EP2445484A1

EP2445484A1 - Aprepitant in the form of a solid solution

Info

Publication number: EP2445484A1
Application number: EP09776827A
Authority: EP
Inventors: Rainer Alles
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2009-06-24
Filing date: 2009-06-24
Publication date: 2012-05-02
Also published as: WO2010149183A1

Abstract

The invention relates to a method for producing an intermediate containing aprepitant and matrix material, wherein aprepitant is present in the form of a solid solution.

Description

Aprepitant in the form of a solid solution

The invention relates to a process for the preparation of an intermediate containing aprepitant and matrix material, wherein aprepitant prevails in the form of a solid solution

According to the EMEA review report, aprepitant is a neurokinin 1 receptor antagonist (hereafter referred to as the "NK1 receptor antagonist") that blocks the binding of a chemical substance (substance P) to the NK1 receptors in the human body NKI receptor antagonists such as aprepitant block the receptors and can prevent nausea and vomiting

The IUPAC name of aprepitant [INN] is 5 - [[(2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy] -3- (4- fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3H-1,4-triazole-3-one

The chemical structure of aprepitant is shown in formula (1) below

(1) Aprepitant

The synthesis of aprepitant has been described in US 5,719,147

Is aprepitant under the trade name Emend ^® as a hard gelatin capsule containing 40, 80 or 125 mg aprepitant marketed Aprepitant is only sparingly soluble in order to ensure the required bioavailability in aqueous environment, crystalline aprepitant must be used in nanoparticular form (see WO 03/49718 and EMEA "Scientific Discussion" for Emend ^®, 2004)

However, nanoparticulation (= conversion into a nanoparticulate composition by means of comminution processes, in particular grinding processes) of aprepitant involves some disadvantages. First, the nanonization results in an active substance with undesirably low flowability. Furthermore, the nanonized active substance is more difficult and expensive due to liver-damaging side effects from the point of view of occupational safety handle by the strong Enlargement of the surface during nanonization also increases the oxidation sensitivity of the drug.

Aprepitant is also obtainable by coprazipation in amorphous form, see WO 2007/016582 Al. However, active ingredients in amorphous form often show disadvantageous properties in terms of storage stability. WO 2008/1 10534 describes a pellet layering process for the production of aprepitant particles. However, these are not advantageous to tablets processed.

Object of the present invention was therefore to overcome the disadvantages mentioned above. It is intended to provide the active ingredient in a form which has good flowability, thus making it possible not only to process capsules but also to ensure good compression into tablets. It is also intended to provide the active ingredient in a form that does not tend to agglomerate. Furthermore, a uniform distribution of the active ingredient should be ensured. A grinding of the active ingredient to nanoparticles should be avoided.

Furthermore, aprepitant should be provided in a form which allows a high uniformity of content (content uniformity), especially at low drug content.

It was also an object of the present invention to provide aprepitant in a form which allows the patient to be flooded as uniformly as possible. Both interindividual and intraindividual deviations should be largely avoided. The uniformity of the solubility profile for aprepitant formulations is important here, in particular because of the narrow therapeutic breadth of the aprepitant.

Furthermore, the active ingredient should be provided in a form which ensures good solubility and good bioavailability while maintaining good storage stability.

Finally, it is intended to provide an aprepitant formulation which allows for administration (particularly with the above advantages) independently of meals.

The objects could be solved unexpectedly by converting aprepitant, in particular crystalline aprepitant, into the form of a solid solution.

The invention therefore relates to processes for the preparation of an intermediate containing aprepitant and matrix material, wherein aprepitant is present in the matrix material in the form of a solid solution, comprising the steps (a) mixing aprepitant and matrix material IaI, and

(b) extruding the mixture.

The resulting intermediate is a solid solution of aprepitant in stabilized form and is also an object of the present invention.

The invention furthermore relates to pharmaceutical formulations containing the inventive aprepitant in the form of a solid solution or in the form of the intermediate according to the invention.

Finally, the subject of the invention is the use of a pharmaceutical formulation containing an NKI receptor antagonist, in particular aprepitant, in the form of a solid solution for the prevention or treatment of nausea and / or vomiting, the administration taking place independently of the meals.

In the context of this invention, the term "aprepitant" encompasses 5 - [[(2R, 3S) -2 - [(IR) -I- [3,5-bis (trifluoro-methyl) phenyl] ethoxy] -3- (4- fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3H-1,4-triazol-3-one according to formula (1) above. In addition, the term "aprepitant" includes all pharmaceutically-acceptable salts, hydrates and solvates thereof. For example, aprepitant can be used in the form of the hydrochloride. Preferably, aprepitant is used in the form of the free base.

The term "solid solution" in the context of this invention is to be understood as meaning that aprepitant is predominantly distributed in a molecular manner in a matrix which is in a solid state of aggregation at 25.degree. Molecularly dispersed means here that substantially no aprepitant particles are present anymore. In the context of this invention, it should be the case that substantially no aprepitant particles are present if no aprepitant particles can be identified by means of confocal Raman spectroscopy.

To determine the presence or absence of particular aprepitant, a Raman spectrometer NTEGRA-Spektra Nanofinder from NT-MDT is preferably used. The following parameters were used in the measurements carried out (laser 488 nm (Ar laser), grating 600, objective 10Ox, PH 100 μm).

In the context of this invention, the solid solution of aprepitant according to the invention is present in stabilized form, namely in the form of an intermediate containing molecularly dispersed aprepitant and a matrix material. In particular, the intermediate according to the invention consists essentially of molecularly disperse aprepitant and matrix material. If, as described below, a crystallization inhibitor is additionally used, the intermediate according to the invention can be composed essentially of molecularly dispersed aprepitant, matrix material and Kristallisatlonsinhibitor consist The term "substantially" here indicates that, if necessary, small amounts of solvent etc. may be included

The matrix material is generally a substance which is suitable for stabilizing aprepitant in the form of a solid solution. Preferably, the matrix material is a polymer

Matrix material also substances that behave polymer-like examples are

Fats and Waxes Furthermore, the matrix material comprises solid, non-polymeric

Compounds which preferably have polar side groups Examples of these are sugar alcohols or disaccharides. Finally, the term comprises matrix material

Surfactants, in particular surfactants, which are in solid form at room temperature

Another object of the invention is a method for identifying a pharmaceutical Hdfsstoffs, which is suitable as a matrix material for a solid aprepitant solution, and thus can be used for the preparation of the intermediate according to the invention The method comprises the steps

a) Provision of aprepitant, a pharmaceutical excipient which is in solid state at 25 ° C., and a 1 l mixture of aprepitant and hips; b) heating the solid adjuvant twice by means of DSC and identification of the glass transition temperature of the excipient (Tg _HUf ) , c) heating the active substance aprepitant twice by means of DSC and identification of the glass transition temperature of the active ingredient (Tg _nPR j, d) heating a mixture of aprepitant and heme 1 1 1 twice by means of DSC and identification of the glass transition temperature of the mixture (Tg _Mlx ), and e) Selection of the excipient as "suitable" if Tg ^ lies between Tg _Hllf and Tg _nP ^

Here two Aufwarmkurven by means of DSC was added The curves are usually from 20 ° C to a maximum of 20 ⁰ C below the decomposition range of the added substance to be tested, the term "1 1 mixture" refers to a mixture of 50 wt -% aprepitant and 50 percent -% hemp produced by mixing

For this purpose, a device of Mettler Toledo DSC 1 can be used. It is used at a heating rate of 1-20 ° C / min, preferably 5-15 ° C / min or with a cooling rate of 5-25 ° C / min, preferably 10 -20 ° C / min, worked

The invention also provides an intermediate of molecularly disperse aprepitant and a pharmaceutical excipient as matrix material, wherein the

Hüfsstoff was identified according to the above method, and preferably the

Weight ratio of aprepitant to matrix material 5 1 to 1 50, more preferred The invention also relates to the use of a pharmaceutical excipient obtainable by a process according to claim 13 for the preparation of a pharmaceutical formulation comprising an NK1 receptor antagonist, in particular aprepitant, in the form of a solid solution

The material used for the production of the inventive intermediate matrix material is preferably a polymer usable for the preparation of the intermediate polymer preferably has a glass transition temperature (Tg) of great 20 ⁰ C, more preferably from 30 ⁰ C to 130 ⁰ C, in particular from 40 ⁰ C to 120 ° C A polymer having an appropriately selected Tg prevented by immobilization of the rear formation of the molecular dispersion to aprepitant colloids or particles

The term "glass transition temperature" (Tg) refers to the temperature at which amorphous or teύkπstalline polymers transition from the solid state to the liquid state. There is a marked change in physical characteristics, such as hardness and elasticity. Below the Tg is usually a polymer glassy and hard, above the Tg it goes into a rubbery to viscous state on the determination of the glass transition temperature is carried out in the context of this invention by means of dynamic Differenzkaloπmetrie (DSC)

For this purpose, a device of Mettler Toledo DSC 1 can be used. It is used at a heating rate of 1 -20 ° C / min, preferably 5-15 ° C / min or with a cooling rate of 5-25 ⁰ C / min, preferably 10-20 ⁰ C / min worked

Further, the polymer usable for the preparation of the intermediate preferably has a number average molecular weight of 1,000 to 500,000 g / mol, more preferably 2,000 to 90,000 g / mol. If the polymer used for the preparation of the intermediate is in water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of 0.1 to 18 mPa / s, more preferably 0.5 to 15 mPa / s, in particular 1 to 8 mPa / s, measured at 25 ^° C.

Hydrophilic polymers are preferably used for the preparation of the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, ester groups, keto groups, sulfonate, carboxylate and quaternary ammonium groups

The intermediate according to the invention may comprise, for example, the following hydrophilic polymers as matrix material: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), microcrystalline cellulose, polyvinylpyrrolidone, Polyvlnylacetat (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ^® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably, polyethylene glycol, co-block polymers of the polyethylene glycol, in particular co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ^®, BASF), polyethylene oxide and mixtures of said polymers.

Polyvinylpyrrolidone, preferably having a weight-average molecular weight of 10,000 to 60,000 g / mol, in particular 12,000 to 40,000 g / mol, copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of 45,000 to 75,000 g / mol and / or polymers are preferably used as the matrix material the acrylic acid and its salts, in particular having a weight-average molecular weight of 50,000 to 250,000 g / mol, and HPMC, in particular having a weight-average molecular weight of 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of 10 to 35% and a proportion at hydroxy groups from 1 to 35%. Furthermore, preference may be given to using microcrystalline cellulose, in particular those having a specific surface area of 0.7-1.4 m ² / g. The specific surface area is determined using the gas adsorption method of Brunauer, Emmet and Teller. The determination of the weight average molecular weight is usually carried out by means of light scattering method.

In a first particularly preferred embodiment, the matrix material used is a copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of 45,000 to 75,000 g / mol. The copolymer can be characterized by the following structural formula:

In a second particularly preferred embodiment, polymers of acrylic acid or salts thereof (also referred to as acrylic polymers) are used as the matrix material. This is preferably a polymer composed of structures according to the general formulas (2) and (3).

In the formulas (2) and (3) 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 or an ethyl radical;

R _{3 is} a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a

Methyl;

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 group or -CH ₂ -CH ₂ -N (CH ₃ J ₂ or -CH ₂ -CH ₂ -N (CHs) ₃ ⁺ Halogen ^'

(In particular Cl) as a substituted alkyl radical.

The acrylic polymer usually contains structures according to formulas (2) and (3) in molar ratios of 1:40 to 40: 1. The ratio of structures according to formula (2) to structures according to formula (3) is preferably 2: 1 to 1 1, in particular 1: 1. If R _{4 is} -COO-CH ₂ -CH ₂ -N (CH ₃ I ₃ ⁺ Cl-, the ratio of structures of the formula (2) to structures of the formula (3) is preferably 20 : 1 to 40: 1.

If an alternating polymerization in the ratio of 1 1, preferably results in a polymer according to the formula (2 + 3)

(2 + 3) Particularly preferred are polyacrylates according to the above formulas (2) and (3), wherein R ₁ and R _{3 are} alkyl, especially methyl, R _{2 is} methyl or butyl, preferably methyl, and R _{4 is} -COO-CH ₂ -CH ₂ -N (CH J is ₂ ₃ preferably, amounts in this case the ratio of structures of the formula (2) to structures of the formula (3). 1: 1 a suitable polymer has in particular a weight average molecular weight from 50,000 to 250,000 g / mol, more preferably from 120,000 up to 180,000 g / mol, on

In a preferred embodiment, the intermediate according to the invention contains aprepitant and matrix material, the weight ratio of aprepitant to matrix material being 5: 1 to 1:50, more preferably 2: 1 to 1:20, even more preferably 1 to 1 to 10, in particular 1: 2 to 1: 5 amounts.

In a preferred embodiment, the intermediate according to the invention is a "single-phase" intermediate. By this is meant that matrix material and molecularly dispersed aprepitant are substantially homogeneously distributed.

It is preferred that the type and amount of the matrix material and the amount of the aprepitant be chosen so that the resulting intermediate has a glass transition temperature (Tg) of 20 ⁰ C or greater, preferably 20 ⁰ C to 120 ⁰ C.

It is preferred that the type and amount of the polymer be chosen so that the resulting intermediate storage is stable. By "storage stable" is meant that in the intermediate according to the invention after 3 years of storage at both 25 ° C and 60% relative humidity and at 30 ⁰ C and 65% relative humidity, the proportion of crystalline aprepitant - based on the total amount of aprepitant - not more than 30% by weight, preferably not more than 10% by weight, more preferably not more than 5% by weight, in particular not more than 2% by weight.

In a preferred embodiment, the intermediates according to the invention additionally contain, in addition to aprepitant and matrix material, a crystallization inhibitor based on an inorganic salt, an organic acid or a high molecular weight polymer having an average molecular weight of greater than 500,000 g / mol.

In the context of this invention, these polymers suitable as crystallization inhibitors are also referred to as "highly viscous polymers." Their weight-average molecular weight is usually below 5,000,000 g / mol. A preferred highly viscous polymer is povidone K90. The crystallization inhibitor is preferably ammonium chloride, citric acid or povidone K 90 (according to Ph. Eur. 6.0).

The crystallization inhibitor may generally be used in an amount of from 1 to 30% by weight, preferably from 2 to 25% by weight, more preferably from 5 to 20% by weight, based on the total weight of the intermediate.

The preferred embodiments of aprepitant, matrix material and the optional crystallization inhibitor have been explained above. In the process according to the invention, these starting materials are processed by means of melt extrusion to give an intermediate which contains aprepitant in the form of a solid solution.

The inventive melt extrusion process comprises the steps:

(a) mixing aprepitant and matrix material and optionally

Crystallization inhibitor, and (b) extruding the mixture.

In step (a), aprepitant is mixed with the matrix material, preferably in a mixer. If the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, it may also be added in step (a). With regard to the nature and amount of the crystallization inhibitor, reference is made to the above statements.

The mixing can be done in conventional mixers. This premixing takes place, for example, in compulsory mixers, container mixers, drum mixers or in free-fall mixers. When mixed in compulsory mixers usually times of 1 to 20, preferably 3 to 15 minutes are needed to achieve a homogeneous mixture. When using free-fall mixers for example by means of Turbula ^® T 1OB (Bachofen AG, Switzerland) or container mixers eg CM 500 (J. Engelsmann AG, Germany) or drum mixers such as type Rhonradmischer (J. Engelsmann AG, Germany) are usually times of 10 to 20 Minutes needed to produce the homogeneous mixture.

In a preferred embodiment, aprepitant is used in particulate form in step (a). This is preferably aprepitant in non-micronized form. Preferably, aprepitant having a volume average particle size of from 20 to 300 μm, more preferably from 30 to 200 μm, even more preferably from 40 to 100 μm, is used. In step (b), the mixture is extruded. The mixture from step (a) is usually processed in the extruder to a homogeneous melt.

As extruder conventional melt extruder can be used. The screw profile of the extruder preferably contains kneading blocks. The shearing forces generated thereby contribute to the melting of the mixture and thus to the dissolution of the active ingredient in the matrix material. For example, a Leistritz Micro 18 is used.

The extrusion temperature depends on the type of matrix material. It is usually between 50 and 250 ^° C., preferably between 100 and 200 ^° C. The extrusion preferably takes place at an outlet pressure of 10 bar to 100 bar, more preferably at 20 to 80 bar.

The cooled melt is comminuted usually by a rasp (eg Comill ^® U5) and, consequently, subjected to uniform grain size.

The process conditions in this embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D50) of 150 to 1000 μm, more preferably a D50 of 250 to 600 μm.

The term "average particle diameter" in the context of this invention refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry. In particular, a Mastersizer 2000 from Malvern Instruments was used for the determination (wet measurement with ultrasound 60 sec, 2000 rpm, the evaluation being carried out according to the Fraunhofer model and preferably a dispersant being used in which the substance to be measured does not dissolve). 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 volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value.

The resulting process product, ie the intermediate according to the invention which is obtainable by the process according to the invention, is usually used for the preparation of a pharmaceutical formulation, in particular for the preparation of a pharmaceutical formulation for oral administration. For example, the formulations may be bottled in sachets or capsules. Preferably, the formulations can be compressed into tablets. The invention therefore relates to a pharmaceutical formulation comprising the intermediate according to the invention and pharmaceutical excipients

These are the auxiliaries known to the person skilled in the art, for example those described in the European Pharmacopoeia

Examples of auxiliaries used are disintegrants, release agents, emulsifiers, pseudo-emulsifiers, fillers, additives for improving the powder flowability, lubricants, wetting agents, gelling agents and / or lubricants. If desired, further auxiliaries can be used

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

From 1 to 50% by weight, more preferably from 2 to 25% by weight, in particular from 5 to 15% by weight, of aprepitant and

50 to 99% by weight, more preferably 75 to 98% by weight, in particular 85 to 95% by weight, of pharmaceutically acceptable auxiliaries

In this information, the amount of Matrixmater ial, which was used for the preparation of the intermediate according to the invention, as hüftsstoff calculated that is, the amount of active ingredient refers to the amount of aprepitant (in the form of the free base), which is included in the formulation

It has been found that the intermediates according to the invention are suitable for being able to serve both as the basis for an immediate release dosage form (immediate release or short "/ J") and also with modified release (modified release or "MR") IR formulations are preferred

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

(i) 1 to 80% by weight, more preferably 5 to 60% by weight, in particular 20 to 50% by weight of the intermediate according to the invention and (ii) 1 to 30% by weight, more preferably 5 to 25% by weight, in particular 10 to 20% by weight of disintegrant, based on the total weight of the formulation

As disintegrants are generally referred to substances which 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, sodium carboxymethyl starch and crospovidone In a preferred embodiment for an MR formulation, a relatively small amount of disintegrants is used. In this preferred embodiment therefore contains the inventive pharmaceutical formulation

(i) from 1 to 50% by weight, more preferably from 2 to 25% by weight, in particular from 5 to 15% by weight, of aprepitant and

(ii) 0 to 10% by weight, more preferably 0 to 1 to less than 5% by weight, in particular 1 to 4% by weight, of disintegrant, based on the total weight of the formulation

In the case of the MR formulation, croscarmellose or crospovidone is preferred as disintegrants

Furthermore, the usual retardation techniques can be used for the MR formulation

In a preferred embodiment, the formulation according to the invention contains from 2 to 8% by weight, more preferably from 3 to 7% by weight, in particular from 4 to 6% by weight, of release agent, based on the total weight of the formulation. This embodiment is used in particular for the production of tablets

By release agents are usually understood substances which reduce the agglomeration in the core bed. Examples are talc, silica gel, polyethylene glycol (preferably with 2000 to 10,000 g / mol weight-average molecular weight) and / or glycerol monostearate

Furthermore, the pharmaceutical formulation (both for IR and for MR) preferably contains one or more of the abovementioned excipients. These are explained in more detail below

The formulation according to the invention may further comprise fillers. Fillers are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small amounts of active ingredient (eg less than 70% by weight). That is, fillers produce a sufficient tableting mass by "stretching" the active ingredients Thus, fillers are usually used to obtain a suitable tablet size

Examples of preferred fillers are lactose, lactose derivatives, starches, starch derivatives, treated starches, cellulose and derivatives thereof, for example microcrystalline cellulose, 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, sugar alcohols can be used as fillers. Examples of suitable Sugar alcohols are mannitol, sorbitol, xyhtol, isomalt, glucose, fructose, maltose and mixtures thereof

Fillers are usually used in an amount of from 1 to 60% by weight, more preferably from 10 to 40% by weight, based on the total weight of the formulation

An example of an additive to improve the Pulverfließfahigkeit is dispersed Süiciumdioxid, z is known Preferably, under the trade name Aerosü ^® B Süiciumdioxid with a specific surface area of 50 to 400 m ² / g, as determined by gas adsorption according to Ph Eur, 6 rest 2 9 26, used

Additives for improving the powder flowability are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation

Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, which on the one hand lies between the punches moving up and down in the die bore and the die wall and, on the other hand, between the tablet web and the die wall stearic acid, adipic acid, Natπumstearylfumarat (Pruv ^®), magnesium stearate and / or talc is

Lubricants are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation

It is in the nature of pharmaceutical excipients that they partially perform several functions in a pharmaceutical formulation. In the context of this invention, therefore, the unambiguous delimitation is favored by the fiction that a substance used as a particular hips is not also considered as another pharmaceutical For example, microcrystalline cellulose - if used as a filler - not additionally used as a disintegrant (although microcrystalline cellulose also shows a certain explosive effect)

The pharmaceutical formulation of the invention is preferably compressed into tablets. The intermediates according to the invention are preferably compressed into tablets by direct compression or, alternatively, subjected to dry granulation prior to compression to form the tablet

A further aspect of the present invention therefore relates to a process comprising the steps of (I) providing the intermediate according to the invention and one or more (in particular the above-described) pharmaceutical excipients, (II) optionally compaction into a scoop;

(III) if appropriate comminution of the slug to a suitable size, preferably by means of granulation and

[TV] compression of the resulting granules into tablets.

The above method preferably comprises only steps (I) and (TV), ie it is carried out as direct compression, if the intermediates according to the invention have a bulk density of greater than 0.5 g / cm ³ (determined according to Ph. Eur., 4th edition, 2.2.42). The above process preferably comprises all steps (I) to [TV), ie it is carried out as a dry granulation process when the intermediates according to the invention have a bulk density of greater than 0.5 g / cm ³ .

In step (I), aprepitants in the form of the solid solution (i.e., in the form of the intermediate of the invention) and adjuvants are preferably mixed. The mixing can be done in conventional mixers. Alternatively, it is possible (in the case of dry granulation) that the aprepitant according to the invention is first mixed with only a part of the excipients (eg 50 to 95%) before compaction (II), and that the remaining part of the excipients after the granulation step (III ) is added.

In optional step (II) of the process according to the invention, the mixture from step (I) is compacted into a rag. The compaction conditions are usually selected so that the intermediate according to the invention is in the form of a compactate (slug), the density of the compactate being 0.8 to 1.3 g / cm ³ , preferably 0.9 to 1.20 g / cm ³ , in particular 1.01 to 1, 15 g / cm ³ . The term "density" here preferably refers to the "true density" (ie not to the bulk density or tamped density). The true density can be determined with a gas pycnometer. Preferably, the gas pycnometer is a helium pycnometer, in particular the device AccuPyc 1340 Helium Pycnometer manufactured by Micromeritics, Germany is used.

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 optional step (III) of the process, the slugs formed in step (II) are shredded to an appropriate size. The comminution, preferably granulation, can be carried out by methods known in the art.

In a preferred embodiment, the process conditions are chosen so that the resulting particles (granules) have a volume average particle size Have ((D50) value) of 50 to 800 microns, more preferably from 100 to 750 microns, even more preferably 150 to 500 .mu.m, in particular from 200 to 450 microns In a preferred embodiment, the crushing of Schulpe in a Siebmuhle 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 granules resulting from step (III) can be processed into pharmaceutical dosage forms. For this purpose, the granules are filled, for example, in sachets or capsules. Preferably, the granules resulting from step (III) are pressed into tablets (= step IV).

In step (FV) of the process, the granules obtained in step (III) are compressed into tablets, which means that they are compressed into tablets. The compression can be carried out using tableting machines known in the art

Examples of suitable tabletting machines are eccentric presses or concentric presses. For example, a Fette 102i (Fette GmbH, Germany) can be used. In the case of concentric presses, a pressing force of 3 to 50 kN, preferably 10 to 45 kN, is usually used

In step (IV) of the process, pharmaceutical excipients may optionally be added to the granules from step (III)

The amounts of gums added in step (IV) usually depend on the type of tablet to be prepared and on the amount of gums already added in steps (I) or (II)

The tableting conditions are preferably chosen so that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg

The process according to the invention is preferably further carried out such that the tablet according to the invention contains aprepitant in an amount of 10 mg to 400 mg, more preferably from 20 mg to 200 mg, in particular 40 mg to 150 mg. The invention relates in particular to tablets containing 40 mg , 80 mg or 125 mg aprepitant in the form of a solid solution

Furthermore, the resulting tablets preferably have a hardness of from 50 to 200 N, more preferably from 80 to 150 N. The hardness is determined according to Ph Eur 6 0, Section 2 9 8 In addition, the resulting tablets preferably have a fineness of less than 5%, particularly preferably less than 2%, in particular less than 1.0%. The fineness is determined in accordance with Ph Eur 6 0, Section 2 9 7

Finally, the tablets according to the invention usually have a content content of from 90 to 110%, preferably from 97 to 103%, in particular from 99 to 101%, of the average content. The "Content Undeformity" is according to Ph Eur 6 0, section 2 9 6 determined

The release profile of the tablets according to the invention usually has a released content of at least 60%, preferably at least 75%, in particular at least 90%, in the case of an IR formulation according to the USP method after 10 minutes

The active substance release is hereby wassπger in vitro at 37 ⁰ C in 900 ml HCl solution (+ 0.5 wt -% SDS) at pH 1, 2, according to US-Pharmacopeia (USP), where the measurement in the Blattruhrerapparatur at 100 Revolutions per minute is performed SDS here means sodium dodecyl sulfate

The above information on hardness, friability, content unsafety and release profile are in this case preferably based on the unformed tablet for an IR formulation. For a modtfted release tablet, the release profile refers to the overall formulation

The tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably perfumed). Also "chewable tablets" or "disperse tablets" are understood to mean a tablet for the production of a moist suspension for oral use

In the case of tablets which are swallowed whole, it is preferred that they are coated with a film layer. The conventional tablet coating methods used in the prior art may be used. However, the ratios of active ingredient to excipient mentioned above refer to the uncoated one tablet

In general, three different routes are possible within the scope of this invention. Films Without Influence on Drug Release, Enteric Films, and Retard Films Films Without Effect on Drug Release are Preferably Used These are usually water soluble (preferably have a water solubility greater than 250 mg / ml , determined according to the column elution method according to EU guideline RL67-548-EWG, appendix V, chapter A6). Enteric-coated films possess a pH-dependent detachment usually non-water soluble (preferably having a water solubility of less than 10 mg / ml).

Usually, macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, such as e.g.

Carrageenan. Preferred examples of film formers that do not affect the

Have drug release (e l) are methylcellulose (MC),

Hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP) and mixtures thereof. The polymers mentioned should usually have a weight-average molecular weight of 10,000 to

150,000 g / mol.

Preference is given to using HPMC, in particular HPMC having a weight-average molecular weight of from 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH ₃ groups of from 1.2 to 2.0.

The layer thickness of the coating (film) is usually 1 to 100 μm, preferably 5 to 50 μm.

As described above, the pharmaceutical formulation according to the invention can preferably be pressed into tablets. Alternatively, it is also possible for the pharmaceutical formulation according to the invention to be divided into suitable administration forms, such as, for example, Sachets or capsules is bottled.

A further aspect of the present invention therefore relates to a method comprising the steps

(I) providing the intermediate according to the invention and one or more (in particular the above-described) pharmaceutical excipients;

(II) optionally compaction into a scoop;

(III) optionally granulation or comminution of the slug to a suitable granule size and

(IV) filling the resulting process product into suitable administration forms, in particular in capsules or sachets. With regard to the steps (I) to (III), reference is made here to the above explanations.

The invention thus also relates to capsules or sachets containing the pharmaceutical formulation according to the invention, the dosage forms preferably containing aprepitant in an amount of 10 mg to 400 mg, more preferably from 20 mg to 200 mg, in particular 40 mg to 150 mg. The invention relates in particular to capsules containing 40 mg, 80 mg or 125 mg of aprepitant in the form of a solid solution. The inventive method ensures a technically advantageous production method in an advantageous space-time yield The inventors have also found that the inventive intermediates containing aprepitant in the form of a solid solution, can be administered particularly advantageous independently of the meals

The invention therefore relates to the use of a pharmaceutical formulation containing an NKI receptor antagonist, in particular aprepitant, in the form of a solid solution for the prevention or treatment of nausea and / or vomiting, wherein the administration takes place independently of the meals

The invention will be illustrated by the following examples

EXAMPLES

Example 1: Preparation of the Inteπnediats by melt extrusion

approach

Aprepitant 15 kg

Kollidon ^® VA 64 45 kg

Was aprepitant with Kollidon ^® VA 64 (Tg about 110 ⁰ C) in the ratio 1 4 melted in the melt extruder at temperatures between 100 and 200 ⁰ C and in a temperature cascade extruded was a Dusenplatte with hole diameter of 1 mm applied, the twin-screw extruder Leistritz ^® micro 18 Was provided with various screw elements A kneading unit was installed to ensure the required mixing and solution of the active ingredient in the polymer

The obtained and cooled extrudate (= intermediate) was sieved with a sieve having a mesh size of 1.00 mm on a Comill ^® U5

An analysis by means of confocal Raman spectroscopy (Raman spectrometer NTEGRA Spectra Nanofmder NT-MDT, laser 488 nm (Ar laser), grating 600, objective 10Ox, PH 100 microns) revealed that in the resulting intermediate no particular aprepitant was detectable

Example 2: Preparation of the Inteπnediats by melt extrusion

Example 1 was repeated, but instead of Kollidon ^® VA 64, an acrylic polymer according to general formula (2 + 3), wherein R ₁ to R ₃ is methyl, and R ₄ is -COO-CH ₂ -CH ₂ - Was added N _(CH3 J ₂ (Tg ca. 50 ⁰ C), is used. Also, with the acrylic polymer as the matrix material aprepitant could be produced in the form of a solid solution.

Example 3: Filling in capsules

Intermediate according to Example 1 320 mg

Sodium lauryl sulfate 0.8 mg

Highly dispersed silica 1 mg

The sieved intermediate was mixed with the other excipients in the Turbula ^® TlOB mixer for 15 minutes and filled on a capsule filler machine (Bonapache ^® IN-CAP XL). Capsules of the size 2 were used.

Example 4: Filling in capsules

Intermediate according to Example 1 320 mg

Sodium lauryl sulfate 0.8 mg

Microcrystalline cellulose 40 mg

Highly dispersed silica 2 mg

The ingredients were mixed on a Turbula ^® Tlob 15 minutes, and then filled in a capsule full machine (Bonapache IN-CAP ^® XL). Capsules of size 1 were used.

Example 5: Compression into tablets

Pharmaceutical formulation:

Intermediate according to Example 1 320 mg

Talc 6 mg Microcrystalline cellulose 30 mg

Lactose 20 mg

Aerosil ^® 1, 3 mg

Magnesium stearate 2.6 mg

Laminating:

HPMC 3 mg

PEG 0.5 mg

Talc 1 mg

Titanium Dioxide 0.4 mg Dye 0, 1 mg The intermediate obtained from Example 1 was premixed with talc and with talc, microcrystalline cellulose, lactose, sodium bicarbonate, Aerosil ^® and magnesium stearate (Turbula ^® Tlob) and into a tablet pressed (Fette ^® 102 i) This tablet was placed in a pan-coater , eg Lodige ^® LHC 25 with HPMC coated the coating solution further contained dye, PEG, talc and titanium dioxide

Comparative Example 1: PeUets according to WO 03/049718

A pharmaceutical formulation in granulated form containing cellulose pellets with a nanoparticulate aprepitant layer applied thereon in accordance with WO 03/049718 (composition according to the table on page 26 of the preparation process on pages 26 to 31) was prepared

Example 6: in vitro solubility profile

The in vitro dissociation behavior of granulated intermediate according to Example 1 (= aprepitant in the form of a solid solution) and aprepitant pellets according to Comparative Example 1 (= aprepitant in nanoparticulate form) was compared

Example 6a

The drug release was in vitro at 37 ° C in 900 ml wassπger HCl solution (+ 0.5 wt -% SDS) at pH 1.2, determined according to US Pharmacopeia (USP), the measurement in Blattruhrerapparatur II at 100 Revolutions per minute is performed

The following resolution rates were achieved

Example 6b

The drug release was in-vitro 4.5 according to US Pharmacopeia (USP) determined at 37 ⁰ C in 900 ml of an aqueous Natπum- formate buffer at pH, wherein the measurement in the Blattruhrerapparatur II carried out at 75 revolutions per minute The following dissolution rates were achieved

Claims

claims

A process for the preparation of an intermediate containing aprepitant and matrix material, wherein aprepitant is present in the matrix material in the form of a solid solution comprising the steps

(a) mixing aprepitant and matrix material, and

(b) extruding the mixture

2. The method according to claim 1, wherein in step (a) aprepitant and Matπxmateπal in a weight ratio of 2 1 to 1 10 are used

3 Process according to claim 1 or 2, wherein the matrix material used is a polymer, preferably a polymer having a glass transition temperature (Tg) of 30 ° C. to 130 ° C.

4. The method according to any one of claims 1 to 3, wherein is used as Matrixmateπal an acrylic polymer or a Vinylpyrrohdon-vinyl acetate copolymer

5 The method according to any one of claims 1 to 4, wherein the glass transition temperature (Tg) of the resulting intermediate 20 ⁰ C to 120 ⁰ C amounts

6. The method according to any one of claims 1 to 5, wherein in step (a) additionally a crystallization inhibitor based on an inorganic salt, an organic

Acid, a viscous polymer or mixtures thereof is used

A method according to claim 6, wherein the crystallization inhibitor is citric acid, ammonium chloride, povidone K 90 or mixtures thereof

8 intermediate, obtainable by a process according to one of claims 1 to 7

9 Pharmaceutical formulation containing aprepitant in the form of an intermediate according to claim 8, and at least one pharmaceutical excipient, preferably in the form of a tablet

10 tablet according to claim 9, comprising

(i) 5 to 60% by weight of intermediate and

(ii) 5 to 25% by weight of disintegrant, based on the total weight of the tablet 1 1 tablet according to claim 10, characterized in that it is an alkaline disintegrating agent, in particular sodium bicarbonate

A tablet according to any one of claims 9 to 11 having a hardness of 80 to 250 N, a fricidity of less than 3% and a content uniformity of 95 to 105%.

A method of identifying a pharmaceutical excipient suitable as a matrix material for aprepitant in the form of a solid solution, comprising

steps

a) providing aprepitant, a pharmaceutical Hüfsstoffs which is present at 25 ⁰ C in the solid state, and a 1 1 mixture of aprepitant and Hüfsstoff, b) two repeated heating of the solid Hüfsstoffs by DSC and identify the glass transition temperature of the Hüfsstoffs (Tg _J1111 O , c) heating the active substance aprepitant by DSC twice and identifying the glass transition temperature of the active ingredient (Tg _nPRE ), d) heating the 1 l mixture of aprepitant and heme twice by means of DSC and identifying the glass transition temperature of the mixture (Tg _Mlx ), and e) Selection of the hip as "suitable", provided Tg _Mlx between Tg _Hllf and

TgAPR _E holds

Use of a pharmaceutical heme, obtainable by a process according to claim 13, for the preparation of a pharmaceutical formulation containing an NKI receptor antagomost, in particular aprepitant, in the form of a solid solution

Use of a pharmaceutical formulation containing an NKI receptor antagonist, in particular aprepitant, in the form of a solid solution for the prevention or treatment of nausea and / or vomiting, the administration taking place independently of the meals