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WO2010043408A2 - Fésotérodine microencapsulée - Google Patents

Fésotérodine microencapsulée Download PDF

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Publication number
WO2010043408A2
WO2010043408A2 PCT/EP2009/007445 EP2009007445W WO2010043408A2 WO 2010043408 A2 WO2010043408 A2 WO 2010043408A2 EP 2009007445 W EP2009007445 W EP 2009007445W WO 2010043408 A2 WO2010043408 A2 WO 2010043408A2
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WO
WIPO (PCT)
Prior art keywords
fesoterodine
pharmaceutical
shell
weight
metabolites
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2009/007445
Other languages
German (de)
English (en)
Other versions
WO2010043408A3 (fr
Inventor
Katrin Rimkus
Frank Muskulus
Sandra Brueck
Jana Paetz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ratiopharm GmbH
Original Assignee
Ratiopharm GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of WO2010043408A2 publication Critical patent/WO2010043408A2/fr
Publication of WO2010043408A3 publication Critical patent/WO2010043408A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the invention relates to microencapsulated fesoterodine.
  • the invention relates to a pharmaceutical intermediate composed of a core (a) and a shell (b), wherein (a) the core contains fesoterodine and / or metabolites as active ingredient and (b) the shell contains one or more pharmaceutical excipients which modify the release of the drug, as well as a process for the preparation of the intermediate.
  • the invention relates to a pharmaceutical composition comprising the intermediate according to the invention, in particular in the form of tablets.
  • Fesoterodine is an antimuscarinic used to treat overactive bladder. Fesoterodine significantly improved the symptoms of the overactive bladder, which were felt to be very stressful by the patients. In all clinically relevant endpoints of both Phase III studies (2, 3) (urge incontinence events / 24 h, micturition frequency, median micturition volume), statistically significant improvements were achieved over placebo. Fesoterodine is currently marketed under the trade name TOVIAZ ®.
  • fesoterodine 2 - [(1R) -3- (diisopropylamine) -1-phenylpropyl] -4- (hydroxymethyl) phenyl isobutyrate.
  • the chemical structure of fesoterodine is shown in formula (1) below:
  • Synthesis routes for fesoterodine can be derived from EP 1 077 912 Bl. Salts of fesoterodine are described in EP 1 230 209 B1.
  • Fesoterodine is not particularly resistant to hydrolysis. Taking this fact into account, WO 2007/141298 has proposed fesoterodine tablet formulations which contain an active ingredient and a stabilizer against hydrolysis, the
  • Stabilizer is preferably xylitol. Furthermore, the drug had to turn into a matrix Polymer were incorporated, so that a prolonged release could be achieved. It was also found that the amount of decomposition products was only advantageous if the proposed formulations were prepared by classical wet granulation. Direct compression resulted in higher levels of undesirable decomposition products.
  • An object of the present invention was therefore to provide a dosage form with modified release, wherein the active ingredient should be released as completely as possible.
  • the formulations proposed in the prior art require a high amount of polymer. As a result, only a relatively low active ingredient content [drug load] is possible.
  • the formulations described in WO 2007/141298 show a fesoteric acid content of 5% by weight or less.
  • a further object of the invention was therefore to provide fesoterodine in a form which enables a formulation with a high active ingredient content, preferably with an active ingredient content of more than 5%.
  • Fesoterodine is used to treat overactive bladder. This indication requires that patients always carry the dosage forms with them. However, the currently marketed Toviaz ® tablets have only a storage stability up to 25 0 C. This is unsatisfactory especially in the summer months. It was therefore a further object of the invention to provide fesoterodine in a form that is suitable for a formulation with a shelf life in practical use up to 30 0 C. In addition, it was an object of the invention to provide a pharmaceutical active ingredient for the treatment of overactive bladder, which has substantially the same solubility as the formulations shown in WO 2007/141298, in particular the example formulations shown in Table 1, and in consequence in an oral Administration is essentially bioequivalent to it.
  • fesoterodine is a very active substance because it is rapidly and largely completely activated in the body by non-specific esterases.
  • the invention therefore relates to a pharmaceutical intermediate containing microencapsulated fesoterodine and / or fesoterodin metabolites.
  • Fesoterodine is a prodrug. After oral ingestion, the pro-drug is activated to the active metabolite by esterases in the human body.
  • the present invention generally relates to fesoterodine and its metabolites.
  • fesoterodine therefore generally refers in the context of the present application to fesoterodine and / or its metabolites.
  • metabolites are understood as meaning all substances which arise during the metabolism of fesoterodine, in particular during metabolisation in the human
  • the metabolites are fesoterodine 5-HM according to the following structure (2):
  • Fesoterodine-5-HM Fesoterodine-5-HM
  • the term “fesoterodine” or “fesoterodine metabolite” basically includes both the “free base” described above in structures (1) and (2) and pharmaceutically acceptable salts thereof. This may be one or more salts, which may also be present in a mixture.
  • salt it is meant herein that the amine group of fesoterodine or the fesoterodine metabolite has been protonated to form a positively charged nitrogen atom associated with a corresponding counteranion.
  • the term “fesoterodine and / or fesoterodine metabolites” is also referred to as “fesoterodine (metabolite)".
  • the salts used are preferably acid addition salts.
  • suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, fumarates, hydrogen fumarates, tartrates, hydrogentartrates, maleate, nitrates, sulfonates, oxalates and / or succinates.
  • the pharmaceutically acceptable salt is particularly preferably hydrogen fumarate.
  • the pharmaceutically acceptable salt is furthermore preferably fumarate.
  • fesoterodine hydrogen fumarate, fesoterodine fumarate, fesoterodine tartrate, fesoterodine 5-HM hydrogen fumarate, fesoterodine 5-HM fumarate or mixtures thereof are preferably used as the active ingredient in the present invention.
  • FIG. 1 The microencapsulated fesoterodine according to the invention is illustrated by FIG. In FIG. 1,
  • the pharmaceutical intermediate according to the invention is not so-called "microspherules".
  • the active ingredient is embedded in a polymer matrix without the formation of a capsule shell.
  • microspheres not according to the invention are depicted in FIG. In FIG. 2,
  • the present invention is not a pharmaceutical preparation for oral administration with controlled release of active ingredient in the small intestine, wherein, as described in WO 2008/0056506, the drug release is selectively effected in the small intestine by forming at least two diffusion layers.
  • the present invention therefore preferably does not disclose a controlled release pharmaceutical preparation for oral administration in the small intestine based on drug carriers provided with at least one active agent and provided with an inner layer for controlling drug release and an enteric coating layer disposed thereon in that the inner layer is formed from at least two diffusion layers whose permeability to the diffusing active substance decreases from the inside to the outside.
  • the subject of the invention is a pharmaceutical intermediate composed of a core (a) and a shell (b), wherein
  • the core contains fesoterodine and / or fesoterodine metabolites as active ingredient and
  • the shell contains one or more pharmaceutical excipients which modify the release of the active ingredient.
  • the core (a) preferably contains the active ingredient in particulate form, i. the core is preferably active ingredient particles, in particular one or more active substance particles.
  • the core may include fesoterodine (metabolite) and pharmaceutical excipients.
  • the core is completely enveloped / encapsulated.
  • enveloped or “encapsulated” also encompasses those cases where at least 70%, more preferably at least 80%, particularly preferably at least 90%, of the surface of the core are enveloped.
  • the core generally contains fesoterodine and / or fesoterodine metabolites as the active ingredient. It is preferred that the core consists essentially of fesoterodine and / or fesoterodine metabolites. The term "substantially” indicates here that the core may optionally still contain small amounts of moisture, solvents, pharmaceutical auxiliaries, etc.
  • the core contains fesoterodine (metabolite) in granulated or compressed form. That is, it is preferably a core (a) through
  • Granulation or compression of fesoterodine (metabolite), optionally in the presence of pharmaceutical excipients is preferred.
  • a compression for example by means of eccentric press.
  • eccentric presses usually a pressing force of 1 to 20 kN, preferably from 2.5 to 10 kN, applied.
  • these preferably have a weight-average particle size of 0.1 to 4 mm, more preferably 0.5 to 3.5 mm, even more preferably 1 to 0 to 3.0 mm, in particular from 1, 5 to 2.5 mm.
  • the weight mean particle size is determined by sieve analysis in the context of this application (preferably using a Retsch AS ® 2000). This is the D50 value.
  • the cores in addition to fesoterodine (metabolite) they may also contain pharmaceutical excipients.
  • the cores may contain (a) in addition to fesoterodine (metabolite) also lubricants and / or additives to improve the flowability.
  • the cores contain (a)
  • the envelope (b) contains or consists of one or more pharmaceutical excipients which modify the release of the active ingredient.
  • the sheath (b) is preferably present in one layer, i. it is preferably not a shell of at least two layers.
  • modified release in the context of this invention is extended (delayed release), repeated action release, prolonged release, sustained release or prolonged release release). Preferably, it is a sustained release.
  • the shell (b) comprises the components (b 1) a non-water-soluble substance and (b2) a pore binder.
  • the shell (b) may consist essentially of the components (bl) and (b2).
  • the component (bl) is preferably a non-water-soluble polymer or a non-water-soluble substance with polymer-like properties.
  • non-water-soluble means that the substance has a water solubility of less than 10 mg / l, measured at 25 ° C.
  • the non-water-soluble substance preferably has a solubility of 8 mg / l or less, in particular from 0.01 to 5 mg / 1 (determined according to the column elution method according to EU Directive RL67-548-EEC, Annex V Chapter A6).
  • the non-water-soluble polymer (b l) usually has a weight-average molecular weight of 50,000 to 2,500,000 g / mol, preferably 150,000 to 2,000,000 g / mol, more preferably 350,000 to 1,500,000 g / mol.
  • non-water-soluble polymers examples include acrylate-based polymers, e.g. Acrylates, methacrylates; Cellulose derivatives such as ethylcellulose (EC), methylcellulose (MC), cellulose acetylphthalates, hydroxypropylmethylcellulose phthalate; synthetic polymers such as polyvinyl alcohol and derivatives thereof, polyvinyl acetate, polyvinyl chloride, nylon, polyamide, polyethylene and polylactide-co-glycolides. Likewise, mixtures of the polymers mentioned are possible.
  • acrylate-based polymers e.g. Acrylates, methacrylates
  • Cellulose derivatives such as ethylcellulose (EC), methylcellulose (MC), cellulose acetylphthalates, hydroxypropylmethylcellulose phthalate
  • synthetic polymers such as polyvinyl alcohol and derivatives thereof, polyvinyl acetate, polyvinyl chloride, nylon, polyamide, polyethylene and polylactide-co-glycolides
  • polyvinyl alcohol is used.
  • polymethacrylates as component (bl) is therefore preferably a polymer composed of structures according to the general formulas (3) and (4).
  • R 1 is a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a methyl radical, in particular a methyl radical;
  • R 2 is a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a C 1 to C 4 alkyl radical, in particular a methyl radical, ethyl radical or butyl;
  • R 3 is a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a methyl radical
  • R 4 is an organic radical, preferably a carboxylic acid group or a derivative thereof, more preferably a group of the formula -COOH, -COOR 5 ,
  • R 5 is an alkyl radical or a substituted alkyl radical, preferably methyl, ethyl, propyl or butyl as the alkyl radical or -CH 2 -CH 2 -N (CH 3 ) 2 or -CH 2 -CH 2 -N (CH 3 J 3 + halogen "(in particular Cl " ) as a substituted alkyl radical.
  • the acrylic polymer (bl) contains structures according to the formulas (3) and (4) usually in molar ratios of 1:40 to 40: 1.
  • the ratio of structures according to formula (2) to structures according to formula (3) 2 is preferably: 1 to 1: 1, in particular 1: 1. If R 4 is -COO-CH 2 -CH 2 -N (CH 3 J 3 + Cr, the ratio of structures of the formula (3) to structures of the formula (4) is preferably 20: 1 to 40: 1.
  • ethyl cellulose is used as the non-water-soluble polymer (bl).
  • Ethylcellulose for example, in the form of the commercially available system Aquacoat ® ECD (FMC BioPolymer, about 24.5 to 29.5% of ethylcellulose in aqueous solution) can be used.
  • waxes and fats can be used as non-water-soluble substances (with polymer-like properties).
  • Suitable waxes or fats are solid at 25 ° C.
  • solid paraffin or beeswax is suitable.
  • Suitable fats include glycerol monostearate and glycerol palmitostearate. Also, mixtures thereof can be used. Further, mixtures containing non-water-soluble polymers and non-water-soluble substances having polymer-like properties can be used.
  • the shell (b) further comprises a pore builder (b2).
  • a pore-forming agent is generally a substance which is water-soluble and dissolves on contact of the shell (b) with water, so that water can penetrate into the resulting pores.
  • the pore-forming agent preferably has a water solubility of 100 mg / l at a temperature of 25 ° C., more preferably of more than 250 mg / l.
  • the pore-forming agent may be a water-soluble polymer (b2-l). Further, the pore-forming agent may be a water-soluble salt (b2-2).
  • Suitable water-soluble polymers preferably have hydrophilic groups.
  • suitable hydrophilic groups are hydroxy, ethers, esters and amino.
  • the hydrophilic polymer usable for the preparation of the intermediate preferably has a weight-average molecular weight of from 1,000 to 90,000 g / mol, more preferably from 2,000 to 50,000 g / mol.
  • the resulting solution preferably exhibits a viscosity of 0.1 to 8 mPa / s, more preferably 0.5 to 7 mPa / s, in particular from 1 to 6 mPa / s, measured at 25 ° C.
  • the intermediate according to the invention may comprise, for example, the following hydrophilic polymers as pore formers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); Polyvinylpyrrolidone, polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ® , BASF) and mixtures of the polymers mentioned.
  • hydrophilic polymers as pore formers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); Polyvinylpyrrolidone, polyalkylene glycols, such as polypropylene glycol
  • Polyethylene glycol is preferably used, in particular having a weight-average molecular weight of 2,000 to 10,000 g / mol.
  • the pore-forming agent may be a water-soluble salt (b2-2).
  • Pharmaceutically acceptable inorganic salts are preferred. Examples of suitable salts are NaCl, KCl and Na 2 SO 4 .
  • the shell (b) may consist of the components (bl) and (b2).
  • the shell contains, in addition to the non-water-soluble substance (bl) and the pore-forming agent (b2) additionally a polymer with a pH-dependent water solubility (b3) and / or plasticizer (b4).
  • the addition of the polymer with pH-dependent water solubility (b3) can unexpectedly favorably influence the pharmacokinetic data of the resulting formulation.
  • the component (b3) is a polymer having less water solubility in the acid than in the neutral or alkaline.
  • the polymer (b3) at pH 3 has a water solubility which is reduced by at least 50% compared with pH 7.
  • the polymer (b3) has a water solubility of at least 10, more preferably at least 50 mg / l, more preferably at least 250 mg / l at 25 ° C., at a pH of 5 or higher.
  • component (b3) is a carboxyl group-containing polymer.
  • the polymers (b3) usually have a number average molecular weight of> 10,000 to 90,000, preferably from 20,000 to 70,000 g / mol.
  • Suitable polymers with pH-dependent water solubility are cellulose acetate trimellitate (CAT), Polvyinylacetatphthalat, hydroxypropylmethyl cellulose phthalate (HPMCP), in particular having a weight average molecular weight of 40,000 to 60,000, carboxymethyl ethyl cellulose (CMEC), polyvinyl acetate phthalate (PVAP) 1 anionic methacrylates (for example, Eudragit ® L30), cellulose acetate phthalate (CAP) and shellac.
  • CAT cellulose acetate trimellitate
  • HPMCP hydroxypropylmethyl cellulose phthalate
  • CMEC carboxymethyl ethyl cellulose
  • PVAP polyvinyl acetate phthalate
  • CAP cellulose acetate phthalate
  • polymers are also conceivable which fulfill both the definition of (b2) and of (b3).
  • a polymer is used only as either component (b2) or component (b3).
  • the shell further contains plasticizer as component (b4).
  • plasticizer is generally meant materials which are capable of lowering the glass transition temperature of the non-water-soluble polymer (bl) (ie, a mixture of (bl) and (b4) has a lower glass transition temperature than component (bl) alone ).
  • plasticizers examples include glycerol, citrates such as triethyl citrate, tributyl citrate, acetyl citrate, phthalates such as dibutyl phthalate, diethyl phthalate, dimethyl phthalate, sebacates such as dibutyl sebacate or diethyl sebacate.
  • alkylene glycols such as ethylene glycol, propylene glycol, butylene glycol (1,4-butanediol) or polyalkylene glycols such as polyethylene glycol, preferably having a weight average molecular weight of 300 to 1,500 g / mol, can be used.
  • Triethyl citrate and / or dibutyl sebacate are preferably used, in particular triethyl citrate is used as plasticizer (b4). It is likewise possible to use mixtures of said plasticizers.
  • the shell (b) contains preferably 70 to 99 wt .-%, more preferably 75 to 95 wt .-%, particularly preferably 80 to 93 wt .-%, in particular 85 to 92 wt .-% of non-water-soluble polymer (bl).
  • the shell (b) further preferably contains 1 to 20 wt .-%, more preferably 2 to 15 wt .-%, particularly preferably 3 to 12 wt .-% pore former (b2).
  • the shell (b) also preferably contains 0 to 20 wt .-%, more preferably 2 to 15 wt .-%, particularly preferably 3 to 12 wt .-% polymer having a pH-dependent solubility (b3).
  • the shell (b) also contains preferably 0 to 20 wt .-%, more preferably 2 to 15 wt .-%, particularly preferably 3 to 12 wt .-%, a plasticizer (b4).
  • the shell contains (b)
  • (b2) 0, 1 to 20 wt .-% pore former, more preferably 0.5 to 15 wt .-%, in particular 0, 1 to 10 wt .-%, and
  • (b4) 0 to 20% by weight, more preferably 2 to 15% by weight, in particular 3 to 12% by weight
  • the shell (b) consists essentially of the components (bl) to (b3). It is particularly preferred that the sheath (b) consists essentially of the
  • core (a) and shell (b) used are preferably chosen so that the core is completely enveloped.
  • the core is thus preferably completely encapsulated.
  • the intermediates according to the invention are preferably in the form of a particulate composition, the volume-average particle diameter (D50) usually being 60 to 500 ⁇ m, preferably 75 to 350 ⁇ m, more preferably 90 to 300 ⁇ m, particularly preferably 100 to 250 ⁇ m, in particular 110 to 220 microns, is.
  • D50 volume-average particle diameter
  • average particle diameter in the context of this invention refers, unless stated otherwise, to the D50 value of the volume-average
  • the average particle diameter also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by weight of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50 wt .-% of the particles have a larger diameter than the D50 value.
  • the intermediates according to the invention are preferably in the form of a particulate composition, the weight-average particle size being from 0.15 to 5 mm, from 0.6 to 4.0 mm, more preferably from 1.5 to 3.3 mm, in particular from 1.8 to 2.8 mm.
  • the weight-average particle size is determined by sieve analysis as described above.
  • the second embodiment is preferably used when the cores (a) have been granulated or compressed as above.
  • the weight ratio of core (a) to shell (b) is 5: 1 to 1:20, preferably 1: 1 to 1:10, more preferably 1: 1.5 to 1: 8, in particular 1: 2 to 1: 5.
  • the weight ratio of core (a) to shell (b) is 15: 1 to 1: 5, preferably 10: 1 to 1: 3, more preferably 8: 1 to 1: 2, especially 6: 1 to 1: 1.
  • the second embodiment is preferably used when the cores (a) have been granulated or compressed as above.
  • the intermediate of the invention i.e., the microencapsulated fesoterodine
  • the intermediate of the invention is generally preparable by a process wherein the polymer shell is applied to the fesoterodin core.
  • the invention therefore provides a process for the preparation of the pharmaceutical intermediate according to the invention, comprising the steps:
  • step (i) providing fesoterodine and / or fesoterodine metabolites in particulate form; (ii) providing a solution containing sheath-forming pharmaceutical excipients; (iii) spraying the solution of step (ii) onto the particles of fesoterodine and / or fesoterodine metabolites; and (iv) removal of the solvent.
  • step (i) in a first embodiment of the method according to the invention fesoterodine and / or fesoterodin metabolites with a average particle size (D5O) of 50 to 250 .mu.m, more preferably from 55 to 150 .mu.m, in particular from 60 to 120 .mu.m, are used.
  • the cores (a) used in step (i) preferably have a weight-average particle size of 0.1 to 4 mm, more preferably 0.5 to 3 , 5 mm, more preferably from 1, 0 to 3.0 mm, in particular from 1, 5 to 2.5 mm, on.
  • step (ii) pharmaceutical excipients which are suitable for forming the shell (b) are dissolved or suspended in a solvent or solvent mixture, preferably completely dissolved.
  • these pharmaceutical excipients are the above-described components (bl), (b2), (b3) and / or (b4).
  • the above statements on the intermediate according to the invention are also applicable to the process according to the invention.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • acetone butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • acetone acetone
  • butanol ethyl acetate
  • heptane pentanol
  • pentanol pentanol
  • an ethanol / water mixture or water is used.
  • the shell-forming substances preferably the components (bl), (b2) and optionally (b3) and / or (b4), are usually present in the solution / suspension in a concentration of 5% to 95% by weight,
  • step (iii) the solution from step (ii) is sprayed onto the fesoterodin and / or fesoterodin metabolite particles.
  • the spraying takes place in the fluidized bed.
  • step (iv) the solvent is removed, preferably completely removed.
  • the removal of the solvent is preferably carried out by high temperature and / or low pressure.
  • the residual solvent content in the shell (b) is preferably less than 2 wt .-%.
  • steps (i) to (iv) take place in one operation and preferably in one apparatus.
  • the residence time of solvent on the active substance should be as short as possible, preferably less than 10 minutes, in particular less than 5 minutes.
  • the process according to the invention is carried out in a fluidized-bed granulator, for example in a Glatt® GPCG 3 (Glatt GmbH, Germany).
  • a Glatt® GPCG 3 Glatt GmbH, Germany.
  • the intermediate of the invention i.e., the encapsulated fesoterodine of the invention
  • the intermediate of the invention is commonly used to prepare a pharmaceutical formulation.
  • the invention therefore relates to a pharmaceutical formulation containing the intermediate according to the invention and pharmaceutical excipients.
  • the ratio of active ingredient to auxiliaries is preferably chosen so that the resulting formulations
  • Wt .-% in particular 2 to 20 wt .-% fesoterodin and / or fesoterodin metabolites
  • auxiliaries used are disintegrants, release agents, pseudo-emulsifiers, fillers, additives to improve the powder flowability, lubricants, wetting agents and / or lubricants.
  • the formulation according to the invention may contain fillers.
  • Fillers are generally to be understood as substances which serve to form the tablet body in the case of tablets with small amounts of active ingredient. That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.
  • Examples of preferred fillers are lactose, lactose derivatives, starch,
  • Starch derivatives treated starch, talc, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, calcium sulfate, hydrogenated
  • silified microcrystalline cellulose eg Prosolv® ®, Save Painters & Söhne, Germany
  • the preferably used silified microcrystalline cellulose is commercially available and has a silica content of 1 to 3 wt .-%, preferably of 2 wt .-%, on.
  • combinations of said fillers may be used, for example, a combination of lactose and microcrystalline cellulose is advantageously used.
  • Fillers are usually used in an amount of from 1 to 90% by weight, more preferably from 10 to 80% by weight, more preferably from 20 to 60% by weight, based on the total weight of the formulation.
  • disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water.
  • Suitable disintegrants are, for example, organic disintegrants such as carrageenan, croscarmellose and crospovidone.
  • alkaline disintegrants are meant disintegrating agents which when dissolved in water produce a pH of more than 7.0, for example NaHCO 3 or Na 2 CO 3 .
  • Disintegrants are usually used in an amount of 0 to 20% by weight, more preferably 1 to 15% by weight, especially 2 to 10% by weight, based on the total weight of the formulation. When granulated or compressed cores (a) are used, it is preferred that no disintegrant be used.
  • silica such as known under the trade name Aerosil ®.
  • Silica with a specific surface area of 50 to 400 m 2 / g, determined after gas adsorption according to Ph. Eur., 6th edition 2.9.26., Is preferably used, in particular if granulated or compressed cores (a) are used.
  • Additives to improve the powder flowability are usually used in an amount of 0.1 to 3 wt .-%, based on the total weight of the formulation.
  • Lubricants can be used.
  • Lubricants are generally used to reduce sliding friction.
  • the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall.
  • Suitable lubricants are for example stearic acid, adipic acid, sodium stearyl fumarate is (Pruv ®) and / or magnesium stearate.
  • Lubricants are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation.
  • release agents can be used.
  • release agents are usually understood substances which reduce the agglomeration in the core bed. Examples are talc, silica gel, and / or glycerol monostearate. Release agents are usually used in an amount of 0 to 3 wt .-%, based on the total weight of the formulation.
  • the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
  • a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
  • microcrystalline cellulose - if used as a filler - not additionally used as a disintegrant (although microcrystalline cellulose also shows a certain explosive effect).
  • the formulation according to the invention preferably contains no humectants selected from glucose, glucose derivatives and sugar alcohols.
  • the formulation according to the invention particularly preferably contains no isomalt, xylitol, sorbitol, polydextrose, dextrose and mixtures thereof.
  • the formulation of the invention can be administered in different dosage forms. Preferably, it is compressed into tablets. Alternatively, the formulation according to the invention can be filled into capsules, sachets or stickpacks.
  • the pharmaceutical formulation of the invention in the form of tablets is used.
  • the invention therefore provides a process for the preparation of a tablet comprising the pharmaceutical formulation according to the invention, comprising the steps
  • step (a) intermediate according to the invention and further (above-described) pharmaceutical excipients are mixed.
  • the mixing can be done in usual
  • Mixers done.
  • the mixing in compulsory mixers or Free fall mixers are made (eg by means of Turbula T 1OB (Bachofen AG, Switzerland)).
  • the mixing time can be, for example, 1 to 15 minutes.
  • step (b) compression into tablets occurs.
  • the compression can be done with tableting machines known in the art.
  • the compression is preferably carried out in the absence of solvents.
  • Suitable tableting machines are eccentric presses or concentric presses.
  • a Fette 102i (Fette GmbH, Germany) can be used.
  • a pressing force of from 2 to 40 kN, preferably from 2.5 to 35 kN is usually used.
  • the Korsch ® EKO is used.
  • step (c) of the process according to the invention the tablets from step (b) are film-coated.
  • the usual in the prior art method for filming tablets can be used.
  • macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac.
  • the layer thickness of the coating is usually 1 to 100 .mu.m, preferably 10 to 90 / im.
  • the optionally applied film has substantially no effect on the release.
  • they are preferably films without influence on the drug release.
  • neither enteric film coatings nor delayed-release coatings are preferably used.
  • the Tablettier quiz are further preferably selected in the inventive method so that the resulting tablets have a ratio of tablet height to weight of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg.
  • the resulting tablets preferably have a hardness of 50 to 250 N, more preferably from 80 to 200 N, in particular from 1 10 to 170 N. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8.
  • the resulting tablets preferably have a friability of less than 5%, particularly preferably less than 3%, in particular less than 2%. The friability is calculated according to Ph.Eur. 6.0, Section 2.9.7. certainly.
  • the tablets according to the invention usually have a uniformity of content from 90 to 110%, preferably from 95 to 105%, in particular from 98 to 102% of the average content.
  • the "Content Uniformity” is according to Ph. Eur.6.0, Section 2.9.6. certainly.
  • the tablets according to the invention are produced not by means of direct compression but by means of dry granulation and subsequent compression.
  • the method according to the invention comprises the following steps:
  • One aspect of the present invention therefore relates to a dry granulation process comprising the steps
  • step (a2) of the process according to the invention the mixture from step (a) is compacted into a rag.
  • This is dry compaction, i. the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.
  • the compaction is preferably carried out in a roll granulator.
  • the rolling force is usually 5 to 70 kN / cm, preferably 10 to 60 kN / cm, more preferably 15 to 50 kN / cm.
  • the gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, in particular 1.8 to 2.8 mm.
  • the slug is granulated.
  • the granulation can be carried out by methods known in the art.
  • the granulation is carried out with the device Comil ® U5 (Quadro Engineering, USA).
  • the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.2 to 0.85 g / ml, more preferably 0.3 to 0.8 g / ml, especially 0.4 to 0.7 g / ml , exhibit.
  • the Hausner factor is usually in the range of 1, 03 to 1, 3, more preferably from 1, 04 to 1, 20 and especially from 1, 04 to 1, 15.
  • Sub "Hausner factor” is understood here as the ratio of tamped density to bulk density.
  • the granulation is carried out in a sieve mill.
  • the mesh size of the sieve insert is usually 0, 1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1.8 mm.
  • the formulations according to the invention have a release rate of less than
  • the invention thus relates to microencapsulated fesoterodine and / or fesoterodine metabolites according to the present invention for the treatment of the overactive bladder.
  • Inlet temperature 70 ° C
  • product temperature 40 0 C
  • volume flow 50 m 3 / h spray pressure: 1.5 bar.
  • the solution was used to cover 150 g of fesoterodine 5-HM fumarate in a fluid bed apparatus (Glatt GPCG 3).
  • Example 3 Direct compression into tablets
  • microencapsulated fesoterodine obtained from Example 1 or Example 2 was compressed to tablets on a rotary press.
  • 512 g of the intermediate were weighed out and 1,400 g of Avicel ® 102, 1122 g of lactose monohydrate, 237 g croscarmellose sodium, 100 g Povidone ® mixed for 15 minutes in a mixer (Turbula ® Tlob) and passed through a 500 micron sieve.
  • the sieved material was mixed with 6 g talcum and 3 g fumaric acid for 3 minutes and then compressed into tablets.
  • fesoterodine was mixed together with Aerosil ® and magnesium stearate for 10 minutes on a free - fall mixer (Turbula ® TlOB) and then pressed into cores on an eccentric press (Korsch ® EKO).
  • the cores had a content of 4 mg of active ingredient and had a weight-average diameter of about 2 mm.
  • Example 4 The preparation was carried out as Example 4, the coating material consisted of Aquacoat ® ECD 69%, triethyl citrate 6%, polyethylene glycol 10% and 15% water.
  • Example 4 The preparation was carried out as Example 4, the shell material consisted of Aquacoat ® ECD 67%, triethyl citrate 6%, polyethylene glycol 15% and 12% water.
  • Cores were prepared according to Example 4. 300 g of cores were coated with 145 g of a shell-forming film from Aquacoat ® ECD 77%, 6% triethyl citrate, polyethylene glycol, 2%, 0.5% hydroxypropyl and 14.5% water in a fluidized bed system (Glatt GPC 3.1).
  • a microencapsulated core was then in each case in Microcellac ® (75% lactose, 25% microcrystalline cellulose) and 1% magnesium stearate enclosed and compressed to obtain tablets having a total weight of 320 mg and a hardness of 150 N (the form of 12.5 x 6 , 5 mm, content 4 mg).

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Abstract

L'invention concerne de la fésotérodine microencapsulée. L'invention concerne en particulier un intermédiaire pharmaceutique composé d'un noyau (a) et d'une enveloppe (b), (a) le noyau contenant de la fésotérodine et/ou des métabolites comme principe actif et (b) l'enveloppe contenant un ou plusieurs excipients pharmaceutiques qui modifient la libération du principe actif, ainsi qu'un procédé de production de cet intermédiaire. L'invention concerne en outre une composition pharmaceutique contenant l'intermédiaire selon l'invention, en particulier sous forme de comprimés.
PCT/EP2009/007445 2008-10-17 2009-10-16 Fésotérodine microencapsulée Ceased WO2010043408A2 (fr)

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EP08018241 2008-10-17
EP08018241.3 2008-10-17

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WO2010043408A3 WO2010043408A3 (fr) 2010-07-01

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117884A1 (fr) * 2010-03-22 2011-09-29 Cadila Healthcare Limited Compositions pharmaceutiques stables comprenant de la fésotérodine
WO2012098499A1 (fr) 2011-01-18 2012-07-26 Pfizer Limited Dispersion moléculaire solide
EP2508175A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Composition pharmaceutique contenant de la fésotérodine ou un sel ou un solvate de celle-ci
EP2508173A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Composition pharmaceutique stable comportant de la fésotérodine
WO2013054337A1 (fr) * 2011-07-04 2013-04-18 Cadila Healthcare Limited Compositions pharmaceutiques à libération prolongée de fésotérodine
WO2013160909A1 (fr) * 2012-03-19 2013-10-31 Astron Research Limited Composition stable de fésotérodine
WO2015188794A1 (fr) 2014-06-09 2015-12-17 Zentiva, K.S. Formulation stabilisée de fésotérodine
WO2019132832A1 (fr) 2017-12-25 2019-07-04 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions de comprimés de fumarate de fésotérodine
CN110151720A (zh) * 2019-05-09 2019-08-23 合肥信风科技开发有限公司 含非索罗定的药用组合物及其制备方法
WO2019221684A2 (fr) 2017-12-25 2019-11-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de comprimé bicouche de fésotérodine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI1880718T1 (sl) * 2006-07-10 2011-11-30 Pfleger R Chem Fab Farmacevtski pripravki za oralno dajanje z nadzorovanim sproščanjem zdravila v majhne intestinke kolone in postopek njihove priprave

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117884A1 (fr) * 2010-03-22 2011-09-29 Cadila Healthcare Limited Compositions pharmaceutiques stables comprenant de la fésotérodine
CN106420662A (zh) * 2011-01-18 2017-02-22 辉瑞有限公司 固体分子分散体
WO2012098499A1 (fr) 2011-01-18 2012-07-26 Pfizer Limited Dispersion moléculaire solide
US9668998B2 (en) 2011-01-18 2017-06-06 Pfizer Limited Solid molecular dispersion of fesoterodine hydrogen fumarate and polymeric binder
EP2508173A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Composition pharmaceutique stable comportant de la fésotérodine
WO2012136838A1 (fr) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Composition pharmaceutique comprenant de la fésotérodine
WO2012136839A1 (fr) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Formulation sèche et composition pharmaceutique comprenant une fésotérodine ou un sel ou un solvate de celle-ci
EP2508175A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Composition pharmaceutique contenant de la fésotérodine ou un sel ou un solvate de celle-ci
WO2013054337A1 (fr) * 2011-07-04 2013-04-18 Cadila Healthcare Limited Compositions pharmaceutiques à libération prolongée de fésotérodine
WO2013160909A1 (fr) * 2012-03-19 2013-10-31 Astron Research Limited Composition stable de fésotérodine
WO2015188794A1 (fr) 2014-06-09 2015-12-17 Zentiva, K.S. Formulation stabilisée de fésotérodine
WO2019132832A1 (fr) 2017-12-25 2019-07-04 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions de comprimés de fumarate de fésotérodine
WO2019221684A2 (fr) 2017-12-25 2019-11-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulation de comprimé bicouche de fésotérodine
CN110151720A (zh) * 2019-05-09 2019-08-23 合肥信风科技开发有限公司 含非索罗定的药用组合物及其制备方法

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