WO2014016371A1

WO2014016371A1 - Micronized aleglitazar

Info

Publication number: WO2014016371A1
Application number: PCT/EP2013/065701
Authority: WO
Inventors: Dominique Meergans
Original assignee: Ratiopharm Gmbh
Priority date: 2012-07-27
Filing date: 2013-07-25
Publication date: 2014-01-30

Abstract

The present invention relates to micronized aleglitazar, preferably in the form of a composition together with a hydrophilizing agent. The invention further relates to a method of preparing dosage forms containing micronized aleglitazar.

Description

Micronized Aleglitazar

Background of the invention

"Aleglitazar" is reported to be the INN name o (S)-2-methoxy-3-[4-[2-(5-methyl- 2-phenyloxazol-4-yl )ethoxy]benzo[b]thiophen-7-yl] propionic acid and is characterized by the following chemical formula (I):

formula (I)

In US 2007/024984 Al the synthesis of the compound aleglitazar is described in detail. Aleglitazar is reported to belong to the class of Peroxisome Proliferator- Activated Receptor agonists (hence a PPAR modulator). In the field of molecular biology PPARs are a group of nuclear receptor proteins. The function of this group is to work as transcription factors regulating the expression of genes. Since there are various types of PPARs, PPARa, PPAR and PPARy, they can play different roles in the regulation of cellular differentiation, development, metabolism and tumorigenesis. Aleglitazar exhibits dual acting activity and thus it can show affinity to PPARa as well as to PPARy. Thus, it may combine the advantageous effects of a PPARa- activation (increasing HDL, lowering LDL and triglycerides, lipoproteins) with the advantageous effects of PPARy-activation (insulin resistance and glucose levels are decreased). Due to its positive therapeutic effects to multiple symptoms, aleglitazar might be a medical drug.

Aleglitazar, for example aleglitazar sodium, may form primary pin-like particles of 1 to 5 μιη. However, these primary particles tap into agglomerates of over 100 μιη. These resulting agglomerates are reported to involve some difficulties in view of their processability. For example, the processability of aleglitazar agglomerates and/or the pharmaceutical formulations containing the respective aleglitazar agglomerates may be improved, especially when prepared on a large scale. As one option, a spray granulation process is reported to handle the above- mentioned problem. Reference can be made to WO 2010/084066. However, said process is regarded to be still improvable, in particular in view of content uniformity, especially when small amounts of active agent are used. Moreover, the processability, e.g. the flowability and/or compressibility, appears to be increasable, in particular, if the ideal process conditions are not exactly met. Further, said process is time consuming and not advantageous in view of cost efficiency.

Hence, it was an object of the present invention to overcome the drawbacks of the prior art formulations.

Furthermore, aleglitazar free acid has a very low solubility in highly acidic media potentially leading to precipitation of the drug in the stomach, thus leading to a lower resorption of the active ingredient. An additional object of the invention was to overcome this drawback.

A further object of the invention was to avoid solvents, in particular organic solvents. In particular, it was an object of the invention to provide an aleglitazar-containing formulation which can be advantageously produced even on a larger scale. The formulations should show advantageous processability (e.g. superior flowability). Consequently, it was an object of the invention to provide the active agent in a form which possesses superior processability and compressibility. If compressed, the resulting dosage form should exhibit a high level of hardness and low friability.

Further, the resulting dosage form should have a particularly even distribution of active agent (content uniformity) even with a low content of active agent.

Moreover, it was an object of the invention to provide aleglitazar in a form having superior storage properties. In particular, it is intended to achieve a storage stability of 12 months at 40° C and 75% atmospheric humidity.

Summary of the invention

According to the present invention, the above objectives are achieved by using a specific form of aleglitazar, namely micronized aleglitazar. More specifically, the drawbacks of the above-mentioned known aleglitazar-containing preparations can be overcome by using compositions containing micronized aleglitazar for processing dosage forms.

Thus, the subject of the present invention is micronized aleglitazar. In addition, the subject of the invention is a composition comprising micronized aleglitazar (a), a hydrophilizing agent (b) and optionally one or more further excipients (c). Moreover, micronized aleglitazar or the composition of the invention possesses desirable properties and overcomes the drawbacks of the prior art. The subject of the invention also relates to methods of preparing micronized aleglitazar or hydrophilized micronized aleglitazar in the form of the composition of the invention. Further, it was found that the composition of the invention as well as the corresponding dosage forms can be very stable over a long period. This is important since aleglitazar is applied in low doses and even little degradation of the active agent can lower its beneficial effects.

It was found that the low solubility in highly acidic media could be overcome by the use of surfactants either alone or in combination with other excipients.

Micronized aleglitazar of the invention or a composition of the invention can be processed into dosage forms.

Hence, a further subject of the invention relates to a dosage form comprising micronized aleglitazar according to the invention or a composition comprising micronized aleglitazar and hydrophilizing agent.

Surprisingly, it was found that the dosage form of the present invention can reproducibly exhibit required content uniformity.

Additionally, the subject of the invention relates to a method of producing said dosage forms comprising the steps of providing the composition of the invention containing aleglitazar (a) in micronized form;

optionally granulating the composition of step (i);

mixing the composition of step (i) or the granulates of step (ii) with optionally one or more excipient(s) (c);

optionally granulating the mixture from step (iii); and processing the mixture of step (iii) or the granulates from step (iv) into a dosage form.

Finally, the subject of the invention relates to PPAR-modulator in a micronized form for the use as a drug treating patients with diabetes mellitus type II. Detailed description of the invention

In the context o this invention, the term "aleglitazar" refers to ( S )-2-methoxy-3- [4-[2-( -methyl-2-phenyloxazol-4-yl )ethoxy]benzo[b]thiophen-7-y I ] propionic acid in accordance with formula (I) above. In addition, the term "aleglitazar" as used in the present application can refer to aleglitazar in the form of the free acid as well as to its pharmaceutically acceptable salts, hydrates, solvates, polymorphs and mixtures thereof. The pharmaceutically acceptable salts can be obtained by reaction, preferably with an inorganic base. Thereby, the carboxylic hydrogen atom of aleglitazar can be replaced by a metal atom, for example an alkali metal atom. In a preferred embodiment aleglitazar is used in the form of its sodium salt.

The expression "micronized aleglitazar" can be used in the context of this invention to designate aleglitazar in particulate form which can have an average particle diameter (D50) of 0.1 to 75 μιη, preferably 0.5 to 50 μιη, more preferably 1 to 20 μιη, particularly preferably 1.5 to 15 μιη and especially 2 μιη to 9 μιη.

The expression "average particle diameter" can relate in the context of this invention to the D50 value of the average particle diameter determined by means of laser diffractometry. In particular, a Malvern Instruments Mastersizer 2000 can be used to determine the diameter (preferably wet measurement with ultrasound 60 sec, 2,000 rpm, preferably shading 6%, preferably dispersed in liquid paraffin, the evaluation being performed according to the Fraunhofer model). The average particle diameter, which is 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 which corresponds to the D50 value. Similarly, 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. In a preferred embodiment the Dio value of the integral volume distribution is from 0.01 to 7 μιη, preferably from 0.05 to 5 μιη, more preferably from 0.1 to 3.5 μιη and especially from 0.5 to 1.5 μιη. 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 which corresponds to the D₉₀ value. In a preferred embodiment the D₉₀ value of the integral volume distribution is from 10 to 250 μιη, preferably from 15 to 175 μιη, more preferably from 20 to 150 μιη and especially from 25 to 100 μπι.

In a preferred embodiment the ratio of the D₉₀ value to the D₁₀ value of the micronized aleglitazar is between 1 : 1 and 20 : 1, more preferably between 1.1 : 1 and 15 : 1 , even more preferably between 1.5 : 1 and 13 : 1 and especially between 2 : 1 and 5 : 1. It appears that a small ratio of the D₉₀ value to the D₁₀ value seems to be favourable for good distribution of the active agent within the composition and therefore assures that the above-mentioned objects are achieved.

In a preferred embodiment, the aleglitazar of the invention can be present in micronized and hydrophilized form, namely in the form of a composition containing micronized aleglitazar (a) and a hydrophilizing agent (b); and optionally further excipients (c).

In a particularly preferred embodiment the composition of the present invention and the corresponding dosage form comprise aleglitazar as the sole pharmaceutical active agent. In an alternative embodiment the composition of the present invention and the corresponding dosage form can comprise aleglitazar in combination with further pharmaceutical active agent(s). The "hydrophilizing agent" (b) in the context of this invention can be a substance which is capable of accumulating on aleglitazar (chemically or physically) and increasing the hydrophilicity of the surface. In a preferred embodiment, the hydrophilizing agent (b) may be a hydrophilic polymer, which means a polymer with hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, carboxy, sulphonate. In addition, a hydrophilic polymer suitable for preparing a composition according the invention may have a weight-average molecular weight of 1,000 to 500,000 g/mol, more preferably 2,000 to 250,000 g/mol, even more preferably 2,500 to 100,000 g/mol. When said polymer used as the hydrophilizing agent (b) is dissolved in water in an amount of 2% by weight, the resulting solution preferably can have a viscosity of 1 to 20 mPas, more preferably 1 to 5 mPas, even more preferably 2 to 4 mPas, measured at 25° C and determined in accordance with Ph. Eur., 6.0, chapter 2.2.10. The weight average molecular weight is determined by gel permeation chromatography.

Furthermore, the hydrophilizing agent (b) can also encompass solid, non-polymeric compounds which preferably contain polar side groups. Examples of these can be sugar alcohols or di saccharides. The term "sugar alcohols" in this context can also include monosaccharide.

Thus, the composition of the invention may, for example, comprise the following hydrophilizing agents (b): polysaccharides, such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC, especially sodium and calcium salts), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and their salts, polyacrylamide, polymethacrylates, vinyl pyrrolidone-vinyl acetate copolymers (such as Kollidon^® VA64, BASF), polyoxyethylene/polyoxypropylene block polymer (Poloxamer^®), gelatine, polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol, mannitol, sorbitol, meglumin, xylitol, isomalt, sucrose, lactose, glucose, fructose, maltose and mixtures thereof.

A particularly preferred the hydrophilizing agent is a combination comprising mannitol and meglumin. Further, it has been found that preferably "brittle" hydrophilizing agents (b) can be used especially advantageously for the production of a composition according the invention. Hydrophilizing agents (b) can generally be classified with regard to the change in the shape of the particles under compression pressure (compaction). 'Plastic' hydrophilizing agents are characterized by showing plastic deformation of the particles upon exertion of a compressive force, whereas particles of 'brittle' hydrophilizing agents, when compressive force is exerted, tend to break into smaller particles. Brittle behaviour on the part of the hydrophilizing agent (b) can be quantified by the increase in the surface area in a compressed part. In the art, it is customary to classify the brittleness in terms of the "yield pressure". According to a simple classification, the values for the "yield pressure" here are low for plastic substances but on the other hand high in the case of friable substances [Duberg, M., Nystrom, 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. « Methode rapide de determination du comportement a la compression pour des etudes de preformulation «, Pharm. Acta Helv., 57, 136- 143 (1982)] . The "yield pressure" describes the pressure that has to be reached for the substance (i.e. the hydrophilizing agent) to begin flowing plastically.

The "yield pressure" can preferably be calculated using the reciprocal of the gradient of the Heckel plot, as described in York, P., Drug Dev. Ind. Pharm. 18, 677 (1992). The measurement in this case can preferably be made according to the "ejected tablet" method at 25° C and a deformation rate of 0.1 mm/s.

In a preferred embodiment of the present invention, the hydrophilizing agent can have a "yield pressure" of at least 80 MPa, preferably 90 to 300 MPa.

Examples of preferred hydrophilizing agents (b) having the above-described "yield pressure" can be microcrystalline cellulose, sucrose and lactose. Especially lactose is preferred. In a preferred embodiment, the composition of the invention can contain micronized aleglitazar (a) and hydrophilizing agent (b), the weight ratio of micronized aleglitazar to hydrophilizing agent being 1 : 1 to 1 : 250 , preferably 1 : 2 to 1 :200, more preferably 1 : 3 to 1 : 150, even more preferably 1 : 4 to 1 : 100, especially 1 : 5 to 1 : 50.

It is preferable that the type and amount of the hydrophilizing agent (b) can be selected such that at least 80% of the surface of the resulting composition particles can be covered with hydrophilizing agent, more preferably at least 90% of the surface, particularly preferably at least 95% of the surface, especially at least 99% of the surface.

The subject of the invention can be a method of preparing the micronized aleglitazar of the invention or the composition of the invention.

Micronized aleglitazar in accordance with the invention is preferably obtainable by milling. The composition of the present invention is preferably prepared by co- milling, preferably co-micronizing (= jointly milling, preferably jointly micronizing) aleglitazar, hydrophilizing agent and optionally one or more further excipients.

The milling can be performed in conventional milling apparatuses, as non limiting examples such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder, rotor mill. A planetary mill is preferably used. An air jet mill is most preferably used.

In a preferred embodiment, the invention relates to a process for preparing the composition of the invention, comprising the steps of (gl) providing aleglitazar (a) and hydrophilizing agent (b) and optionally one or more excipients (c) and

(g2) milling or micronizing the mixture from step (gl). In a preferred embodiment of the invention, step (gl) of providing aleglitazar (a) and hydrophilizing agent (b) can comprise mixing the compounds (a) and (b) and optionally one or more excipients (c). Thus, crystalline (non-mi cronized or conventional) aleglitazar (a) and hydrophilizing agent (b) and optionally one or more excipients (c) can be mixed in step (gl). Step (g2) of micronizing the mixture from step (gl) can preferably be carried out by milling. The mixing may take place before or even during the milling, i.e. steps (gl) and (g2) may be performed simultaneously. The milling conditions can be selected such that at least 80% of the surface of the resulting composition particles is covered with hydrophilizing agent, more preferably at least 90% of the surface, particularly preferably at least 95% of the surface, especially at least 99% of the surface. The milling is generally performed in conventional milling apparatuses, such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder, rotor mill. A planetary mill is preferably used. An air jet mill is most preferably used. The milling time is usually 0.5 minutes to 1 week, preferably 2 minutes to 50 hours, more preferably 15 minutes to 24 hours.

The process conditions in this embodiment are preferably selected such that the resulting composition particles can have an average particle diameter (D50) of 0.1 to 200 μιη, preferably 0.5 to 50 μιη, more preferably 1 to 25 μιη, particularly preferably 1.5 to 25 μιη and especially 2 μιη to 15 μιη.

An alternatively preferred process for preparing the composition of the invention comprises the steps of

(hi) providing aleglitazar (a) and a first part of hydrophilizing agent (b) and one or more excipients (c) and;

(h2) micronizing the mixture from step (hi); (h3) adding a further part of hydrophilizing agent (b) and micronizing said mixture and one or more excipients (c) ; and

(h4) optionally repeating step (h3) one to five times. In a preferred embodiment of the invention step (hi) of providing aleglitazar (a) and a first part of hydrophilizing agent (b) and optionally one or more excipients (c) can comprise mixing the compounds (a) and (b). Thus, crystalline (non- micronized) aleglitazar (a) and hydrophilizing agent (b) and optionally one or more excipients (c) can be mixed in step (hi).

Step (h2) of micronizing the mixture from step (hi) can preferably be carried out by milling. The mixing may take place before or even during the milling, i.e. steps (hi) and (h2) may be performed simultaneously. The milling conditions can be selected such that at least 80% of the surface of the resulting composition particles is covered with hydrophilizing agent, more preferably at least 90% of the surface, particularly preferably at least 95% of the surface, especially at least 99% of the surface. The milling can be performed in conventional milling apparatuses, as non limiting examples such as in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disk mill, mortar grinder, rotor mill. A planetary mill is preferably used. An air jet mill is most preferably used. The milling time is usually 0.5 minutes to 1 week, preferably 2 minutes to 50 hours, more preferably 15 minutes to 24 hours.

The process conditions in this embodiment can preferably be selected such that the resulting composition particles can have an average particle diameter (D50) of 0.1 to 100 μιη, preferably 0.5 to 500 μιη, more preferably 1 to 25 μιη, particularly preferably 1.5 to 20 μιη and especially 2 μιη to 15 μιη. In a preferred embodiment of the invention step (h3) of adding a further part of hydrophilizing agent (b) and optionally one or more excipients (c) can preferably be performed by an accompanying mixing step. Step (h4) of optionally repeating step (h3) one to five times may depend on the number of parts into which the initial hydrophilizing agent (b) is divided.

Using this method, an even distribution of active agent within the composition can be achieved.

The above-described process can lead to the composition of the invention containing micronized aleglitazar and hydrophilizing agent and optionally one or more excipients (c). The subject of the invention therefore can relate to compositions obtainable by this method.

The one or more excipient(s) (c) optionally used in the composition according to the invention can be preferably selected from the excipients described below. More preferably, the optionally one or more excipient(s) (c) used in the above process can be preferably selected from surfactants and fillers, in particular from sodium lauryl sulfate and disodium phosphate as well as sodium dihydrogen phosphate. Further, it is preferred that composition of the present invention additionally comprises basic components, preferably basic buffer salts. Basic buffer salts can be present in an amount of 1 to 30 wt.-%, based on the weight of the composition. The micronized aleglitazar of the invention and the composition of the invention (i.e. the hydrophilized and micronized aleglitazar of the invention) can be employed to prepare dosage forms.

Thus, a subject of the invention can be a dosage form containing micronized aleglitazar of the invention or a composition of the invention as well as one or more pharmaceutical excipient(s) (c). These can be excipients (c) with which the person skilled in the art is familiar, such as those described in the European Pharmacopoeia. Further, regarding the above-mentioned pharmaceutically acceptable excipients, the application refers to "Lexikon der Hilfsstoffe fiir Pharmazie, Kosmetik und angrenzende Gebiete", edited by H. P. Fiedler, 4^th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London. Examples of excipients (c) used to prepare the dosage form of the invention can preferably be disintegrants (cl), anti-sticking agents (c2), surfactants (c3), fillers (c4), glidants (c5), binders (c6) and/or lubricants (c7).

Disintegrants (cl) are reported to be compounds which can enhance the ability of the dosage form to break into smaller fragments when in contact with a liquid, preferably water. Suitable disintegrants can be, for example, organic disintegrants such as crosslinked PVP, carrageenan, croscarmellose, starch, sodium carboxymethyl starch and crospovidone. Alkaline disintegrants can preferably be used. The term "alkaline disintegrants" means disintegrants which, when dissolved in water, produce a pH level of more than 7.0.

More preferably, inorganic alkaline disintegrants can be used, especially salts of alkali metals and alkaline earth metals. Preferred examples here are sodium, potassium, magnesium and calcium. As anions, carbonate, hydrogen carbonate, phosphate, hydrogen phosphate and dihydrogen phosphate can preferably be used. Examples are sodium hydrogen carbonate, calcium hydrogen carbonate.

Crospovidone and/or croscarmellose can particularly preferably be used as disintegrants.

Disintegrants (cl) can be used from 0.5 to 15% by weight, preferably 1.0 to 10% by weight, more preferably 1.5 to 7% by weight, based on the total weight of the dosage form. Anti-sticking agents (c2) are reported to be substances which reduce agglomeration in the core bed. Examples are talcum, silica gel, polyethylene glycol (preferably with 2,000 to 10,000 g/mol weight-average molecular weight) and/or glycerol monostearate. Examples of preferred anti-sticking agents are talcum and polyethylene glycol (Mg 3,000-6,000 g/mol), carrageenan. Preferably, an anti- sticking agent (c2) can be used when micronized aleglitazar is used in the dosage form.

Anti-sticking agents (c2) can be used in an amount of 0.1 to 5% by weight, more preferably 0.5 to 3% by weight, based on the total weight of the dosage form.

Surfactants (c3) are reported to be substances lowering the interfacial tension between two phases, thus enabling or supporting the formation of dispersions or working as a solubilizer. Examples of preferred surfactants include but are not limited to alkyl sulfates (for example sodium lauryl sulfate), alkyltrimethylammonium salts, alcohol ethoxylates and the like. Sodium lauryl sulfate can particularly be used as a surfactant.

Surfactants (c3) can preferably be used in an amount from 0.1 to 5% by weight, more preferably from 0.3 to 3% by weight even more preferably from 0.5 to 2% by weight, based on the total weight of the dosage form.

Fillers (c4) or diluents can be used to increase the bulk volume and weight of a low-dose drug to a limit at which a pharmaceutical dosage form can be formed. Therefore, the normal purpose of fillers is to obtain a suitable tablet size. Fillers may fulfil several requirements, such as being chemically inert, non-hygroscopic, biocompatible, easily processable and possessing good biopharmaceutical properties. Examples of preferred fillers are lactose, lactose derivatives, microcrystalline cellulose, starch, starch derivatives, treated starch, talcum, 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. Prosolv^® (Rettenmaier & Sonne, Germany) can likewise be used.

Fillers are normally used in an amount of 1 to 80% by weight, more preferably 30 to 60% by weight, based on the total weight of the dosage form.

Glidants (c5) can be used to improve the flowability. Traditionally, talc was used as glidant, but it is nowadays nearly fully replaced by colloidal silica (for example Aerosil^®). Preferably, the silica has a specific surface area of 50 to 400 m²/g, more preferably 150-250 m /g, measured by gas adsorption according to Ph. Eur., 6.0, Chapter 2.9.26, multipoint method, volumetric determination.

Glidants (c5) can be used in an amount of 0.1 to 3% by weight, preferably 0.2 to 2.0% by weight, based on the total weight of the dosage form.

Binders (c6) or adhesives are reported to be substances that ensure that granulates or tablets can be formed with the required mechanical strength. Binders can be, for example, starch, sucrose, gelatine, polyvinylpyrrolidone, cellulose derivates, preferably hydroxypropyl methylcellulose and microcrystalline cellulose.

Binders (c6) can be used in an amount of 0.1 to 15% by weight, preferably 2- 10% by weight, based on the total weight of the dosage form.

Lubricants (c7) can be used in order to reduce sliding friction. In particular, the intention is to reduce the sliding friction occurring during tablet pressing between the die and the die wall, on the one hand, and between the edge of the tablet and the die wall, on the other hand. The lubricant can be preferably a stearate or fatty acid, more preferably an earth alkali metal stearate, such as magnesium stearate. The lubricant can be suitably present in an amount of 0 to 3 wt.%, preferably about 0.1 to 1.0 wt.% of the total weight of the dosage form.

Lubricants are generally used in an amount of 0.1 to 3% by weight, based on the total weight of the dosage form. In this regard it is generally noted that due to the nature of pharmaceutical excipients it cannot be excluded that a certain compound meets the requirements of more than one of the components (b) and (cl) to (c7). For example, in the present dosage form microcrystalline cellulose may act both as hydrophilizing agent (b) and as filler (c4).

However, in order to enable an unambiguous distinction, it is preferred in the present application that one and the same pharmaceutical compound can only function as one of the compounds (b) or (cl) to (c7). For example, if lactose is added as hydrophilizing agent (b), it cannot additionally be added as filler (c4).

In a preferred embodiment of the dosage form of the present invention, the active agent (aleglitazar) is present in an mount of 0.01 to 50 o by weight, preferably from 0.1 to 5 c, more preferably 0.2 to 1.5 o, by weight, based on the total weight of the dosage form.

In a preferred embodiment the dosage form is a solid oral dosage form, preferably a tablet or a capsule, more preferably a tablet. In a further preferred embodiment the dosage form, the oral dosage form can have a content uniformity wherein the acceptance value is at most 15, preferably 0.1 - 10, more preferably 1 - 7.5, in particular at most 2 - 6.5. The acceptance value of the content uniformity is determined by assaying 10 individual dosage forms and calculating the corresponding acceptance value in accordance with Ph. Eur., 5.3, Chapter 2.9.40.

Another subject of the present invention is a method of producing a dosage form comprising the steps of (i) providing the composition of the present invention containing aleglitazar (a) in a micronized form;

(ii) optionally granulating the composition of step (i); (iii) mixing the composition of step (i) or the granulates of step (ii) with optionally one or more excipient(s) (c);

(iv) optionally granulating the mixture from step (iii), ; and

(v) processing the mixture of step iii) or the granulates from step (iv) into a dosage form.

In step (i), a composition of the present invention containing micronized aleglitazar (a) is provided. This composition can be prepared by the above- mentioned process for preparing a composition according to the invention.

In an alternative embodiment of the present invention micronized aleglitazar can be provided in step (i).

Step (ii) of optionally granulating the composition from step (i) can be performed, for example, by "slugging", using a large heavy-duty rotary press to compact the composition to slugs and afterwards breaking up the slugs to granulates with a hammer mill or by roller compaction, using for example roller compactors by Powtec or Alexanderwerk. In a preferred embodiment, step (iii) can be characterized by mixing the composition of step (i) or the granulates of step (ii) with one or more excipient(s) (c). The mixing (iii) can be carried out with conventional mixing devices. In order to ensure an even distribution, mixing in intensive mixers is preferable. Suitable mixing devices can preferably be compulsory mixers or free fall mixer, for example like Turbula^® T 10B (Bachofen AG, Switzerland). Mixing can be carried out for example for 1 minute to 1 hour, preferably for 5 to 30 minutes.

The excipient(s) (c) used in step (iii) can preferably be selected from disintegrants (cl), anti-sticking agents (c2), surfactants (c3), fillers (c4), glidants (c5), binders (c6) and/or lubricants (c7).

In a preferred embodiment crosslinked PVP (used as disintegrant), sodium lauryl sulfate (used as surfactant), lactose and microcrystalline cellulose (used as fillers), povidone (used as binder), sodium stearyl fumarate (used as lubricant) and microcrystalline cellulose and lactose (used as filler) can be used as excipients.

In an alternative embodiment mixing (iii) can be conducted such that the composition of step (i) or the granulates of step (ii) can be mixed with only a part of the excipient(s) in a mixing device, for example in a high shear or tumbler mixer. After this first mixing step a next part of the excipient(s) can be added, which may be followed by a next mixing step. This procedure can be repeated until the last part of the excipient(s) is used, preferably one to five times. This kind of mixing can assure an even distribution of active agent and provide a mass for further processing in step (iv), for example for a tabletting process.

In a further alternatively preferred embodiment it is possible that the composition of step (i) or the granulates of step (ii) initially can be mixed with only a part of the excipient(s) (for example 25 to 95%). This mixture can preferably be granulated in step (iv). After granulation, a next part of the excipient(s) can be added and a next mixing (iii) and/or granulation step (iv) can be performed. In the case of multiple granulation steps, the excipients should preferably be mixed in before the first granulation step, between multiple granulation steps or after the last granulation step. The procedure can be repeated as many times as the number of parts the initial amount of excipient(s) was divided in. This specific combination of mixing and granulating step can assure an even distribution of active agent. It is preferred that if step (iv) is carried out, the granulation is performed in the absence of solvents, especially in the absence of organic solvents.

Preferably, step (iv) comprises a compaction sub-step and a subsequent granulation sub -step.

The compacting conditions in steps (ii) and/or (iv) can preferably be selected such that the slugs have a density of 0.75- 1.1 g/cm . The term "density" here preferably relates to the "pure density" (i.e. not to the bulk density or compacted density). The pure density can be determined with a gas pycnometer. The gas pycnometer is preferably a helium pycnometer; in particular, the AccuPyc 1340 helium pycnometer from the manufacturer Micromeritics, Germany, is used.

The compaction sub-step can preferably be carried out in a roll granulator.

The rolling force can be preferably 2 to 50 kN/cm, more preferably 4 to 30 kN/cm, especially 10 to 25 kN/cm.

The gap width of the roll granulator can be, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, especially 1.8 to 2.8 mm. The compacting apparatus used can preferably have a cooling means. In particular, the cooling can be such that the temperature of the compacted material does not exceed 50°C, especially 40°C.

In a preferred embodiment, the granulation conditions are selected such that the resulting particles (granulates) have an average particle diameter (D50) of 50 to 600 μιη, more preferably 100 to 500 μιη, even more preferably 150 to 400 μιη, especially 200 to 350 μιη.

In addition, the granulation conditions are preferably selected such that the resulting granulates 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. The Hausner factor is usually in the range from 1.03 to 1.3, more preferably from 1.04 to 1.20 and especially from 1.04 to 1.15. The "Hausner factor" in this context means the ratio of compacted density to bulk density.

In a preferred embodiment, the granulation is performed in a screen mill. In this case, the mesh width of the screen insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, especially 0.8 to 1.8 mm. In step (v) the mixture resulting from step (iii) or the granulates of step (iv) can be further processed into an oral dosage form. Step (v) can preferably comprise compressing the mixture resulting from step (iii) or the granulates of step (iv) into tablets or filling the mixture resulting from step (iii) or the granulates of step (iv) into devices like sachets, stick-packs or capsules.

In particularly preferred embodiment step (v) of processing the mixture resulting from step (iii) or the granulates of step (iv) into an oral dosage form can include compressing the mixture resulting from step (iii) or the granulates of step (iv) into tablets.

The compression step (v), preferably a direct compression step, is preferably carried out on a rotary press, e.g. on a Fette^® 102i (Fette GmbH, Germany) or a Riva^® piccola (Riva, Argentina).

The amounts of excipient(s) added in step (ii) or (iii) can depend on the type of tablet to be produced and the amount of excipient(s) already added. During compression, the additives to improve powder flowability described above and the lubricants described above can preferably be used. Compression force can for example range from 1 to 50kN, preferably 3 to 40kN.

The tabletting conditions are preferably selected such that the resulting tablets have a ratio of tablet height to weight of 0.005 to 0.3 mm/mg, particularly preferably 0.05 to 0.2 mm/mg.

In addition, the resulting tablets preferably have a hardness of 30 to 400 N, more preferably 50 to 250 N. The hardness is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.8. In addition, the resulting tablets preferably have a friability of less than 10%, more preferably less than 8%, particularly preferably less than 5%. The friability is determined in accordance with Ph. Eur., 6.0, Chapter 2.9.7. The tablets produced by the method of the invention may be tablets which can be swallowed unchewed (non-film-coated or preferably film-coated). They may likewise be chewable tablets or dispersible tablets. "Dispersible tablet" here means a tablet to be used for producing an aqueous suspension for swallowing.

In the case of tablets which are swallowed unchewed, it is preferable that they be coated with a film layer. For this purpose, the methods of film coating tablets as standard in the state of the art may be employed. The above-mentioned ratios of active agent to excipient, however, relate to the uncoated tablet.

For film coating, macromolecular substances are preferably used, such as modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and/or shellack. HPMC is preferably used, especially HPMC with a number- average molecular weight of 10,000 to 150,000 g/mol and/or an average degree of substitution of - OCH₃ groups of 1.2 to 2.0.

The thickness of the coating is preferably 1 to 100 μιη, more preferably 10 to 80 μπι.

The above details regarding hardness and friability preferably relate to the non- film-coated tablet. In an alternatively preferred embodiment of step (v) dependent dosing systems (for example an auger) or preferably independent dosing systems (for example MG2, Matic (IMA)) can be used for filling the mixture resulting from step (iii) or the granulates of step (iv) into sachets or capsules, preferably hard gelatine capsules. Another preferred embodiment of the invention can be a micronized PPAR- modulator with dual acting activity (i.e. affinity to PPARa as well as to PPARy) for treating patients with diabetes mellitus type II having a value of triglyceride of 200-600 mg/dl. A triglyceride value of more than 200 mg/dl is reported to be harmful for a normal person.

For the determination of the triglyceride value the taking of a blood sample from a fasting person, preferably from a person having fasted for 12- 16 hours, is unavoidable. Afterwards, the sample can be searched for example by chromatography, preferably by gas chromatography using a temperature-modelling device. The invention will now be explained with reference to the following examples. EXAMPLES

Example 1: Micronization

2 g crystalline aleglitazar was milled for 30 minutes at 350 rpm in a Retsch ball mill.

The following average particle diameters were found:

D₉₀ = 63 μιη; ϋ₅₀ = 18 μιη, D₁₀ = 5 μιη Example 2a: Dosage form prepared by Co-milling of Aleglitazar Aleglitzar, sodium lauryl sulfate, disodium phosphate and sodium dihydrogen phosphate and a quarter of mannitol were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125μιη mesh size. Afterwards another quarter of mannitol was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125μιη mesh size. Then the remained part of mannitol was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125μιη mesh size. After sieving of Prosolv SMCC 90 and croscarmellose sodium through 500μιη mesh size, both excipients were added to the milled intermediate and blended together in a tumble mixer for 10 minutes. After addition of magnesium stearate blending was continued for further 3 minutes. The final composition was compressed to tablets on a rotary press (Riva Piccola) with 6mm biconvex tablet punches to a tablet hardness of 60 N each containing

Aleglitazar sodium 0.1500 mg (based on the free acid)

Sodium lauryl sulfate 0.3125 mg

Mannitol 50.215 mg

Disodium phosphate 0.5530 mg

Sodium dihydrogen phosphate 0.0210 mg

Microcrystalline cellulose + Silicone Dioxide 46.500 mg

Croscarmellose sodium 1.2500 mg

Magnesium stearate 1.0000 mg total 100.000

Example 2b: Dosage form prepared by Co-milling of Aleglitazar Aleglitzar, sodium lauryl sulfate, disodium phosphate and sodium dihydrogen phosphate and a quarter of mannitol were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125μιη mesh size. Afterwards another quarter of mannitol was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125μιη mesh size. Then the remained part of mannitol was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125μιη mesh size. After sieving of Prosolv SMCC 90 and croscarmellose sodium through 500μιη mesh size, both excipients were added to the milled intermediate and blended together in a tumble mixer for 10 minutes. After addition of magnesium stearate blending was continued for further 3 minutes. The final composition was compressed to tablets on a rotary press (Riva Piccola) with 6mm biconvex tablet punches to a tablet hardness of 60 N each containing Aleglitazar sodium 0.1500 mg (based on the free acid)

Sodium lauryl sulfate 1.0000 mg

Mannitol 49.5275 mg

Disodium phosphate 0.5530 mg

Sodium dihydrogen phosphate 0.0210 mg

Microcrystalline cellulose + Silicone Dioxide 46.500 mg

Croscarmellose sodium 1.2500 mg

Magnesium stearate 1.0000 mg total 100.000 mg

Example 2c: Dosage form prepared by Co-milling of Aleglitazar

0.167 g Aleglitzar sodium, 1.000 g, sodium lauryl sulphate and 16.503 g Pearlitol SD 200 were milled in a mortar and subsequently sieved through 125 μιη mesh size. Afterwards another 16.503 g Pearlitol was added and the resulting blend was milled again and subsequently sieved through 125 μιη mesh size. Then, once more 16.503 g Pearlitol was added and the resulting blend was milled and afterwards was sieved through 125 μιη mesh size. After sieving 20.000 g Avicel PH 101 and 0.625 g Solutab through 500 μιη mesh size, both excipients were added to the milled intermediate and blended together in a tumble mixer for 5 minutes at 23 rpm. The blend was granulated with a solution of 5.000 g Meglumine in 16.7 g water. After being dried, the granulate was sieved through 630 μιη mesh size. After sieving through 630 μιη mesh size, 0.625 g Solutab and 22.070g Prosolv SMCC 90 were added and the resulting mixture was blended for 10 minutes. After the addition of 1.000 g magnesium stearate blending was continued for further 3 minutes. The final composition was compressed to tablets each containing

Aleglitazar sodium 0.1671 mg (0.17 %)

Sodium lauryl sulfate 1.0000 mg (1.00 %)

Pearlitol 49.510 mg (49.51 %)

Avicel^® 20.000 mg (20.00%)

Meglumine 5.0000 mg (5.00%)

Prosolv^® SMCC 22.070 mg (22.07 %) Solutab 1.2500 mg (1.25 %)

Magnesium stearate 1.000 mg (1.00 %) total 100.000 mg (100%)

Example 3: Dosage form prepared by Co-milling of Aleglitazar

Aleglitzar, sodium lauryl sulfate, disodium phosphate and sodium dihydrogen phosphate and a quarter of lactose were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125μιη mesh size. Afterwards another quarter of lactose was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125μιη mesh size. Then the remained part of lactose was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125μιη mesh size. After sieving of Prosolv SMCC 90 and croscarmellose sodium through 500μιη mesh size, both excipients were added to the milled intermediate and blended together in a tumble mixer for 10 minutes. After addition of magnesium stearate blending was continued for further 3 minutes. The final composition was compressed to tablets on a rotary press (Riva Piccola) with 6mm biconvex tablet punches to a tablet hardness of 60 N each containing

Aleglitazar sodium 0.1500 mg (based on the free acid)

Sodium lauryl sulfate 0.3125 mg

Lactose 50.215 mg

Disodium phosphate 0.5530 mg

Sodium dihydrogen phosphate 0.0210 mg

Microcrystalline cellulose + Silicone Dioxide 46.500 mg

Croscarmellose sodium 1.2500 mg

Magnesium stearate 1.0000 mg total 100.000 mg Example 4: Dosage form prepared by Co-milling of Aleglitazar

Aleglitzar, sodium lauryl sulfate, meglium and a quarter of mannitol were milled together in a planetary ball mill from Retsch for 5 minutes at 150 rpm and subsequently sieved through 125μιη mesh size. Afterwards another quarter of mannitol was added to the blend and milling was continued for 5 minutes at 150 rpm. Subsequently the blend was sieved through 125μιη mesh size. Then the remained part of mannitol was added to the blend and milling was continued for further 5 minutes at 150 rpm. Afterwards the blend was sieved through 125μιη mesh size. After sieving of Prosolv SMCC 90 and croscarmellose sodium through 500μιη mesh size, both excipients were added to the milled intermediate and blended together in a tumble mixer for 10 minutes. After addition of magnesium stearate blending was continued for further 3 minutes. The final composition was compressed to tablets on a rotary press (Riva Piccola) with 6mm biconvex tablet punches to a tablet hardness of 60 N each containing

Aleglitazar sodium 0.1500 mg (based on the free acid)

Sodium lauryl sulfate 0.3125 mg

Mannitol 50.215 mg

Meglumin 0.5740 mg

Microcrystalline cellulose + Silicone Dioxide 46.500 mg

Croscarmellose sodium 1.2500 mg

Magnesium stearate 1.0000 mg Total 100.000 mg

Example 5: Content uniformity Test

The homogeneity of the active substance distribution of the dosage form according to Example 2 of the present invention and a comparative dosage form prepared by wet-granulation, wherein dissolved aleglitazar was used, was evaluated by the standard deviation of the assay of ten individual tablets according to Ph. Eur.5.3, chapter 2.9.40 (uniformity of dosage units). The results are shown in Table 1 below.

The dosage form according to the present invention has a mean assay of 98.93% and the standard deviation is 2.25 %. The dosage from according to W02010/084066 has a mean assay of 101.03 % and the standard deviation 2.93 %.

Table 1

As the sample of the dosage form according to the present invention has a significantly lower acceptance value than the reference example as prepared by spray granulation.

Claims

1. Micronized aleglitazar.

2. Aleglitazar according to claim 1 , wherein the average particle size (D₅₀) is 0.1 to 50 μπι.

3. A composition containing aleglitazar (a) according to claim 1 or 2 and hydrophilizing agent (b).

4. The composition according to claim 3, wherein the hydrophilizing agent (b) is a hydrophilic polymer and/or a sugar alcohol, preferably a sugar alcohol.

5. The composition according to claim 3 or 4, wherein the hydrophilizing agent (b) is a compound having a yield pressure of at least 80 MPa.

6. The composition according to any one of claims 3 to 5, wherein the weight ratio of aleglitazar (a) to hydrophilizing agent (b) is 1 : 1 to 1 :250, preferably 1 :5 to 1 :50.

7. The composition according to any one of claims 3 to 6, obtainable by jointly milling aleglitazar (a) and hydrophilizing agent (b) and optionally one or more excipients (c).

8. A dosage form comprising micronized aleglitazar according to claim 1 or 2 or a composition according to any one of claims 3 to 7 and optionally further comprising one or more pharmaceutical excipient(s) (c).

9. The dosage form according to claim 8, comprising aleglitazar in an amount of 0.01 to 50%o by weight, preferably of 0.1 to 5%o by weight, based on the total weight of the dosage form.

10. The dosage form according to claim 8 or 9, wherein the dosage form is a solid oral dosage form, preferably a tablet or a capsule.

1 1. The dosage form according to claim 1 1 , wherein the acceptance value of the content uniformity of the dosage form is at most 6.8

12. A method of producing the dosage form according to any one of claims 7- 1 1 comprising the steps of

(i) providing a composition according to claims 1 to 7;

(ii) optionally granulating the composition of step (i);

(iii) mixing the composition of step (i) or the granulates of step (ii) with optionally one or more excipient(s) (c);

(iv) optionally granulating the mixture of step (iii); and

(iv) processing the mixture of step (iii) or the granulates from step (iv) into a dosage form.

13. PPAR- modulator with dual acting activity in micronized form for the use as a drug for treating patients with diabetes mellitus type II.

14. PPAR- modulator according to claim 13, wherein the PPAR- modulator is aleglitazar.