EP2309995A1

EP2309995A1 - Pharmaceutical formulation for lowering pulmonary blood pressure

Info

Publication number: EP2309995A1
Application number: EP09777743A
Authority: EP
Inventors: Katrin Rimkus; Frank Muskulus; Sandra Brueck; Jana Paetz; Dunja Kotschenreuther
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: DE102008037324A1; CA2733651A1; US20110189243A1; WO2010017917A1

Abstract

The invention relates to pharmaceutical formulations for lowering pulmonary blood pressure, comprising micronized ambrisentan, preferably in the form of an intermediate, together with a hydrophilicizing agent. The invention further provides methods of producing pharmaceutical formulations comprising micronized ambrisentan.

Description

Pharmaceutical formulation for pulmonary reduction of blood pressure

The invention relates to pharmaceutical formulations for pulmonary lowering of blood pressure containing micronized ambrisentan, preferably in the form of an intermediate together with a hydrophilicizing agent. The invention further relates to processes for the preparation of pharmaceutical formulations containing micronized ambrisentan.

Ambrisentan is an endothelin receptor antagonist and is approved for the treatment of pulmonary hypertension (pulmonary hypertension). Ambrisentan displaces the endothelin-1, the strongest known endogenous antibody, as an antagonist

Blood vessel constrictive, selective from its ETIA receptors, thus lifting the

Endothelin 1 effect on, so that the vessels dilate and so through the

Endothelin caused by increased (pulmonary) blood pressure, which leads 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, whereby the tableting by means of

Direct compression takes place (see EMEA Assessment Report for Volibris, 2008, Procedure No. EMEA / H / C / 000839). However, it has been shown that tablets that

Replacement Blade (RULE 26) produced by direct compression of "untreated" crystalline ambrisentan could be improved in terms of their bioavailability. Furthermore, it is problematic to realize with this method, a high drug content (eg 70%) in the tablet. Furthermore, it has been shown that with low active ingredient content (eg 15%), the uniformity of the active ingredient distribution (Content Unity) should be improved.

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. The resulting tablets are said to have high hardness and low friability.

Furthermore, the active ingredient should be provided in a formulation that ensures good solubility with good storage stability at the same time. Furthermore, a camp stability of 12 months at 40 ⁰ C and 75% humidity is to be achieved. After such storage, the impurities should be less than 2% by weight, in particular less than 1% by weight.

Furthermore, it should be possible that the active ingredient content can be varied over a wide range. Preferably, an active ingredient content of 10 to 70 wt .-% should be achievable. Furthermore, the resulting tablet should have a particularly uniform distribution of active ingredient, in particular, the resulting tablet should have a uniform distribution of active ingredient at low drug levels (about 10 to 20 wt.%).

The objects could be solved unexpectedly by micronization of ambrisentan, preferably by micronization and hydrophilization of ambrisentan, in particular by micronization, hydrophilization and wet granulation of ambrisentan.

The invention therefore micronized ambrisentan.

The invention further provides an intermediate containing micronised ambrisentan and a hydrophilizing agent.

The invention furthermore relates to processes for the preparation of micronized ambrisentan or of hydrophilized micronized ambrisentan in the form of the intermediate according to the invention.

Finally, the invention relates to pharmaceutical formulations containing the micronized ambrisentan according to the invention or the According to the invention, micronized and hydrophilic 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. Preferably, for all embodiments of this invention, the term "ambrisentan" is ambrisentan in crystalline form, i. preferably more than 90% by weight of the ambrisent used is in crystalline form, in particular 100%.

The term "micronized ambrisentan" in the context of this invention refers to particulate ambrisentan, which generally has an average particle diameter of from 0.1 to 200 .mu.m, preferably from 0.5 to 100 .mu.m, more preferably from 1 to 50 .mu.m, more preferably from 1.5 to 30 microns and especially from 2 to 20 microns or from 1.5 microns to 25 microns and in particular from 2 microns to 10 microns.

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, 2000 rpm, ultrasound 60 sec., Preferably shading 4 to 13%, preferably dispersion in liquid paraffin, evaluation by means of the Fraunhofer method). The average particle diameter, also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by 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. Analogously, the D10 value of the integral volume distribution is defined as the particle diameter at which 10% by volume of the particles have a smaller diameter than the diameter which corresponds to the D10 value. Accordingly, the D90 value of the integral volume distribution is defined as the particle diameter at which 90% by volume of the particles have a smaller diameter than the diameter corresponding to the D90 value.

In a preferred embodiment, the ambrisentan according to the invention is present in micronized and hydrophilized form, namely in the form of an intermediate which contains micronized ambrisentan and a hydrophilizing agent. In particular, the intermediate according to the invention consists essentially of micronized ambrisentan and hydrophilizing agent. The term "essentially" indicates here indicates that possibly even small amounts of solvent etc. may be included.

The "hydrophilizing agent" in the context of this invention is generally a substance which is capable of attaching to ambrisentan (chemically or physically) and increasing the hydrophilicity of the surface.

The hydrophilizing agent may be hydrophilic polymers. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, carboxy, sulfonate. Further, the hydrophilic 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 50,000 g / mol. When the polymer used as the hydrophilizing agent is dissolved in water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of 1 to 20 mPas, more preferably 1 to 5 mPas, still more preferably 2 to 4 mPas determined at 25 ⁰ C and in accordance with Ph. Eur., 6th edition, chapter 2.2.10.

Furthermore, the hydrophilizing agent also comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides.

The intermediate according to the invention may comprise, for example, the following hydrophilic polymers as hydrophilizing agents: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), microcrystalline cellulose ; Polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (beispiels- as Kollidon ^® VA64, BASF), polyoxyethylene / polyoxypropylene block polymer (poloxamer ^®), gelatin, poly-alkylene glycols such as polypropylene glycol or, preferably, Polyethylene glycol, and mixtures thereof.

Also, as the hydrophilizing agent, it is preferable to use sugar alcohols and / or disaccharides such as mannitol, sorbitol, xylitol, isomalt, sucrose, lactose, glucose, fructose, maltose and mixtures thereof. The term sugar alcohols here also includes monosaccharides.

In the context of this invention, it was also unexpectedly found that, in particular, "brittle" hydrophilicizing agents can be used particularly advantageously. Hydrophilizing agents can generally be classified by changing the particle shape under pressing pressure (compression): plastic hydrophilicizing agents are characterized by plastic deformation, while brittle auxiliaries, under the action of a pressing force, break the particles into smaller particles. A brittle behavior of the hydrophilizing agent can be quantified by increasing the surface area in one pressing. In the art, it is common to classify brittleness by the so-called "yield pressure". According to a simple classification, the values for the "yield pressure" are small for plastic substances, but large for brittle substances [Duberg, M., Nyström, C, 1982. Studies on direct compression of tablets VI. Evaluation of methods for the estimation of particle fragmentation during compaction. Acta Pharm. Suec. 19, 421-436; Humbert-Droz P., Mordier D., Doelker E. "Method rapid determination of the comportment Ia compression pour the etudes de preformulation", Pharm. Acta HeIv., 57, 136- 143 (1982)). The "yield pressure" describes the tension that has to be reached in order for the substance (ie the hydrophilizing agent) to begin to flow plastically.

Preferably, the "yield pressure" will be determined from the reciprocal of the slope of the Heckel plot, as described in York, P., Drug Dev. Ind. Pharm. 18, 677 (1992). The measurement is preferably carried out according to the "ejected tablet" method at 25 ⁰ C and a deformation rate of 0, 1 mm / s.

In the context of the present invention, a hydrophilicizing agent is considered to be a brittle hydrophilicizing agent if it has a yield pressure of at least 80 MPa, preferably 90 to 300 MPa.

Examples of preferred brittle hydrophilicizing agents are microcrystalline cellulose, lactose and sucrose.

In a preferred embodiment, the intermediate of the invention contains micronized ambrisentan and hydrophilizing agent, wherein the weight ratio of micronised ambrisentan to hydrophilizing agent is 50: 1 to 1: 5, more preferably 20: 1 to 1: 1, even more preferably 15: 1 to 2: ₁ especially 15: 1 to 5: 1.

It is preferred that the type and amount of the hydrophilizing agent be chosen so that at least 50% of the surface of the resulting intermediate particles are covered with hydrophilizing agent, more preferably at least 60% of the surface, more preferably at least 80% of the surface, especially at least 95% of the surface , If appropriate, the intermediate according to the invention may comprise, instead of or preferably in addition to the hydrophilizing agent, an emulsifier and / or pseudo-emulsifier. Here, the pseudo-emulsifiers explained in more detail below are preferably used.

The invention thus relates to a process for the preparation of the micronized ambrisentan or the intermediate according to the invention. In this embodiment, the intermediate of the invention contains micronized ambrisentan and hydrophilizing agent and / or pseudo-emulsifier, wherein the weight ratio of micronised ambrisentan to hydrophilizing agent and / or pseudo-emulsifier 50: 1 to 1: 5, more preferably 20: 1 to 1: 1, even more preferably 15: 1 to 2: 1, in particular 15: 1 to 5: 1.

Micronized ambrisentan according to the invention is usually obtainable by grinding.

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

(al) mixing crystalline ambrisentan and hydrophilizing agent, and (bl) grinding the mixture from step (a1).

Crystalline (non-micronized) ambrisentan and hydrophilizing agent are mixed in step (a1). The mixture is ground in step (bl). The mixing can be done before or during the milling, i. steps (a1) and (bl) can be done simultaneously.

The milling conditions are selected so that at least 50% of the surface area of the resulting intermediate particles is covered with hydrophilizing agent, more preferably at least 60% of the surface, more preferably at least 80% of the surface, especially at least 95% of the surface.

Milling is generally carried out in conventional grinding equipment, for example in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disc mill, mortar mill, rotor mill. An air jet mill is preferably used.

The meal is usually 0.5 minutes to 1 hour, preferably 2 minutes to 50 minutes, more preferably 5 minutes to 30 minutes. The process conditions in this embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D ₅₀ ) of from 0.1 to 250 μm, more preferably from 0.5 to 50 μm, in particular from 1 to 25 μm or from 1 μm to 20 microns have.

The process described above leads to the intermediate according to the invention comprising micronized ambrisentan and hydrophilizing agent. The invention therefore also intermediates, obtainable by this method.

The present inventors have found that the objects underlying the invention in an alternative embodiment can also be achieved by an intermediate containing micronized ambrisentan, optionally in combination with ambrisentan in the form of a solid solution, and hydrophilizing agent.

In an alternative embodiment, the invention thus relates to a process for the preparation of the intermediate containing ambrisentan in micronized form (and optionally partially in the form of a solid solution) and a hydrophilizing agent. The preparation is preferably carried out by a so-called "pellet layering". The invention thus relates to a method comprising the steps

(a2) suspending the crystalline ambrisentene and the hydrophilizing agent in a solvent or solvent mixture, and (b2) spraying the suspension of step (a2) onto a carrier core.

In step (a2), ambrisentan and the hydrophilizing agent described above are suspended in a solvent or solvent mixture, i. Ambrisentan leads at least partially in crystalline form.

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

Suitable hydrophilicizing agents in this alternative 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 suspension of step (a2) is sprayed onto a carrier core. Suitable carrier cores are particles consisting of pharmaceutically compatible excipients, 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.

The micronized ambrisentan according to the invention and the intermediate according to the invention (i.e., the hydrophilized and micronized ambrisentan according to the invention or the hydrophilic ambrisentan in crystalline form) are usually used for the preparation of a pharmaceutical formulation.

The invention therefore relates to a pharmaceutical formulation comprising micronized ambrisentan according to the invention or intermediate according to the invention and pharmaceutical auxiliaries.

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, emulsifiers, 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 70 wt .-%, more preferably 2 to 30 wt .-%, in particular 5 to 20 wt.% Micronized ambrisentan and

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

In this information, the amount of hydrophilizing agent, optionally to

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 micronized ambrisentan contained in the intermediate. It has been shown that a targeted choice of the disintegrant solves the tasks described above particularly preferably.

In a preferred embodiment, the pharmaceutical formulation according to the invention contains

(I) 1 to 70 wt .-%, more preferably 2 to 30 wt .-%, in particular 5 to 20 wt .-% micronized ambrisentan and

(ii) 0.5 to 25% by weight, more preferably 2 to 20% by weight, in particular 3 to 15% by weight or 1 to 25% by weight, more preferably 3 to 20% by weight, in particular 5 to 15 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 are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water. Suitable disintegrants are e.g. organic disintegrants such as 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.

Crospovidone and / or croscarmellose are particularly preferably used as disintegrating agents, 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.

Release agent (iii) is particularly important when the micronized ambrisentan is used as the intermediate of the invention. 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 (Mg 3000-6000 g / mol), carrageenan.

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

(iv) 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, tara gum (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, for example soaps, preferably alkali salts of higher fatty acids. Salts of bile acid (alkali metal salts); cationic emulsifiers, eg benzalkonium chloride, cetylpyridinium chloride, cetrimide; nonionic emulsifiers, for example, sorbitan derivatives, in particular sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyethylene glycol derivatives / polyoxyethylene derivative, especially polyoxyethylene (20) sorbitan monostearate, polyoxyethylene stearate, polyoxyethylene stearyl ether. It is also possible to use partial fatty acid esters of polyhydric alcohols, for example glycerol monostearate, fatty acid esters of sucrose, fatty acid esters of polyglycol or casein. Furthermore, mixtures of the substances mentioned can be used. 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 to form the tablet body in the case of tablets with small amounts of active ingredient (for example 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, chitin, cellulose and derivatives thereof, 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 Prosolv® ^® (Rettenmaier & Söhne, Germany) can be used.

Fillers are usually used in an amount of from 1 to 80% by weight, more 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 hydrophilizing agent - not additionally used as a release agent (although PEG 4000 also shows a release effect). Also, for example, microcrystalline cellulose - if used as a hydrophilicizing agent - not additionally used as a disintegrating agent (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 shown that the properties of the resulting tablets can be improved if the pharmaceutical formulation according to the invention is subjected to wet granulation or suspension granulation before being pressed into the tablet.

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

(I) providing micronised ambrisentan or preferably intermediate according to the invention and pharmaceutical auxiliaries,

(II) wetting or suspending the substances from step (I) with, or in a granulating solution,

(III) granulating the moistened substances or granulating with suspended matter and

V) drying and optionally sieving the resulting granules.

In step (I), ambrisentan or the intermediate according to the invention and pharmaceutical excipients are provided. The pharmaceutical excipients are preferably the adjuvants described above. The substances are preferably mixed. The mixing can be done in conventional mixers. To ensure a uniform distribution, mixing in so-called intensive mixers is preferred. For example, the mixing can take place in compulsory mixers or free-fall mixers. Alternatively, mixing may occur during steps (II) and (III).

The substances from step (I) are moistened with a granulating liquid or are suspended in a granulating liquid. Suitable granulating liquids are, for example, water, alcohols and mixtures thereof. Preference is given to a mixture of water and ethanol.

The steps (I) to (IV) can be carried out in conventional granulation. Preference is given here to the "one-pot process" or the "fluidized-bed process".

In a one-pot process, the substances from step (I) are moistened with granulating liquid and granulated. The steps (II) and (III) are preferably carried out at the same time. The granules are then dried and optionally sieved. A suitable granulating machine is e.g. Diosna Pl / 6.

In the fluidized bed process, the substances from step (I) are suspended in granulation liquid and sprayed to dryness. Mixing, moistening, granulating and drying are done in one go. The granules are optionally subsequently sieved. A suitable fluidized bed apparatus is e.g. Smooth GPCG 3.

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, especially from 200 to 350 μm.

Furthermore, the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.2 to 0.85 g / ml, more preferably 0.3 to 0.8 g / ml, especially 0.4 to 0.7 g / ml exhibit. The Hausner factor is usually in the range of 1, 03 to 1, 3, more preferably from 1, 04 to 1, 20 and in particular from 1, 04 to 1, 15. In this case, "Hausner factor" is the ratio of tamped density understood to bulk density.

The resulting from step (IV) granules can be processed into pharmaceutical dosage forms. For this purpose, the granules are filled, for example, in sachets or capsules. The granulate resulting from step (IV) is preferred compressed into tablets. The pressing step (V) will be described below. The invention thus relates to tablets obtainable by compression of a granulate obtained from step (IV).

In step (V) of the process, the granules obtained in step (IV) are compressed into tablets, i. There is a compression to tablets. The compression can be done with tableting machines known in the art.

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

The amounts of excipients added in step (V) usually depend on the type of tablet to be prepared and on the amount of excipients already added in step (I). Preferably, in compression, the powder flowability improving additives and lubricants described above are used.

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. However, the above-mentioned ratios of active ingredient to excipient relate to the unpainted tablet.

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 40 to 100 N 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 8%. 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 15% of the average content, preferably 90 to 110%, in particular 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.

In addition to the preferred wet granulation described above, it is alternatively also possible for the pharmaceutical formulation according to the invention to be subjected to dry granulation before being pressed into the tablet.

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

(I-T) providing the micronized ambrisentan or the intermediate according to the invention and one or more pharmaceutical excipients (especially those described above); (II-T) Compaction into a scab; and (III-T) granulation of the slug.

In step (I-T), ambrisentan and adjuvants are preferably mixed. The mixing can be done in conventional mixers. Alternatively, it is possible that the micronized and preferably hydrophilized ambrisentan is first mixed with only part of the auxiliaries (eg 50 to 95%) before compaction (II), and that the remaining part of the excipients after the granulation step (III-T) is added. In the case of multiple compaction, the admixing of the excipients should preferably take place before the first compaction step, between several compaction steps or after the last granulation step.

In step (II-T) of the alternative method of the invention, the mixture of step (IT) is compacted into a slug. It is preferred that this is a dry compaction, ie the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents. The compaction conditions in step (HT) are preferably chosen such that the slug has a density of 0.75-1.1 g / cm ³ .

The term "density" in this case preferably refers to the "true density" (ie not to the bulk density or tamped density) .The purity can be determined using a gas pycnometer Preferably, the gas pycnometer is a helium pycnometer, in particular the device AccuPyc 1340 Helium pycnometer manufactured by Micromeritics, Germany.

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 (III-T) 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 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-T) is recycled once or several times for compaction (H-T). The granulate from step (III-T) is preferably recycled 1 to 5 times, in particular 2 to 3 times.

The granules resulting from step (III-T) can be processed into pharmaceutical forms of administration as described above for wet granulation. For this purpose, the granules are filled, for example, in sachets or capsules. Preferably, the granules resulting from step (III-T) are compressed into tablets. 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. However, the above-mentioned 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: Micronizing and Direct Compression

20 g of crystalline ambrisentan were micronised in a ball mill PM 100 (Retsch) together with 2 g of polaxomer as hydrophilizing agent for 30 minutes at 350 rpm.

The micronized drug was combined in water with 2 g of povidone / 4 g of Arabic

Rubber suspended. This suspension is for the granulation of 100 g of Avicel ^®, 50 g

Lactose, 20 g carboxymethyl starch used (Diosna P l).

The granules were dried and then screened (Comil U5, 1.25 mm).

The granulate was mixed with 1 g of Aerosil ^®, 2 g of magnesium stearate and 30 g of Avicel ^® to a tablet capable mixture in a free fall mixer together for an additional 5

Mixed minutes.

The tablets had a hardness of 40 - 100 N, combined with a friability of less than 10%. Example 2: Micronization and wet granulation

20 g of crystalline ambrisentan were micronised in a jet mill Jetmill Alpine 50 AS at 4-6 bar (Hosokawa). Subsequently, the active ingredient with 2 g of PEG (Lutrol ^® ) as a hydrophilizing agent for 5 min. mixed to ensure a uniform coating over the particles.

The micronized drug was suspended in water along with 0.5 g of HPMC / 1 g of Arabic gum. This suspension was used to granulate 90 g of corn starch, 12 g of crospovidone (Diosna P l).

The granules were dried and then screened (Comil U5, 1.25 mm).

To the granules was added either 0.8 g Aerosil ^® and 1.6 g magnesium stearate, and 20 g Starch 1500th Everything was mixed into a tableted mixture in a tumbler mixer for an additional 5 minutes.

The tablets had a hardness of 40 - 100 N, combined with a friability of less than 10%.

The tablets were coated with 4 g HPMC (Pharmacoat ^® 603), 0.5 g of titanium dioxide, 0.5 g talcum and 0.3 PEG in a drum coater (Lödige LHC 25) coated from aqueous solution.

Example 3: Micronization

2 g of crystalline ambrisentan were ground in a ball mill from Retsch for 30 minutes at 350 rpm. The following mean particle sizes were determined:

d90 = 63 μm; d50 = 18 μm, d10 = 5 μm

Example 4: wet granulation

0.77 g of ambrisentan according to Example 3

15.00 g of corn starch

1.05 g PVP

7.50 g of water l, 68 g of Aerosil ^® 2.77 g of corn starch 0.21 g of magnesium stearate 0.15 g of sodium stearyl fumarate

Ambrisentan, Malsstärke and PVP were granulated with water. The granules were dried at 40 ^° C. for 60 minutes. Aerosil ^®, corn starch and magnesium stearate were sieved through a 1000 .mu.m sieve, added to the granules and mixed for 3 minutes. Pruv ^® was supplemented and mixed again. The mixture was compressed into tablets of 155 mg. The active substance content is 5 mg.

Example 5: Direct tableting

0.20 g ambrisentan according to Example 3 5.34 g corn starch 0.06 g magnesium stearate 0.20 g of Prosolv ^® (siliconized MCC) 0.07 g Aerosil ^®

Ambrisentan and corn starch were mixed together in the Turbula TlOB mixer for 15 minutes at 32 rpm. Magnesium stearate was added and mixed for an additional 3 minutes. Then Prosolv® ^® and Aerosil ^® were added to improve the flowability. The mixture was pressed directly into tablets of 147 mg.

Example 6: Direct tableting

0.77 g of ambrisentan according to Example 3

19.60 g of calcium hydrogencarbonate

0.42 g of sodium carboxymethyl starch

0.21 g of magnesium stearate

Ambrisentan, calcium bicarbonate and sodium carboxymethyl starch were weighed together and mixed for 15 minutes. Magnesium stearate was added and mixed for an additional 3 minutes. The mixture was pressed directly into tablets of 140 mg. The active ingredient content was 5 mg.

Example 7: Direct tableting

0.77 g of ambrisentan according to Example 3

19.39 g Microcelac ^® (75% lactose monohydrate and 25% microcrystalline cellulose) 0.63 g Croscarmellose sodium 0.21 g magnesium stearate Ambrisentan, Microcelac ^® and croscarmellose sodium were weighed together and mixed for 15 minutes. Magnesium stearate was added and mixed for an additional 3 minutes. The mixture was pressed directly into tablets of 140 mg. The active ingredient content was 5 mg.

Example 8: Micronization and Direct Tableting

0.77 g of ambrisentan

19.39 g Microcelac ^® (75% lactose monohydrate and 25% microcrystalline cellulose) 0.63 g Croscarmellose sodium 0.21 g magnesium stearate

And ambrisentan Microcelac ^® were milled for 30 minutes at 350 rpm in a ball mill. To the mixture is added croscarmellose sodium and magnesium stearate and mixed for an additional 3 minutes. The mixture is pressed directly into tablets of 140 mg. The active substance content is 5 mg.

Example 9: Micronization and Direct Tableting

0.77 g ambrisentane 4.81 g MCC

14.16 g calcium hydrogen phosphate 1.05 g sodium carboxymethyl starch 0.21 g magnesium stearate

Ambrisentan and MCC were ball milled at 350 rpm for 30 minutes in a ball mill. To the mixture was added sodium carboxymethyl starch and calcium hydrogen phosphate and mixed for 10 minutes. Thereafter, magnesium stearate was added and mixed for an additional 3 minutes. The mixture was pressed directly into tablets of 140 mg. The active ingredient content was 5 mg.

Example 10: Micronization and Direct Tableting

0.77 g ambrisentane 4.81 g sucrose 14.16 g calcium hydrogen phosphate 1.05 g sodium carboxymethyl starch 0.21 g magnesium stearate

Ambrisentan and sucrose were ball milled for 30 minutes at 350 rpm. To the mixture was added sodium carboxymethyl starch and

Calcium hydrogen phosphate added and mixed for 10 min. After that was Magnesium stearate added and mixed for another 3 minutes. The mixture was pressed directly into tablets of 140 mg. The active ingredient content was 5 mg.

Example 11: Micronization and wet granulation

0.77 g of ambrisentan

4.81 g MCC (TeU 1)

9.14 g MCC (TeU 2)

1.05 g PVP 7.50 g Water l, 20 g Aerosü ^®

2.77 g of calcium hydrogen phosphate

1.05 g of sodium carboxymethyl starch

0.21 g of magnesium stearate

Ambrisentan and MCC (part 1) were ball milled for 30 minutes at 350 rpm. From the milling, MCC (TeU 2) and PVP was a granules with

Water produced. The granules were dried at 40 ⁰ C overnight. Aerosü ^® ,

Calcium hydrogen phosphate, sodium carboxymethyl starch and magnesium stearate were sieved through a 1000 μm sieve, added to the granules and mixed for three minutes. The mixture was pressed into tablets of 140 mg. The active ingredient content was 5 mg.

Example 12: Micronization and wet granulation

0.77 g of ambrisentan

4.81 g MCC (TeU 1)

9, 14 g MCC (TeU 2)

1.05 g PVP 14.50 g water

1.20 g Aerosü ^®

2.77 g of calcium hydrogen phosphate

1.05 g of sodium carboxymethyl starch

0.21 g of magnesium stearate

Ambrisentan and MCC (TeU 1) were ball milled for 30 minutes at 350 rpm. From the milling a suspension was prepared with water. This was sprayed onto MCC (TeU 2) and PVP and granules made. The

Granules were dried at 40 ⁰ C overnight. AerosU ^®, calcium hydrogen phosphate, sodium carboxymethyl starch and magnesium stearate were a 1000 .mu.m sieve sieved, added to the granules and mixed for 3 minutes. The mixture was compressed into tablets of 140 mg. The active ingredient content was 5 mg.

Claims

claims

1. Micronized ambrisentan.

2. ambrisentan according to claim I ₁ wherein the average particle diameter is 0, 1 to 50 microns.

3. Intermediate containing ambrisentan according to claim 1 or 2 and a hydrophilizing agent.

4. Intermediate according to claim 3, wherein the weight ratio of ambrisentan to hydrophilizing agent 1: 1 to 25: 1, preferably 5: 1 to 15: 1.

5. Intermediate according to claim 3 or 4, obtainable by co-micronizing ambrisentan and hydrophilizing agent.

6. Intermediate according to one of claims 3 to 5, wherein it is the hydrophilicizing agent is a hydrophilic polymer or a sugar alcohol.

7. Intermediate according to one of claims 3 to 6, wherein the hydrophilizing agent is a brittle compound having a yield pressure of at least 80 MPa.

8. Intermediate containing micronized ambrisentan, optionally in combination with a solid solution of ambrisentan, obtainable by a process comprising the steps

(a) suspending ambrisentan and hydrophilizing agent in a solvent or solvent mixture, and

(b) spraying the suspension of step (a) onto a core.

9. A pharmaceutical formulation containing micronized ambrisentan according to any one of claims 1 to 7 and pharmaceutical excipients.

10. Pharmaceutical formulation according to claim 9, containing a pseudo-emulsifier.

11. A pharmaceutical formulation according to claim 9 or 10, containing an alkaline disintegrant.

12. A process for the preparation of a pharmaceutical formulation according to any one of claims 9 to 11, comprising the steps

(I) providing micronized ambrisentan according to any one of claims 1 to 7 and pharmaceutical excipients,

(II) moistening or suspending the substances from step (I) with, or in a granulation solution,

(III) granulating the moistened or suspended substances, and

(IV) drying and optionally sieving the resulting granules.

A tablet obtainable by compressing a granule according to claim 12.

14. A tablet according to claim 13 having a hardness of 40 to 150 N and a friability of less than 10%.

15. A tablet according to claim 13 or 14 having a content uniformity of 85 to 115% of the average content.