WO2010043408A2

WO2010043408A2 - Microencapsulated fesoterodine

Info

Publication number: WO2010043408A2
Application number: PCT/EP2009/007445
Authority: WO
Inventors: Katrin Rimkus; Frank Muskulus; Sandra Brueck; Jana Paetz
Original assignee: Ratiopharm Gmbh
Priority date: 2008-10-17
Filing date: 2009-10-16
Publication date: 2010-04-22
Also published as: WO2010043408A3

Abstract

The invention relates to microencapsulated fesoterodine. In particular, 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 the active ingredient, and (b) the shell contains one or more pharmaceutical adjuvants, which modify the release of the active ingredient, and to a method for producing the intermediate. Furthermore, the invention relates to a pharmaceutical composition containing the intermediate according to the invention, specifically in the form of tablets.

Description

Microencapsulated fesoterodine

The invention relates to microencapsulated fesoterodine. In particular, 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. Furthermore, 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 ^®.

The IUPAC name of fesoterodine [INN] is 2 - [(1R) -3- (diisopropylamine) -1-phenylpropyl] -4- (hydroxymethyl) phenyl isobutyrate. The chemical structure of fesoterodine is shown in formula (1) below:

(1) Fesoterodine

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.

It is often a problem with matrix tablets that a considerable part of the active substance (about 20%) is generally not released. 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 different types of excipients (on the one hand xylitol, on the other hand retarding polymers) for moisture protection and retardation. Likewise, several steps are necessary for the production. On the other hand, it was an object of the present invention to provide a formulation in which hydrolysis protection and retardation can be achieved with as far as possible one auxiliary substance type and can be achieved with as far as possible one working step.

In order to achieve the desired sustained release, 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. Thus, 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%.

The preparation processes described in the prior art prefer a classic wet granulation process. Here, the active ingredient usually comes in contact with solvents for a long time. However, due to the sensitivity of the drug, this should be avoided.

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.

Finally, from a toxicological point of view, it can be stated that fesoterodine is a very active substance because it is rapidly and largely completely activated in the body by non-specific esterases. Thus, it was an object of the invention to provide a "safe" fesoterodine formulation, wherein too rapid flooding is prevented.

The above-mentioned objects could be solved unexpectedly by microencapsulation of fesoterodine.

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. Of the

The term "fesoterodine" therefore generally refers in the context of the present application to fesoterodine and / or its metabolites. In this context, metabolites are understood as meaning all substances which arise during the metabolism of fesoterodine, in particular during metabolisation in the human

Body arise.

Preferably, the metabolites are fesoterodine 5-HM according to the following structure (2):

(2) Fesoterodine-5-HM For the purposes of this application, 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. By "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. For the purposes of this application, the term "fesoterodine and / or fesoterodine metabolites" is also referred to as "fesoterodine (metabolite)".

The salts used are preferably acid addition salts. Examples of 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.

In the case of fesoterodine or fesoterodine metabolite, the pharmaceutically acceptable salt is particularly preferably hydrogen fumarate. Hydrogen fumarate is a compound according to the formula HOOC-CH = CH-COO ^' , wherein the double bond has E configuration. In the case of fesoterodine or fesoterodine metabolite, the pharmaceutically acceptable salt is furthermore preferably fumarate. Fumarate is a compound according to the formula OOC-CH = CH-COO ^" , wherein the double bond has E configuration.

Thus, 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.

The microencapsulated fesoterodine according to the invention is illustrated by FIG. In FIG. 1,

1 drug particle containing fesoterodine and / or fesoterodine metabolite

2 case.

However, the pharmaceutical intermediate according to the invention is not so-called "microspherules". In the case of the microspheres, in contrast to the microcapsules, the active ingredient is embedded in a polymer matrix without the formation of a capsule shell. For comparison, microspheres not according to the invention are depicted in FIG. In FIG. 2,

1 active substance particles containing fesoterodine and / or fesoterodine metabolite 2 matrix. Also, 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.

Thus, the subject of the invention is a pharmaceutical intermediate composed of a core (a) and a shell (b), wherein

(a) the core contains fesoterodine and / or fesoterodine metabolites as active ingredient and

(B) 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. In addition, the core may include fesoterodine (metabolite) and pharmaceutical excipients.

It is particularly preferred in the context of this invention that the core is completely enveloped / encapsulated. In the context of this invention, however, the term "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.

Fesoterodine and / or fesoterodine metabolite having a water content of 0.1 to 5% by weight, more preferably 0.3 to 3% by weight, is preferably used for the core.

In a preferred embodiment, 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. Preferred is a compression, for example by means of eccentric press. In the case of using eccentric presses usually a pressing force of 1 to 20 kN, preferably from 2.5 to 10 kN, applied.

In the case of granulated or compressed cores (a), 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.

In the case of granulated or compressed cores (a) in addition to fesoterodine (metabolite) they may also contain pharmaceutical excipients. In general, reference is made in this regard to the pharmaceutical excipients described below. Preferably, the cores contain (a) in addition to fesoterodine (metabolite) also lubricants and / or additives to improve the flowability. Particularly preferably, the cores contain (a)

90 to 100% by weight, in particular 92.0 to 99.0% by weight of fesoterodine (metabolite); 0 to 10 wt .-%, in particular 0.5 to 4 wt .-% additives for improving the flowability; 0 to 10 wt .-%, in particular 0.5 to 4 wt .-% lubricant, based on the total weight of the core (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.

The term 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.

In a preferred embodiment, the shell (b) comprises the components (b 1) a non-water-soluble substance and (b2) a pore binder. Alternatively, 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.

For the purposes of the present invention, the term "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.

Examples of suitable non-water-soluble polymers are 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.

Preferably, polyvinyl alcohol is used. Furthermore, the polymethacrylates Eudragit ^® NE, Eudragit ^® RS / RL (Evonik). In the case of polymethacrylates as component (bl) is therefore preferably a polymer composed of structures according to the general formulas (3) and (4).

In the formulas (3) and (4) mean:

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.

Most preferably, 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.

As non-water-soluble substances (with polymer-like properties), waxes and fats can be used. Suitable waxes or fats are solid at 25 ^° C. For example, 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.

In addition to the non-water-soluble substance (bl), 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.

In principle, two preferred embodiments of the pore-forming agent are possible. On the one hand, 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. Examples of suitable hydrophilic groups are hydroxy, ethers, esters and amino. Further, 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.

If the polymer (b2-l) used as pore-forming agent is dissolved in water in an amount of 2% by weight, 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.

Polyethylene glycol is preferably used, in particular having a weight-average molecular weight of 2,000 to 10,000 g / mol.

Alternatively, 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 .

In principle, mixtures of said pore formers are possible.

The shell (b) may consist of the components (bl) and (b2). In a preferred embodiment, 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).

It has unexpectedly been found that the addition of the polymer with pH-dependent water solubility (b3) can unexpectedly favorably influence the pharmacokinetic data of the resulting formulation. It is preferred that the component (b3) is a polymer having less water solubility in the acid than in the neutral or alkaline. In particular, the polymer (b3) at pH 3 has a water solubility which is reduced by at least 50% compared with pH 7.

It is further preferred that 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.

It is preferred that 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.

Examples of 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.

In principle, polymers are also conceivable which fulfill both the definition of (b2) and of (b3). In the context of this invention, however, a polymer is used only as either component (b2) or component (b3).

As described above, in a preferred embodiment, the shell further contains plasticizer as component (b4). By "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 ).

Examples of suitable plasticizers are 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. Also, 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 individual areas mentioned can be combined as desired. For example, the shell contains (b)

(bl) 75 to 95% by weight, more preferably 80 to 90% by weight, non-water-soluble

polymer

(b2) 0, 1 to 20 wt .-% pore former, more preferably 0.5 to 15 wt .-%, in particular 0, 1 to 10 wt .-%, and

(b3) 0 to 20% by weight of polymer having a pH-dependent solubility, and / or

(b4) 0 to 20% by weight, more preferably 2 to 15% by weight, in particular 3 to 12% by weight

% Plasticizer, based on the total weight of the shell (b).

It is further preferred that the shell (b) consists essentially of the components (bl) to (b3). It is particularly preferred that the sheath (b) consists essentially of the

Ingredients (bl), (b2) and (b4) consists.

The amounts of core (a) and shell (b) used are preferably chosen so that the core is completely enveloped. The core is thus preferably completely encapsulated.

In a first embodiment, 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 μm, preferably 75 to 350 μm, more preferably 90 to 300 μm, particularly preferably 100 to 250 μm, in particular 110 to 220 microns, is.

The term "average particle diameter" in the context of this invention refers, unless stated otherwise, to the D50 value of the volume-average

Particle diameter, which was determined by laser diffractometry. Especially For the determination of the volume-average particle diameter, a Mastersizer 2000 from Malvern Instruments was used (wet measurement, 2000 rpm, liquid paraffin as dispersant, ultrasound 60 sec., evaluation according to the Fraunhofer method). 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.

In a second embodiment, 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.

Typically, in the intermediate according to the invention, 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. In an alternative embodiment, in the intermediate according to the invention, 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) 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:

(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.

It is preferred that in 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. In a second embodiment (ie in particular in the case of granulated or compressed cores (a)), 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.

In 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. In particular, 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. Preferably, 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, preferably 20% to 70 wt .-%, in particular 30 to 40% wt .-%, based on the total weight of the solution / suspension before.

In the subsequent step (iii), the solution from step (ii) is sprayed onto the fesoterodin and / or fesoterodin metabolite particles. Preferably, the spraying takes place in the fluidized bed.

In 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 .-%.

It is preferred that 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.

In a preferred embodiment, the process according to the invention is carried out in a fluidized-bed granulator, for example in a Glatt® GPCG 3 (Glatt GmbH, Germany). In addition to the method described above, intermediates obtainable by the process according to the invention are also the subject of this invention.

The intermediate of the invention (i.e., the encapsulated fesoterodine 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.

These are the adjuvants known to those skilled in the art, for example those described in the European Pharmacopoeia.

The ratio of active ingredient to auxiliaries is preferably chosen so that the resulting formulations

0.1 to 50 wt%, more preferably 0.5 to 40 wt%, even more preferably 1 to 30

Wt .-%, in particular 2 to 20 wt .-% fesoterodin and / or fesoterodin metabolites, and

50 to 99.9 wt .-%, 60 to 99.5 wt .-%, more preferably 70 to 99 wt .-%, in particular 80 to 98 wt .-% pharmaceutically acceptable excipients.

In this information, the amount of shell material (b) and optionally also the amount of excipients in the core (a), which was used for the preparation of the intermediate according to the invention, calculated as an adjuvant. That is, the amount of active ingredient refers to the amount of fesoterodine and / or fesoterodine metabolites contained in the formulation.

Examples of 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

Vegetable oil and kaolin. Also, silified microcrystalline cellulose (eg Prosolv® ^®, Save Painters & Söhne, Germany) can be used. The preferably used silified microcrystalline cellulose is commercially available and has a silica content of 1 to 3 wt .-%, preferably of 2 wt .-%, on. Also, 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.

As 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. Alternatively used are alkaline disintegrants. By alkaline disintegrating agents 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.

An example of an additive to improve the powder flowability is dispersed 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.

Furthermore, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, 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.

Furthermore, release agents can be used. By 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.

It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. For the purposes of this invention, 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. For example, microcrystalline cellulose - if used as a filler - not additionally used as a disintegrant (although microcrystalline cellulose also shows a certain explosive effect).

It is an advantage of the present invention that moisture stabilizers can be dispensed with. 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.

Preferably, 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

(a) mixing the intermediate according to the invention with pharmaceutical excipients; (b) compression to tablets, optionally with the addition of further pharmaceutical excipients; and (c) optionally, filming the tablets.

In step (a) intermediate according to the invention and further (above-described) pharmaceutical excipients are mixed. The mixing can be done in usual

Mixers done. For example, 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.

In 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.

Examples of suitable tableting machines are eccentric presses or concentric presses. For example, a Fette 102i (Fette GmbH, Germany) can be used. In the case of rotary presses, a pressing force of from 2 to 40 kN, preferably from 2.5 to 35 kN, is usually used. In the case of eccentric presses usually a pressing force of 1 to 20 kN, preferably from 2.5 to 10 kN, applied. For example, the Korsch ^® EKO is used.

In optional step (c) of the process according to the invention, the tablets from step (b) are film-coated. In this case, the usual in the prior art method for filming tablets can be used.

Preferably, 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.

It is preferred that the optionally applied film has substantially no effect on the release. Thus, they are preferably films without influence on the drug release. In the context of this invention, neither enteric film coatings nor delayed-release coatings are preferably used.

The Tablettierbedingungen 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.

Furthermore, 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. In addition, 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.

Finally, 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.

In an alternative embodiment, the tablets according to the invention are produced not by means of direct compression but by means of dry granulation and subsequent compression. In this case, 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

(al) mixing fesoterodine with an adhesion promoter and optionally further pharmaceutical excipients; (a2) compaction into a scab; (a2) granulation of the slug;

(B) compression of the resulting granules into tablets, optionally with the addition of other pharmaceutical excipients; and

(c) optionally, filming the tablets.

In 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.

In step (a3) of the process, the slug is granulated. The granulation can be carried out by methods known in the art. For example, the granulation is carried out with the device Comil ^® U5 (Quadro Engineering, USA). Furthermore, 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.

In a preferred embodiment, the granulation is carried out in a sieve mill. In this case, 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

60% of active ingredient after 24 hours measured according to USP (paddle, 900 ml assay medium in phosphate buffer at pH 6.8 and 37 ⁰ C), preferably at 50 rpm.

The intermediates and / or formulations according to the invention are preferred for

Treatment of over active bladder used. The invention thus relates to microencapsulated fesoterodine and / or fesoterodine metabolites according to the present invention for the treatment of the overactive bladder.

The invention will be illustrated by the following examples.

EXAMPLES

Example 1 Production of the Microencapsulated Fesoterodine According to the Invention

100 g of fesoterodine fumarate were in a fluidized bed apparatus (Glatt GPCG 3) with

75 g of a dispersion of ethyl cellulose and 5 g PEG 6000 coated.

The following parameters have been selected on the device:

Inlet temperature: 70 ° C, product temperature: 40 ⁰ C, volume flow 50 m ³ / h, spray pressure: 1.5 bar.

Example 2 Preparation of the Microencapsulated Fesoterodine According to the Invention

76 g of ethyl cellulose was dissolved together with 20 g of PEG 6000 in 90% ethanol.

The solution was used to cover 150 g of fesoterodine 5-HM fumarate in a fluid bed apparatus (Glatt GPCG 3).

The following parameters were selected on the device: Inlet temperature: 60 ⁰ C, product temperature 35 ° C, volume flow 45m3 / h. Example 3: Direct compression into tablets

The microencapsulated fesoterodine obtained from Example 1 or Example 2 was compressed to tablets on a rotary press. For this purpose, 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.

Example 4: Direct compression of compressed cores

Core (a):

For a batch of 300 g kernels, 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.

300 g of these cores (a) were mixed with 145 g of a shell-forming film (B) of Aquacoat ^® ECD 77% (bl), triethyl citrate (6% (b4), polyethylene glycol 2% (b2) and 15% water in a fluidized bed system Smooth GPC 3.1) coated.

An intermediate were then respectively (sheathed core) in Microcellac ^® (75% lactose, 25% microcrystalline cellulose) and 1% magnesium stearate trapped and compressed to a total weight of 320 mg and a hardness of 150 N to obtain tablets (form 12, 5 x 6.5 mm, content 4 mg). Example 5

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 6

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.

Example 7

The preparation was carried out as in Example 4, wherein in each case two intermediates (= microencapsulated cores) in Microcellac ^® (75% lactose, 25% microcrystalline cellulose) and 1% magnesium stearate were included and pressed to tablets having a total weight of 320 mg and a hardness of 150 N (form 12.5 x 6.5 mm, content 8 mg).

Example 8

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).

Claims

claims

1. Pharmaceutical Intermediate containing microencapsulated Fesoterodln and / or Fesoterodin metabolites.

2. Pharmaceutical Intermediate, composed of a core (a) and a shell (b), wherein

(a) the core contains fesoterodine and / or fesoterodine metabolites as active ingredient; and (b) the shell contains one or more pharmaceutical excipients containing the

Modify release of the active ingredient, wherein preferably the weight ratio of core (a) to shell (b) is 15: 1 to 1: 5.

3. Intermediate according to claim 2, wherein the shell comprises the constituents

(bl) non-water-soluble substance, preferably non-water-soluble polymer, and (b2) comprises pore-forming agent.

4. Intermediate according to claim 3, wherein the shell additionally contains the components (b3) polymer with a pH-dependent solubility, and / or

(b4) comprises plasticizer.

5. Intermediate according to claim 3 or 4, wherein the shell (bl) 75 to 95 wt .-% non-water-soluble polymer

(b2) 0, 1 to 20 wt .-% pore former

(b3) 0 to 20% by weight of polymer having a pH-dependent solubility, and (b4) 0 to 20% by weight of plasticizer.

6. Intermediate according to one of claims 1 to 5, wherein the intermediates are in the form of a particulate composition and the weight-average particle diameter is 1.5 to 4.5 mm.

7. Intermediate according to one of claims 1 to 6, wherein the active ingredient is fesoterodine hydrogen fumarate, fesoterodine fumarate, fesoterodine tartrate, fesotero- din-5-HM hydrogen fumarate or fesoterodine 5-HM fumarate.

8. A process for the preparation of a pharmaceutical intermediate according to any one of claims 1 to 7 comprising the steps: (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.

9. The method of claim 8, wherein in step (i) fesoterodine and / or fesoterodin metabolites are used with a weight-average Tecktegröße of 0.5 to 3.5 mm.

10. Intermediate, obtainable by a process according to claim 8 or 9.

11. A pharmaceutical formulation containing an intermediate according to any one of claims 1 to 7 and 10 and one or more pharmaceutical excipients.

12. A pharmaceutical formulation according to claim 1 1, wherein the active ingredient content is more than 5.0 wt .-% to 15 wt .-%, based on the total weight of the formulation.

13. A process for the preparation of a tablet containing a pharmaceutical formulation according to claim 11 or 12, comprising the steps:

(A) mixing an intermediate according to any one of claims 1 to 7 and 10 with pharmaceutical excipients;

(b) compression to tablets, optionally with the addition of further pharmaceutical excipients; and

(c) optionally, filming the tablets.

14. A tablet having a friability of less than 3%, with a content uniformity of 95 to 105% and a hardness of 80 to 200 N, containing a pharmaceutical formulation according to claim 11 or 12.

15. Microencapsulated fesoterodine and / or fesoterodine metabolite for the treatment of overactive bladder.