole capsule formulations of Example 3 and 4 (Formulations F and G) is shown in Table 7.
  • the batch size for the active ingredient layering is 1 kg
  • the batch size for the functional slow release film-coating of the active pellets is 480.378 g (Formulation F) and 492.528 g (Formulation G), corresponding to a theoretical batch size of 6000 capsules each.
  • the batch formula for the pramipexole pellet formulation of Example 5 (Formulation H) is shown in Table 8.
  • the batch size for the active ingredient layering is 1 kg
  • the batch size for the functional slow release film-coating of the active pellets is 562.008 g, corresponding to a theoretical batch size of 6000 capsules each.
  • microcrystalline cellulose is mixed with I g of pramipexole. Then this mixture is mixed with 90 g of microcrystalline cellulose. The mixture is extruded in a twin screw extruder with an adequate amount of water (or binder solution), diameter of dye is 0.7 mm. The resulting extrudates are rounded in a spheronizer at 400 rpm. After drying pellets are sieved, the fraction of 0.8-1.1 mm is used for retardation as described in the previous examples. Table 9 provides some further examples of wet extrusion TABLE 9 Further Examples for Wet Extrusion Example Pramipexole Microcrystalline No.
  • Table 10 provides some further examples of melt extrusion TABLE 10 Examples for Melt Extrusion Example Pramipexole PEG 6000 Poloxamer No. [g] [g] 188 [g] 10 1 59 40 10a 0.5 59.5 40 10b 2 58 40 10c 0.5 69 30
  • microcrystalline cellulose is mixed with 1 g of pramipexole. Then this mixture is mixed with 60 g of microcrystalline cellulose and 30 g of carbomer 971P. The mixture is extruded in a twin screw extruder with an adequate amount of water (or binder solution), diameter of dye is 0.7 mm. The resulting extrudates are rounded in a spheronizer at 400 rpm. After drying, pellets are sieved, the fraction of 0.8-1.1 mm is filled into capsules.
  • Table 12 provides some further examples of wet extrusion TABLE 12 Further Examples for Extended Release Pellets Prepared by Wet Extrusion Example Microcrystalline Extended release No.
  • agglomeration of active ingredient with excipients is promoted by the addition of low melting point, lipophilic binders, such as waxes, fats, fatty acids, fatty acid alcohols, and more water soluble polymers, such as poloxamers or polyethylene glycols.
  • the binder is usually added to the other components as a powder.
  • the binder is liquefied by heat generated either by friction during the mixing phase or by a heating jacket.
  • Excipients suitable are, e.g., lactose, microcrystalline cellulose, and dibasic calcium phosphate.

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JP2008509193A (ja) 2008-03-27
EA200700388A1 (ru) 2007-08-31
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WO2006015943A3 (en) 2007-02-08
HK1107780A1 (en) 2008-04-18
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EG26209A (en) 2013-04-28
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AU2005271193A1 (en) 2006-02-16
UA95993C2 (ru) 2011-09-26
US20090130197A1 (en) 2009-05-21
US20100086589A1 (en) 2010-04-08
US8715728B2 (en) 2014-05-06
UA97084C2 (ru) 2011-12-26
EP2431026A1 (en) 2012-03-21
BRPI0513848A (pt) 2008-05-20
CA2576386A1 (en) 2006-02-16
CN101022788B (zh) 2010-11-10
MX2007001850A (es) 2007-03-28
EA201001086A1 (ru) 2011-10-31
WO2006015943A2 (en) 2006-02-16
EP2431027A1 (en) 2012-03-21
CN101022788A (zh) 2007-08-22
UA88477C2 (ru) 2009-10-26
JP4971159B2 (ja) 2012-07-11
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EP1778201A2 (en) 2007-05-02
KR20130003040A (ko) 2013-01-08
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