EP2309996A2

EP2309996A2 - Amorphous ambrisentan

Info

Publication number: EP2309996A2
Application number: EP09777744A
Authority: EP
Inventors: Kathrin Rimkus; Frank Muskulus; Sandra Brueck; Jana Paetz
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2008-08-11
Filing date: 2009-08-07
Publication date: 2011-04-20
Also published as: WO2010017918A3; WO2010017918A2; US20120022087A1; CA2732931A1

Abstract

The invention relates to amorphous ambrisentan, preferably together with a surface stabilizer, in the form of a stable intermediate. The invention further relates to methods for the production of stable amorphous ambrisentan, and to pharmaceutical formulations comprising stable amorphous ambrisentan.

Description

Amorphous ambrisentan

The invention relates to amorphous ambrisentan, preferably together with a surface stabilizer in the form of a stable intermediate. The invention further relates to processes for the preparation of stable amorphous ambrisentan and pharmaceutical formulations containing stable amorphous ambrisentan.

Ambrisentan is an endothelin receptor antagonist and is approved for the treatment of pulmonary hypertension (pulmonary hypertension). Ambrisentan, as an antagonist, displaces endothelin-1, the strongest known endogenous blood vessel constrictor, selectively from its ET IA receptors, thereby abrogating the endothelin-1 effect, causing the vessels to dilate, thus increasing the endothelin-induced (pulmonary) Blood pressure is counteracted, whereby it comes to a (pulmonary) blood pressure reduction.

The IUPAC name of ambrisentan [INN] is (2S) -2- (4,6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3,3-di (phenyl) propanoic acid. The chemical structure of ambrisentan is shown in formula (1) below:

(D

The synthesis of ambrisentan has been described by Riechers et al., J. Med. Chem. 39 (11), 2123 (1996) and in WO 96/1 1914, and results in a white, crystalline solid.

Ambrisentan is marketed under the trade name Volibris ^® as film-coated tablets. Volibris contains ambrisentan in crystalline form, with tabletting by direct compression (see EMEA Assessment Report for Volibris, 2008, Procedure No. EMEA / H / C / 000839). To the required bioavailability too ensure crystalline ambrisentan is preferably used in micronized form.

However, some disadvantages are associated with the micronization of ambrisentan. First, micronization results in an undesirably lower active ingredient

Flowability. Furthermore, the micronized active ingredient is more difficult to compress, occasionally there is uneven distribution of active ingredients within the pharmaceutical formulation to be compressed. Due to the strong enlargement of the

Surface during micronization also increases the sensitivity to oxidation of the drug.

Object of the present invention was therefore to overcome the disadvantages mentioned above. It should provide the active ingredient in a form that has good flowability and good compression possible. Furthermore, a uniform distribution of the active ingredient should be ensured. Micronization of the active ingredient should be avoided.

Furthermore, the active ingredient should be provided in a form which ensures good solubility and at the same time good storage stability. Furthermore, a storage stability of 12 months at 40 ⁰ C and 75% humidity is to be achieved. The impurities should be after such storage <2 wt .-%, in particular <1 wt .-%.

The problems could be solved unexpectedly by converting crystalline ambrisentan into an amorphous state, in particular into a stabilized amorphous state.

The invention therefore relates to amorphous ambrisentan in stabilized form.

In particular, the invention relates to an intermediate containing amorphous ambrisentan and a surface stabilizer, preferably a polymer having a glass transition temperature (Tg) greater than 25 ⁰ C, wherein the weight ratio of ambrisentan to surface stabilizer 1: 50 to 2: 1. The intermediate represents amorphous ambrisentan in stabilized form.

The invention further provides various processes for the preparation of amorphous ambrisentan or of stabilized amorphous ambrisentan in the form of the intermediate according to the invention.

Finally, the invention relates to pharmaceutical formulations containing the inventively stabilized ambrisentan in the form of the intermediate. In the context of this invention, the term "ambrisentan" comprises (2S) -2- (4,6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3,3-di (phenyl) propanoic acid according to formula (1) above. In addition, the term "ambrisentan" includes all pharmaceutically acceptable salts and solvates thereof.

The term "amorphous" is used in the context of this invention as a term for the state of solids in which the building blocks (atoms, ions or molecules, ie in the case of amorphous ambrisentan the ambrisentan molecules) no periodic arrangement over a larger area (= remote order) exhibit. In amorphous materials, the building blocks are usually not completely random and arranged purely statistically, but distributed so that a certain regularity and similarity with the crystalline state in terms of distance and orientation of the nearest neighbors can be seen (= Nahordnung). Consequently, amorphous substances preferably have close proximity but no long-range order.

Solid amorphous materials are isotropic in contrast to the anisotropic crystals. They usually have no defined melting point, but gradually go over slow softening in the liquid state. Their experimental differentiation of crystalline materials can be done by X-ray diffraction, which gives them no sharp, but usually only a few diffuse interferences at small diffraction angles.

Crystalline ambrisentan has the following characteristic peaks in the DSC analysis: exothermic at 157 ° C, endothermic at 180 ° C, exothermic at 181 ° C. The amorphous ambrisentan according to the invention, however, usually shows a softening range of 40 to 70 ⁰ C, preferably from 45 to 65 ⁰ C. The determination of melting point and softening range in the context of this invention by means of differential scanning calorimetry (DSC).

The amorphous ambrisentan according to the invention may consist of amorphous ambrisentan. Alternatively, it may still contain minor amounts of crystalline ambrisentan constituents, with the proviso that no defined melting point of crystalline ambrisentan can be recognized in the DSC. Preferred is a mixture containing 60 to 99.999% by weight of amorphous ambrisentan and 0.001 to 40% by weight of crystalline ambrisentan, more preferably 90 to 99.99% by weight of amorphous ambrisentan and 0.01 to 10% crystalline ambrisentan, more preferred 95 to 99.9 wt .-% amorphous ambrisentan and 0.1 to 5% crystalline ambrisentan.

In a preferred embodiment, the ambrisentan according to the invention is in a stabilized form, namely in the form of an intermediate, the amorphous

Ambrisentan and a surface stabilizer contains. In particular, that exists Intermediate according to the invention essentially of amorphous ambrisentan and surface stabilizer. The term "essentially" here indicates that, if appropriate, even small amounts of solvent etc. may be present.

The surface stabilizer is generally a material which inhibits the recrystallization of amorphous to crystalline ambrisentane. Preferably, the surface stabilizer is a polymer. Furthermore, the surface stabilizer also includes substances that behave polymer-like. Examples are fats and waxes. Furthermore, the surface stabilizer comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides. Finally, the term surface stabilizer comprises surfactants, in particular surfactants, which are in solid form at room temperature.

The polymer which can be used for the preparation of the intermediate preferably has a glass transition temperature (Tg) of greater than 25 ^° C., more preferably from 40 ^° C. to 150 ^° C., in particular from 50 ^° C. to 100 ^° C. A polymer with appropriately selected T g is prevented by immobilization the recrystallization of the amorphous ambrisentane particularly advantageous.

The "glass transition temperature" (Tg) is the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In this case, a significant change in physical characteristics, z. As the hardness and elasticity. Below the Tg, a polymer is usually glassy and hard, above the Tg it turns into a rubbery to viscous state. The determination of the glass transition temperature is carried out in the context of this invention by means of differential scanning calorimetry (DSC).

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

Further, the polymer usable for the preparation of the intermediate preferably has a number-average molecular weight of from 1,000 to 500,000 g / mol, more preferably from 2,000 to 50,000 g / mol. When the polymer used to prepare the intermediate is dissolved in water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of 1 to 20 mPaxs, more preferably either 1 to 5 mPaxs, and still more preferably from 2 to 4 mPa.s or (in particular in the case of HPMC) 12 to 18 mPa.s, measured at 25 ⁰ C, and in accordance with Ph. Eur., 6th edition, chapter 2.2.10 determined. Hydrophilic polymers are preferably used to prepare the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, sulfonate, carboxylate and quaternary ammonium groups.

The intermediate according to the invention may comprise, for example, the following polymers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); Polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and their salts, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon VA64, BASF), gelatin polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol; Gelatin and mixtures thereof.

Also, as surface stabilizer, sugar alcohols such as mannitol, sorbitol, xylitol may preferably be used. Cetyl palmitate, carnauba wax are preferably used as waxes. Glycerol fatty acid esters, for example glycerol palmitate, behenate, laurate, stearate, PEG-glycerol fatty acid ester are preferably used as fats.

Polyvinylpyrrolidone, preferably having a number 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 number average molecular weight of 45,000 to 75,000 g / mol and / or polymers, are preferably used as the surface stabilizer the acrylic acid and its salts, in particular having a number average molecular weight of 50,000 to 250,000 g / mol used. Furthermore, HPMC, in particular having a number average molecular weight of from 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of from 10 to 35% and a proportion of hydroxyl groups of from 1 to 35%, is preferably used. Likewise, preference is given to using HPC, in particular having a number-average molecular weight of 50,000 to 100,000 g / mol. Furthermore, preference is given to using polyethylene glycol having a number-average molecular weight of from 2,000 to 40,000 g / mol, in particular from 3,500 to 25,000 g / mol. Also preferably, a polyethylene-polypropylene block copolymer is used, wherein the polyethylene content is preferably 70 to 90 wt .-%. The polyethylene-polypropylene block copolymer preferably has a number-average molecular weight of from 1,000 to 30,000 g / mol, more preferably from 3,000 to 15,000 g / mol. The determination of the number average molecular weight is usually carried out by means of gel permeation chromatography. In a first particularly preferred embodiment, the surface stabilizer 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 (2):

In a second particularly preferred embodiment, polymers of acrylic acid or its salts (also referred to as acrylic polymers) are used as surface stabilizer. This is preferably a polymer composed of structures according to the general formulas (4) and (3).

In the formulas (4) 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 alkyl radical or -CH ₂ -CH ₂ -N (CH ₃ J ₂ or -CH ₂ -CH ₂ -N (CH ₃ J ₃ ⁺ halogen ^¬ in particular Cl) as substituted alkyl radical.

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

If an alternating polymerization in the ratio 1: 1, preferably results in a polymer according to the formula (4 + 3)

Particular preference is given to polyacrylates according to the above formulas (4) and (3), where R ₁ and R _{3 are} alkyl, in particular methyl, R _{2 is} methyl or butyl, preferably methyl, and R _{4 is} -COO-CH ₂ -CH ₂ -N (CH is J ₂ ₃ in this case, preferably, the ratio of structures of the formula (2) to structures of the formula (3). 1: 1. a suitable polymer has in particular a number average molecular weight of 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 of the invention comprises amorphous ambrisentan and surface stabilizer, wherein the weight ratio of ambrisentan to surface stabilizer is from 1:50 to 2: 1, more preferably 1:20 to 1: 1, even more preferably 1:15 to 1: 2, especially 1: 12 to 1: 5.

In a preferred embodiment, the intermediate according to the invention is a "single-phase" intermediate. By this is meant that

Surface stabilizer and amorphous ambrisentan are homogeneously distributed at the molecular level. In the DSC analysis, those for crystalline ambrisentan occur characteristic peaks at 157 ° C exothermic, 180 ⁰ C endothermic and 181 ° C exothermic no longer on.

It is preferred that the type and amount of the surface stabilizer be chosen so that the resulting intermediate has a glass transition temperature (Tg) of more than 20 ⁰ C, preferably> 40 ⁰ C. The Tg of the intermediate should not be above 90 ⁰ C.

It is preferred that the type and amount of the polymer be chosen so that the resulting intermediate is storage stable. By "storage-stable" is meant that in the intermediate according to the invention after 3 years of storage at 25 ⁰ C and 50% relative humidity, the proportion of crystalline ambrisentan - based on the total amount of ambrisentan - a maximum of 60% by weight, preferably at most 30 wt. %, more preferably at most 15 wt .-%, in particular at most 5 wt .-% is.

The intermediates according to the invention can be obtained by various preparation processes. Depending on the preparation method, the intermediates are obtained in different particle sizes. The intermediates according to the invention are usually in particulate form and have an average particle diameter (D ₅₀ ) of 50 to 750 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, preferably shading 4 to 13%, preferably dispersion in liquid paraffin, the evaluation being carried out according to the Fraunhofer model). 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 invention further provides a process for the preparation of the amorphous ambrisentan or the intermediate according to the invention. Hereinafter, six preferred embodiments for such a method will be explained.

In a first preferred embodiment, the invention relates to a freeze-drying process, ie a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps

(al) dissolving the crystalline ambrisentane and the surface stabilizer in a solvent or solvent mixture, and

(bl) freeze-drying the solution from step (a1).

In step (a), ambrisentan, preferably ambrisentan and the surface stabilizer described above, are dissolved in a solvent or solvent mixture, preferably completely dissolved.

Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preferably, a mixture of water and DMSO is used.

Suitable surface stabilizers in this embodiment are in particular modified celluloses such as HPMC and sugar alcohols such as mannitol and sorbitol. It is also particularly preferred to use polyvinylpyrrolidone, especially with the molecular weights given above.

The solution from step (al) is cooled to about 10 to 50 ^C C below the freezing point (ie brought to freezing). Subsequently, the solvent is 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 ⁰ C. Sublimation is preferably at a pressure of less than 0.1 mbar.

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

The process conditions in this first embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D50) of from 5 to 250 μm, more preferably from 20 to 150 μm, in particular from 50 to 100 μm.

In a second preferred embodiment, the invention relates to a "pellet layering process", ie a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps (a2) dissolving the crystalline ambrisentan and the surface stabilizer in a solvent or solvent mixture, and (b2) spraying the solution of step (a2) onto a carrier core.

In step (a2), ambrisentan, preferably ambrisentan and the surface stabilizer described above, are dissolved in a solvent or solvent mixture, preferably completely dissolved.

Suitable surface stabilizers in this second embodiment are in particular modified celluloses such as HPMC, sugar alcohols such as mannitol and sorbitol and polyethylene glycol, in particular polyethylene glycol having a molecular weight of from 2,000 to 10,000 g / mol.

In step (b2), the solution from step (a2) is sprayed onto a carrier core. Suitable carrier cores are particles consisting of pharmaceutically acceptable adjuvants, in particular so-called "neutral pellets". Pellets are preferably used, which are available under the trade name Cellets ^® and contain microcrystalline cellulose.

Preferably, step (b2) takes place in a fluidized-bed dryer, for example in a Glatt GPCG 3 (Glatt GmbH, Germany).

The process conditions in this second embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of 50 to 750 μm, more preferably of 100 to 500 μm.

In a third preferred embodiment, the invention relates to a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps

(a3) dissolving the crystalline ambrisentane and the surface stabilizer in a solvent or solvent mixture, and (b3) spray-drying the solution of step (a3).

The third embodiment is particularly preferred. In step (a3), ambrisentan, preferably ambrisentan and the surface stabilizer described above, are dissolved in a solvent or solvent mixture, preferably completely dissolved.

Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preferably, a DMSO / water mixture is used.

Suitable surface stabilizers in this embodiment are in particular modified celluloses such as HPMC, polyvinylpyrrolidone and copolymers thereof and sugar alcohols such as mannitol and sorbitol. Also particularly preferred are acrylic polymers, in particular the above-described under the formulas (3) and (4) acrylic polymers.

In the subsequent step (b3), the solution from step (a3) is spray-dried. The spray-drying is usually carried out in a spray tower. For example, a Büchi B-191 is suitable (Büchi Labortechnik GmbH, Germany). Preferably, an inlet temperature of 100 ⁰ C to 150 ⁰ C is selected. The amount of air is for example 500 to 700 liters / hour and the aspirator preferably runs at 80 to 100%.

The process conditions are preferably chosen in this third embodiment so that the resulting intermediate particles have a volume-average particle diameter (D ₅₀₎ of 5 to 250 microns, preferably greater of 20 to 150 _/ an, in particular from 50 to 100 microns.

In a fourth preferred embodiment, the invention relates to a melt extrusion process, i. a process for the preparation of the intermediate according to the invention, comprising the steps

(a4) mixing crystalline ambrisentan and polymeric surface stabilizer, and (b4) extruding the mixture.

In step (a4), crystalline ambrisentan is preferably mixed with the surface stabilizer in a mixer. In this embodiment of the method according to the invention, a surface stabilizer in polymeric form is used. Suitable polymeric surface stabilizers in this fourth embodiment are in particular polyvinylpyrrolidone and copolymers thereof (in particular a copolymer according to the above formula (2)), and also polyvinyl alcohols, methacrylates and HPMC. Also, polyethylene glycol, especially with the molecular weights given above, is preferably used.

In step (b4), the mixture is extruded. In this case, conventional melt extruders can be used. For example, a Leistritz Micro 18 is used.

The cooled melt is comminuted by a rasping screen (e.g., Comill U5) and concomitantly subjected to a uniform grain size.

The extrusion temperature depends on the type of polymeric surface stabilizer. Usually, it is between 40 and 250 ⁰ C, preferably between 80 and 160 ⁰ C.

The cooled melt is preferably comminuted by a rasp screen and thus subjected to a uniform grain size.

The process conditions in this fourth embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D ₅₀ ) to 1000 μm, more preferably a D ₉₀ of 500 to 1000 μm.

In a fifth preferred embodiment, the invention relates to a so-called "hot melt process", i. a process for the preparation of the intermediate according to the invention, comprising the steps

(a5) introducing crystalline ambrisentan into a surface stabilizer melt, and (b5) applying the melt to a carrier pellet.

In step (a5), crystalline ambrisentan is dissolved in a melt of the surface stabilizer, preferably completely dissolved. In this embodiment, waxes and fats are preferably used as the surface stabilizer. An example of a preferably used surface stabilizer is poloxamer ^®.

In step (b5), an application is carried out, preferably a spraying of the melt from step (b2) onto a carrier core. Suitable carrier cores are Teflchen 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.

The process conditions in this fifth embodiment are preferably selected so that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of from 50 to 750 /, more preferably from 100 to 500 μm.

In a sixth preferred embodiment, the invention relates to a milling process, i. a process for the preparation of the intermediate according to the invention, comprising the steps

(a6) mixing crystalline ambrisentan and surface stabilizer, and (b6) grinding the mixture of step (a6), wherein the milling conditions are selected to transition from crystalline to amorphous ambrisentane.

Crystalline ambrisentan and surface stabilizer are mixed in step (a6). The mixture is ground in step (b6). The mixing can be done before or during the milling, i. Steps (a6) and (b6) can be done simultaneously.

The milling conditions are chosen so that a transition from crystalline to amorphous ambrisentan occurs.

Milling is generally carried out in conventional grinding devices, 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.

Suitable surface stabilizers in this sixth embodiment are in particular modified celluloses such as HPMC, sugar alcohols such as mannitol and sorbitol and polyethylene glycol, in particular polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol. Also, polyvinylpyrrolidone is preferably used.

The process conditions in this sixth embodiment are preferably selected such that the resulting intermediate particles have a volume average

Particle diameter (D ₅₀ ) of 5 to 250 μm, more preferably of 10 to 150 μm, 20 to 80 .mu.m, in particular, or of 20 to 150 microns of, more preferably from 50 to 100 _/ an, have.

The amorphous ambrisentan of this invention and the intermediate of the invention (i.e., the stabilized amorphous ambrisentan stabilized in accordance with the invention) are commonly used to prepare a pharmaceutical formulation.

The invention therefore relates to a pharmaceutical formulation comprising amorphous ambrisentan according to the invention or intermediate according to the invention as well as pharmaceutical excipients.

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

Examples of auxiliaries used are disintegrants, release agents, pseudo-emulsifiers, fillers, additives to improve the powder flowability, lubricants, wetting agents, gelling agents and / or lubricants.

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

1 to 50 wt .-%, more preferably 2 to 30 wt .-%, in particular 5 to 20 wt .-% amorphous ambrisentan and

50 to 99 wt .-%, more preferably 70 to 98 wt .-%, in particular 80 to 95 wt .-% pharmaceutically acceptable excipients.

For this information, the amount of surface stabilizer, which may be

Preparation of the intermediate according to the invention was used, calculated as an adjuvant. That is, the amount of active ingredient refers to the amount of amorphous

Ambrisentan contained in the intermediate.

It has been found that a high amount of disintegrants solves the tasks described above with particular preference.

In a preferred embodiment, therefore, contains the inventive pharmaceutical formulation

(I) 1 to 50 wt .-%, more preferably 2 to 30 wt .-%, in particular 5 to 20 wt .-% amorphous ambrisentan and

(Ii) 1 to 30 wt .-%, more preferably 2 to 25 wt .-%, in particular 3 to 15 wt .-% or 5 to 30 wt .-%, more preferably 10 to 25 wt .-%, in particular 12 to 22 wt .-% disintegrant, based on the total weight of the formulation. Furthermore, the pharmaceutical formulation preferably contains one or more of the abovementioned excipients.

As disintegrants in general substances are referred to accelerate the disintegration of a dosage form, in particular a tablet, after introduction into water. Suitable disintegrants are e.g. organic disintegrants like

Carrageenan, croscarmellose, sodium carboxymethyl starch and crospovidone.

Preferably used are alkaline disintegrants. By alkaline disintegrating agents are meant disintegrating agents which when dissolved in water produce a pH of more than 7.0.

More preferably, inorganic alkaline disintegrants are used, especially salts of alkali and alkaline earth metals. Preferred are sodium, potassium, magnesium and calcium. As anions, carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples are sodium hydrogencarbonate, sodium hydrogenphosphate, calcium hydrogencarbonate and the like.

Sodium bicarbonate is particularly preferably used as disintegrant, in particular in the abovementioned amounts.

In a further preferred embodiment, the pharmaceutical formulation additionally contains

(Iii) release agent, preferably in an amount of 0.1 to 5 wt .-%, more preferably 0.5 to 3 wt .-%, based on the total weight of the formulation.

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.

Examples of preferred release agents are talc and polyethylene glycol 4000, agar and / or carrageenan.

In a further preferred embodiment, the pharmaceutical formulation additionally contains a

(iv) emulsifier and / or pseudo-emulsifier, preferably in an amount of 0, 1 to 5 wt .-%, more preferably 0.5 to 3 wt .-%, based on the total weight of the formulation. Pseudo-emulsifiers are usually (preferably polymeric) substances which, when added to a solution, increase the viscosity of this solution. The addition of 5% by weight of pseudo-emulsifier to distilled water at 20 ^° C. preferably leads to an increase in the viscosity of at least 1%, preferably at least 2%, in particular at least 5%.

As pseudo-emulsifiers plant gums are preferably used. Plant gums are polysaccharides of natural origin which cause the above viscosity increase.

Examples of suitable pseudo-emulsifiers are agar, alginic acid, alginate, chicle, dammar, marshmallow extracts, gellan (E 418), guar gum (E 412), gum arabic (E 414), maple gum gum, spruce juice gum, locust bean gum E 410 ), Karaya (E 416), Konjac flour (E 425), obtained from the konjac root, Tarakernmehl (E 417), tragacanth (E 413), xanthan (E 415), preferably produced by bacterial fermentation, and / or lecithin.

Preferably used are gum arabic, agar and / or lecithin.

Possible emulsifiers are anionic emulsifiers, e.g. Soaps, preferably alkali salts of higher fatty acids salts of bile acids (alkali salts); cationic emulsifiers, e.g. Benzalkonium chloride, cetylpyridinium chloride, cetrimide; nonionic emulsifiers, e.g. Sobitan derivatives, especially sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyethylene glycol derivatives / polyoxyethylene derivative, especially polyoxyethylene (20) sorbitan monostearate, polyoxyethylene stearate or

Polyoxyethylene. Partial fatty acid esters of polyhydric alcohols, e.g. Glycerol monostearate, fatty acid esters of sucrose, fatty acid esters of polyglycol or casein. Also, mixtures of these substances are possible. In addition to constituents (i) to (iv), the formulation according to the invention may also comprise further abovementioned pharmaceutical auxiliaries. These are explained in more detail below.

The formulation according to the invention preferably contains fillers. Fillers are generally to be understood as meaning substances which serve for the formation of the tablet body in the case of tablets with small amounts of active ingredient (eg less than 70% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermassse. So fillers are usually used to obtain a suitable tablet size. Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, talc, calcium phosphate, hydrogen 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 Prosolv® ^® (Rettenmaier & Söhne, Germany) can be used.

Fillers are usually used in an amount of from 1 to 80% by weight, more preferably from 15 to 70% by weight, particularly preferably from 30 to 60% by weight, based on the total weight of the formulation.

An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ^®. Preference is given to using silica having a specific surface area of from 50 to 400 m ² / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition, Sept. 2, 1966.

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

Furthermore, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall. Suitable lubricants are e.g. Stearic acid, adipic acid, sodium stearyl fumarate and / or magnesium stearate.

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

It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. For the purposes of this invention, the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient. For example, PEG 4000, if used as a surface stabilizer, is not additionally used as a release agent (although PEG 4000 also shows a release effect). Also, for example, microcrystalline cellulose - if used as a surface stabilizer - 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 prior art proposes direct compression of ambrisentan formulation (see EMEA Assessment Report for Volibris, 2008, Procedure No. EMEA / H / C / 000839).

However, it has been found that the properties of the resulting tablets can be improved if the pharmaceutical formulation according to the invention is subjected to dry granulation prior to compression to the tablet.

The subject of the present invention is therefore a method comprising the steps

(I) providing the amorphous ambrisentan or the intermediate according to the invention and one or more pharmaceutical excipients (especially those described above);

(II) compaction to a scab; and

(III) Granulation or comminution of the scab.

In step (I), ambrisentan and auxiliaries are preferably mixed. The mixing can be done in conventional mixers. Alternatively, it is possible that the amorphous ambrisentan is first mixed with only a part of the excipients (e.g., 50 to 95%) before compaction (II), and that the remaining part of the excipients is added after the granulation step (Ui). In the case of multiple compaction, the admixing of the excipients should preferably take place before the first compacting step, between several compacting steps or after the last granulating step.

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

The compaction conditions in step (II) are preferably selected such that the slug has a density of 1.03 to 1.3 g / cm ³ , in particular from 1.05 to 1.2 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, it is in the Gas pycnometer to a helium pycnometer, in particular, the device AccuPyc 1340 Helium Pycnometer of the manufacturer Micromeritics, Germany is used.

The compaction is preferably carried out in a roll granulator.

Preferably, the rolling force is 2 to 50 kN / cm, more preferably 4 to 30 kN / cm, especially 10 to 25 kN / cm.

The gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, in particular 1.8 to 2.8 mm.

The compacting device used preferably has a cooling device. In particular, it is cooled in such a way that the temperature of the compactate 50 ⁰ C, in particular 40 ⁰ C does not exceed.

In step (Ui) of the process, the slug is granulated. The granulation can be carried out by methods known in the art.

In a preferred embodiment, the granulation conditions are selected such that the resulting particles (granules) have a volume average particle size (d ( ₅₀ ) value) of 50 to 600 microns, more preferably 100 to 500 microns, even more preferably 150 to 400 microns , in particular from 200 to 350 microns.

In a preferred embodiment, the granulation is carried out in a sieve mill. In this case, the mesh size of the sieve insert is usually 0, 1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1, 8 mm.

In a preferred embodiment, the process is adapted such that a multiple compaction takes place, wherein the granulate resulting from step (III) is recycled once or several times for compaction (II). The granules from step (III) are preferably recycled 1 to 5 times, in particular 2 to 3 times.

The resulting from step (III) granules 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 compressed into tablets (IV).

In step (IV) of the process, the granules obtained in step (III) are compressed into tablets, ie they are compressed into tablets. The compression can be done with tableting machines known in the art. In step (IV) of the process, pharmaceutical excipients may optionally be added to the granules from step (III).

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

The tabletting 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.

Furthermore, the resulting tablets preferably have a hardness of 35 or 50 to 200 N, more preferably from 60 or 80 to 150 N. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8.

In addition, the resulting tablets preferably have a friability of less than 10%, particularly preferably less than 5%, in particular less than 3%. The friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.

Finally, the tablets according to the invention usually have a "content uniformity" of 85 to 115%, preferably from 90 to 110%, in particular from 95 to 105%, of the average content. The "Content Uniformity" is according to Ph. Eur.6.0, Section 2.9.6. certainly.

The release profile of the tablets according to the invention usually has a released content of at least 30%, preferably at least 50%, in particular at least 70%, according to the USP method after 10 minutes.

The above information on hardness, friability, content uniformity and release profile in this case relate preferably to the uninfiltrated tablet.

The tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably film-coated). It can also be chewable tablets or disperse tablets. "Disperstablette" is here understood to mean a tablet for the production of an aqueous suspension for oral use.

In the case of tablets which are swallowed whole, it is preferred that they be coated with a film layer. In this case, the usual in the prior art method for filming tablets can be used. The above However, said ratios of active ingredient to excipient relate to the unpainted tablet.

Preferably, macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac.

Preference is given to using HPMC, in particular HPMC having a number 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 is preferably 10 to 100 μm.

The invention will be illustrated by the following examples.

EXAMPLES

Example 1: Preparation of the Inteπnediats by grinding

5 g of crystalline ambrisentan were co-milled with 25 g of HPMC in a ball mill PM 100 (Retsch) for 2-3 hours at a rotation speed of 350 rpm.

Example 2: Preparation of the Intermediate by Lyophilization

5 g of crystalline ambrisentan were dissolved with 10 g of mannitol in DMSO / water and frozen at - 50 ⁰ C until no electrical conductivity was measurable. Subsequently, the solvent was sublimed at a temperature of 10 ⁰ C below the eutectic temperature of the mixture under 1 mbar vacuum. When no change in pressure was evident, the mixture was warmed slowly to room temperature.

Example 3: Production of the Intermediate by Melt Extrusion

5 kg of crystalline ambrisentan were mixed with 50 kg of copolymer of polyvinylpyrrolidone and polyvinyl acetate (Povidone ^® VA 64, F. BASF) premixed. This mixture was extruded with increasing temperature cascade to 150 ⁰ C on a twin-screw extruder (Leistritz Micro 18). The cooled strands were then screened by means of Comill. Example 4: Preparation of the Intermediate by Pellet Layering

100 g of crystalline ambrisentan were dissolved in a water / DMSO solution and sprayed together with 500 g of PEG 4000 as a solution onto inert cellets (ethylcellulose pellets).

For this work was done in the "Heinen Minibatch". Supply air temperature 60-80 ^C C, product temperature 30-40 ⁰ C, spray pressure 1 - 2.5 bar, nozzle 1 - 2 mm.

Example 5 Production of the Intermediate by "Hot Melt Coating"

50 g of crystalline ambrisentan was dissolved in 700 g of molten GeIu cire ^® (fatty acid glycerol PEG ester) at 60 ° C. This melt was hot melted onto "Sugarspheres":

For this purpose, a "Hüttlin spheric coater Unilab-05 / -5-TJ" was used: supply air temperature 250 ° C, microclimate 100 ° C, spray pressure 0.4 bar.

Example 6: Preparation of the Intermediate by Spray Drying

10 g of crystalline ambrisentan were dissolved with 20 g of povidone 25 and 10 g of lactose in water / DMSO. The solution is spray-dried in the "Büchi". The following parameters are set for this purpose: aspirator 95%, air flow 700 m ³ / h, supply air 130 ^° C.

Example 7: Preparation of tablets

For the preparation of tablets, the following formulation was used.

1. Intermediate according to Example 6 30 g

2. talc 1 g 3. siliconized microcrystalline cellulose) 90 g

4. Sodium hydrogencarbonate 25 g

5. Silica 0.5 g 6 Na stearyl fumarate 1 g

Ingredients 1 and 2 were premixed for 5 min on a tumbler (Turbula TB 10). This mixture was compacted with 70% of ingredients 3-5 by roller compactor and screened at 1.25 mm. The compact was mixed with the remaining substances and compressed into tablets. Example 8: Preparation of the Inteπnediats by grinding

5, 12 g ambrisentan and 10.00 g Polyvinylpyrrolldon (Mw 25 kDa) were mixed in a Turbula ^® Tlob and milled for two hours (at 350 rpm, Retsch mill, PM100, 4 balls).

Example 9: Preparation of the inteinidiidate by lyophilization

5.12 g of ambrisentan, 10.00 g of polyvinylpyrrolidone (Mw 25 kDa) and 800.00 g of phosphate buffer (pH 7.4) were weighed together and the solution was stirred for 30 min. stirred on the magnetic stirrer. The lyophilization was carried out with a Christ Epsilon 2-4.

Example 10: Preparation of the Inteπnediats by melt extrusion

0.26 g of ambrisentan and 0.50 g of PEG 20000 were processed analogously to Example 3.

Example 11: Preparation of the Intermediate by Melt Extrusion

0.26 g of ambrisentan and 0.50 g of PEG 4000S were processed analogously to Example 3.

Example 12: Preparation of the Intermediate by Melt Extrusion

0.26 g of ambrisentan and 0.50 g of Pluronic F68 (Pluronic = PEG-PPO block copolymer) were processed analogously to Example 3. A DSC of the resulting amorphous ambrisentan intermediate is shown in FIG.

Example 13: Melt (in the DSC crucible)

Various binary mixtures of ambrisentan and polymer in a ratio of 1: 5 were prepared. The mixtures were heated at a rate of

Heated to 10 ° C / minute, annealed for 3-5 minutes and then cooled rapidly to -50 ° C.

Mixture with Eudragit EPO: heating to 160 ⁰ C, cooling rate 50 ° C / min

Kollidon ^® 25: heating to 160 ⁰ C, cooling rate 50 ° C / min Kollidon ^® VA 64: heating to 145 ⁰ C, cooling rate 30 ° C / min

Klucel ^® (= HPC) heating to 160 ⁰ C, cooling rate 50 ° C / min

Example 14: Preparation of the Intermediate by Spray Drying

0.64 g and 6.25 g ambrisentan Eudragit ^® EPO were dissolved and then spray dried together in 250 g HCl buffer (pH 1.2). Example 15: Preparation of tablets

3.65 g of intermediate according to Example 14

4.66 g calcium hydrogen phosphate 0.18 g sodium carboxymethyl starch 0.66 g sodium bicarbonate 0.09 g magnesium stearate 0.09 g talc

0.41 g Natriumsteaiylfumarat 0.09 g Aerosil ^® (SiO ₂₎

Intermediate according to Example 14, calcium hydrogen phosphate, sodium carboxymethyl starch and sodium bicarbonate were mixed and sieved together for 20 minutes. Furthermore, magnesium stearate was added and mixed for 3 minutes. Then talc, sodium stearyl ^fumarate and Aerosil® were added and mixed again for 3 minutes. From the mixture tablets of 149 mg were pressed (containing 5 mg ambrisentan).

Claims

claims

1. Intermediate containing amorphous ambrisentan and a surface stabilizer, wherein the weight ratio of ambrisentan to

Surface stabilizer is 1: 50 to 2: 1.

2. Intermediate, characterized in that it is the surface stabilizer is a polymer, preferably a polymer having a glass transition temperature (Tg) greater than 25 ⁰ C.

3. Intermediate according to claim 1 or 2, characterized in that it is a single-phase intermediate.

4. Intermediate according to one of claims 1 to 3, characterized in that the glass transition temperature (Tg) of the intermediate is more than 20 ⁰ C.

5. A process for the preparation of an intermediate according to any one of claims 1 to 4 comprising the steps

(al) dissolving crystalline ambrisentan and surface stabilizer in a solvent or solvent mixture, and

(bl) freeze-drying the solution from step (a1).

6. A process for the preparation of an intermediate according to any one of claims 1 to 4 comprising the steps

(a2) dissolving crystalline ambrisentan and surface stabilizer in a solvent or solvent mixture, and (b2) spraying the solution of step (a2) onto a carrier core.

7. A process for the preparation of an intermediate according to any one of claims 1 to 4 comprising the steps

(a3) dissolving crystalline ambrisentan and surface stabilizer in a solvent or solvent mixture, and (b3) spray-drying the solution of step (a3).

8. A process for the preparation of an intermediate according to any one of claims 1 to 4 comprising the steps (a4) mixing crystalline ambrisentan and surface stabilizer, and

(b4) extruding the mixture.

9. A process for the preparation of an intermediate according to any one of claims 1 to 4 comprising the steps

(a5) introducing crystalline ambrisentan into a melt of the

Surface stabilizer, and (b5) applying the melt to a carrier pellet.

10. A process for the preparation of an intermediate according to any one of claims 1 to 4 comprising the steps

(a6) mixing crystalline ambrisentan and surface stabilizer, and

(b6) grinding the mixture from step (a6), wherein the milling conditions are selected such that a transition from crystalline to amorphous ambrisentan occurs.

11. Intermediate, obtainable by a process according to one of claims 5 to 10.

12. Pharmaceutical formulation containing amorphous ambrisentan in the form of an intermediate according to one of claims 1 to 4 and 11.

13. A pharmaceutical formulation according to claim 12, comprising

(i) from 1 to 50% by weight of amorphous ambrisentan and (ii) from 3 to 25% by weight of disintegrant, based on the total weight of the

Dosage form.

14. Pharmaceutical formulation according to claim 13, characterized in that it is an alkaline disintegrant, in particular sodium bicarbonate.

15. A pharmaceutical formulation according to any one of claims 12 to 14, comprising

(üi) 0, 1 to 5 wt .-% release agent.

16. A pharmaceutical formulation according to any one of claims 12 to 15, comprising

(iv) 0, 1 to 5 wt .-% emulsifier and / or pseudoemulsifier, based on the total weight of the dosage form.

17. A pharmaceutical formulation according to any one of claims 12 to 16, obtainable by dry granulation.

18. A process for the preparation of a pharmaceutical formulation according to any one of claims 12 to 17, comprising the steps

(I) providing the amorphous ambrisentene according to claim 1 or the intermediate according to any one of claims 2 to 6 and 13 and one or more pharmaceutical excipients; (II) compaction to a scab; and

(III) granulation of the slug.

19. Tablets obtainable by compression of a pharmaceutical formulation according to one of claims 12 to 17.