CA2265766C - Rapidly disintegrating pellets - Google Patents

Rapidly disintegrating pellets Download PDF

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Publication number
CA2265766C
CA2265766C CA002265766A CA2265766A CA2265766C CA 2265766 C CA2265766 C CA 2265766C CA 002265766 A CA002265766 A CA 002265766A CA 2265766 A CA2265766 A CA 2265766A CA 2265766 C CA2265766 C CA 2265766C
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Prior art keywords
pharmaceutical composition
pellets
weight
agent
active substance
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CA002265766A
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French (fr)
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CA2265766A1 (en
Inventor
Michaela Opitz
Hendrick Von Buren
Rolf-Dieter Gabel
Geoffrey Lee
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Roche Diagnostics GmbH
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Roche Diagnostics GmbH
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/20—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by expressing the material, e.g. through sieves and fragmenting the extruded length
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Abstract

The invention concerns pharmaceutical forms of administration that are in the form of pellets which contain a retarding agent in which the release rate of the active substance is not delayed or is substantially identical compared to corresponding pellets that contain no retarding agent. The release rate of these rapidly disintegrating pellets is at least about 90 % within a time period of 30 minutes. In addition the present invention also concerns processes for the production these pellets.

Description

CA 02265766 l999-03- 10Rapidly disintegrating pelletsThe invention concerns pharmaceutical forms ofadministration that are in the form of pellets whichcontain at least one rounding agent required to produceextrusion pellets which acts as a retardant ordisintegration-retarding agent which is suitable fordelaying the release time of active substances, whereinthe release of the active substance from the pellet(pellet A) is not less than that of a correspondingreference core pellet (pellet B) which does not containthis rounding agent as a pharmaceutical auxiliarysubstance. The release rate of these rapidlydisintegrating pellets is at least about 90 % within atime period of 30 minutes. In addition the presentinvention also concerns processes for the productionthese pellets.Pellets are usually used for modified release drugforms. They have considerable advantages compared toconventional pharmaceuticals with a modified release ofthe active substance such as e.g. the avoidance of dose-dumping and local intolerances, minimized intra- andinterindividual variations, independent of stomachemptying times, mixing of various retarded pellets,mixing of pellets with different (optionallyincompatible) active substances and improvement ofbioavailability.The following principles are often used to producepellets with a modified release of the active substance:CA 02265766 l999-03- 10a) modification of the active substance release with theaid of coatings or b) matrix systems.Coatings that are resistant to gastric juice are stablein the acidic environment of the stomach and slowlydissolve by salt formation in a weakly acidic or basicrange. Since, however, pellets are substantiallyindependent of the stomach emptying rhythms, gastricjuice-resistant coatings only lead to a short-term delayof the release of active substance.Coatings are also used which are insoluble in thegastro—intestinal tract and release the dissolved activesubstance by means of diffusion through the coat. Inthis case the release rate can for example be set bymeans of the diffusion coefficients, the film thickness,the concentration gradient, the osmotic pressure and theuse of pore formers. However, in the case of poorlysoluble active substances the amount of liquid diffusingthrough the coat into the core is not sufficient todissolve the active substance so that only a part of thetotal dose is released.In order to circumvent these disadvantages time-controlled systems have been developed in recent yearsin which the envelope bursts after a certain delay time.The release profile can be adjusted by mixing pelletcollectives with various coatings. These systems aredistinguished by being independent of intraindividualand interindividual variations, they release thecomplete dose of active substance and are suitable forreadily soluble as well as for poorly solublepharmaceutical substances.CA 02265766 l999-03- 10Milosovich (US 3,247,066) developed a drug form withcontrolled release of the active substance based onsmall pellets which contain a colloid that swells inwater and are coated with an indigestible envelope.Digestive fluid passes into the core containingdisintegrant by means of diffusion which then swells andbursts the core.A further variant of this multilayered so-called timecontrolled explosion system (abbreviated: TCES) (cf. EP0 210 540 B1) in which a layer directly under theenvelope which contains disintegrant causes the coatingto burst.Bayer AG (patent DD 297 767) developed a pelletformulation with a time controlled release that wasproduced by rotor granulation. With the aid of arelease-controlling double layer composed of an externalindigestible lacquer layer and an inner coat whichcontrols the migration of the water towards the core,moisture reaches the core containing disintegrant whichthen bursts the envelope.However, the formulations produced in US 3,247,066, inEP 0 210 540 B1 and DD 297 767 were not produced bymeans of extrusion and rounding so that it was notpossible to obtain pellets with a narrow particle-sizedistribution.Double-coated granulates are known from EP 0 421 921 B1which are obtained by extrusion of the wet granulatemass and which are moulded into spherical pellets with adiameter of 0.3 to 1.5 mm. However, these are pelletswhich achieve a time controlled release by a gastricCA 02265766 l999-03- 10juice-resistant but intestinal juice-soluble film andnot by a burst mechanism.Although an advantage of extrusion processes over rotorgranulation is that a narrow distribution of particlesizes can be achieved, a fundamental disadvantage ofextrusion pellets is that it is not possible to dispensewith certain pharmaceutical additives such asmicrocrystalline cellulose for their production sincethey give the extrudate the required plastic-rigidproperties required for rounding. In this case suchadditives in most cases also act as retarding agentsi.e. they lead to a delayed (retarded) release of theactive substance. This retardation which is often aninevitable consequence is not desirable in all cases.Retarding agents (in particular microcrystallinecellulose), can form a matrix system which prevents thedisintegration of the pellets so that overall pelletswith retarding properties with regard to the release ofthe active substance are obtained. Furthermore theadditives used as rounding agents also acts asdisintegration retarding agents i.e. they prevent therapid decay of the pellets into smaller particles.Especially in the case of poorly soluble medicinalsubstances these effects cause a considerable delay inthe release of the active substance and a retardation ofthe drug release. Hence active substances that have astrongly pH-dependent solubility profile and which arepoorly soluble especially in the basic intestinal juiceare characterized by the formation of a dense matrixsystem with microcrystalline cellulose. In such casesthe release profile cannot be varied as desired by meansof the composition and the thickness of the coatingsince the leaching of the drug from the matrix and therate of disintegration of the pellets play an importantCA 02265766 l999-03- 10role in the release properties.Therefore the object of the invention was to providesuch pellets that rapidly disintegrate and release theactive substance in as short a time as possible from thecore pellets although the pellets contain rounding aidswhich among others act as retarding agents and/or asdisintegrating retarding agent.It was surprisingly found that pellet cores whichcontain a) a rounding agent acting as a retarding agentor as a disintegration-retarding agent b) a tabletdisintegrant (also referred to as intensive disintegrantin the following) and c) at least one auxiliarysubstance selected from the group comprising surfactantsand binding agents and d) optionally fillers orcombinations of these auxiliary substances, disintegratewell. Furthermore the corresponding active substancesare rapidly released from the core pellets andessentially without delay compared to a pellet whichdoes not have this rounding agent or retarding agent.This applies particularly to poorly soluble activesubstances. In particular the core pellets contain anintensive disintegrant, a surfactant and a binding agentin addition to the rounding agent. It is also possibleto use a binding agent e.g. polyvinylpyrrolidone (PVP)instead of the surfactant. In a preferred variant a PVPis additionally added to the pellet core in addition tothe surfactant.A further advantage of the pellets according to theinvention is that they have a narrow particle sizedistribution: At least 90 % of the particles have adiameter of about 0.6 - 1.2 mm. Moreover the pelletsCA 02265766 l999-03- 10also disintegrate relatively rapidly when they containactive substances which have a strong pH-dependentsolubility profile. The pellets usually have a diameterbetween 0.5 - 2 mm, depending on the perforated diskused for the extrusion.The rapidly disintegrating pellets according to theinvention (also referred to as core pellet A in thefollowing) have a release rate of the active substancewhich is not delayed despite the presence of therounding agent that acts as a retarding agent ordisintegration-retarding agent. The release of theactive substance is essentially not retarded. Therelease is relatively rapid and, in particular, it iscomparable with the pellet which can be produced by analternative process to the extrusion process and whichdoes not contain this retarding agent or disintegration-retarding agent (also referred to as core pellet B inthe following or reference pellet). The core pelletsaccording to the invention do not have a delayed releaseof the active substance. The release rate of such corepellets is preferably at least 90 % after 30 minutes.The pellets according to the invention (core pellets A)contain the common pharmaceutical disintegrantspreferably in an amount of 5 - 50 % and surfactants inan amount of 0.1 - 20 %. Binding agents can beadvantageously added in an amount of 1 — 10 %. Micro-crystalline cellulose (e.g. Avicel®) as a rounding aidis in particular present in an amount of 5 - 70 %. Thepercentages refer to the weight percentages of thepellet cores if not stated otherwise.Rounding agents that are suitable for the production ofCA 02265766 l999-03- 10extrusion pellets are all common auxiliary substancesknown in the literature which enable a rounding of thepharmaceutical mass obtained by extrusion primarily in arod shape. Microcrystalline cellulose and derivativesthereof such as e.g. Avicel®, Avice1® PH 101, AvicelcPH 105 or Avicel® PH 200 are for example suitable.Provided these rounding aids delay the release of theactive substance compared to other pellets which do notcontain this auxiliary substance or provided theserounding aids delay the disintegration of the pelletsinto smaller particles (disintegration-retardingagents), they are suitable within the sense of thepresent invention as so-called retarding agents for theproduction of the core pellets according to theinvention.All common pharmaceutical binding agents come intoconsideration as binding agents e.g. gelatin, micro-crystalline cellulose, L-HPC, starch, standard hydroxy-propylmethyl cellulose derivatives and polyvinyl-pyrrolidone (PVP) derivatives. However, polyvinyl-pyrrolidone (PVP) derivatives are particularly preferredas binding agents since these do not impair but ratherfavour the disintegration of the pellets despite havingexcellent binding properties so that according to theinvention it is even possible to omit the surfactant ifPVP is used in combination with an intensivedisintegrant.All standard pharmaceutical auxiliary substances can beused as tablet disintegrants (disintegration aids) orintensive disintegrants for pharmaceutical purposeswhich have strong swelling properties in aqueous mediaand which are distinguished by volume enlargementthrough the uptake of water. The term tabletCA 02265766 l999-03- 10disintegrant relates to those pharmaceutical auxiliarysubstances which enable rapid disintegration of tabletsin water or in gastric juice and that enable the releaseof drugs in absorbable form. Depending on the mechanismof action these are substances that increase theporosity of solid forms of administration and have alarge absorption ability for water (starch, cellulosederivatives, alginates, dextrans, cross-linkedpolyvinylpyrrolidone and others), as well as wettingagents that allow wetting of the solid forms ofadministration (such as e.g. polyethylene glycolsorbitan fatty acid ester). Sodium carboxymethylcellulose, modified corn starch (e.g. Starch®1500) andsodium carboxymethyl starch (Explotab® or Primojel®)are preferably used. Primojel® is particularlypreferred.Standard pharmaceutical surface active substances areused as surfactants such as ionic and non-ionicsurfactants, such as benzalkonium chloride, polyoxy—ethylene-polyoxypropylene copolymers (e.g. Pluronic®F68), polyethylene glycol glycerol ester, alkylsulfates, preferably sodium dodecylsulfate (Texapon®)and stearic acid or alkali or alkaline earth saltsthereof (Mg or Na salts) or stearates such as e.g. PEG-400—stearate (Mirj®).Optionally one or several standard pharmaceuticalfillers are also added. The amount of filler can be upto 80 %. Fillers that are used according to theinvention are carbohydrates such as sugars preferablyglucose, lactose and sucrose, sugar alcohols such asmannitol and sorbitol, starch, starch derivatives anddibasic calcium phosphate. However, all known fillersare in principle suitable.CA 02265766 l999-03- 10Particularly preferred formulations according to theinvention comprise 15 - 25 % microcrystalline cellulose,15 ~ 25 % disintegrant, 2 - 10 % surfactant and/or 3 -7 % polyvinylpyrrolidone (all data in % by weight) aswell as optionally further binders or fillers.Active substances within the sense of the invention arebasically all drugs that come into consideration for thetherapeutic treatment of humans. Those active substancesare preferred that are poorly soluble. Poorly solubleactive substances within the sense of the presentinvention are those that are referred to in generalpharmacopeias (e.g. USP XXII) as not easily solubleactive substances. Such active substances have forexample a solubility of less than 0.1 mg/ml, inparticular of less than 0.05 mg/ml or less than 0.01mg/ml in an aqueous medium or whose solubilityproperties are strongly pH dependent. Active substancesare for example (+/-)-1—(9H-carbazol-4-yloxy)-3-[(2-(2-methoxyphenoxy)—ethyl)—amino]-2-propanol (INN:Carvedilol), 2-{4—[2-[(4—chloro-benzoyl)-amino]ethyl]-phenoxy}—2—methylpropionic acid (INN: Bezafibrat), INN:Glibenclamid or 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulfonyl]—urea (INN: Torasemid). These activesubstances are poorly soluble. In particular Carvedilolhas a strongly pH-dependent solubility profile and isparticularly poorly soluble in the intestinal juice.However, these substances and in particular Carvedilolare released very well from the pellets according to theinvention.In order to check the disintegration of pellets it ispossible to use generally known methods and instrumentsthat are described in standardized form inpharmacopeias. A standardized paddle apparatus (37°C,CA 02265766 l999-03- 10-10-90 rpm) can therefore be used to measure thedisintegration time. The disintegration time is stoppedas soon as 90 % of the pellets have disintegrated intosmaller agglomerates. The release rate of the activesubstance (data in % in relation to a certain unit oftime) is also determined according to generallystandardized methods (cf. European pharmacopoiea or USPharmacopoiea).Surprisingly the pellets according to the invention havea disintegration rate of at least 90 % after 30 minutesand already after 20, 10 or 5 or 2 minutes in the caseof particularly preferred embodiments. At least 90 % ofthe active substance has been released after 30 minutes.After 10 minutes the active substance has been releasedfrom the core pellets by at least 50 %, preferably atleast 70 % and especially by at least 90 %. Surprisinglyit was also possible to achieve these release rates withpoorly soluble active substances. The release isdetermined in an aqueous medium, the pH of the solutionbeing adjusted to a value at which the active substancehas an optimal solubility.Thus Texapon® and Carvedilol pellets containingdisintegrant have already disintegrated even after 2minutes and already exhibit ca. 70 % release of activesubstance after 5 minutes. The disintegration isadvantageously further accelerated by the use ofPluronic® F 68 so that already after 5 minutes morethan 90 % of the Carvedilol has been released. Thesepellet cores according to the invention which have notbeen coated are thus suitable as alternatives to a non-retarded monolithic pharmaceutical form.CA 02265766 l999-03- 10-11-.Pellets according to the invention particularlyadvantageously contain a combination of a tabletdisintegrant together with either a surfactant and/or abinding agent. It is particularly preferred to combine adisintegrant with a surfactant or to combine adisintegrant with a binding agent. The addition of acombination of a disintegrant with one of the auxiliarysubstances mentioned (surfactant and/or binding agent)leads to a better release rate than the addition ofdisintegrant alone (cf. Tables 1 and 2).The pellets according to the invention are produced bymixing the active substances with the pharmaceuticalauxiliary substances 1, and subsequently granulating,extruding and rounding. The extrusion/rounding processaccording to the invention enables in contrast to rotorgranulation the pellets to be produced with a verynarrow particle size distribution. If a perforated diskis used with a hole diameter of 1 mm, about 90 % of thepellets have a diameter of about 0.6 - 1.2 mm.For the production of the pellets according to theinvention a neutral starter core is not necessary it ispossible to incorporate much larger doses of activesubstance. According to the invention amounts of activesubstance of up to at least 80 % (% by weight) arefeasible. The amount of active substance is preferablyfor example at least 30 %, 50 % or 70 %. Carvedilolpellets can be produced without any difficulty withinthe sense of the present invention with a content ofactive substance of 70 % and these decay in less than 10minutes, in particular less than 5 minutes or less than2 minutes.CA 02265766 l999-03- 10-12-In a special embodiment the core pellets according tothe invention can also be coated with coatings e.g. tomodify the release of active substance or to cover anunpleasant taste. In the sense of the present inventionthe rapidly disintegrating core pellets can also beprovided with a coating in order to develop time-controlled systems by coating the rapidly disintegratingswelling pellets according to the invention in which thecoating bursts after a certain delay time. The coreformulations according to the invention are particularlywell suited as a base for the development of a drug formwith a modified release of active substance in which atime-controlled release of the active substance isachieved by the bursting of a film since the swellingpressure that develops in the pellet core after uptakeof moisture is sufficient to tear open an indigestiblecoating. Especially in the case of poorly water-solublepharmaceutical substances such burst systems offer theadvantage over diffusion pellets that the dose of activesubstance is released relatively rapidly and completelyfrom the drug form. The delay time can be varied between10 minutes and 5 hours by the composition and the filmcoating thickness of the film as well as by theformulation of the rapidly disintegrating core.It is known that a thick film layer alone can delay thestart of release for a long time, this however, resultsin a slower release of active substance after thecoating bursts. Larger amounts of coating additionallyrequire more time to apply the coating which isuneconomical. Surprisingly the film coating thickness ofthe pellets according to the invention can be keptrelatively low by selection of suitable film additives.The rapidly disintegrating pellets can additionally beCA 02265766 l999-03- 10-13-coated with readily soluble films (e.g. hydroxypropylmethylcellulose) or with films which dissolve pH-dependently in the gastrointestinal tract (gastricjuice-resistant coatings). The pellets can also becoated with layers of various film formers or variousformulations of the same film former. Coated pelletswhich release the active substance after various delaytimes as well as rapidly disintegrating non—coatedpellets can be mixed in order to achieve diverse releaseprofiles (e.g. pulsed release, release according to a 0order kinetics or nth order kinetics, sigmoidalrelease). The rapidly disintegrating pellets can becoated by common pharmaceutical methods e.g. in afluidized bed or coating pan.Calculated from the time that the release begins, thecoated rapidly disintegrating pellets according to theinvention have a release of at least 50 % after 180minutes. The amount of coating applied can be variedsuch that the proportion by weight of the film former isbetween 1 and 70 % relative to the pellet core weight.Preferred coating materials for the production of coatedpellets whose film is burst by the swelling of the pelletcore are preferably ethyl cellulose e.g. Aquacoat® andmethacrylic ester copolymers e.g. EudragiH® RL/ Rs.Materials that can be used for readily soluble films aree.g. cellulose derivatives (such as e.g. hydroxypropyl-methyl cellulose) or amino-alkylmethacrylate copolymers(e.g. Eudragit® E). Dicarboxylic acid derivatives ofcellulose compounds (e.g. hydroxypropylmethyl cellulosephthalate, hydroxypropylmethyl cellulose succinate) aswell as methacrylic acid copolymers (e.g. Eudragit® L,Eudragit® S) are suitable as film formers for pH-dependent soluble coatings.CA 02265766 l999-03- 10-14-The following film additives can be used: Softeningagents in an amount of 0.1 - 50 %, detackifiers (0.1 -70 %) as well as, especially in the case of films thatare burst by the swelling of the pellet core, substanceswhich can accelerate or delay the diffusion of therelease liquid into the core and can consequently modifythe delay time until the release of active substancestarts (0.1 — 50 %). Furthermore it is possible to addpore formers, aroma substances, dyes, pigments as wellas fillers.All common pharmaceutical softening agents can be usedas softening agents. Acetylated fatty acid glycerides,acetyl—triethyl citrate, acetyl-tributyl citrate,dibutyl phthalate, diethyl phthalate, dimethylphthalate, glycerol triacetate, propylene glycol,polyethylene glycol, polyoxyethylene-polyoxypropylenecopolymers, castor oil and tributyl citrate arepreferred. Triethyl citrate is particularly preferred.All common pharmaceutical detackifiers can be used asdetackifiers. Talcum, Aerosil®, kaolin and micronizedsilicic acid are preferred. Glycerol esters and ethersof higher fatty acids e.g. glycerol monostearate,polyethylene glycol-32-glyceryl laurate are particularlypreferred.Additives that come into consideration that can controlthe diffusion of water into the pellet core arehydrophobizing additives (e.g. waxes, talcum, fattyacids and fatty acid esters) as well as substances thataccelerate diffusion (e.g. surfactants, fatty acidesters and fatty acid ethers). Montanglycol wax,glycerol monostearate, stearic acid and stearic acidCA 02265766 2005-02-03-15..derivatives and polyethylene glycol-glyceryl esters,glycerylbehenate, glycerylpalmito—stearate, cetylpalmitate are particularly preferred.The coated and/or non—coated pellets according to theinvention can be pressed according to known processesinto tablets also together with standard pharmaceuticalauxiliary substances or be filled into capsules orsachets or embedded in matrices. The formulations areequally suitable for readily and poorly water-solubleactive substances. The capsules contain the activesubstance in an amount of up to 350 mg, in particular 1- 200 mg, preferably 10 - 100 mg. Pellet tablets cancontain the active substance in an amount of up to 1000mg, preferably 1 - 500 mg and in particular 10 - 250 mg.Finally it is intended to elucidate the invention inmore detail by the application examples.Application examples:Example 1:1250 g Carvedilol, 1682.5 g lactose, 1150 gmicrocrystalline cellulose, 172.5 g sodium dodecylsulfate, 345 g Povidor?K 25 and 1150 g Primojel‘ arehomogenized in an intensive mixer. The powder mixture isgranulated in ca. 3500 ml distilled water. Subsequentlythe wet mass is extruded in a (twin-screw) extruder atroom temperature. The extrudate is then formed intopellets in a rounder. After drying on a fluidized bed,the pellets are screened (mesh size 0.6 - 1.25 mm).* trade-markCA 02265766 l999-03- 10-16-Example 2:Pellets of the following formulation are producedanalogously to example 1:Parts by weightCarvedilol 21.75hydroxypropylmethylcellulose 2910 3.00lactose 29.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Povidon K 25 3.00Primojel 20.00distilled water 66.70Example 3:Pellets of the following formulation are producedanalogously to example 1:Parts by weightCarvedilol 21.75hydroxypropylmethylcellulose 2910 3.00lactose 37.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Primojel 15.00distilled water53.85CA 02265766 l999-03- 10-17-Example 4:Pellets of the following formulation are producedanalogously to example 1:Parts by weightCarvedilol 21.75lactose 39.25microcrystalline cellulose 10.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 20.00distilled water 45.00Example 5:Pellets of the following formulation are producedanalogously to example 1:Parts by weightCarvedilol 21.75lactose 9.25microcrystalline cellulose 40.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 20.00distilled water81.80CA 02265766 l999-03- 10-18..Example 6:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75lactose 49.25microcrystalline cellulose 10.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 10.00distilled water 43.00Example 7:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75lactose 19.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 30.00distilled water66.70CA 02265766 l999-03- 10-19-Example 8:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75lactose 29.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Povidon K 25 6.00starch 1500 20.00distilled water 33.30Example 9:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 43.50lactose 7.5microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 20.00distilled water58.70CA 02265766 l999-03- 10-20-Example 10:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75hydroxypropylmethylcellulose 2910 3.00lactose 22.25microcrystalline cellulose 20.00sodium dodecylsulfate 5.00Primojel 20.00distilled water 69.50Example 11:weight percentageCarvedilol 21.75lactose 31.75microcrystalline cellulose 20.00Pluronic F 68 0.50Povidon K 25 6.00Primojel 20.00distilled water 43.00Carvedilol, lactose, microcrystalline cellulose,Primojel and Povidon K 25 are mixed. Pluronic F 68 isdissolved in distilled water. The powder mixture isgranulated with this solution. Subsequently it isextruded, rounded, dried and screened analogously toexample 1.CA 02265766 l999-03- 10_ 21 _Example 12:weight percentageCarvedilol 21.75lactose 31.25microcrystalline cellulose 20.00Pluronic F 68 1.00Povidon K 25 6.00Primojel 20.00distilled water 43.00Carvedilol, lactose, microcrystalline cellulose,Primojel and Povidon K 25 are mixed. Pluronic F 68 isdissolved in distilled water. The powder mixture isgranulated with this solution. Subsequently it isextruded, rounded, dried and screened analogously toexample 1.Example 13:weight percentageCarvedilol 21.75lactose 30.25microcrystalline cellulose 20.00Pluronic F 68 2.00Povidon K 25 6.00Primojel 20.00distilled water 43.00Carvedilol, lactose, microcrystalline cellulose,Primojel and Povidon K 25 are mixed. Pluronic F 68 isdissolved in distilled water. The powder mixture isgranulated with this solution. Subsequently it isextruded, rounded, dried and screened analogously toexample 1.CA 02265766 l999-03- 10-22..Example 14:weight percentageCarvedilol 21.75lactose 29.25microcrystalline cellulose 20.00Pluronic F 68 3.00Povidon K 25 6.00Primojel 20.00distilled water 64.00Carvedilol, lactose, microcrystalline cellulose,Primojel and Povidon K 25 are mixed. Pluronic F 68 isdissolved in distilled water. The powder mixture isgranulated with this solution. Subsequently it isextruded, rounded, dried and screened analogously toexample 1.Example 15:weight percentageCarvedilol 21.75lactose 27.25microcrystalline cellulose 20.00Pluronic F 68 5.00Povidon K 25 6.00Primojel 20.00distilled water 33.00Carvedilol, lactose, microcrystalline cellulose,Primojel and Povidon 25 are mixed.Pluronic® F 68 isdissolved in distilled water. The powder mixture isgranulated with this solution. Subsequently it isextruded, rounded, dried and screened analogously toexample 1.CA 02265766 l999-03- 10.. .-Example 16:weight percentageCarvedilol 21.75lactose 29.25microcrystalline cellulose 20.00Mirj 3.00Povidon K 25 6.00Primojel 20.00distilled water 61.00Carvedilol, lactose, microcrystalline cellulose,Primojel and Povidon K 25 are mixed. Mirj is dissolvedin distilled water. The powder mixture is granulatedwith this mixture. Subsequently it is extruded, rounded,dried and screened analogously to example 1.Example 17:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75lactose 24.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00polyethylene glycol—32-glyceryl 3.00lauratePovidon K 25 6.00Primojel 20.00distilled water 43.00Carvedilol, lactose, microcrystalline cellulose, sodiumCA 02265766 l999-03- 10-24.-dodecylsulfate, Povidon K 25 and Primojel are mixed.Polyethylene glycol—32-glyceryl laurate is dissolved indistilled water. The powder mixture is granulated withthis mixture. Subsequently it is extruded, rounded,dried and screened analogously to example 1.Example 18:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75glucose 29.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 20.00distilled water 42.85Example 19:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75hydroxypropylmethylcellulose 2910 3.00microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Primojel 15.00sucrose 37.25distilled water42.85CA 02265766 l999-03- 10-25-Example 20:Pellets of the following formulation are producedanalogously to example 1:weight percentagelactose 71.00microcrystalline cellulose 10.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 10.00distilled water 20.50Example 21:Pellets of the following formulation are producedanalogously to example 1:weight percentageGlibenclamid 21.75lactose 29.25microcrystalline cellulose 20.00sodium dodecylsulfate 3.00Povidon K 25 6.00Primojel 20.00distilled water25.00CA 02265766 l999-03- 10-26-Example 22:Pellets of the following formulation are producedanalogously to example 1:weight percentageCarvedilol 21.75lactose 32.25microcrystalline cellulose 20.00Povidon K 25 6.00Primojel 20.00distilled water 72.40Example 23:only one disintegrant (no surfactant) was used as areference but which alone did not enable the pellets todisintegrate. Pellets of the following formulation areproduced analogously to example 1:weight percentageCarvedilol 21.75hydroxypropylmethylcellulose 2910 3.00lactose 40.25microcrystalline cellulose 20.00Primojel 15.00distilled water 53.85CA02265766 1999-03-10-27.Table 1Example Appearance Disintegration Release[min] > 90 % [min]1 ++ <5 10-152 ++ <5 15-203 ++ <5 204 ++ <5 125 ++ <5 206 + <3 n.d.7 - 10 30-408 ++ <5 n.d.9 ++ <3 2510 ++ 3 2511 ++ 2 n.d.12 ++ <2 n.d.13 ++ <2 n.d.14 ++ <2 515 ++ <2 n.d.16 ++ <3 1017 ++ <3 5-1018 0 <5 n.d.19 ++ <10 3020 + <5 n.d.21 + <5 n.d.22 ++ 4 2023 ++ no disintegration 120Legend for table 1:+ round oval++round0 oval — oval-rod-likerodsn.d.not determinedCA 02265766 l999-03- 10-28..Example 24:With the following composition of the formulation thepellets disintegrated within less than 3 minutes:Components of the formulation weight disintegrationpercentageCarvedilol 70% < 3 minuteslactose D200 1%microcrystalline cellulose 10%PVP K 25 6%sodium carboxymethyl starch 10%sodium dodecylsulfate 3%water 39%Example 25:with the following composition of the formulation inwhich the content of Carvedilol is below 25 % nodisintegration of the pellets is observed.Carvedilol 21.75% no disintegrationlactose D200 49.25%microcrystalline cellulose 20%PVP K 25 6%sodium dodecylsulfate 3%water 22%CA 02265766 l999-03- 10-29-.Example 26:The following formulation is prepared analogously toexample 24 in which the amount of sodium dodecylsulfateis omitted and the amount of lactose is increasedaccordingly. No disintegration of the pellets isobserved.Carvedilol 21.75% no disintegrationlactose 52.25%microcrystalline cellulose 20%PVP K 25 6%water 22%Example 27:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weight [%]ethylcellulose (Aquacoat®) 15 %triethyl citrate 3 %glycerol monostearate 0.75 %distilled water q.s.CA 02265766 l999-03- 10-30-Example 28:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %glycerol monostearate 1 %distilled water q.s.Example 29:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 25 %triethyl citrate 5 %glycerol monostearate 1.25 %distilled water q.s.CA 02265766 l999-03- 10-31-Example 30:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %stearic acid 2 %distilled water q.s.Example 31:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %PEG—32-glyceryl laurate 2 %distilled water q.s.CA 02265766 l999-03- 10-32-Example 32:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %montanglycol wax 3 %distilled water q.s.Example 33:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %talcum 10 %distilled water q.s.CA 02265766 l999-03- 10-33..Example 34:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %montanglycol wax 3 %distilled water q.s.Example 35:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weightPEG—32-glyceryl laurate 2.5 %distilled water q.s.Subsequently a film with the following composition isapplied:Components of the formulation weight percentagerelative to the pelletcore weightethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %montanglycol wax 3 %distilled water q.s.CA 02265766 l999-03- 10-34-Example 36:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weight [%]ethylcellulose (Aquacoat®) 20 %triethyl citrate 4 %montanglycol wax 3 %PEG-32-glyceryl laurate 2 %distilled water q.s.Example 37:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weight [%]Eudragit RS 20 %triethyl citrate 4 %glycerol monostearate 0.75 %distilled water q.s.CA 02265766 l999-03- 10-35-Example 38:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to thepellet core weighthydroxypropylmethyl cellulose 2910 5 %glycerol monostearate 0.5 %Macrogol 6000 1 %distilled water q.s.Example 39:Rapidly disintegrating pellets according to example 1are coated in the fluid bed (Hfittlin ball coater) with afilm of the following composition:Components of the formulation weight percentagerelative to the pelletcore weight [%]Eudragit L 30 D 10 %triethyl citrate 0.5 %glycerol monostearate 0.05 %Polysorbat 80 0.01 %distilled water q.s.CA 02265766 l999-03- 10-36-Table 2:Example delay time [min] release> 50 % [min](calculated from the time ofactive substance release27 40 5028 120 12029 180 15030 180 12031 60 4032 180 10033 100 8034 50 3035 15 536 90 4537 40 12038 5 1039 > 120 min in 10 min in artificialartificialgastric juiceintestinal juice

Claims (42)

CLAIMS:
1. A pharmaceutical composition comprising pellets containing:
(a) an active substance;
(b) 5 - 70 % by weight rounding agent which acts as an active-substance release retardant or a particle-disintegration retardant;
(c) 5 - 50 % by weight tablet disintegrant; and (d) at least one of:
(1) 0.1 - 20 % by weight surfactant, and (2) 1 - 10 % by weight binding agent.
2. A pharmaceutical composition as claimed in claim 1, wherein the rounding agent contained is microcrystalline cellulose.
3. A pharmaceutical composition as claimed in claim 1 or 2, wherein the pellets contain a surfactant.
4. A pharmaceutical composition as claimed in any one of claims 1 to 3, wherein the release rate of the active substance from the pellets is at least 90%
after 30 minutes.
5. A pharmaceutical composition as claimed in any one of claims 1 to 4, comprising microcrystalline cellulose, one or several disintegrants, one or several surfactants and/or one or several binding agents.
6. A pharmaceutical composition as claimed in any one of claims 1 to 5, wherein the at least one active substance is carvedilol, bezafibrat, glibenclamid or torasemid.
7. A pharmaceutical composition as claimed in any one of claims 1 to 6, wherein the proportion of active substance is up to 80 % by weight.
8. A pharmaceutical composition as claimed in any one of claims 1 to 7, wherein the disintegration time of the pellets is no more than 30 minutes.
9. A pharmaceutical composition as claimed in any one of claims 1 to 8, wherein the pellets are coated with a film that retards the release of the active substance.
10. A pharmaceutical composition as claimed in claim 9, wherein the release of the active substance starts after 10 minutes to 5 hours.
11. A pharmaceutical composition as claimed in any one of claims 1 - 10, wherein the disintegrant is sodium carboxymethylcellulose, modified corn starch or sodium carboxymethyl starch.
12. A pharmaceutical composition as claimed in any one of claims 1 - 11, wherein the binding agent is a polyvinylpyrrolidone derivative.
13. A pharmaceutical composition as claimed in any one of claims 1 - 12, wherein the surfactant is benzalkonium chloride, a polyoxyethylene-polyoxy-propylene copolymer, a polyethylene glycol glyceryl ester, sodium dodecylsulfate or PEG-400 stearate.
14. A pharmaceutical composition as claimed in any one of claims 1 - 13, wherein the filler is a carbohydrate or dibasic calcium phosphate.
15. A pharmaceutical composition as claimed in claim 14, wherein the filler is a carbohydrate selected from sugars, sugar alcohols, starch and starch derivatives.
16. A pharmaceutical composition as claimed in any one of claims 1 - 13, wherein the filler is a carbohydrate selected from glucose, lactose, sucrose, mannitol and sorbitol.
17. A pharmaceutical composition as claimed in any one of claims 1 - 16, wherein said rounding agent is microcrystalline cellulose.
18. A pharmaceutical composition as claimed in claim 17, wherein said microcrystalline cellulose is in an amount of 15 - 25 % by weight.
19. A pharmaceutical composition as claimed in any one of claims 1 - 18 containing 5 - 50 % by weight disintegrant.
20. A pharmaceutical composition as claimed in any one of claims 1 - 18 containing 15 - 25 % by weight disintegrant.
21. A pharmaceutical composition as claimed in any one of claims 1 - 20 containing 0.1 - 20 % by weight surfactant.
22. A pharmaceutical composition as claimed in any one of claims 1 - 20 containing 2 - 10 % by weight surfactant.
23. A pharmaceutical composition as claimed in any one of claims 1 - 22 containing 1 - 10 % by weight binding agent.
24. A pharmaceutical composition as claimed in any one of claims 1 - 22 containing 3 - 7 % by weight binding agent.
25. A pharmaceutical composition as claimed in claim 12, wherein it contains no surfactant.
26. A pharmaceutical composition as claimed in any one of claims 1 to 5, further comprising one or several fillers.
27. A pharmaceutical composition as claimed in any one of claims 1 to 5 or 26, further comprising one or several film formers.
28. A pharmaceutical composition as claimed in any one of claims 1 to 27, wherein the pellets have a diameter of 0.5 to 2 mm.
29. A process for the production of a pharmaceutical composition as claimed in any one of claims 1 - 28, wherein the at least one active substance is mixed with the rounding agent, tablet disintegrant and at least one auxiliary substance, subsequently granulated, extruded and rounded to form pellets.
30. A process according to claim 29, wherein said pellets are made available as tablets, capsules or sachets.
31. A process according to claim 29, including coating said pellets.
32. A process according to claim 29, wherein said pellets are made available as tablets, and including coating said tablets.
33. A process as claimed in claim 29, 30, 31 or 32, wherein the pellets contain ethyl cellulose and methacrylic ester copolymers as coating materials for coated pellets.
34. A process as claimed in claim 29, 30, 31 or 32, wherein the pellets contain cellulose derivatives or aminoalkyl-methacrylate copolymers as coating materials for readily soluble films.
35. A process as claimed in any one of claims 22 to 34, wherein the pellets contain dicarboxylic acid derivatives or cellulose compounds and methacrylic acid copolymers as coating materials for pH-dependent soluble coatings.
36. A process as claimed in any one of claims 33 to 35, wherein the coating materials contain 0.1 - 50 % softening agents, 0.1 - 70 % detackifiers and 0.1 -50 % additives as film additives to control the diffusion of water into the pellet core.
37. A process as claimed in any one of claims 29 to 36, wherein the pellets contain acetylated fatty acid glycerides, acetyl-triethyl citrate, acetyl-tributyl citrate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerol triacetate, propylene glycol, polyethylene glycol, polyoxy-ethylene-polyoxypropylene copolymers, castor oil, triethyl citrate or tributyl citrate as softening agent.
38. A process as claimed in any one of claims 29 to 37, wherein the pellets contain triethyl citrate as softening agent.
39. A process as claimed in any one of claims 29 to 38, wherein the pellets contain talcum, aerosil, micronized silicic acid or kaolin as detackifier.
40. A process as claimed in any one of claims 29 to 39, wherein the pellets contain montanglycol wax, glycerol monostearate, stearic acid or stearic acid derivatives and polyethylene glyceryl esters, glyceryl behenate, glyceryl palmitostearate or cetyl palmitate as additives that control the diffusion of water into the pellet core.
41. A pharmaceutical composition in the form of core pellets containing:

an active substance and 5 - 70 % by weight of rounding agent in which the inherent retarding effect of the rounding agent is abolished, obtained by extruding a pharmaceutical mixture containing said rounding agent, a tablet disintegrant in an amount of 5 to 50 % by weight, and at least one of:
(1) 0.1-20 % by weight surfactant, and (2) 1-10 % by weight binding agent.
42. Use of at least one tablet disintegrant in combination with at least one auxiliary substance selected from the group consisting of surfactants and binding agents to produce a pharmaceutical composition as claimed in any one of claims 1 - 24, 26, 27 or 41.
CA002265766A 1996-09-12 1997-09-09 Rapidly disintegrating pellets Expired - Lifetime CA2265766C (en)

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US6224909B1 (en) 2001-05-01
US6379706B2 (en) 2002-04-30
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DK0925060T3 (en) 2003-04-07

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