EP2566461A2 - Solid tapentadol in non-crystalline form - Google Patents

Solid tapentadol in non-crystalline form

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Publication number
EP2566461A2
EP2566461A2 EP11717513A EP11717513A EP2566461A2 EP 2566461 A2 EP2566461 A2 EP 2566461A2 EP 11717513 A EP11717513 A EP 11717513A EP 11717513 A EP11717513 A EP 11717513A EP 2566461 A2 EP2566461 A2 EP 2566461A2
Authority
EP
European Patent Office
Prior art keywords
tapentadol
intermediate
preferably
form
crystalline
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.)
Withdrawn
Application number
EP11717513A
Other languages
German (de)
French (fr)
Inventor
Jana Paetz
Daniela Stumm
Wolfgang Albrecht
Alexandre Mathieu
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
Priority to EP10004758 priority Critical
Application filed by ratiopharm GmbH filed Critical ratiopharm GmbH
Priority to EP11717513A priority patent/EP2566461A2/en
Priority to PCT/EP2011/002247 priority patent/WO2011138037A2/en
Publication of EP2566461A2 publication Critical patent/EP2566461A2/en
Application status is Withdrawn legal-status Critical

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

The invention relates to solid tapentadol in non-crystalline form in conjunction with a surface stabilizer in the form of a stable intermediate. The intermediate according to the invention comprises preferably tapentadol in an amorphous state or in the form of a solid solution. The invention further relates to the production of tapentadol in solid, non-crystalline form and of pharmaceutical formulations containing solid, non-crystalline tapentadol.

Description

Solid tapentadol in non-crystalline form

The invention relates to solid tapentadol in non-crystalline form together with a surface stabilizer in the form of a stable intermediate. In the novel intermediate tapentadol is preferably present in an amorphous form or in the form of a solid solution. The invention further relates to methods for the preparation of tapentadol in solid, non-crystalline form and pharmaceutical formulations containing solid, non-crystalline tapentadol.

Tapentadol is an analgesic, wherein the effect on two molecular mechanisms based. Firstly tapentadol activated as the opioids ^ receptors and thus dampens pre- and postsynaptic the transmission of pain stimuli in the spinal cord and brain. On the other tapentadol acts as a norepinephrine reuptake inhibitor, thereby increasing the concentration of this neurotransmitter substance in the synaptic cleft.

In this invention, the term "tapentadol" 3- (3-dimethylamino-l-ethyl-2-methyl-propyl) phenol is understood according to the following chemical formula (1).

Tapentadol (1)

3- (3-dimethylamino-l-ethyl-2-methyl-propyl) -phenol has two centers of asymmetry, so that the connection in the form of four different stereoisomers may be present. In this invention, 3- (3-dimethylamino-l-ethyl-2-methyl-propyl) can exist as a mixture of all four diastereomers in any mixing ratio, but also as a mixture of two or three of the four stereoisomers, or in stereoisomerically pure form phenol. Preferred stereoisomers are in this case (+) - (1S.2S) - 3- (3-dimethylamino-l-ethyl-2-methyl-propyl) phenol and (-) - (lR, 2R) -3- (3-dimethylamino l -ethyl-2-methyl-propyl} phenol, which is preferably as 1: 1 - mixture (racemate), or more preferably may be used in isomerically pure form in particular, (lS, 2R) -3- (3-dimethylamino-l -. ethyl-2-methyl-propyl) phenol (hereinafter also referred to as "(1R, 2R) -

(1r.2r) tapentadol (2) In this invention, tapentadol can be usually used in the form of free base or in the form of a pharmaceutically acceptable salt. The salts may be acid addition salts. Examples of suitable salts include hydrochlorides (eg monohydrochloride). Tapentadol is preferably used in free base form or in the form of the monohydrochloride. Tapentadol- monohydrochloride is particularly preferred.

Particularly in the context of this invention (lR, 2R) -Tapentadolmonohydrochlorid is used as an active ingredient. Alternatively, (lR, 2R) -Tapentadolbase is used as an active ingredient. Mixtures of said Tapentadole are also possible.

Synthesis routes for tapentadol crystalline and its use as an analgesic are described in EP 0693475 Al.

The inventors of the present application, however, were faced in the development of pharmaceutical formulations tapentadol with the fact that crystalline tapentadol can exist both as free base and as hydrochloride at various crystalline polymorphic forms. However, the individual polymorphs are optionally not stable, but tend to convert to other crystalline polymorphous forms. For example, the Tapentadolhydrochlorid frequently used can be transformed with the action of heat Form A in Form B, see WO 2006/00441 A2. This process is reversible again with decreasing temperature. Furthermore, the polymorphic forms described in WO 2009/071310 A, B and C of the Tapentadolbase have a different solubility profile.

The different solubility profile leads the patient to an undesirably uneven rise in level of the active ingredient. It is an object of the present invention to provide stable tapentadol-Intermediate ready to be made into a dosage form (after storage) allows gleichmaßige possible flooding in the patient. Both inter-individual and intra-individual variations are to be largely avoided.

It is an object of the present invention to overcome the aforementioned drawbacks. It should be provided in a form of the active ingredient, which has good flowability and thus makes it possible to ensure a good mixture was compressed to tablets by solvent-free manufacturing processes. It should be provided in a form in addition to the active ingredient, which does not tend to agglomerate. Further, should be guaranteed a uniform distribution of the active ingredient. Micronization of the drug should be avoided.

The dosage forms of tapentadol should be provided to ensure good solubility and bioavailability at the same time good storage stability.

All of the above tasks to be solved (drug load) in particular for a high drug content, in particular to ensure good patient compliance (compliance with medical therapy guidance from the patient). Furthermore, the tasks should both an immediate release formulation (immediate release or shortly "IR") and modified release (modified release or shortly "MR") is dissolved. In the case of oral dosage forms, modified release (MR) is to complete as possible a release of active ingredient can be achieved. Therefore, conventional slow-release matrix formulations should be avoided, as not release these usually up to 20% active ingredient. Furthermore, it must have a relatively high amount of excipient used in the matrix tablets of the prior art; this is not always beneficial and should be avoided. Moreover, it is required in the MR formulations of the prior art is that high-viscosity polymers are used. This is often not desirable, eg from toxicity considerations. It should therefore be provided a formulation of modified release, avoiding large amounts of highly viscous polymers. The objects could be solved unexpectedly by conversion of tapentadol, particularly crystalline tapentadol, in a solid, non-crystalline form, particularly in a stabilized amorphous form or in the form of a solid solution. Tapentadol object of the invention is therefore in solid, non-crystalline form, wherein the tapentadol is present together with a surface stabilizer. As part of this application, two possible embodiments for tapentadol are explained here in solid, non-crystalline form. The invention therefore relates in a first embodiment is an intermediate containing amorphous tapentadol and a surface stabilizer. This intermediate is amorphous tapentadol is stabilized.

In a second embodiment, the invention is an intermediate containing tapentadol in the form of a solid solution and a surface stabilizer. In this second embodiment, the surface stabilizer acts as a "matrix material" is present dispersed in the tapentadol molecularly disperse. The intermediate is a solid solution of tapentadol is in a stabilized form. The invention further Various methods for preparing solid, non-crystalline tapentadol in the form of intermediates of the invention.

Finally, the invention relates to pharmaceutical formulations containing solid, non-crystalline or tapentadol according to the invention, the invention stabilized tapentadol in the form of intermediates of the invention.

The first embodiment of the present invention relates to amorphous tapentadol. The term "amorphous" is used in this invention as a description of the state of solid materials, in which the components (atoms, ions, or molecules, that is, in the case of amorphous tapentadol the Tapentadolmoleküle) no periodic array over a wider range (= Remote Procedure) respectively. In amorphous materials the building blocks are usually not completely randomly and statistically placed, but distributed so that a certain regularity and similarity with the crystalline state with respect to distance and orientation of the nearest neighbors can be identified (= short-range order). Amorphous substances therefore preferably comprise a short-range order, but no long-range order. Further, usually has an amorphous material, in particular amorphous tapentadol, an average particle size of more than 300 nm. Solid amorphous materials are isotropic, unlike the anisotropic crystals. They usually have no definite melting point, but go slow gradually soften in the liquid state. Their experimental distinction of crystalline substances can be performed using X-ray diffraction, the sharp, but usually only a few diffuse interference at low diffraction angles provides for them.

In the first embodiment of this invention, the term "amorphous tapentadol" preferably refers to a substance consisting of amorphous tapentadol. Alternatively, "amorphous tapentadol" still contain small amounts of crystalline Tapentadolbestandteilen, with the proviso that it can be seen no defined melting point of crystalline tapentadol in DSC. Preferably, a mixture containing from 90 to 99.99 wt.% Amorphous tapentadol and 0.01 to 10% crystalline tapentadol, more preferably 95 to 99.9 weight .-% of amorphous tapentadol and 0, 1 to 5% crystalline tapentadol. The determination of the crystalline content is performed by quantitative X-ray diffractometry by the method of Hermans and Weidinger.

In the context of this first embodiment of the invention, the tapentadol invention is in stabilized form, namely in the form of an intermediate containing amorphous tapentadol and a surface stabilizer. In particular, the intermediate of the invention consists essentially of amorphous tapentadol and surface stabilizer. Provided that - as described below - in addition, a crystallization inhibitor is used as intermediate of the invention may consist essentially of amorphous tapentadol, surface stabilizer and crystallization inhibitor. The term "substantially" in this case has indicated that, if appropriate, small amounts of solvent, etc. may be included.

The second embodiment of the present invention relates tapentadol in the form of a solid solution. The term "solid solution" is to be understood in the context of this invention so that tapentadol in a matrix at 25 ° C and a pressure of

101 kPa is present in the solid state, is molecularly disperse distribution.

It is preferred that in this second embodiment intermediate of the invention (containing tapentadol in the form of a solid solution) containing substantially no crystalline or amorphous tapentadol. In particular less than 15 intermediate of the invention comprises wt .-%, more preferably less than 5 wt .-% of amorphous or crystalline tapentadol, based on the total weight of the intermediate present in the Tapentadols. By "crystalline" is generally understood as substances that build their smallest components of crystal structures, but also those substances which consist of tiny crystallites. The atoms, ions or molecules that make up the respective crystal substance, form characteristic arrangements, which repeat periodically, and therefore have long-range order on. Crystals are therefore anisotropic. An experimental identification of crystalline materials can be carried out using X-ray diffraction, which provides sharp interference pattern for crystalline materials. In contrast, an X-ray diffraction of amorphous substances does not provide sharp, but usually only a few diffuse interference at low diffraction angles.

It is therefore preferred to be understood by "molecular dispersion" that an X-ray diffraction analysis of the Tapentadols contained in the inventive embodiments provides no sharp interference pattern, but at most a few diffuse interference at low diffraction angles.

It is further preferred to "molecular dispersion" means that no intermediate of the invention tapentadol particles having a particle size greater than 300 nm, more of greater than 200 nm, in particular greater than 100 nm, preferably contains. The determination of particle size takes place in this connection by means of confocal Raman spectroscopy. The measuring system is preferably made of a Ntegra spectra Nano Finder the company NT-MDT.

In the second embodiment of this invention, the inventive solid solution of tapentadol is in a stabilized form, namely in the form of an intermediate containing molecularly dispersed tapentadol and a surface stabilizer (as the matrix material). In particular intermediate of the invention consists essentially of molecularly disperse tapentadol and matrix material. Provided that - as described below - in addition, a crystallization inhibitor is used, the intermediate of the present invention can consist essentially of molekulardispersem tapentadol, surface stabilizer and crystallization inhibitor. The term "substantially" in this case has indicated that, if appropriate, small amounts of solvent, etc. may be included.

In a preferred embodiment of the intermediate of the invention the surface stabilizer is used as the solid support for the non-crystalline tapentadol. Thus, the intermediate of the invention includes a surface stabilizer as a solid support, is applied to the solid carrier is not crystalline tapentadol. Preferably, non-crystalline tapentadol is applied to the surface stabilizer, that is, non-crystalline tapentadol is adsorbed on the surface of the surface stabilizer, preferably substantially uniformly adsorbed. The intermediate of the invention is thus preferably not a purely physical mixture of non-crystalline tapentadol and Oberflächenstabüisator.

Both embodiments of the present invention relate to an intermediate that contains a Oberflächenstabüisator. In the Oberflächenstabüisator is generally a substance which is suitable tapentadol to stabüisieren in amorphous form or in the form of a solid solution. It is preferable that in the Oberflächenstabüisator to a substance which is solid at 30 ° C. It is preferable that in the Oberflächenstabüisator a polymer. Furthermore, the Oberflächenstabüisator also includes substances that behave polymer-like. Examples include fats and waxes. Furthermore, the Oberflächenstabüisator includes solid, non-polymeric compounds, preferably having polar side groups. Examples include sugar alcohols or disaccharides. Another object of the invention is a method of identifying a pharmaceutical Hüfsstoffes suitable as Oberflächenstabüisator for fixed, non-crystalline (ie amorphous or tapentadol for tapentadol in the form of a solid solution), and thus can be used to HersteUung of the intermediate of the invention. The method comprises the steps of: a) providing a pharmaceutical Hüfsstoffs which exists at 25 ° C in the solid state. For this, the pharmaceutical Hüfsstoffe mentioned in the European Pharmacopoeia can be chosen in general.

b) twice, successively heating the solid Hüfsstoffs by DSC. Here, two warm-up curves are recorded by means of DSC. The curves are usually added from 20 ° C up to 20 ° C below the decomposition range of the substance to be tested.

To this end, a device from Mettler Toledo DSC can be used. 1 It is equipped with a heating rate of 1 -20 ° C / min, preferably 5 15 ° C / min and at a cooling rate of 5 - worked 20 ° C / min - 25 ° C / min, preferably 10 degrees. c 'suitable' as a) Selection of Hüfsstoffs, provided in the second DSC curve warm-up, it can be seen a glass transition point of 20 ° C to 120 ° C, preferably from 25 ° C to 100 ° C.

The invention also intermediates, the solid, non-crystalline tapentadol (ie amorphous tapentadol or tapentadol in the form of a solid solution) and a pharmaceutical Hüfsstoff selected by means of the method described above contain. The material used for the preparation of the intermediate of the invention the surface stabilizer is preferably a polymer. The solvent usable for the preparation of the intermediate polymer preferably has a glass transition temperature (Tg) and / or a melting point of greater than 20 ° C, preferably from 25 ° C to 220 ° C, more preferably from 30 ° C to 180 ° C, more preferably from 40 ° C to 100 ° C. A polymer having an appropriately selected Tg prevented by immobilization of the recrystallization of the amorphous Tapentadols or prevents the regression of molecular Tapentadoldispersion to colloids or particles.

As a "glass transition temperature" (Tg) refers to the temperature above at which amorphous or partially crystalline polymers from the solid state to the liquid state. Here occurs a significant change of physical characteristics such. As hardness and elasticity,. Below the Tg a polymer is usually glassy and hard, above the Tg, it turns into a rubber-like to viscous state. The determination of the glass transition temperature is in the context of this invention using dynamic Differenzkalorlmetrie (DSC). To this end, a device from Mettler Toledo DSC can be used. 1 It is equipped with a heating rate of 1 -20 ° C / min, preferably 5 15 ° C / min and at a cooling rate of 5-25 ° C / min, preferably carried out 10-20 ° C / min.

Further, preferably, the points might be used for preparing the intermediate polymer has a weight average molecular weight of 1,000 to 500,000 g / mol, more preferably from 2000 to 120,000 g / mol, even more preferably from 5000 to 90,000 g / mol, in particular from 10,000 to 75,000 g / mol, , The resulting solution is the polymer used for the preparation of the intermediate dissolved in water in an amount of 2 wt .-%, so typically exhibits a viscosity of less than 3000 mPa «s, preferably from 0, 1 to 2500 mPa-s, more preferably from 0.5 to 200 mPa * s, even more preferably from 1, 5 to 20 mPa's, particular from 2.0 to 15 mPa 's, measured at 20 ° C, and preferably in accordance with Ph. Eur., 6th edition, chapter 2.2.9 (capillary) is determined.

for the preparation of the intermediate hydrophilic polymers are preferably used. These refer to polymers having hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups. Hydroxy groups are preferred. The intermediate of the invention may comprise, for example, the following hydrophilic polymers as surface stabilizer: polysaccharides, such as hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC) (for example, L-HPC low substituted hydroxypropyl cellulose); microcrystalline cellulose, polyvinyl pyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ® VA64, BASF and Povidone ® VA64), polyalkylene glycols such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of the polyethylene glycols, particularly co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ®, BASF), and mixtures of said polymers.

It is preferred that the polymers used as surface stabilizer exhibit substantially no emulsifier. That is, the surface stabilizer used should preferably have no combination of hydrophilic and hydrophobic groups (in particular, hydrophobic fatty acid groups). Further, it is preferred that the intermediate of the present invention does not contain polymers having a weight average molecular weight of more than 150,000 g / mol. Such polymers, if appropriate, affect the dissolution properties in an undesirable manner.

As the surface stabilizer is particularly preferably used polyvinyl pyrrolidone, preferably having a weight average molecular weight from 10,000 to 80,000 g / mol, in particular from 12,000 to 60,000 g / mol, a copolymer of vinylpyrrolidone and vinyl acetate, particularly having a weight average molecular weight of 40,000 to 70,000 g / mol and / or polyethylene glycol, in particular having a weight average molecular weight of 2,000 to 10,000 g / mol, and HPMC, especially with a weight average molecular weight from 20,000 to 90,000 g / mol and / or preferably in a proportion of methyl groups of 10 to 35% and a proportion of hydroxy groups of 1 to 35%. Further, microcrystalline cellulose may preferably be used in particular those having a specific surface of 0.7 to 1, 4 m 2 / g. The determination of the specific surface area by gas adsorption method is carried out according to Brunauer, Emmet and Teller. The weight average molecular weight is preferably determined by gel permeation chromatography. The copolymer of vinylpyrrolidone and vinyl acetate preferably has the following structural unit.

The copolymer of vinyl pyrrolidone and vinyl acetate has shown here is particularly preferably a weight average molecular weight of 50,000 to 80,000g / mol. As surface stabilizer are furthermore particularly preferred co-block polymers of polyethylene glycol and polypropylene glycol, ie polyoxyethylene polyoxypropylene block polymers. Preferably, these have a weight average molecular weight of 1,000 to 20,000 g / mol, more preferably from 1500 to 12,500 g / mol, in particular 5,000 to 10,000 g / mol. These block polymers are preferably obtainable by condensation of propylene oxide with propylene glycol, and subsequent condensation of the resulting polymer with ethylene oxide. That is, preferably the ethylene oxide is present as "end block" before. Preferably, the block copolymers have a weight ratio of propylene oxide to ethylene oxide of 50: 50 to 95: 5, more preferably from 70: 30 to 90: 10 on. The block polymers preferably have a viscosity at 25 ° C of 200 to 2000 mPa-s, more preferably from 500 to 1500 mPa * s, particularly of 800 to 1200 mPa * s at.

Further, the surface stabilizer also includes solid, non-polymeric compounds, preferably having polar side groups. Examples include sugar alcohols or disaccharides. Examples of suitable sugar alcohols and / or disaccharides are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose, and mixtures thereof. The term sugar alcohols here also includes monosaccharides. In particular, mannitol, isomalt and sorbitol is used as a surface stabilizer. Furthermore, the surface stabilizer may also preferably silicates, more preferably magnesium aluminum silicates, more preferably magnesium aluminiummetasilikate, particularly preferably Al 2 0 3 MgO l, 7Si0 2 xH 2 0 (for example distributed as Neusilin ®) include. In a preferred embodiment, intermediate of the invention containing solid, non-crystalline tapentadol (ie amorphous tapentadol or tapentadol in the form of a solid solution) and surface stabilizer, wherein the weight ratio of solid, non-crystalline tapentadol to surface stabilizer 10: 1 to 1: 10, more preferably 5: 1 to 1: 3, more preferably 3: 1 to 1: 2, in particular 2: 1 to 1: 1, 5 is. For example, tapentadol and surface stabilizer, in a ratio of 1: are used. 1

In a particularly preferred embodiment, intermediate of the invention containing solid, non-crystalline tapentadol hydrochloride (ie amorphous tapentadol hydrochloride or tapentadol hydrochloride in the form of a solid solution) and magnesium aluminum silicate as a surface stabilizer, preferably Al 2 0 3 MgO l, 7Si0 2 xH 2 0, where typically the weight ratio of solid, non-crystalline tapentadol hydrochloride to the magnesium aluminum silicate 5: 1 to 1: 3, more preferably 4: 1 to 1: 2, more preferably 3: 1 to 1: 1, 5, more preferably 2: 1 to 1: 1.4, in particular 1, 8: 1 to 1: 1, 3. For example, tapentadol hydrochloride and magnesium aluminum silicate in a ratio of 1: 0 are used 1: 1, in particular 1, 0th

It is preferred that the type and amount of the surface stabilizer are chosen such that the resulting intermediate having a glass transition temperature (Tg) of more than 18 ° C, preferably more than 20 ° C, even more preferably more than 25 ° C. The resulting intermediate further has a Tg of less than 180 ° C, more preferably of less than 120 ° C, especially less than 80 ° C.

It is preferred that the type and amount of the polymer are selected so that the resulting intermediate is stable on storage. By "storage-stable" is meant that in the intermediate of the invention after 3 years storage at 25 ° C and 50% relative humidity, the proportion of crystalline Tapentadol - based on the total amount of tapentadol - maximum of 60 wt .-%, preferably at most 30 wt. - % more preferably at most 15 wt .-%, particularly 5 wt .-% maximum, is.

It is advantageous if the surface stabilizer is used in particulate form, wherein the volume average particle size (D50) μπι less than 500, preferably 5 to 250 μτη, more preferably 25 to 150 μπι, is. In a preferred embodiment intermediates of the invention (in addition to amorphous tapentadol or tapentadol in the form of a solid solution dh) and surface stabilizer in addition to solid, non-crystalline tapentadol or a crystallization inhibitor based on an inorganic salt, an organic acid, a silicate or a polymer having a weight average molecular weight (Mw) of greater than 500,000 g / mol. This, as crystallization inhibitor suitable polymers are referred to in this invention as "highly viscous polymer". Their weight-average molecular weight is typically less than 5,000,000 g / mol. A preferred high viscosity polymer is polyvinylpyrrolidone (povidone).

It is preferable that in the crystallization inhibitor is ammonium chloride, citric acid, Magnesiumaluminiummetasilikat (especially marketed as Neusilin ®), or Povidone K 90 (according to Ph. Eur. 6.0). The crystallization inhibitor can be more used preferably from 5 to 20 wt .-%, based on the total weight of the intermediate in general in an amount of 1 to 30%, preferably from 2 to 25 wt .-%. The Intermediate invention are obtainable by different production processes. Depending on the production process, the intermediates are obtained in different particle sizes. Typically, intermediates of the invention are in particulate form and have an average particle diameter (D 50) 1-750 μτη, preferably 5 to 400 μτη on, depending on the manufacturing process.

The term "average particle diameter" is determined in this invention by means of laser diffractometry. In particular, a Mastersizer was used to determine 2000 by Malvern Instruments (wet measurement with ultrasound for 60 seconds, 2000 rpm, with the evaluation according to the Fraunhofer model is carried out), and preferred to use a dispersant in which the substance to be measured does not dissolve at 20 ° C.

The "average particle diameter", which is also referred to as D50-value of the integral volume distribution is defined in this invention as the particle diameter at which 50 volume% of the particles have a diameter smaller than the diameter corresponding to the D50-value , Likewise, then 50% by volume of the particles have a diameter greater than the D50 value. In a preferred embodiment, intermediate of the invention, in particular the intermediate containing non-crystalline tapentadol hydrochloride, a water content of 0.01 to 15 wt .-%, more preferably 0.50 wt .-% to 12 wt .-%, more more preferably from 1, 5 to 10 wt .-%, especially 4 to 9% by weight, on. The residual water content is determined by the Karl Fischer method, wherein a coulometer is used at 160 ° C. a Metrohm 831 KF Coulometer with titration cell without diaphragm is preferably used. Typically, a sample of 20 mg intermediate is analyzed. It was found unexpectedly that a deviating water content to undesirably high recrystallization rate leads. It has been shown that a different water content would adversely affect the fluidity and with a high content of active substance (drug load) and the uniformity of content (Content Unjformlty).

The invention further provides processes for preparing the intermediates according to the invention. Hereinafter, five preferred embodiments of such methods will be explained. The methods (1) to (3) are in this case both for the preparation of amorphous tapentadol (- embodiment of the first intermediate of the invention) and of tapentadol in the form of a solid solution preferably (second embodiment of the intermediate of the invention). Method (4) and (5) are preferably used for the preparation of amorphous tapentadol. In particular method (3) for the preparation of amorphous tapentadol and / or tapentadol is used in the form of a solid solution.

In a first preferred method, the invention relates to a "method Pelletlayering-", ie, a method of preparing an intermediate according to the invention, comprising the steps of:

(Al) dissolving the Tapentadols and the surface stabilizer in an

Solvent or solvent mixture, and

(Bl) spraying the solution from step (al) to a support core.

In step (al) tapentadol and the surface stabilizer described above is dissolved in a solvent or solvent mixture, preferably completely dissolved. this crystalline tapentadol is preferably used. It is further preferred that tapentadol is used in the form of the acid addition salts described above, for example, tapentadol monohydrochloride can be advantageously employed. Alternatively Tapentadolbase can be used.

Suitable solvents are for example water, alcohol (eg methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol or mixtures thereof. a mixture of water and ethanol is preferably used.

Suitable surface stabilizers are suitable in this first procedure, particularly modified celluloses, such as HPMC (preferably having a weight average molecular weight from 20,000 to 90,000 g / mol), sugar alcohols such as mannitol, isomalt and sorbitol, and polyethylene glycol, especially polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol. Further, it is preferably a copolymer of vinylpyrrolidone and vinyl acetate, used in particular with a weight-average molecular weight of 50,000 to 80,000g / mol.

Provided that the produced intermediate to contain a crystallization inhibitor based on an inorganic salt or an organic acid or of a highly viscous polymer, in addition, it can also be added in step (al). The type or quantity of the crystallization inhibitor, reference is made to the above statements. In step (bl) is carried out a spraying of the solution of step (al) to a support core. As the carrier cores are particles consisting of pharmaceutically acceptable excipients, in particular so-called "neutral pellets". Pellets are preferably used, which are available under the trade name Cellets ® and containing a mixture of lactose and microcrystalline cellulose or Sugarspheres representing a mixture of starch and sugar.

Is preferably carried out step (bl) in a fluidized bed dryer, for example, in a Glatt GPCG ® 3 (Glatt GmbH, Germany). Typically, with air inlet temperatures of 50 to 100 ° C, preferably from 60 to 80 ° C, with product temperatures of 25 to 50 ° C, preferably from 30 to 40 ° C and with a spray pressure 0.9 to 2.5 bar, preferably 1-1, 5 bar, worked.

Depending on the choice of starting materials in step (al) and the process parameters in step (b 1) may contain in amorphous form or in the form of a solid solution, the resulting intermediate tapentadol.

The process conditions are preferably selected in this initial procedure is that the resulting intermediate particles μτη a volume average particle diameter (D50) of 50 to 800, more preferably μηι 150-550, in particular 180 to 350 μπι having.

In a second preferred method, the invention relates to a spray drying process for preparing the intermediate of the invention, comprising the steps of

(A2) dissolving of tapentadol and the surface stabilizer in a solvent or solvent mixture, and

(B2) spray drying the solution of step (a2).

In step (a2) tapentadol and the above-described matrix material is dissolved in a solvent or solvent mixture, preferably completely dissolved. crystalline tapentadol is preferably used. It is further preferred that tapentadol is used in the form of the acid addition salts described above, for example, tapentadol dihydrochloride can be advantageously employed.

Suitable solvents are for example water, alcohol (eg methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol or mixtures thereof. An ethanol / water mixture is preferably used. Suitable surface stabilizers, particularly modified celluloses, such as HPMC are suitable in this procedure (preferably having a weight average molecular weight from 20,000 to 90,000 g / mol), polyvinylpyrrolidone and copolymers thereof, for example copolymers with vinyl acetate, polyvinylpyrrolidone or copolymers thereof preferably has a weight average molecular weight from 20,000 to 80,000 g / mol, as well as sugar alcohols such as mannitol, isomalt and sorbitol.

Provided that the produced intermediate to contain a crystallization inhibitor based on an inorganic salt or an organic acid or of a highly viscous polymer, in addition, it can also be added in step (a2). The type or quantity of the crystallization inhibitor, reference is made to the above statements.

In the subsequent step (b2) is carried out by spray drying the solution of step (a2). Spray drying is usually carried out in a spray tower. For example, a Buchi B-191 is suitable (Buchi Labortechnik GmbH, Germany). an inlet temperature of 100 ° C to 150 ° C is preferably selected. The amount of air is, for example 500 to 700 liters / hour and the aspirator runs preferably at 80 to 100%.

Depending on the choice of starting materials in step (a2) and the process parameters in step (b2) may contain the resulting intermediate tapentadol in amorphous form or in the form of a solid solution. The process conditions are preferably chosen in this second procedure is that the resulting intermediate particles μπι a volume average particle diameter (D50) of 1 to 250, more preferably μπι from 2 to 100, μτη still more preferably 3 to 50 in, especially from 4 to 25, respectively. In a further preferred embodiment of the spray-drying may contain one or more adjuvants, in particular, fillers such as microcrystalline cellulose, can be added. In this case, the resultant intermediate particles have μτη a volume average particle diameter (D50) of 1 to 250, more preferably μπι from 2 to 150, even more preferably μτη from 5 to 120, especially from 10 to 90 μτ η .. In a third preferred method, the invention relates to a melt processing, preferably melt-extrusion process, ie a process for preparing the intermediate of the invention, comprising the steps of

(A3) mixing of tapentadol and surface stabilizer, and

(B3) melt processing, preferably extruding the mixture, wherein the melt processing conditions, preferably extrusion conditions are chosen such that a transition takes place from a crystalline to non-crystalline tapentadol.

In step (a3) ​​is preferably mixed with the crystalline tapentadol surface stabilizer in a mixer. In this procedure, the inventive method is preferably a matrix material (ie, a surface stabilizer) is used in polymeric form. It is further preferred that tapentadol is used in the form of free base. Alternatively Tapentadol- HCl can be used, for example. As polymeric surface stabilizers, in particular polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohols, methacrylates, PEG and HPMC are suitable in this third procedure. The weight average molecular weight of the polymers used is usually from 4000 to 80,000 g / mol, preferably 6000-80000 g / mol.

Provided that the produced intermediate to contain a crystallization inhibitor based on an inorganic salt or an organic acid or of a highly viscous polymer, in addition, it can also be added in step (a3). The type or quantity of the crystallization inhibitor, reference is made to the above statements.

In step (b3) a melt processing is carried out, preferably an extrusion of the mixture. As part of the melt processing (b3) tapentadol is with the - processed surface stabilizer so that tapentadol is embedded in non-crystalline form in the surface stabilizer - preferably polymeric, especially thermoplastic. Melt processing can be preferably carried out as melt granulation or melt extrusion.

The mixture of step (a3) ​​is usually processed in the extruder to a homogeneous melt. The extrusion conditions are selected so that a transition from crystalline to non-crystalline carried tapentadol.

As usual extruder melt extruder can be used, such as a Leistritz Micro ® 18. The melt processing temperature or extrusion temperature depends on the type of matrix material. Usually, it is between 80 and 250 ° C, preferably between 100 and 180 ° C, in particular between 105 to 150 ° C. The extrusion is preferably performed at an outlet pressure of 10 bar to 100 bar, more preferably from 20 to 80 bar.

The cooled melt is usually (by a rasp for example Comil comminuted 'and, consequently, subjected to a uniform grain size. It has been unexpectedly found that the grain size of the resulting intermediate (especially in the case of melt extrusion as well as intermediates, the method according to the invention by the other were obtained) on the release properties has considerable influence.

Thus, it is preferred that intermediates, which are used for a pharmaceutical modified release formulation, to be screened with a sieve with a mesh size of greater than 0.71 mm. In particular, here sieves with a mesh size of greater than 0.71 mm to 1 is used 5 mm.

It is also preferred that intermediates, which are used for a pharmaceutical immediate release formulation, be with a sieve having a mesh size of 0.71 mm or smaller sieved. In particular, screens are used with a screen size from 0.4 to 0.71 mm here.

Depending on the choice of starting materials in step (a3) ​​and the process parameters in step (b3) may include the resulting intermediate tapentadol in amorphous form or in the form of a solid solution. In particular, it has been found suitable that the extruder is provided with a kneading unit, if tapentadol is to be obtained in the form of a solid solution. The kneading unit shall be so designed that an intensive mixing is ensured so that a solution of tapentadol is guaranteed in the surface stabilizer.

The process conditions are preferably selected in this third procedure is that the resulting intermediate particles have a volume-average particle diameter (D50) from 150 to 1000 μτα, more preferably have a D50 of 200 to 600 / <m.

Instead of granulating the extrudate a "direct injection" can also be carried out. In this case, the inventive method comprises the step of

(C3) injection molding of the extrudate into molds for pharmaceutical dosage forms. Examples are forms for tablets.

In a fourth preferred method, the invention relates to a freeze-drying process, ie a process for preparing the intermediate of the invention, comprising the steps of (a4) solving the Tapentadols, preferably the crystalline Tapentadols and the surface stabilizer, in a solvent or solvent mixture, and

(B4) freeze-drying the solution of step (a4).

In step (a4) is dissolved tapentadol, preferably crystalline tapentadol and the surface stabilizer described above in a solvent or solvent mixture, preferably completely dissolved. It is further preferred that tapentadol is used in the form of the acid addition salts described above, for example, tapentadol monohydrochloride can be advantageously employed. Alternatively Tapentadolbase can be used.

Suitable solvents are for example water, alcohol (eg methanol, ethanol, isopropanol), whore suitable sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol or mixtures thereof. a mixture of water and ethanol is preferably used.

(- weight from 20,000 to 90,000 g / mol preferably having a weight average molecular), and sugar alcohols such as isomalt, mannitol and sorbitol as surface stabilizers, particularly modified celluloses, such as HPMC are suitable in this procedure.

Provided that the produced intermediate to contain a crystallization inhibitor based on an inorganic salt or an organic acid or of a highly viscous polymer, in addition, it can also be added in step (a4). The type or quantity of the crystallization inhibitor, reference is made to the above statements.

The solution from step (a4) is cooled to about 10 to 50 ° C below the freezing point (ie brought to freezing). The solvent is then removed by sublimation. This is preferably done when the conductivity of the solution is less than 2%. The sublimation temperature is preferably determined by the intersection of product temperature and Rx - 10 ° C. is sublimated preferably at a pressure of less than 0, 1 mbar.

After sublimation, the lyophilized intermediate is warmed to room temperature.

The process conditions are preferably selected in this fourth procedure is that the resulting intermediate particles μτα a volume average particle diameter (D50) of 0.5 to 250, more preferably μπι from 1 to 150, in particular from 5 to 100 μηι having.

In a fifth preferred procedure, the invention relates to a grinding process, ie a process for preparing the intermediate of the invention, comprising the steps of

(A5) mixing of tapentadol, preferably of crystalline tapentadol and surface stabilizer, and

, Preferably amorphous tapentadol is performed (b5) milling the mixture of step (a5), the milling conditions are preferably selected so that a transition from crystalline to non-crystalline.

Preferably crystalline tapentadol and surface stabilizer are mixed in step (a5). The mixture is milled in step (b5). The mixing can take place before or during the grinding, ie steps (a5) and (b5) can occur simultaneously.

Provided that the produced intermediate to contain a crystallization inhibitor based on an inorganic salt or an organic acid in addition, this may also in step (a5) or (b5) are added. The type or quantity of the crystallization inhibitor is made to the foregoing.

The milling conditions are preferably selected so that a transition from crystalline to amorphous takes place tapentadol.

The grinding is generally carried out in conventional grinding apparatus, preferably in a ball mill, for example in a Retsch PM ® 100. The meal is usually 10 minutes to 10 hours, preferably 30 minutes to 8 hours, more preferably 2 hours to 6 hours.

As surface stabilizers, in particular polyvinylpyrrolidone, modified celluloses, such as HPMC, sugar alcohols such as isomalt and sorbitol, and polyethylene glycol, especially polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol are suitable in this fifth procedure.

The process conditions are preferably chosen in this fifth procedure so that the resulting intermediate particles have a volume-average particle diameter (D 50) of from 0, 1 to 350 / in, more preferably from 1 to 120 μπι, in particular from 5 to 90 μπι having. In a sixth preferred method, the invention relates to a process for the preparation of the inventive intermediate, comprising the steps of

(A6) dissolving the Tapentadols, preferably the crystalline Tapentadols, in a solvent or solvent mixture,

(B6) adding the surface stabilizer, and

(C6) removing the solvent or of the solvent mixture, preferably wherein tapentadol is adsorbed in non-crystalline form at the surface of the surface stabilizer.

In step (a6) is tapentadol, preferably crystalline tapentadol, dissolved in a solvent or solvent mixture, preferably completely dissolved. the release of the tapentadol with stirring, for example using the methods known from prior art stirrers is preferred reached.

Suitable solvents are for example water, alcohol (eg methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol or mixtures thereof. a mixture of water and alcohol, preferably ethanol and / or isopropanol is preferably used.

In step (b6) the addition of the surface stabilizer is carried out, preferably with stirring with the above stirrers. The surface stabilizer is preferably added in solid form. Here, a solution or, preferably, a suspension may form. The addition of the surface stabilizer may preferably also take place in portions.

Step (b6) may comprise the further stirring the resulting solution or suspension. This is preferably the formation of a homogeneous distribution of the components.

As surface stabilizers, in particular magnesium aluminum silicates such as Al 2 0 3 MgO l, 7Si0 2 xH 2 0, sugar alcohols such as mannitol, isomalt and sorbitol, and polyethylene glycol are suitable in this procedure, in particular polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol. Further, it is preferably a copolymer of vinylpyrrolidone and vinyl acetate, particularly having a weight average molecular weight of 50,000 to 80,000g / mol, or polyvinyl pyrrolidone, preferably having a weight average molecular weight from 10,000 to 80,000 g / mol. Magnesium aluminum silicates are particularly preferred. The use of magnesium aluminum silicate in this embodiment leads to an intermediate with particularly good flowability. The removal of the solvent or of the solvent mixture (c6) may be warming up to or slightly above the boiling point of the solvent or of the solvent mixture is evaporated by heating, is preferred. Alternatively, the evaporation of the solvent or of the solvent mixture under reduced pressure can be carried out. Furthermore, the solvent or the solvent mixture may be vaporized by heating and under reduced pressure. For evaporation of the solvent or of the solvent mixture known in the prior art devices can be used, for example, the Rotavapor ® R-210 / R215 Buchi or Laborota 20 large Heidolph rotary evaporator.

The steps (a6), (b6) and (c6) are preferably carried out so that tapentadol is "mounted" onto the surface stabilizer. That is, the steps (a6), (b6) and (c6) are preferably carried out so that non-crystalline tapentadol adsorbed on the surface of the surface stabilizer, is preferably substantially uniformly adsorbed.

The intermediate of the invention (ie, the inventive stabilized non-crystalline tapentadol) is commonly used for the preparation of a pharmaceutical formulation.

By "intermediate" it is meant a pharmaceutical composition the present invention which is not yet available in the form of a dosage form to be administered. To produce a dosage form to be administered (in this application referred to as "pharmaceutical formulation"), the intermediate can be filled, for example in sachets or capsules or, preferably compressed into tablets. The processing of the intermediate in a pharmaceutical formulation can be carried out with or without the addition of pharmaceutical excipients. Auxiliaries are preferably added.

The invention therefore provides a pharmaceutical formulation containing intermediate of the invention as well as pharmaceutical adjuvants. These are the known to the expert excipients, such as those described in the European Pharmacopoeia.

Examples of excipients used are disintegrants, release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, lubricants, wetting agents, gelling agents and / or lubricants. If appropriate, other auxiliaries can still be used. The ratio of active ingredient to excipients is preferably selected such that the resulting formulations

1 to 80 wt .-%, more preferably 5 to 60 wt .-%, in particular 10 to 40 wt .-% non-crystalline tapentadol, and

20 to 99 wt .-%, more preferably 40 to 95 wt .-%, in particular 60 to 90 wt .-% pharmaceutically acceptable excipients.

These figures, the amount of surface stabilizer that has been used to prepare the intermediate of the invention, calculated as adjuvant. That is, the amount of active ingredient refers to the amount of non-crystalline tapentadol that is included in the formulation.

It has been shown that intermediates of the invention are suitable for both modified can briefly as a basis for a dosage form with immediate release [immediate release or shortly "IR") and modified release (release or "MR") are used.

In a preferred embodiment for an IR formulation is used a relatively high amount of disintegrant. In this preferred embodiment, therefore, the pharmaceutical formulation of the invention

1 to 30 wt .-%, more preferably 3 to 15 wt .-%, particularly 5 to 12 wt .-% disintegrant, based on the total weight of the formulation. Furthermore, it is preferred that these IR formulation containing intermediate of the invention, which was equipped with a sieve having a mesh size of 0.71 mm or smaller sieved. Also, the intermediate was prepared by means of melt granulation for this preferred IR formulation. Suitable disintegrants are generally referred to substances which accelerate the disintegration of a dosage form, especially a tablet, after introduction into water. Suitable disintegrants are, for example organic disintegrating agent such as carrageenan, croscarmellose and crospovidone. alkaline disintegrating agents may also be used. Under alkaline disintegrants disintegrants are to understand that generate when dissolved in water a pH of more than 7.0.

More preferably inorganic alkaline disintegrants are used, in particular salts of alkali and alkaline earth metals. Preferred here sodium, potassium, magnesium and calcium may be mentioned. As anions, carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples include sodium bicarbonate, sodium hydrogen phosphate, calcium hydrogen carbonate and the like.

Particularly preferred is crospovidone or sodium bicarbonate as a disintegrant, especially in the amounts mentioned above, is used.

In a preferred embodiment for an MR formulation a relatively small amount is used of disintegrant. In this preferred embodiment, therefore, the pharmaceutical formulation of the invention

0 to 10 wt .-%, more preferably 0.5 to 8 wt .-%, particularly 1 to 5 wt .-% disintegrant, based on the total weight of the formulation.

Furthermore, it is preferred that these MR formulation contains intermediate of the invention, which was sieved with a sieve having a mesh size of greater than 0.71 mm. Also, the intermediate was prepared by means of melt granulation for this preferred MR formulation.

In the case of MR formulation croscarmellose or crospovidone is preferable as the disintegrant.

Furthermore, the pharmaceutical formulation preferably contains (for both IR and MR) one or more of said excipients in the European Pharmacopoeia. These are explained in more detail below. The formulation of the invention preferably contains fillers. Among fillers, substances are to be understood in general, the (wt .-%, for example less than 70), which serve to form a good quantity to be processed, in particular for formation of the tablet body in tablets with low amounts of active compound. That is, fillers produce by "stretching" the active compounds sufficient mass, particularly tabletting mass.

Examples of preferred fillers are starch, starch derivatives, processed starch, talc, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride and / or potassium chloride. Also, siliconized microcrystalline cellulose (Prosolv® ®, Rettenmaier & Söhne, Germany) can be used.

Fillers are usually used in an amount of 0 to 40 wt .-%, more preferably from 1 to 25 wt .-%, based on the total weight of the formulation. Furthermore adjuvants used to improve the powder flowability. An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ®. Is preferably silica having a specific surface area of 50 to 400 m 2 / g, especially 100 to 250 m 2 / g, as determined by gas adsorption according to Ph. Eur., 6th edition 2.9.26. Used.

Additives to improve the powder flowability are typically used in an amount of 0, 1 to 3 wt .-%, based on the total weight of the formulation.

Further, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction to be reduced, which is during tableting the one hand between the die bore in the up and down moving punches and the die wall, and on the other hand between tablets web and die wall. Suitable lubricants are for example stearic acid, adipic acid, sodium stearyl fumarate (Pruv ®, for example) and / or magnesium stearate is. Lubricants are usually added in an amount of 0, 1 to 5 wt .-%, preferably 0.5 to 3 wt .-%, based on the total weight of the formulation.

It is in the nature of pharmaceutical excipients, that these partially more than one role in a pharmaceutical formulation. In this invention, the fiction applies for unambiguous definition therefore preferable that a substance which is used as a particular excipient is not at the same time also used as further pharmaceutical excipient. For example, mannitol is used as long as surface stabilizer, not even used in addition as a filler.

The pharmaceutical formulation of the invention is preferably compressed into tablets. This wet granulation is used for the currently marketed under the name Nucynta ® products. It has, however, shown that the properties of the resulting tablets can be improved (eg with regard to the drug stability) when the wet granulation is avoided.

The intermediates of the invention are, therefore, pressed into tablets or by direct compression subject before pressing to a tablet dry granulation. Intermediate having a bulk density of less than 0.5 g / ml are preferably processed by dry granulation.

A direct compression is particularly preferred, is carried out when the preparation of the intermediate (by melt extrusion (steps a3) and (b3) or Pelletlayering (process steps (al) and (bl)}.

A dry granulation is particularly preferred, or grinding (process steps (a5) and (b5)) is carried out when the preparation of the intermediate means of spray drying ((steps a2) and (b2)), freeze drying (a4) and (b4) (method steps).

A further aspect of the present invention relates to a process comprising the steps Trockengranulier-

(I) providing the intermediate of the invention and one or more

(In particular those described above) pharmaceutical excipients;

(II) compacting into a slug; and

(III) granulating or crushing the flakes. In step (I) intermediate of the invention and auxiliary agents are preferably mixed. The mixing can be effected in conventional mixers. Alternatively, it is possible that the tapentadol intermediate (50 to 95%, for example) is first with only a part of the excipients are mixed prior to compaction, (II), and that the remaining part of the excipients after the granulation step (III) is added. should in the case of multi fachkompaktierung admixing the excipients preferably prior to the first compaction step, carried out between a plurality of compacting steps or after the final granulation.

In step (II) of the process according to the invention is compacted, the mixture of step (I) into a slug. It is preferred that it is a dry compaction, that is, the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.

The compacting is usually chosen so that intermediate of the invention in the form of a compacted material (slug) is present, wherein the density of the intermediate from 0.8 to 1, 3 g / cm 3, preferably 0.9 to 1, 20 g / cm 3, in particular from 1 01 to 1 15 g / cm 3.

The term "density" refers here preferably to the "true density" (that is, not on the apparent density or compressed density). The true density can be measured with a gas pycnometer. Preferably The gas pycnometer a helium pycnometer, especially the AccuPyc 1340 helium pycnometer from the manufacturer Micromeritics, used Germany.

The compaction is preferably carried out in a roll granulator. The rolling force is usually 5 to 70 kN / cm roll width, preferably 10 to 60 kN / cm, more preferably 15 to 50 kN / cm.

The gap width of the roll 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 (III) of the process, the slug is granulated. The granulation can be carried out with methods known in the art.

In a preferred embodiment, the granulation conditions are chosen such that the resulting particles (pellets) have a volume average particle size (D (50) value) of 50 to 800 μτη, more preferably μιη 100-650, more preferably 130-500 μτη, in particular 180-350 μτη. In a preferred embodiment, the granulation is performed in a screening mill. In this case, the mesh size of the sieve insert is usually from 0, 1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, particularly 0.8 to 1, 8 mm.

From step (III) the resulting granules may be processed into pharmaceutical dosage forms. For this purpose, the granules are filled, for example in sachets or capsules. from step (III) is preferred resulting granules compressed into tablets (= step IV).

In step (IV) of the process are pressed, the granules obtained in step (III) into tablets, ie there is a compression into tablets. The compression can be done by means known in the art tableting machines. Eccentric or rotary presses are used. In the case of rotary presses is usually a pressing force of 2 to 40 kN, preferably from 2.5 to 35 kN applied. In the case of eccentric is usually a pressing force of 1 up to 20 kN, preferably from 2.5 to 10 kN applied. For example, the Riva Piccola is used. In step (IV) of the process, pharmaceutical excipients are optionally added to the granules of step (III). The amounts of excipients are added in step (IV), usually depend on the type of tablet to be produced and on the amount of excipients which has been added already in the steps (I) or (II). In the case of direct compression, only the steps (I) and (IV) of the process described above are carried out.

The tableting conditions are preferably chosen so that the resulting tablets have a ratio of tablet height to weight from 0.005 to 0.3 mm / mg, more preferably 0.01 to 0.2 mm / mg.

The inventive method is preferably carried out so that the tablet of the invention tapentadol in an amount of more than 20 mg to 50 mg, more from 30 mg to 350 mg, especially 50 mg to 250 mg, preferably contains. The subject of the invention are tablets containing 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg or 350 mg tapentadol in non- crystalline form.

Further, preferably, the resulting tablets have a hardness of 50 to 300 N, more preferably from 80 to 250 N, particularly 100 to 220 N, on. The hardness is according to Ph.Eur. 6.0, Section 2.9.8 determined.

Moreover, the resulting tablets preferably have a friability of less than 3%, particularly preferably less than 2%, in particular less than 1%. The friability, according Ph.Eur. 6.0, Section 2.9.7 determined.

Finally, tablets of the invention typically comprise a uniformity of content [Content Uniformity) of 95 to 105%, preferably 98 -102%, in particular 99-101% of the average content. (This means that all tablets have an active ingredient content between 95 and 105%, preferably 98-102%, in particular between 99 and 101% of the average drug content.) The "Content uniformity" is in accordance with Ph. Eur.6.0, Section 2.9.6 , certainly. The release profile of the tablets of the invention in the case of the IR formulation according to the USP method (type II paddle, 0, 1 n HCl, 37 ° C, 75 rpm) after 10 minutes, usually a released content of at least 30%, preferably at least 60 %, in particular at least 90%, on. The release profile of the tablets of the invention usually has, in the case of an MR formulation according to USP method (Type II, paddle, 0, 1 n HCl, 37 ° C, 75 rpm) after 60 minutes a content released 10%, preferably 20%, in particular 30%, on.

The above information about hardness, friability, content uniformity and release profile preferably relate here to the film-coated tablet for an IR formulation. For a modified release tablet, the release profile refers to the total formulation.

The polymers prepared by the present process tablets may be tablets that are swallowed whole (unbefilmt or preferably film-coated). Also it may be chewable or dispersible tablets. "Dispersible" a tablet for preparation of an aqueous suspension is understood to mean for oral use.

In the case of tablets which are swallowed whole, it is preferred that these are coated with a film layer. Here, the usual in the art of film-coating tablets may apply. However, the ratios of active ingredient to the excipient mentioned above refer to the uncoated tablet.

For the film-coating macromolecular substances are preferably used, for example, modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, Zein and / or shellac, or natural gum, such as carrageenan.

The layer thickness of the coating is preferably 1 to 100 μτη, in particular 5 μτα to 75 miles. The pharmaceutical formulations of the invention are usually characterized by a release and absorption, which take advantage of values of AUC [, Area other curve "area max under the plasma concentration curve from 0 to 48 hours after oral administration), advantageous values of C (maximum plasma level), and advantageous values of T result max (the time of reaching the maximum plasma concentration after peroral administration).

In a preferred embodiment, the oral administration of the formulations according to the invention leads to a human patient to a plasma level profile defined by a T max with respect to the active ingredient, tapentadol from about 0.5 to 4, preferably, 1, 5, 3.0 hours for IR formulations and 0.5 to 7.0 preferably 1, characterized from 0 to 6.0 hours for MR formulations. In a preferred embodiment, the oral administration of the formulations according to the invention leads to a human patient to a plasma level profile that is characterized by a C max with respect to the active ingredient, tapentadol of about 35-210 ng / ml, preferably 40 to 180 ng / ml for IR formulations, and 5 to 90 ng / ml, preferably 10 to 60 ng / ml for MR characterized formulations.

In a preferred embodiment, the oral administration of the formulations of the invention / ml leads to a human patient to a plasma level profile that is characterized by an AUC regarding the active agent tapentadol from about 100 to 1000 ng h / ml, preferably 130 to 850 ng h for IR formulations and about 40-850 ng h / ml, preferably 50 to 800 ng h / ml for MR formulations distinguished.

The plasma levels above values ​​are preferably average values ​​obtained by examination of blood samples of a group of 10 subjects (with an average of 70 kg body weight), the corresponding blood samples 0, 1, 3, 4, 6, 8, 24 and 48 hours after oral administration of the inventive formulation were taken. The determination is preferably carried out as in Bauer, Fromming, leader of "Textbook of Pharmaceutical Technology", 8th edition, 2006, Chapter 7.4, in particular pages 207 to 214, described below.

In a preferred embodiment, the pharmaceutical formulations of the invention as an analgesic, for example for the treatment of chronic back pain, are used. Particularly preferred is the treatment of groups of patients suffering from disorders of blood pressure or cardiac rhythm is.

The invention thus also provides a tablet comprising from 50 to 500 mg of tapentadol, wherein the tablet has a hardness of 50 to 250 N, a friability of less than 3% and a content uniformity of 95 to 105%, and wherein the administration with respect to the tapentadol active ingredient to a T max of 0.5 to 6 hours, preferably 1 to 5 hours, a C max 5-210 ng / ml, preferably from 10 to 180 ng / ml and to an AUC from 40 to 1000 ng h / ml, preferably from 50 to 800 ng h / ml, resulting. In the inventive tablet, tapentadol is preferably in the form of the intermediate of the invention. The administration of the tablet according to the invention is preferably carried out once or twice daily. The invention will be illustrated by the following examples. EXAMPLES

Example la: Preparation of an intermediate containing amorphous

tapentadol HCl

0.2 g of crystalline (l R, 2R) -Tapentadol hydrochloride (Form A) were dissolved under stirring in 2 ml of water and 12 ml isopropanol. To this was added 0.2 g of Al 2 0 3 MgO l, 7Si0 2 xH 2 0 (Neusilin ®), and the suspension was stirred at 23 ° C for 5 minutes. After removing the solvent mixture in a rotary evaporator the intermediate was present as a white solid.

In XRPD sharp, but only a few diffuse interference were visible, see Figure 1. This resulted in that the tapentadol HCl was in an amorphous structure.

The measurements for the X-ray were on a D8 ADVANCE X-ray diffractometer for Pulverdiffraktometrieanwendungen Bruker AXS, Karlsruhe, Germany, carried out and analyzed using the program EVA from Bruker AXS. The following measurement conditions were as follows:

Radiation: CuK

Source: 38 KV / 40mA

2Θ- range / °: 2 <2Θ <55

Step Size / 0: 0017

Example lb: Preparation of an intermediate containing amorphous

tapentadol HCl

2 g of crystalline (lR, 2R) -Tapentadol hydrochloride (Form A) were dissolved with stirring in 10 ml of water and 10 ml isopropanol. To this was added 0.2 g of Al 2 0 3 MgO l, 7Si0 2 xH 2 0 (Neusilin ®), and the suspension was stirred at 23 ° C for 10 minutes. After removing the solvent mixture in a rotary evaporator the intermediate was present as a white solid. In XRPD sharp, but only a few diffuse interference could be seen. This resulted in that the tapentadol HCl was present in an amorphous structure. Example lc Preparation of an intermediate containing amorphous tapentadol HCl

0.2 g of crystalline (l R, 2R) -Tapentadol hydrochloride (Form A) were dissolved with stirring in 3 ml of water and 10 ml isopropanol. To this was added 0.2 g of polyvinylpyrrolidone (Kollidon ® 30) and the suspension stirred at 23 ° C for 5 minutes. After removing the solvent mixture in a rotary evaporator the intermediate was present as a white solid. In XRPD sharp, but only a few diffuse interference could be seen. This resulted in that the tapentadol HCl was present in an amorphous structure.

Example 2a: Preparation of the intermediate containing amorphous tapentadol HCl by lyophilization

Following approach for 100 dosage forms was made.

5 g of crystalline (lR, 2R) -Tapentadol hydrochloride was dissolved in water / ethanol together with 3 g of mannitol. This solution was up to -55 ° C under cooling and allowed to freezing. When the conductivity of less than 2% had been reached, the frozen mass is at a temperature (as determined by the intersection of the product temperature and Rx - 10 °, and a pressure of less than 0, 1 mbar) and the solvent removed by sublimation.

After drying, the lyophilized material was cooled to room temperature (20 - 25 ° C) accommodated.

Further processing was carried out according to Example 5 or the sixth

Example 2b: Preparation of the intermediate containing amorphous tapentadol base by lyophilization

The following mixture for 20 dosage forms was prepared.

1 g of crystalline (l R, 2R) -Tapentadol-base was dissolved in water / ethanol along with 5 g of HPMC. This solution was up to -55 ° C under cooling and allowed to freezing. When the conductivity of less than 2% had been reached, the frozen mass is at a temperature (as determined by the intersection of the product temperature and Rx - 10 °, and a pressure of less than 0, 1 mbar) and the solvent removed by sublimation. After drying, the lyophilized material was cooled to room temperature (20 - 25 ° C) accommodated.

Further processing was carried out according to Example 5 or the sixth Example 3a: Preparation of the intermediate containing tapentadol base in a solid solution form by melt extrusion, in particular for IR formulations

The following approach to 10,000 forms was made.

500 g (lR, 2R) -Tapentadol base (in crystalline form) were combined with 800 g Povidone ® VA64 and at a temperature of 90 cascade - extruded extruder Leistritz Micro 18 - 180 ° C. in a melt. The twin-screw extruder was provided with various screw elements. A kneading unit was installed to ensure the required mixing and solution of Tapentadols in the polymer (surface stabilizer). The extrudates were cooled.

Further processing was carried out by screening on a Comil ® U5 (0.50 mm) according to Example 6a.

Example 3b: Preparation of the intermediate containing tapentadol base in a solid solution form by melt extrusion, in particular for MR formulations following approach 10,000 forms of administration was prepared.

500 g (l R, 2R) -Tapentadol base (in crystalline form) were combined with 800 g Povidone ® VA64 and at a temperature cascade 90-180 ° C is extruded in a melt extruder Leistritz micro 18th The twin-screw extruder was provided with various screw elements. A kneading unit was installed to ensure the required mixing and solution of Tapentadols in the polymer (Oberflächenstabiliator). The extrudates were cooled.

Further processing was carried out by screening on a Comil ® U5 (1, 00 mm) according to Example 6b. Example 4 Preparation of the Intermediate by spray-drying

Following approach for 100 dosage forms was made. 5 g of crystalline (l R, 2R) -Tapentadol base was dissolved with 4 g of HPMC and 0.5 g of citric acid in water / ethanol, and spray-dried in a spray tower Büchi ® TYPE B 191st The following parameters were observed here:

Temperature 130 ° C, spray rate 5-20%, aspirator 35 to 90%, flow control 300 to 700 L / h.

The spray dried material was further dried cabinet for 24 h at 30 ° C in Hordentrocken-. By adding microcrystalline cellulose to spray suspension the release properties could be positively influenced.

The further processing was carried out by screening on a Comil ® U5 (0.71 mm) according to Example 5. Fig.

Example 5: Preparation of tablets by dry granulation

To prepare tablets following formulation was used. 1. Intermediate of Example 4 95 mg

2. Prosolv ® 90,230 mg

3. Magnesium stearate 1 5 mg

4. Aerosil 3.0 mg

5. Crospovidone 4.0 mg

The ingredients 1, 2 and 5 were premixed for 10 min and control sieved through a 1 mm sieve 25 in a free fall mixer (Turbula T10B ®). This mixture was compacted with 70% of the components 3 and 4 by means of roller compactor and screened with a mesh size of 1 25 mm. The compacted material was mixed with the remaining substances and compressed into tablets.

Example 6a: Preparation of tablets by direct compression IR

To prepare tablets following formulation was used. 1. intermediate according to Example 3a 130 mg

2. Calcium hydrogen phosphate 120 mg

3. Magnesium stearate 2 mg

4. Aerosü ® 3 mg

5. Crospovidone 20 mg

6. Na bicarbonate 25 mg

The intermediate from Example 3 was mixed with calcium hydrogen phosphate, sodium bicarbonate and crospovidone 15 minutes in free fall mixer (Turbula ® T10B) and sieved (1, 25 mm) and then the two remaining excipients were added and mixed for 5 minutes. The final mixture was pressed in an eccentric press of type EK0 (Korsch).

Example 6b: Preparation of tablets by direct compression MR

To prepare tablets following formulation was used.

1. intermediate according to Example 3b 130 mg

2. Calcium hydrogen phosphate 120 mg

3. Magnesium stearate 2 mg

4. Aerosü ® 3 mg

5. Crospovidone 10 mg

The intermediate from Example 3b was mixed with calcium hydrogen phosphate and crospovidone 15 minutes in free fall mixer (Turbula T10B ®) and sieved (1, 25 mm) and then the two remaining excipients were added and mixed for 5 minutes. The final mixture was pressed in an eccentric press of type EK0 (Korsch).

Claims

claims
1. intermediate containing tapentadol in solid, non-crystalline form, and one surface stabilizer.
2. intermediate according to claim 1, containing tapentadol in the form of a solid solution and a surface stabilizer.
3. intermediate according to claim 1, containing tapentadol in an amorphous form and a surface stabilizer.
4. Intermediate according to any of claims 1 to 3, characterized in that (lR-2R) -Tapentadol hydrochloride or (lR-2R) -Tapentadol is in the form of free base.
5. Intermediate according to any of claims 1 to 4, characterized in that it is at the surface stabilizer is a magnesium aluminum silicate, a sugar alcohol, polyvinylpyrrolidone or a copolymer of vinylpyrrolidone and vinyl acetate.
6. Intermediate according to one of claims 1 to 5, characterized in that the weight ratio of tapentadol surface stabilizer to 10: 1 to 1: 10th
7. intermediate according to any one of claims 1 to 6, comprising Tapentadol- hydrochloride and magnesium aluminum silicate, wherein the weight ratio of tapentadol hydrochloride to magnesium aluminum silicate 5: 1 to 1: 3.
8. intermediate according to any one of claims 1 to 7, characterized in that it additionally comprises a crystallization inhibitor based on an inorganic salt, an organic acid, a polymer having a weight average molecular weight of more than 500,000 g / mol, a silicate or mixtures thereof.
9. A process for preparing an intermediate according to any one of claims 1 to 8, comprising the steps of
(A6) dissolving the Tapentadols, preferably the crystalline Tapentadols, in a solvent or solvent mixture,
(B6) adding the surface stabilizer, and (c6) removing the solvent or of the solvent mixture, wherein tapentadol is adsorbed in non-crystalline form at the surface of the surface stabilizer.
10. A process for preparing an intermediate according to any one of claims 1 to 8, comprising the steps of
(A2) dissolving of tapentadol and the surface stabilizer in a solvent or solvent mixture, and
(B2) spray drying the solution of step (a2).
1 1. A method of preparing an intermediate (a4) according to any one of claims 1 to 8, comprising the steps of dissolving of tapentadol and the surface stabilizer in an
Solvent or solvent mixture, and
(B4) freeze-drying the solution of step (a4).
12 intermediate, obtainable by a process according to any one of claims 9-1. 1
13. A pharmaceutical formulation comprising non-crystalline tapentadol in the form of an intermediate of any of claims 1 to 8 and 12 and optionally at least one other pharmaceutical excipient.
14. The pharmaceutical formulation according to claim 13, comprising non-crystalline tapentadol in the form of an intermediate of any of claims 1 to 8 and 12, wherein the intermediate was sieved through a sieve having a mesh size of greater than 0.71 mm and it involves a formulation These sustained release;
or
non-crystalline tapentadol in the form of an intermediate of any of claims 1 to 8 and 12, wherein the intermediate was through a sieve having a mesh size of 0.71 mm or less screened and it is an immediate release formulation.
15. Tablet containing 50 to 500 mg of tapentadol, wherein the tablet has a hardness of 50 to 250 N, a friability of less than 3% and a content uniformity of 95 to 105%, and wherein the administration of the drug with respect to a T tapentadol max of 0.5 to 6 hours, resulting in a C max of 5 to 200 ng / ml, as well as to an AUC from 40 to 1000 ng h / ml.
EP11717513A 2010-05-05 2011-05-05 Solid tapentadol in non-crystalline form Withdrawn EP2566461A2 (en)

Priority Applications (3)

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EP11717513A EP2566461A2 (en) 2010-05-05 2011-05-05 Solid tapentadol in non-crystalline form
PCT/EP2011/002247 WO2011138037A2 (en) 2010-05-05 2011-05-05 Solid tapentadol in non-crystalline form

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WO2014023652A1 (en) * 2012-08-06 2014-02-13 Ratiopharm Gmbh Pharmaceutical formulation comprising tapentadol and cyclodextrin
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